Study The Behaviour of Some Unsaturated Ketoacids
toward Some Nucleophiles and Synthesis of Some
Heterocyclic Compounds with Non-Mixed and Mixed
System with Expected Biological Activity
Maher A. El-Hashash, Sameh A.Rizk, Mokhtar A.Aburzeza
Organic Chemistry, Faculty of Science, Ain Shams Univeristy
-Aroylacrylic
acid are convenient polyelectrophilic reagents in the
synthesis of heterocycles, for which the addition reaction of N-, S-,
P- or C- nucleophiles occurs exclusively at the -carbonylelectrophilic center of the molecule[1]. On the other hand aryl-and
hetero aryl substituted (E) -4- oxobut-2- enoic acids and their
derivatives represent an important class of compound with
interesting pharmacologic indications including anti-ulcer and cyto
protective properties[2], Kynurenine-3-hydroxylase[3] and human
cytomegalovirus protease inhibiting activity[4]. Several naturally
occuring acyl-acrylic acids show notable antibiotic activity[5].
The aim of our investigation was to study the
nucleophilic
addition of heterocyclic amines, activated aromatic hydrocarbons,
thio-phenol, barbituric acid and phenol to the , -disubstituted
double bond of (E)-4 (4-acetamido- phenyl)-4-oxo-but-2-enoic
acid (1). The research of a number of investigators has shown that,
addition of carba, aza, and thia nucleophiles to (E)-4- aryl-4-oxobut-2-enoic acids, the oriantation of nucleophilic attack is
determined by the relative stability of the intermediate carbanions,
1
and an unambiguous direction of attack of a nuclesphilic agent to
give
a carbanion
of the
acetophenone type [6] has been
established for 4-aryl-4-oxo-but-2-enioc acids.Also, treatment of
(E)-4- aryl-4-oxo-but-2-enoyl chloride with anthranilic acid has
been investigated.
Part I
A) Reaction with 2-aryl-4 –amino thiadiazole:
Interaction of the 4- (4-acetamidophenyl)-4- oxo-but -2 –
inoic (1) with 2-aryl-5-aminothiadiazole (namely, 2-phenyl, 2-(4chlorophenyl),
2-phthalimidomethyl,
and
2-
styryl;),
2,5-
dimethylpyrazole and barbituric acid in boiling ethanol yielded aza
Michael adduct 2a-f respectively.
2
The reaction possible takes place via the following mechanisms
i,e. the
reaction takes place via 1,4- addition followed by rearrangement to
more thermodynamically stable keto form.
The structure of compound 2 was inferred from:
(i) Correct micro analytical data. (ii) IR spectra of compounds
2 exhibit strong absorption bands in the region 1630-1635, 1670-
3
1680; 1695-1710 cm-1 attributable to υmax of three carbonyl group
and 3200-3270 cm-1 due to υNH. IR spectrum of compound 2c
exhibits strong absorption bands at 1632, 1712, 1770, 1832, 3205
cm-1 attributable to υmax of carbonyl groups and υNH CF Fig. 1.
EI-MS for compound 2c exhibits m/z= 451 (M+- CO2) CF. Fig. 2
and for compound 2b m/z = 358 M+- (CO2+ CH3 CO) CF. fig. 3.
The 1H. NMR spectrum of compound 2b in DMSO (d6) shows the
following signals, ppm 2.09 (s, 3H, CH3-CO), 3.41 and 3.44 (two
double doublet for 2H, diastereotopic protons), 4.12 and 4.22 (dd
1H, stereogenic proton, 6.67 (s, 1H NH attached to thiadiazole
moiety) , 6.71 (s, 1H ,NH attached by aceto group), 7.54, 7.58,
7.78, and 7.83 (8H, ArH) CF. Fig 5. The EI-MS of compound 2e
with exhibits m/z=307(M+ -H2O)
The Structure of compound 2 was established chemically from:
I) Reaction with hydrazine hydrate:
Synthetic 3 (2H)Pyridazinones are important scaffolds in
drug discovery, with many of their analogs being used in the
treatment of various human pathological
described
as
Emorfazone
non-steroidal
states. They were
anti-inflammatory
drugs
e.g.
and related compounds[7], agents for therapeutic
intervention of renal- urologic (e.g. FK-838[8] , cardiovascular e.g.
4
EMD- 57283[9], respiratory (e.g. NIP- 502[10] and dermatologic
diseases e.g. FR-18 1877[11].
According to these examples and due to evident structural
similarity to many 3 (2H) – pyridazinanes bear Heterocyclic
moiety at position 4 and aromatic moiety at position 6 represent
promising synthetic targets.
Here we report a convenient and versatile synthetic approach to
novel 4,6-di-substituted 2,3,4,5- tetrahydro -3 (2H) pyridazinone
derivatives.
Thus, when the acid derivatives
2a, b, c, d and f were
allowed to react with hydrazine hydrate in boiling ethanol or nbutanol afforded
the corresponding 3 (2H)- pyridazinone
derivatives 3a-e respectively.
5
The reaction possibly tank is place via the following route.
The structure of compounds 3 was inferred from :
(i) Correct micro analytical data. (ii) IR spectra of compound
3 revealed strong absorption bands at the region 1630- 1635 cm-1
6
for υC=O (carboxamide group, cyclic and acyclic), 3272 – 3300
cm-1 υNH CF. Fig. 6 for 3a .IR spectrum of compound 3c revealed
strong absorption bonds at 1724 and 1776 cm-1 athibutable to
υc=o of Phthalimide moiety CF. Fig. 7 for 3c .EI-MS exhibits
m/z= 408 (M++ 2) attributable to molecular ion peak CF. Fig. 8
for 3a.The 1H-NMR spectrum of compound 3a in DMSO (d6)
exhibits signals at  ppm 2.51 (s, 3H, CH3CO), 4.41 (2dd, 2H,
diastereotopic protons) 5.5 (m-1H, Stereogenic proton, ABC
system 6.64 (s, 1H, NH amino) 7.2-7.8, (m,9H-ArH) .The EIMS
for 3 b exhibits m/z= 404 (M+ + 2) due to the presence of chlorine
and sulphur CF. fig. 9 for 3b.
EI–MS for 3d exhibits m/z = 325
corresponding to the molecular ion peak. CF. fig. 10 for 3d.
The structure of compound 3a was inferred chemically from
its interaction with ethyl chloro acetate
in the presence of
anhydrous K2CO3 in boiling acetone , afforded O-acyclic
nucleoside analogue ethyl 2-(6- 4-acetamidophenyl)-4- (5-phenyl9, 3, 4-thiadiazol – 2-yl) amino) – 4, 5-dihydropyridazin-3-yl)oxy)
acetate (4).
7
The reaction possibly takes place via the following mechanism.
The reaction takes place via SN2 mechanism and the function of
K2CO3 is pulling Cl atom as KCl.
The structure of the compound 4 was proved from:
Correct micro analytical data (ii) , its IR spectrum revealed strong
absorption bands at 1607, 1753 2928, 2960 and 3428 cm-1
attributable to υmax of two carbonyl, υCH and υNH respectively
CF. Fig. 11. (iii) EI-MS exhibits m/z= 494 (M+ + 2) corresponding
to the molecular ion peak fig.12.
Recently[12] 2(3H)
furanone exhibits rich photochemistry.
Furthermore, due to their common occurrence in nature oxygen
containing heterocycles are frequent and important targets, for
8
synthesis
either
as final products
or as useful
synthetic
intermediates.
II)Reaction with acetic anhydride:
Interaction of the acids 2a, b, c, e, and f with boiling acetic
anhydride , in case of the acids 2a and e afforded the furanone
derivatives 5a and b. With the acid 2b yielded a mixture from
furanone 5c and the ketone 6a. But the compounds 2c and 2f
yielded the ketone 6b and c respectively.The products are outlined
below.
9
The structure of compound 5 was inferred from:
(i) Correct micro analytical data .(ii)IR spectra of compounds 5
revealed strong absorption bonds at the region 1728-1767 cm-1
attributable to υC=O,3157-3252 cm-1attributable to υNH CF fig.13
for 5a. (iii) 1H-NMR spectrum of compound 5a in DMSO (d6)
showed signals at 2.21 (s.3H, CH3CO), 3.75 (d, 1H methine proton
of furanone moiety) 6.76 (s, 2H, NH proton ), 7.51-7.94 (m10H Ar
H and olefinic proton ) CF. fig. 14 for 5a.
The structure of compounds 6 was inferred from:
(i) Correct microanalytical data .(ii) IR spectra exhibit
strong absorption bands at the region1667-1693, 3189-3378 CF.
fig.15 for 6c. EI-MS for compound 6c exhibits m/z = 343 (M+)
CF. Fig. 16.The formation of compounds 5 take place via the
following route.
10
formation of compounds 6 take place via the following
mechanism
The decarboxylation of acids can be calculated from bond energies
and the stabilization energy of the carboxyl group to have  Ho = 7 k cal mol-1 .This does not mean that the reaction goes easily
special structural features are required e.g. electrons attracting
group attached to the -carbon decarboxylation often proceeds
readily at 100-150.
III)Reaction with hydroxylamine:
We studied reactions of acid 2a, b, c, and f with hydroxylamine
hydrochloride in boiling pyridine, for 2a, b, and c , the expected
oximes, which undergo subsequent decarboxylation into the
products 7a-c.
11
The structure of compound 7a–c was inferred from:
(i) Correct micro analytical data , (ii) its IR spectra revealed
strong absorption bands at the region 1630-1640 cm-1, 3200 -3270,
3400-3450 cm-1 attributable to υC=O υNH and υOH and devoid
any band for υC=O of aroyl carbonyl or carboxylic group . CF.
Fig17 for 7a. IR spectrum of compound 7c exhibits two additional
bands at 1729 and 1777 attributable to υC=O of
phthalimide
moiety CF. fig. 18 for 7c . EI- MS for compound 7c exhibits m/z=
405 (M+ - NHCOCH3) CF. fig. 19.The reaction possibly takes
place via the following route.
12
However , the reaction of 4 (4- (a cetylamino) phenyl)- 4-oxo -2[5-(2,4,6-trioxotetrahydropyrimidin- 7 (2H) – y1) – 9, 3, 4.
Thiadiazol – 2- yl] butanoic acid (2f) with NH2 OH. HCl in boiling
pyridine gave the oxime derivative 8 (no decarboxylation takes
place) this may be due to the carboxyl group make intramolecular
hydrogen
bond
with
the
carbonyl
of
pyrimidine
moiety.
The structure of compound 8 was inferred from:
13
(i) Correct micro analytical data . (ii) Its IR spectrum exhibits
strong absorption bands at 1610, 1630, 1703 basin peak centered at
2984, 3136, and 3420 cm-1 attributable to υC=N, υC=O amide
υC=O carboxylic, chelated OH, υNH, and υOH respectively CF.
fig.20 for compound 8 .The
1
H-NMR (DMSO d6) should the
following signals and ppm 2.5 (s, 3H CH3CO), 3.68 (m, 2H, CH3
distereotopic protons), 6.80 (d 2H, 3.5 P- C6H4), 7.25 (d 2H, 2.6
p- C6H4) 7.8-7.9(m,2H CH2), 9.97 (NH of acetamido moiety), 10.4
(s, 1H, NH of pyrimidine moiety) 11.42 (s, 1H, OH of oxime)
12.89 (s, 1H, OH of carboxyl group) CF. Fig. 21.
14
Part II
B) reaction with aromatic hydrocarbon:
It is known that the Friedel–Carfts catalyzed reaction of
unsaturated acid (-aroylacrylicacids)with aromatic Compounds.
The addition occurred in alpha to the carboxyl group .In the
present work, the Friedel–Crafts catalyzed reaction of 4- (4acetoamino) phenyl-4-oxo-but-2-enoic acid (1) with activated
aromatic hydrocarbon has been investigated. Thus, when acid 1
was allowed to react with activated aromatic hydrocarbons namely,
m-xylene and p-xylene yielded 2-aryl – 4(4-acetoamino) phenyl 4- oxo-butanic acids] 9
The reaction was carried out by two methods:
i) A solution of acid 1 in the aromatic hydrocarbon was saturated
with dry hydrogen chloride, then stirred with anhydrous AlCl 3 at
room temp. ii) By heating
a mixture of the acid 1, AlCl3
15
(anhydrous) and the aromatic hydrocarbon on the water bath.Two
different paths can be proposed for the addition reaction.
The first is assuming an initial addition of hydrogen chloride to the
olefinic double bond followed by an alkylation step.
The second route can be outlined in the following equations:
16
.
The structure of compound 9 was inferred from:
(i) Correct micro analytical data , (ii) its IR spectrum revealed
strong absorption band sat the region 1687-1690, 1695-1700 –
basin peak 2524-3079 attributable to υmax of two carbonyl group
and υOH chelated CF fig. 22 for 9a. EI-MS of compound 9a
exhibits m/z = 339 (M+) CF fig. 23.The acid 9 used as key starting
material for synthesis of some interesting compounds via its
reaction
with
hydrazine
hydrate,
acetic
anhydride
and
hydroxylamine hydrochloride.
I. Reaction with hydrazine hydrate:
Phosphodiesterase III (PDE III) has been one of the most studied
targets in the search for new antiplatelet agents[13]. Among the
17
extensive family of PDE III inhibitors, compound containing the 3
(2H)pyridazinone ring have been widely studied[14] and several
pyridazinone, such as zardaverine and pimobendan, have been
selected for further clinical assays[15]
This prompted us to synthesized 3 (2H) pyridazinone rings bear
aryl groups at position 4- and 6- for promising platelet aggregation
inhibitors instead of use Aspirin, Triflusal (triflouro methyl aspirin).
Thus, when the acid 9a and b was allowed to react with hydrazine
hydrate in boiling ethanol afforded N- [4-[5- (2,4-dimethylphenyl)- 6oxo-1,4,5,6-tetrahydropyridazin-3-yl] phenyl] acetamide (10a) and N[4- (2,5-dimethylphenyl)-6-oxo-1,4,5,6, tetrahydropyridazin-3-yl ]
phenyl acetamide (10b).
18
The structure of compounds 10 was inferred from:
(a) Correct micro analytical data, (b) their IR spectra exhibits
strong absorption bands at the region 1683- 1690, 1620-1630,
3286-3288 attributable to υmax of two carbonyl group and υNH
respectively Cf.Fig.24 for 10a. The reaction possibly takes place
via the following mechanism:
II) Reaction with acetic anhydride:
Treatment of the acid 9a and b with warming acetic anhydride
yielded N-[4-[4-(2,4- dimethylphenyl) -5- oxo – 4,5 – dihydrofuran
2 –yl] phenyl] N-cetamide (11a) and N- [4-[4-(2,5 di
19
methylphenyl) -5- oxo – 4,5-dihydrofuran- 2-y1] phenyl] Nacetamide (11b). The reaction takes place
via ring closure
followed by acetylation of the NH group, yielded the desired
products
The reaction possibly takes place via the following mechanism:
The structure of compound 11 was established from:
20
(i) Correct micro analytical data. (ii) IR spectra revealed
strong
absorption bands at region
1763-1765, 1850-1855
attributable for υmax of carbonyl groups and devoid and band for
υNH CF. fig. 25 for 11b.
III) Reaction with hydroxylamine hydrochloride:
In this investigation the authors sought to investigate the
behavior of acid 9 towards hydroxylamine hydrochloride. The
expected products were the oximes 12, which undergo subsequent
cyclization into the oxazinone derivatives 13.
Actually we obtain oxime derivatives 12 as a sole product.
The
structure of compounds 12 was established from:
(i) Correct micro analytical data. (ii) IR spectra exhibits strong
absorption bands at the region 1700-1707, 3200-3210, 3413-3481
21
cm-1 attributable to υC=O, υNH and υOH respectively CF. fig. 26
for 12a .
IV. Behaviour of the pyridazinan derivatives 10 Towards
carbon electrophlic
(i)Reaction with ethyl choroacetate:
Treatment of 3 (2H) pyridazinone derivatives 10a and b with ethyl
chloroacetate in boiling acetone and in the presence of inhydrous
K2CO3 afforded ethyl 2- [3-(4-acetamidophenyl) -5- (2,4- dimethyl
phenyl) -6- oxo-5, 6 -dihydropyridazin – 1 (4H) – yl] acetate and
ethyl 2- [3-(4-acetamidophenyl) – 5 – (2,5-dimethylphenyl)–6oxo-5,6-dihydrophyriduzin-1-(4H)-y1]-acetate (14a and b)
The Structure of the ester 14 was inferred from:
(i) Correct micro analytical data . (ii)IR spectra exhibit strong
absorption bands in the region 1661-1662 ,1730-1732 attributable
to υmax of two carbonyl groups and devoid any band for υNH
22
CF.Fig 27for 14b . The reaction possibly takes place via SN2
mechanism and the function of K2CO3 is facilitate the remove of
the chloride ion (leaving group) as KCl.
(ii)Reaction with CH3COCl (acetyl chloride)
Treatment of the 3(2H)pyridazinone derivatives 10a and b
with acetyl chloride in boiling pyridine afforded N-[4-( 1-acetyl-5(2,4/or2,5-dimethyl phenyl)-6-oxo- 1,4,5,6 tetra hydro pyridazinyl) phenyl]acetamido (15a and b ) respectively.
The reaction takes place by nucleophilic substitution on carbon of
carbonyl of acetyl chloride via tetrahedral mechanisms.
The structure of the compound 15 was inferred from:
(i) Correct microanalytical data .(ii) Its IR spectra exhibit
absorptions at the region 1664-1671cm-1 attributable to υC=O and
23
devoid any band for υNH CF fig 28 for 15b (means acetylation
takes place at nitrogen atom and no O-alkylation obtained. These
results seem to be reasonable because the presence of electron
releasing groups on the pyridazinone at the 4-and 6-positions are
stabilized the keto form to a great extent[16]
C) Reaction with sulphurs nucleophiles:
It was reported that[17] 4- (4-bromophenyl) – 4 –oxo – but- 2enoic acid has antibacterial activity towards staphylococcus aureus,
Escherichia coli and kllebsiella, this was ascribed to the presence
of the highly conjugated system, which many react with
biologically essential SH groups. This prompted us to investigate
the behavior of 4 (4-acetoaminophenyl) - 4- oxo – but – 2-enoic
acid (1)
towards compounds bearing the sulph hydryl group.
When compound 1 was allowed to react with thio- phenol In dry
benzene in the presence of few drops of piperidine as
acatalyst[18],it afforded 4-[4-(acetylamino)phenyl]
-4-oxo-2-
(phenylsulfonyl) butanoic acid 16
24
The reaction possibly takes place via the following mechanism: (i)
(ii)
The structure of compound 16 was established from:
(i) Correct microanalytical data. (ii) IR spectrum reveals
strong absorption at 1689 cm-1 υC=O (carboxyl) 1675 υC=O(aroyl
carbonyl), 2530-3000 (several bands) hydroxyl stretching bonded)
CF. fig. 29. (iii) EI-MS
exhibits m/z = 425 (M+ + 2),
m/z=443(M+)CF.fig.30. (iv)The 1H-NMR spectrum of compound
16 shows signals at  ppm 2.3 (s, 3H, CH3CONH), 3.3 (octet 2H,
CH2, non equivalent diastereotopic methylene protons), 4.4 (q, 1H,
CH stereogenoic protons), 7.47-7.70 (m, 9H ArH), 8.05 (broad
singlet H, NH protons exchangeable with D2O) 12.5 (broad singlet
OH proton. exchangeable with D2O. The thia-Michael adduct
25
product 16 used as a key starting material for synthesis of some
interesting heterocycles e.g. pyridazinones, furanones
and
oxazinones.
I) Reaction with hydrazines:
When compound 16 was submitted to react with hydrazine
hydrate or phenyl hydrazine in boiling alcohol yielded N [4-[ 6oxo-5-(phenysulfanyl)-1,4,5,6-tetrahydro-pyridazin-3yl]phenyl]acetamide
and
N
–
[4-[1-phenyl-6-oxo-5-
(phenylsulfanyl)1,4,5,6,-tetrahydropyridazin-3-yl]phenyl]
acetamide (17a and b) respectively
The structure of compounds 17 was inferred from:
(i) Correct micro analytical data .(ii) IR spectra revealed
strong absorption bands at the region 1600-1605, 1630-1635,16701675, 3279- 3285 cm-1 attributable to υmax of υC=N and υC=N
and υNH respectively CF. Fig. 31 for 17a. (iii) EI-MS exhibits m/z
26
= 337 (M+ - 2) and m/z = 108 (S+ph) CF fig 32 for 17a. Such
spectroscopic data agreed well with the proposed structure.The
reaction possibly takes place to the following route
II) Reaction with acetic anhydride:
Treatment of thia-Michael adduct 16 with boiling acetic anhydride
yielded the furanone derivative N-[4-(5-oxo-4-(phenyl thio) -4, 5dihydrofuran-2-yl) pheny1]- N- acetoacetamide (18).
27
The reaction involving ring closure followed by acetylation . The
reaction possibly takes place via the following mechanism.
The structure of compound 18 revealed strong absorption bands at
1762 and 1843 athributable to υmax of carbonyl groups and devoid
and bands for υNH or υOH CF. Fig. 33 for 18. EI-MS shows m/z=
325 ( M + - COCH3),m/z 107 (S+ph) CF. fig. 34.
III)Reaction with hydroxyl amine hydrochloride
The reaction of compound 16 with hydroxylamine hydrochloride
in boiling pyridine yield amixtaure from the expected products
were either oxime 19, which undergoes subsequent cyclization into
N-[4-[6-oxo-5-(phenylsulfanyl)-5,6-dihydro-4H-1,2-oxazin-3yl]phenyl]acetamido 20
28
The reaction possibly takes place via the following mechanism :
The IR spectrum of compound 19 revealed strong absorption
bunds at 1630, 1707, 3142, 3479 attributable to υmax of carbonyl
groups, υNH and
υOH respectively CF fig. 35 for 19. IR
spectrum of 20 exhibits strong absorption bands at 1786 cm-1
attributable to υC=O of oxazinone nucleus.
29
Part III
D) reaction with carbon acid (or carbon nucleophile)
Barbituric acid hast two active hydrogen atoms at the
5-
position which can be replaced by various substitants to make the
molecule
biologically active[19]. This led us to alkylation of
barbitutic acid by using 4-(4-acetylaminophenyl) -4-oxo-but -2
-
enoic acid (1). So, interaction of barbituric acid with acid 1 in the
presence of NaOH as a catalyst under Michael reaction conditions
yielded
4-(4-acetamidophenyl)-4-oxo-2-(2,4,6trioxo
hexahydropytimidin-5-yl) butanoic acid 21 .
The structure of compound 21 was inferred from:
(i) Correct micro analytical
revealed strong absorption
data. (ii) Its IR spectrum
band at 1640 , 1690, 2527-2891
30
(several bands), and 3079 attributable to υmax of carbonyl groups,
hydroxyl stretching (bonded) and υNH respective CF. Fig 36. (iii)
The 1H-NMR spectrum of compound 21 in DMSO (d6) signals
ppm 2.1 (s, CH3CO), 2.7 (octet,2H,COCH2 ,diasterotopic protons
), 4.7 (dd, 1H, methine proton, stereogenic proton), 5.1 (d, 1H CH
of pyrimidine moiety, 7.60 , 7.65 (two doublet 4 H, Ar H), 12.5
(broad singlet, 4H, NH and OH protons,D2O exchangeable. The
reaction possibly takes place according to the following
mechanism.
31
The work deals also the behavior of compound 21(multifunction
groups)towards some nitrogen nucleophiles and dehydrating agent
e.g. acetic anhydride.
I) Reaction with hydrazine hydrate:
When the acid 21 was submitted to react with hydrazine
hydrate in boiling ethanol afforded a mixture from 1,2 diazapene
derivative 22 and furanone derivative 23.
The structure of 1,2 –diazapene 22 was inferred of from:
(i) Correct micro analytical data. (ii) Its IR spectrum
revealed strong absorption bands at 1640,1723,3313 attributable to
υmax of carboxamide and charboxyl groups
and υNH or υOH
32
respectively CF fig. 37. The IR spectrum of the compound 23
exhibits strong absorptions at 1777 and 3300 cm-1 attributable to
υC=O and υNH.The 1H-NMR spectrum of compound
23 in
DMSO (d6) showed the following signals at and ppm 2.1 (S, 3H ,
CH3CO), 3.37 (2dd, 2H diastreotopic protons), 4.09 (dd, 1H
methine proton, stereogenic proton), 4.20 (d, 1H methine
proton,CH(C=N)2). 6.65-6.82, 7.11-7.46 (two doublet 4H, ArH),
8.85 (s 2H, NH protons) CF. fig. 38.
II. Reaction with pheny hydrazine:
When the acid 21 was allowed to react with phenyl
hydrazine in boiling ethanol yielded N- (4-(6-oxo 2- phenyl – 5
(2,4,6,-trioxohxahydropyrimidin-5-yl)-1,4,5,6-tetrahydropyridazin- 3- y1) phenyl)acetamide (24).
The structure of the compound 24 was inferred from :
33
(i) Correct micro analytical data . (ii) Its IR spectrum revealed
strong absorption bands at 1637, 1677, 3287 cm-1 attributable to
υmax of carbonyl groups and υNH respectively. CF. Fig. 39.
III. Reaction with hydroxylamine hydrochloride:
Interaction of the acid 21 with hydroxylamine hydrochloride in
boiling pyridine produced (E) – N- (4-(1-hydroxyimin.-3- (2,4,6–
trioxohexahydropyrimidin–5-yl)propyl)phenyl)acetamide
(25).
The reaction takes place nucleophilic addition of hydroxylamine to
the carbonyl group followed by decarboxylation (this seems to be
logic because
the  position of the carboxyl is highly
electronegative).
The structure of compound 25 was established from :
34
(i) Correct micro analytical data. (ii) Its IR spectrum reveled
strong absorption bands at 1697, 3188, 3470 attributable to υC=O
, υNH and υOH respectively CF. fig. 40.
The reaction possibly takes place via the following
mechanism.
IV) Reaction with acetic anhydride:
Treatment of the acid 21 with boiling acetic anhydride it yielded
N-(4-(5-oxo-4-(2-oxo-4,6-diacetoxy)-5,6-dihydropyrimidin-5-yl) –
4, 5-dihydrofuran- 2-yl) [phenyl) N -acetylacetamide (26).
35
The structure of compound 26 was established from:
The study of its IR spectrum which
revealed strong
absorption bands at 1763, 1850 attributable to υC=Oand devoid
any band for υNH or υOH CF. Fig. 41. EI-MS shown m/z = 343
(M+-3 CH3CO) CF Fig. 42.
E) Reaction with phenol:
The acid 1 reacted with highly activated aromatic hydro
carbon e.g. phenol in the presence of drops of conc H2SO4 in
boiling ethanol and yielded N-(4-(2-(4-hydroxyphenyl)-5-oxo-2, 5dihydrofur-2-yl) phenyl) acetamide 27.
36
The structure of the furanon 27 was confirmed from:
(i)Correct microanalytical data (ii).Its IR spectrum revealed
strong absorption bands at 1640, 1720 cm-1, 3076, and 3425
attributable to υmax of two carbonyl groups, υNH and υOH
respectively CF Fig.43 .EI-MS exhibits m/z = 308 (M+) CF. fig.
44. The reaction possibly takes place according to the follow in
route:
37
F) Reaction with oxygen nucleophiles:
Epoxides or Oxiranes are useful and important synthetic
intermediates in organic synthesis[20]. Their inherent polarity and
high angle strain of three membered ring make them susceptible to
reaction with a wide variety of reagents including reducing, and
38
oxidizing agent, electrophiles, nucleophilec, acids, and bases[21].
The ring opening of epoxides with different nucleophiles is an
attractive subject in organic transformation[22]. This prompted us
to synthesis and investigate the behavior of 3-(4acetamidobenzoyl) oxiran- 2- carboxylic acid (28) towards
nitrogen containing heterocyclic nucleophiles. Thus, interaction of
acid 1 with H2O2 in the presence of NaOH afforded 3-(4acetamido-benzoyl) oxiran-2- carboxylic acid (28)
The structure of compound 28 was inferred from:
(i) Correct micro analytical data (ii), its IR spectrum revealed
strong absorption bands at 1278, 1630, 1687, (2524, 2649, 2889
different bands), 3080 attributable to υC=O υmax of two carbonyl
group, chelated or bonded OH and υNH respectively Cf. fig. 45.
The reaction possibly takes place according to the following
mechanisms.
39
The reaction is redox reaction, oxidation number of oxygen in
H2O2 = -1 and oxygen in OH = -2 . Interaction of compound 28
with 2-amino – 5 – phenyl -1, 3, 4-thiadiazole afforded 4- (4acetamido phenyl) - 3-hydroxy - 4- oxo – 2- (5- phenyl – 1,3,4 –
thiudiuzol-2 –yl ) amino) butanoic acid (29).
The reaction takes place via region selective ring – opening
of 1,2-epoxide by amino group it carbon atom attached by carboxy
group which has suitable polarity.
40
The structure of compound 29 was proved from:
(i)
Correct microanalytical data .(ii) Its IR spectrum
revealed strong absorption bands at 1630, 1685, 2526, 2650,3200,
3400 cm-1 attributable to υmax of two carbonyl group, υNH
chelated or bonded OH, group CF. fig. 46. (iii) The 1H-NMR
spectrum of compound 29 in DMSO (d6) should signals at  ppm
2.5 (s,3H,H3CCONH), 4,12 (s, 1H) , methine proton attached to
nitrogen), 4.14 (s, 1H) methine proton attached to oxygen), 8.2
(brond singlet 2H, NH proton) 12.5 (broad singlet 2H, OH protons)
Cf. fig. 47 (iv) EI-MS exhibits m/z = 426 (M+), 408 (M+ - H2O,
m/z= 392 ( M+ - CO2) CF. fig. 48. Such spectroscopic data agreed
well with the proposed structure.
The structure of
compound 29 was infered chemically from:
I) Reaction with hydrazine:
When compound 29 was allowed to react with hydrazine
hydrate or phenyl hydrazine in boiling ethanol it yielded N-(4-(4hydroxy-6-oxo-5-
(5-
phenyl-1,3,4-thiadinazol-2-yl) amino)-
1,4,5,6,tetrahydropyridazine or 1-phenylpyridazin-3-yl) phenyl)
acetamide (30a and b respectively.
41
The structure of compound 30 was deduced from:
(i) Correct micro analytical data (ii) 1603, 1630, 1687, 3272,
3440 cm-1 attributable to υC=N, υmax of carbonyl groups υNH
and υOH respectively. CF. Fig.
49 for 30b. The 1H-NMR
spectrum of compound 30 a exhibits signals at  ppm 2.5 (s, 3H
H3C CO), 4.5 (s, 2H, methine protons), 6.73-7.94 (m, 9 H ArH)
8.62- 9.99 (broad singlet 4H, NH and OH protons )exchangeable
inD2O) CF.fig.50 for 30a.
The structure of compound 30a was verified chemically from:
a) Reaction with chloroacetyl chloride:
When compound 30a was allowed to react with chloro
acetylchloride yielded 3-(4-acetamidophenyl)-4,6-dichloroacetoxy5-(5-phenyl-1,3,4-thiadiozol-2-yl)amino–4,5-
dihydropyridazine
(31).
42
The structure of the compound 31 was inferred from:
(i) correct micro analytical data. (ii) Its I spectrum revealed
strong absorption bands at 1697, 1725,1741, 1640, 1722, 1781,
3317 cm-1 attributable to υC-Cl, υmax of carbonyl groups and
υNH respectively CF. fig. 51 .Such
IR data explain that the
compound 30a exists in the presence of chloro acetyl chloride in
lactim form. Treatment of the dichloro derivative with hydrazine
hydrate. yielded the corresponding dihydrazine 32.
43
The reaction takes place via SN2 mechanism rather than
tetrahedral mechanism on the acyl family (kinetically farous), this
due to tetrahedral mechanism suffered from steric hindrance.
The IR spectrum of compound 32 exhibits strong absorption
bands at 1644, 1708, 1729, 1782, 3177 attributable to υmax of
carbonyl groups and υNH respectively CF. fig. 52.
When compound 31 was allowed to react with ammonium
acetate in boiling oil bath it afford the diamino derivative 33.
IR spectrum of compound 33 exhibits
strong absorption
band at 1629, 1723, 3186 cm-1 attributable to υC=O and υNH
respectivel CF fig. 53.
b) Reaction with ethyl chloroformate:
When compound 30a was allowed
to react with ethyl
chloroformate in the presence of anyhydrous K2CO3 and acetone,it
yielded3- (4-acetamidophennyl -4,6-
eth oxycarbonylhydrox-5-
44
(5-phenyl-1, 3,4-thiadiazol -2-yl)amino -4, 5- dihydropyridazine
34
IR spectrum of compound 34 revealed strong absorption bands at
1630, 1725, 1785, 3160 attributable to υmax of carbonyl groups
and υNH CF. fig. 54.
II) Reaction with acetic anhydride:
Treatment of compound 29 with boiling acetic anhydride
yielded N-(4-(3-acetoxy-5-oxo-4-(5-phenyl-1,3,4-thiadiazol-2-yl)
amino)-4,5-dihydrofuran-2-yl,phenyl)acetamide (35).
the reaction takes place via cyclic dehydration followed by
acetylation to give the desired product 35.
45
The structure of compound 35 was inferred from:
(i) correct micro analytical data. (ii) IR spectrum of
compound 35 exhibits strong absorption bands at 1764, 1849, 3154
attributable to υmax of carbonyl groups and υNH. (iii) The 1HNMR spectrum of compound 35 in DMSO (d6) showed signals at
ppm 2.2 (S, 6H, CH3CO of acetomido and CH3CO of acetoxy),
3.88 (S, 1H methine proton, 7.52- 7.66 (m, 9H, ArH), 7.94 (S,
2HNH proton) CF. Fig. 55.
III) Reaction with hydroxylamine hydrochloride.
When 29 was submitted to react with hydroxyl amino
hydrochloride in boiling pyridine afforded the corresponding
oxime 36.
The IR spectrum of compound 36 revealed absorption at
1630, 1683, 3194, 3245 and 3400 cm-1 attributable to υmax of
carbony groups υNH and υOH respectively CF. Fig. 56. The 1HNMR spectrum in DMSO (d6) showed signal at  ppm 2.23 (s,
3H) H3C-CO), 4.25, 4.28 (2 doublet, 2H, methine proton) = 7.53-
46
7.70 (m, 9H) ArH), 7.94 – 7.96 (s, 3H, 3OH, exchangeable by
D2O), 12.7 (broad singlet 1H carboxylic protons) CF. fig.57
EI-
MS exhibits m/z = 420 (M+-H2O), m/z= 395 (M+-CO2) CF fig. 58.
Part IV
G) Reaction with anthranilic acid:
4 (H)-3,1-Benzoxazin- 4 – one derivatives bear saturated
aliphatic
substitants
benezoxazinones),
at
e.g.,
position-2,
(So
CH3,C3H7(iso)
called
dynamic
CH2COCH[23]
CH2CN[24], C3H7 (n) and CH2CH2COOH are among the more
recent heterocyclic
compounds. The electronically unsaturated
character of these rIngs made difficult the synthesis of
satisfactorily stable rings. New organic substituents with special
properties in steric and in an electronic manner- helped to solve
this problems. In the last two decades, our contribution to the
solution of this problem includes the use of bulk substituents
involving strong conjugation power (which so called a static
benzoxazinoneS[25]. We report here the behavior of N-(4-(3-(4oxo-4H-benzo[d][1,3]oxazin-2-yl)prop-2-enoyl)phenyl)acet-amide
(39) towards some nitrogen nucleophiles , with the aim
studying the polar and
of
steric effects on the stability of the
47
oxazinone nucleus. The benzoxazinone derivative 39 was obtained
according to the following scheme.
In which acid 1 reacts with phosphorous pentachloride and
yielded 4-(4-acetamidophenyl-4-oxo-but –2-enoyl chloride (37).
The latter reacts with anthranilic acid in the presence of pyridine
and yielded
2-(4-(4-acetamidophenyl)-4-oxo-but–2-enamido)
benzoic acid (38). Treatment of compound 38 with boiling acetic
anhydride yielded the target product 39, which is a valuable
intermediate in heterocyclic synthesis. The compound 39 is a semi
acid anhydride it may undergo many of the reactions of a true
anhydride.
The IR spectrum of compound 38 exhibits strong absorption
bands at 1630, 1683, 2576, 2675, and 3077 attributable to υmax of
carbonyl groups and υOH chelated and υNH CF fig. 59. The IR
48
spectrum of compound 39 revealed strong absorptions at 16.03,
1630, 1685, 1716, 1766 and 1851 cm-1 attributable to υmax of
C=N, and carbonyl groups CF. Fig. 60
I) Reaction with hydrazine hydrate:
When 4H-3,1-benzoxazin-4-one 39 was allowed to react with
hydrazine
hydrate
in
boiling
ethanol
afforded
3-(4-
acetoamino)phenyl-5-(4H-3,1-benzoxazin-4-one-2-yl)pyrazo-line
(40).
The structure of compound 40 was established from:
(i) correct micro analytical data (ii) Its IR spectrum revealed
strong absorption bands at 1602, 1651, 1709, 1731, 3099, 3319
attributable to υC=N, υC=O and υNH CF. fig. 61 such IR data
indicate that the oxazinone nucleus is highyl stable in this system
(steric and polar factors stabilize this nucleus). The reaction
possibly takes place via nucleophilic addition to the carbonyl
group followed by ring closure.
49
II) Reacton with hydroxylamine hydrochloride:
Treatment of the benzoxazinone derivative 39 with
hydroxylamine hydrochloride in boiling pyridine it afforded 2-(1hydroxyamino
-2-
(4-acetylaminobenzoyl)
ethyl
4H
-3,1-
enzoxazin-4-one (41).
The structure of the compound 41 deduced from:
(i) correct micro analytical data .(ii) Its IR spectrum revealed
strong absorption bonds at 1607, 1630 , 1680 1722, 3200, 3439
cm-1 attributable to υC=N, υC=O, υNH and υOH respectively CF
fig. 62. the reaction takes place via aza Michael addition to, , 50
unsaturated carbonyl moiety rather than , - unsaturated aza
methylene moiety (this seems to reasonable, because polarization
by carbonyl outweighs the polarization of C=N)
III) Reaction with formamide (ammoniulysis):
When the benzoxazinone derivative 39 was allowed to react
with formamide or ammonium acetate at 170oC in an oil bath, the
quinazolinone our derivative 42 was obtained.
The structure of compound 42 was produced from:
(i)
correct micro analytical data (ii) Its IR spectrum revealed strong
absorption bands at 1606, 1630, 1680, 3200, 3438 cm-1 attributable
to υC=N and υmax of carbonyl group, υNH and υOH respectively.
Cf. fig. 63. (iii) Chemically via its reaction with acetyl chloride or
benzoyl chloride and yielded acetoxy and benzoyloxy derivative
43a and b
51
IR spectra of compound 43 exhibit strong absorption at 1744
and 1746, 1690-1685, 1630- 1635, 3200 , 3220 cm-1 attributable to
υmax of carbonyl group and υNH an devoid any band for υOH CF
Fig. 64 for 43a
Formation of compound 42 takes place via hetero – ring
opening followed by recyclization to give the quinazolinone
moiety which undergoes ring closure in the carbonyl group .
52
IV) Reaction with ethyl glycinate:
Interaction of the benzoxazinone 39 with ethyl glycinate
hydrochloride
in dry pyridine yielded the corresponding
quinazolinone 44 .
ethyl 2-(2-(3-(4-acetamidophenyl)-3-oxo-
propen-1-yl)-4-oxo-quinazolin 3(4H)-yl-acetate.
53
IR spectrum of compound 44 revealed strong absorption bands
at 1607, 1630, 1720, 3100 cm-1 attributable to υC=N, υC=O, and
υNH CF. fig. 65.
V)Reaction with semicarbazide:
When the benzoxazinone 39 was allowed to react with
semicarbazide hydrochloride in boiling dry pyridine it yielded the
quinazolinone 45.
IR spectrum of
compound 45 exhibits strong absorption
bands at 1603, 1630, 1688, 3207, 3299, 3397 cm-1 attributable to
υC=N, υmax of carbony 1 groups, υNH, bonded and non bonded
respectively CF fig. 66.
VI)Reaction with thiosemicarbazide:
When the benzoxazinone 39 was submitted to react with
thiosemicurbazide
hydroechloride in drug boiling pyridine it
54
yielded
2-(1-thiocarbamoyl-3(4-acetoamino)pheyl
pyrazolin-5-
yl)4H-3,1- benzoxazine - one (46).
IR spectrum of compound 46 showed stretching frequencies at
1393, 1633, 1735, 3195 cm-1 attributable to υC=S, υC=O, υNH
respectively. Cf. fig. 67.
Conclusion:
Study of the behaviour of benzoxazinone derivative 39
towards nitrogen nucleophiles, results medicated that the
oxazinone nucleus is highly Stable compared by reactivity of
enone structure this many be due to steric and polar effects at the
position 2. This, highly stabilized 4H-3, 1- benzoxazin-4-one
derivatives have no longer contributed
in biological and
pharmaceutical applications but still we need more work in this
topic to make the results more clearer.
55
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