SYNTHESIS AND REACTIONS OF SOME
HETEROCYCLES CONTAINING NITROGEN AND
SULPHUR
By
Wael Abd El-Gayed Ahmed Arafa
A thesis submitted in partial fulfillment
of
The requirements for the degree of
Doctor of Philosophy
In
Chemistry Science
(Organic)
Department of Chemistry
Faculty of Science, Fayoum
FAYOUM UNIVERSITY
2008
SYNTHESIS AND REACTIONS OF SOME
HETEROCYCLES CONTAINING NITROGEN AND
SULPHUR
By
Wael Abd El-Gayed Ahmed Arafa
B. Sc. & M. Sc.
Dr/ G. H. Tammam
Assistant Prof. of Organic Chemistry, Chemistry Department, Faculty of
Science, Fayoum University.
Signature :
Dr/ H. M. M. Bakeer
Assistant Prof. of Organic Chemistry, Chemistry Department, Faculty of
Science, Fayoum University.
Signature :
Dr/ R. M. Abdel-Motelab
Lecturer of Organic Chemistry, Chemistry Department, Faculty of
Science, Fayoum University.
Signature :
Approval Sheet
SYNTHESIS AND REACTIONS OF SOME HETEROCYCLES
CONTAINING NITROGEN AND SULPHUR
By
Wael Abd El-Gayed Ahmed Arafa
B. Sc. & M. Sc.
This thesis for Ph. D. degree has been approved by:
1- Prof. Dr. Dietrich Dpp
Prof. of Organic Chemistry, Chemistry Department, Faculty of Science,
Duisburg University, Germany.
Signature:
2- Prof. Dr. M. A. El-Hashash (D. Sc.)
Prof. of Organic Chemistry, Chemistry Department, Faculty of Science, Ain
Shams University.
Signature:
3- Dr/ G. H. Tammam
Assistant Prof. of Organic Chemistry, Chemistry Department, Faculty of
Science, Fayoum University.
Signature:
4- Dr/ H. M. M. Bakeer
Assistant Prof. of Organic Chemistry, Chemistry Department, Faculty of
Science, Fayoum University.
Signature:
Date of Examination:
/ 2006
Acknowledgments
To Dr. G. H. Tammam,
Assistant Prof. of Organic Chemistry, Chemistry Department, Faculty of
Science, Fayoum University for his support supervision, advice and valuable
criticism.
To Dr. H. M. M. Bakeer,
Assistant Prof. of Organic Chemistry, Chemistry Department, Faculty of
Science, Fayoum University for her continuous guidance, encouragement, kind
assistance and unlimited effort for revising this work.
To Dr. R. M. Abdel-Motelab,
Lecturer of Organic Chemistry, Chemistry Department, Faculty of
Science, Fayoum University for his suggesting and directing the research,
continuous advice and valuable criticism, which made this work possible in its
present form.
To Prof. Dr. A. Y. Elkady,
Professor of Organic Chemistry, Chemistry Department, Faculty of
Science, Fayoum University for his assistance and continuous advice.
To the staff in the Chemistry Department who provide the many services for
their time and assistance.
To my lab-mates and other fellows for their friendship.
To my parents and family for their expectations.
SUMMARY
Part I
A Novel Synthesis of 4-Ylidene-5(4H)- oxazolones Via Trans
Olefination and Some Reactions of the Newly Synthesized
Derivatives
In this work, efforts have been directed toward developing new
synthetic routes for synthesis of 4-substituted-2-phenyl oxazolones as
precursors to variety of azole and azine derivatives of expected biological
activities. The newly synthesized derivatives were obtained on subjecting the
5-oxzaolones to ring transformation under varieties of reagents and reaction
conditions which could effect their rearrangements.
A new facial route for synthesis of 4-arylideneoxazolones 2a-m is
presented. In this methodology, arylmethylene malononitriles 1 were utilized as
a trans-arylidene reagent on their reaction with hippuric acid. The reaction
sequence takes place via Tandem Michael addition/retro Michael reaction with
extrusion of malononitrile. The procedure constitutes a general fashion since
the reaction was amenable to a variety of ylidene malononitriles extended from
that derived from aromatic aldehydes to that derived from acyclic and cyclic
ketones and ketoesters.
R`
R
R
CN
R`
CN
CH2COOH
NHCOPh
Ac2O
N
R
C6H5
p-OCH3C6H4
p-CH3C6H4
p-ClC6H4
2-furyl
2-thiophenyl
C6H5
Ph
2a-m
1
Products
2a
2b
2c
2d
2e
2f
2g
R`
H
H
H
H
H
H
CH3
Products
2h
2i
2j
2k
2l
2m
R
R`
p-CH3C6H4
CH3
p-ClC6H4
CH3
2-thiophenyl
CH3
CH3
CH3
Cyclohexyl
CH2CO2Et
CH3
The reactions of 2m with electrophilic and nucleophilic reagents have
been studied, thereby several ring transformations occur. Compound 2m
couples smoothly with diazotized aromatic amines in cold ethanolic sodium
acetate solution and gave oxazolones 3a, b. Also, compound 2m was
condensed with benzaldehyde in molar ratio 1:1 in the presence of
triethylamine, under fusion condition, to give the oxazolone derivative 4.
On boiling compounds 3a, b in acetic acid they underwent ring
transformation and affording the pyridazine derivatives 5a, b. The
methanolysis or ethanolysis of 3-(5-oxo-2-phenyl-oxazol-4-ylidene)-butyric
acid ethyl ester 2m in the presence of catalytic amount of sodium methoxide or
ethoxide afforded 8 and 10 respectively. The reaction of compound 2m with
nitrogen nucleophiles also has been studied. Thus, the reaction of 2m with
primary aromatic amines, the imidazole derivatives 12a, b were obtained.
Moreover, in the reaction of the oxazolone derivative 2m with equimolar
amount of hydrazine hydrate (in ethanol at room temperature) or phenyl
hydrazine (in boiling ethanol) gave the triazines 14a, b respectively (Scheme
1).
EtOOC
CH3
O
AcOH
ArNH N
N
Ar
N
N
COOEt
CH3
NHCOPh
O
5a, Ar = C6H5
b, Ar = C6H4p-CH3
Ph
3a, Ar = C6H5
b, Ar = C6H4p-CH3
EtOOC
CH3
O
Ph C
H
ArN N Cl
0-5 oC
COOEt
H3C
ROOC
EtOOC
RONa / ROH
N
H
Ph
PhCHO/TEA
Ph
4
CH3
EtOOC
O
ArNH2
Ph
NH2NH2
12a, Ar = C6H5
b, Ar = C6H4p-C
PhNHNH2
EtOH/
CH3 O
CH3 O
NH
NH
N Ar
Ph
EtOH/r.t.
EtOOC
CH3
2m
8, R = CH3
10, R = CH2CH3
EtOOC
N
N
Ph
Ph
14a
14b
Scheme 1
H
Ph
Part II
Reactions of 4-Substituted Oxazolones with ,-Unsaturated Nitriles:
A Novel Synthesis of 1,2,4-Triazol-3-yl Pyrans, Oxazol-4-yl Pyrans
and Their Annulated Derivatives
2-Phenyl-4-phenylhydrazono-4H-oxazol-5-one 1 reacts with 2-(propan2-ylidene)-malono-nitrile, 2-(1-thiophen-2-yl-ethylidene)-malononitrile, 2cyclohexylidene-malononitrile, 2-cyclopentylid-ene-malononitrile, 2-(1-(2oxo-2H-chromen-3-yl)-ethylidene)malononitrile, 3-cyano-4-methyl coumarin,
5-cyano-4-methyl-6-oxo-1-phenyl-1,6-dihydro-pyridazine-3-carboxylic
acid
ethyl ester or 2-aminoprop-1-ene-1,1,3-tricarbo-nitrile in sodium/ dry dioxane
to yield 1,2,4-triazol-3-yl-pyran derivatives 3-11 respectively (Scheme 1).
O
O
Ph
N N
Ph
CN
Ph
CN
N N
Ph
N N
Ph
Ph
6
S
4
5
iii
CN
viii
ii
O
Ph
CN
N N
Ph-NH-N
v
N
Ph
CH3
3
O
O
NC
NC
vii =
H2N
vi
Ph
N N
Ph
N
N
CN
NC
CN
CN
ii =
CH3
iii =
iv =
O
CN
viii =
CH2CN
CH3
CN
CH3
N N
Ph
CN
11
Ph
CN
NC
CN
CH3 vi =
v=
NC
S
Ph
NH2
CONH2
COOEt
i=
H3C
Ph
CN
vii
NC
N N
Ph
Ph
Ph
iv
N N
Ph
Scheme 1
O
NC
H3C
N
N
Ph
COOEt
Also, 4-arylmethylene-2-phenyl-4H-oxazol-5-ones 2 react with
activated nitriles namely 2-(1-aryl-ethylidene)-malononitrile, 2-(1-(2-oxo-2Hchromen-3-yl)ethylidene)-malononitrile, 3-cyano-4-methyl-coumarin or 5cyano-4-methyl-6-oxo-1-phenyl-1,6-dihydro-pyridazine-3-carboxylic
acid
ethyl ester in sodium/dry dioxane to yield 5-aryl-2-phenyloxzaol-4-yl-pyran
derivatives 13-16 respectively (Scheme 2).
NH
CN
O
Ar
Ar/
O
Ph
13a, Ar = C6H5, Ar/ = C6H5
b, Ar = C6H5, Ar/ = C6H4-Cl-p
c, Ar = C6H4-Cl-p, Ar/ = C6H5
d, Ar = C6H4-NO2-p, Ar/ = C6H5
e, Ar = C6H4-OCH3-p, Ar/ = C6H5
f, Ar = C6H5, Ar/ = thiophen-2-yl
i
NH O
NH O
`
O
iii
Ph
O
ArCH
N
N
Ph
Ph
Ph
15
N
N
ii
COOEt
N
Ph
16
2
iv
NH
CN
O
Ph
O
N
Ph
O
NC
i=
Ar`
CN
NC
ii =
CH3 H3C
N
N
O
14
CN
Ph
COOEt
CN
NC
CH3
iii =
CH3
iv =
O
Scheme 2
Ph
Part III
Synthesis and Reactions of Some New 2-Phenyl-4-(Substituted
Thiophen-2-yl-hydrazono)-4H-Oxazol-5-ones
Diazotization
of
2-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3carboxylic acid ethyl ester, 2-amino-5,6-dihydro-4H-cyclopenta-[b]thiophene3-carboxylic acid ethyl ester or 2-amino-4-aryl-thiophene-3-carbonitrile with
sodium nitrite/HCl yielding the diazonium salts which on treating with hippuric
acid/acetic anhydride mixture in the presence of sodium acetate trihydrate
affording the 2-phenyl-4-(substituted thiophen-2-yl-hydrazono)-4H-oxazol-5ones 1a-d.
Y
Z
X
S
Y
Z
NH2
X
S
NaNO2 / HCl
0 oC / AcOH
Y
Z
X
S
N NCl
hippuric acid
Ac2O /AcONa
O
O
NH-N
N
Ph
1a, X = CO2Et, Y-Z = -(CH2)4b, X = CO2Et, Y-Z = -(CH2)3c, X = CN, Y = C6H5, Z = H
d, X = CN, Y = C6H4-OCH3p, Z = H
Oxazolone 1a reacts with some active methylene namely ethyl
cyanoacetate, malononitrile or 5-methyl-2,4-dihydro-pyrazol-3-one in sodium/
dry dioxane to afford the 1,2,4-triazol-3-oynitriles 2a-c respectively. When 2a
was refluxed with hydrazine hydrate, the pyrazole derivative 3 was obtained.
Also, on reacting compound 1a with 2-(1-phenyl-ethylidene)-malononitrile in
sodium/dry dioxane affording the pyranone derivative 4. Compound 1a reacts
with glycine in boiling acetic acid to afford, through ring transformation, the Nsubstituted glycine derivative 5, which on condensing with benzal-dehyde in
the presence of acetic anhydride and catalytic amount of sodium acetate, the
oxazolone derivative 6 was obtained. Treatment of 1a with anthranilic acid or
o-phenelyenediamine in boiling acetic acid, yielding the benzoxazine
derivative 8 and the benzoimidazole 10 respectively (Scheme 1).
CO2Et
S
CO2Et
N
N
Ph
NHCH2COOH
Ph
C Ph
H
CO2Et
S
Ph
iv
vi
O
CO2Et
S
Ph
N
Ph
CO2Et
N
1a
CO2Et
vii
Ph
Ph
iii
CN
O
C
Y
CH
X
H
N
10
CONHNH2
O
N
N
C
ii
S
Ph
2a, X = COOEt, Y = CN
b, X = Y = CN
c, -X-Y- = -CONHCNC
Y
i = H2C ii = NH2NH2 iii =
X
Ph
NH2
vii =
NH2
NH2
N
HO
NH
CN
iv = glycine v = PhCHO,Ac2O, AcONa vi =
CH3
COOH
NH2
Scheme 1
Also, on the reaction of 1a with primary aromatic amines namely aniline
or p-toludine in boiling ethanol afforded the amide 11a, b respectively. The
reaction of 1a and hydrazines namely hydrazine hydrate (at room temperature)
and phenyl hydrazine (in boiling ethanol) yielding the hydrazides 12a, b
respectively. Condensation of compound 12a with benzaldehyde was carried
out in ethanol at reflux temperature giving the Schiffs base 13. On boiling
oxazolone 1a in ethanol containing catalytic amount of triethyl amine afforded
the triazole ester 15 (Scheme 2).
CO2Et
S
N
Ph
N
CONHAr
N
11a, Ar = C6H5
b, Ar = C6H4-CH3p
Ar-NH2
1a
CO2Et
RNHNH2
EtOH / TEA
12a, R = H
b, R = Ph
CO2Et
N
Ph
CONHNHR
N
Ph
N
COOEt
PhCHO
15
CO2Et
S
N
Ph
13
Scheme 2
N
CONHN
N
CHPh
Part IV
Synthesis and Some Reactions of 4-(2-alkyl-2-arylhydrazono)-2Phenyloxazol-5-one Derivatives
A series of new 4-(2-alkyl-2-arylhy-drazono)-2-phenyloxazol-5-ones
derivatives 2a-d were synthesized by reaction of the oxazolones 1a, b with
methyl or ethyl iodides. On the other hand trial to alkylate 1a with methyl
bromoacetate or phenacyl bromide afforded the triazine 6 and pyridinone 10
respectively (Scheme 1).
The reaction of 2a, b with ammonia, primary aromatic amines or
hydrazines gave the acyclic amides 14a, b, 17a-d and hydrazides 20a-d
respectively. Cyclization of 14a, b and 17a, b gave imidazoles 16a, b, and
19a, b respectively. While cyclization of 20a-d afforded triazines 21a, b and
24a, b. Boiling compounds 21a, b in acetic acid containing concentrated HCl
affording the triazinone derivatives 23a, b (Scheme 2).
R
Ar N N
Ph
2 a, Ar = C6H5, R = CH3
b, Ar = C6H4-pCH3, R = CH3
c, Ar = C6H5, R = CH3-CH2
d, Ar = C6H4-pCH3, R =CH3-CH2
Ph
H3CO2C
N
Ph
6
-CO2
R-X / K2CO3
H
Ar N N
CH2CO2CH3
O
CH2CO2CH3 Ph N N
Ph N COOH
N
N O Br
N O
N
K2CO3
H3CO2C
Ph
Ph
Ph
1 a, Ar = C6H5
4
8
b, Ar = C6H4-pCH3
O
2 PhCOCH2Br / K2CO3
O
PhNHN
Br
N
Br
Ph
O
COPh - 2HBr
PhNHN
COPh
N
COPh
COPh
Ph
10
11
Scheme 1
2a, b
CH3COONH4
or HCONH2
CH3
CH3
Ar N N
CH3
Ar N N
CONH2
CH3COOH
NH
NH-COPh
CH3COOH
R=Ph
CONHAr`
20 a, Ar = C6H5, R= H
17a, Ar = C6H5, Ar` = C6H5
b, Ar = C6H5, R = C6H5
b, Ar = C6H5, Ar` = C6H4-CH3-o
c, Ar = C6H4-CH3-p, R = H
c, Ar = C6H5, Ar` = 2-pyridyl
d, Ar = C6H4-CH3-p, R = C6H5
d, Ar = C6H5 Ar` = 2-thiazolyl
14 a, Ar = C6H5
b, Ar = C6H4-CH3-P
CH3
Ar N N
CONHNHR
NH-COPh
NH-COPh
Ar N N
Ar`NH2
R-NHNH2
N
N
H
Ar-N-N
Ar-N-N
CH3COOH
R=H
CH3
N
N
Ph
Ar N N
COCH3
Ph
Ph
O
N Ar`
Ph
Ph
21a, Ar = C6H5
24 a, Ar = C6H5
16 a, Ar = C6H5
19a, Ar = C6H5, Ar` = C6H5
b, Ar = C6H4-CH3-P b, Ar = C6H4-CH3-P b, Ar = C6H5, Ar` = C6H4-CH3-o
b, Ar = C6H4-CH3-P
AcOH/HCl
O
Ar-N=N
N
NH
N
Ph
23 a, Ar = C6H5
b, Ar = C6H4-CH3-P
Scheme 2
