Al- Mustansiriyah J. Sci.
Vol. 23, No 7, 201٢
Synthesis of Heterocyclic Compounds of Cyclohexenone
Derived From Chalcone of Acetophenone
Nabil B. Ayrim
Department of chemistry , college of science , Al-Mustansyriah University
Received 13/11/2011 – Accepted 20/6/2012
‫اﻟﺨﻼﺻﺔ‬
‫ﺗﻢ ﺗﺤﻀﯿﺮ ﻣﺸﺘﻘﺎت ﻟﻠﺴﺎﯾﻜﻠﻮھﯿﻜﺴﯿﻨﻮن ﻣﻦ اﺿﺎﻓﺔ ﻣﺮﻛﺐ اﺛﯿﻞ اﺳﯿﺘﻮاﺳﯿﺘﺎت اﻟ ﻰ ﻣﺮﻛ ﺐ اﻟﺠ ﺎﻟﻜﻮن اﻟﻤﺤﻀ ﺮ ﻣ ﻦ‬
‫ ﺛ ﻢ ﻋﻮﻣ ﻞ‬، NaOH 40 % ‫ﺗﻔﺎﻋ ﻞ اﻻﺳ ﯿﺘﻮﻓﯿﻨﻮن او ﻣﺸﺘ ـﻘﺎﺗﮫ ﻣ ﻊ اﻟﺒﻨﺰاﻟﺪﯾﮭﺎﯾ ﺪ ﻓ ﻲ اﻟﻜﺤ ﻮل ﺑﻮﺟ ـﻮد ﻗﺎﻋـ ـﺪة‬
‫اﻟﺴﺎﯾﻜﻠﻮھﯿﻜﺴﯿﻨﻮن اﻟﻤﺤﻀ ﺮ ﻣ ﻊ اﻟﮭﯿ ﺪرازﯾﻦ اﻟﻤ ﺎﺋﻲ ﻟﺘﺤﻀ ﯿﺮ ﻣﺸ ﺘﻖ اﻟﻜﺎرﺑﻮھﯿﺪرازاﯾ ﺪ اﻟ ﺬي ﺗﻤ ﺖ ﻣﻌﺎﻣﻠﺘ ﮫ ﻣ ﻊ‬
‫ اﺛﯿ ﻞ اﺳﯿﺘﻮاﺳ ﯿﺘﺎت واﻻﺳ ﯿﺘﺎﯾﻞ اﺳ ﯿﺘﻮن ﻟﺘﺤﻀ ﯿﺮ‬، ‫ ﻛﻠﻮروﺛﺎﯾﻮﺳ ﯿﺎﻧﺎت‬، ‫ ﺣ ﺎﻣﺾ اﻟﺨﻠﯿ ﻚ‬، ‫ﺣ ﺎﻣﺾ اﻟﻔﻮرﻣﯿ ﻚ‬
‫ ﺗ ﻢ ﺗﺸ ﺨﯿﺺ اﻟﻤﺮﻛﺒ ﺎت اﻟﻤﺤﻀ ﺮة ﻣ ﻦ‬، ‫ﻣﺸ ﺘﻘﺎت ﺟﺪﯾ ﺪة ﻣﮭﻤ ﺔ ﯾﺘﻮﻗ ﻊ ﻟﮭ ﺎ ﻓﻌﺎﻟﯿ ﺔ ﺑﺎﯾﻮﻟﻮﺟﯿ ﺔ واﻻھﻤﯿ ﺔ اﻟﺼ ﻨﺎﻋﯿﺔ‬
‫ﺧ ﻼل ﺻ ﻔﺎﺗﮭﺎ اﻟﻔﯿﺰﯾﺎوﯾ ﺔ وﻛ ﺬﻟﻚ اطﯿ ﺎف اﻻﺷ ﻌﺔ ﺗﺤ ﺖ اﻟﺤﻤ ﺮاء وﻓ ﻮق اﻟﺒﻨﻔﺴ ﺠﯿﺔ واطﯿ ﺎف اﻟ ﺮﻧﯿﻦ اﻟﻨ ﻮوي‬
. ‫اﻟﻤﻐﻨﺎطﯿﺴﻲ‬
ABSTRACT
Derivatives of cyclo hexenone were prepared from addition of ethylacetoacetate
to chalcone compound which was prepared from the reaction of acetophenone or it's
derivatives with benzaldehyde in ethanol in presence of 40 % NaOH . The
synthesized cyclo hexenone was treated with hydrazine hydrate to prepare
carbohydrazide derivative , which was treated with formic acid , acetic acid , chloro
isothiocyante , ethyl acetoacetate and acetyl acetone to prepare new important
derivatives with expected biological activity . The structures of the synthesized
compounds were confirmed through their physical properties and spectral data .
INTRODUCTION
Chalcones and the corresponding heterocyclic analoge are valuabl
intermediates in organic synthesis [1] , and exhibit multitude of
biological activates [2] . from a chemical point of view , an important
feature of chalcones and their heteroanalogs is the ability to act as
activated unsaturated systems in conjugated addition reaction of
carbanions in the presence of basic catalysis [3,4]. This type of reaction
may be exploited with the view of obtaining highly functionalized
cyclohexene derivatives [5] , but is more commonly used for the
preparation of 3,5-diaryl-6-carbethoxy cyclohexenones via Michael
addition of ethyl acetoacetate . The mentioned cyclohexenones are
efficient synthons in building spiranic compounds [6] or intermediates
in the synthesis of fused heterocycles such as benzoselenadiazoles and
benzothiazoles [7] , benzopyrazoles and benzisoxazoles [8,9] or
carbazole derivatives [10] .
Hydrazinolysis of ester is the conventional methods for preparing
acyl hydrazide [11,12] . However , when this method was applied to an
α,β-unsaturated ester , the predominant product was the corresponding
pyrazolidinone , the result of hydrazinolysis and an undesired
subsequent itramolecular michael-type addition [13] . a number of
natural and synthetic hydrazide derivatives have been reported to exert
99
Synthesis of Heterocyclic Compounds of Cyclohexenone Derived From Chalcone of Acetophenone
Nabil
notably antimicrobial [14,15] as will as antifungal [16,17] and
tuberculostatic [18] activity .
O
O
CHO
C
C
CH3
CH
NaOH 40 %
+
EtOH
R
R
CH
(
O
base
H 3C
C
C H 2 COOC
O
2H 5
O
OC
2H 5
R
(
NH 2 NH 2 .H 2 O
O
O
NHNH
2
R
(
Scheme
O
1
O
S
O
NH
NH NH
O
C
NH N
Cl
CH2 COOC2 H5
CH3
R
R
(
(
NCS
CH3 COCH 2COOC 2H 5
O
Cl
O
NHNH 2
R
(
O
HCOOH
O
O
O
O
CH3COCH 2COCH 3
NH NH C H
CH3
CH3COOH
N
N
CH3
R
(
R
(
O
O
O
NH NH C
R
CH3
R = H , CI
(
Scheme
100
2
Al- Mustansiriyah J. Sci.
Vol. 23, No 7, 201٢
MATERIALS AND METHODS
Melting points were determined in open capillary tube on Gallen
Kamp melting point apparatus and uncorrected. The IR spectra KBr disc
were recorded with Shimadzu-2N , FT-IR-8400S. UV. Spectra were
recorded on Varian UV-Vis spectrophotometer using absolute ethanol
as solvent. 1HNMR spectra were recorded on Bruker spectrophotometer
model ultra shield at 300 MHz in DMSO-d6 solution with the TMS as
internal standard .
Synthesis of compounds (1a ,1b) : [19]
A mixture of acetophenone or derivatives (0.1 mol) and
benzaldehyde (0.1 mol) in ethanol (40 ml) and 40 % NaOH solution
was stirred for (24 hrs.) at RT. The reaction mixture was acidified by 10
% HCl solution , The product formed was filtered and recrystallized
from ethanol to give compounds (1a , 1b) .
Synthesis of compounds (2a , ab): [20]
A mixture of compounds (1a ,1b) (0.01 mol) and ethyl acetoacetate
(0.1 mol) in ethanol (25 ml) was refluxed for (6 hrs.) in the presence of
(3ml) 10 % NaOH solution . The reaction mixture was then poured with
good stirring into (200 ml) ice-cold water until the reaction product
separated as a solid , which was filtered and recrystallized from ethanol
to give compounds (2a , 2b) .
Synthesis of compounds (3a , 3b) : [21]
Compound (2a or 2b) was dissolved in a solution containing ethanol
(30 ml) and hydrazine hydrate (12 ml) and the mixture was refluxed for
(5 hrs.) after cooling the precipitate was filtered and recrystallized from
ethanol to give compounds (3a , 3b).
Synthesis of compounds (4a , 4b) : [22]
A solution of compound (3a or 3b) (1 mmol) in formic acid (20 ml)
was refluxed for (1 hrs.) . The solvent was evaporated and the residue
was crystallized from ethanol to give compounds (4a, ab).
Synthesis of compounds (5a , 5b) : [22]
A solution of compound (3a or 3b) (1 mmol) was refluxed in acetic
acid (20 ml) for (5 hrs.). The reaction mixture was cooled and the
crystalline product was collected by filtration to give compounds (5a,
5b).
Synthesis of compounds (6a , ab) : [22]
To a solution of compound (3a or 3b) (1 mmol) in ethanol (10 ml) ,
phenyl isothiocyante (1 mmol) and sodium hydroxide (40 mg) were
added . The mixture was stirred for (24 hrs.) and the filtrate was
acidified with hydrochloric acid . The precipitate was filtered and
recrystallized from (ethanol : water) to give compounds (6a , 6b).
101
Synthesis of Heterocyclic Compounds of Cyclohexenone Derived From Chalcone of Acetophenone
Nabil
Synthesis of compounds (7a , 7b) : [22]
A mixture of compounds (3a or 3b) (1 mmol) and ethyl acetoacetate
(1 mmol) was condensed without solvent at (145-155 C٥) for 10 min.
The reaction mixture was cooled and refluxed in ethanol (15 ml) for (2
hrs.). The precipitate formed after cooling was collected by filtration
and recrystallized from ethanol to give compounds (7a , 7b).
Synthesis of compounds (8a , 8b) : [22]
A mixture of compound (3a or 3b) (1mmol) with acetyl acetone (1
mmol) and acetic acid (1 ml) was refluxed in ethanol (10 ml) for (5
hrs.). The precipitate which formed after cooling was collected by
filtration and recrystallized from ethanol to give compounds (8a , 8b).
RESULTS AND DISCUSSION
The new derivatives of compounds (1a,1b) were prepared following
the reaction sequences depicated in scheme (1). The starting material for
the synthesis of the targeted compound is chalcone or derivatives
(1a,1b) which was prepared by the reaction of acetophenone or
derivatives with benzaldehyde in ethanol in the presence of 40 % NaOH
solution table (1). The formation of compound (1a) was indicated by
appearance of the carbonyl group band (C=O) at 1654 cm-1 in their IR
spectra combined with disappearance of the (OH) stretching band. In
addition , 1HNMR of compound (1a) showed CH=CH (2H, S) δ= 3.5
ppm and aromatic proton (10 H, m) δ= 6.7-8. UV spectra of compound
(1a) mostly showed intense maxima at 208 nm , 249 nm, 357 nm, which
belonged to (π-π*) and (n-π*) transition respectively. The values of IR
and UV spectra of compound (1a) are reported in table (1).
The IR spectra of compound (2a) showed the ester functional group
absorption band at 1730 cm-1 . The structure of cyclo hexenone a sharp
strong absorption band was noticed at approximately 1664 cm-1 and was
assigned to the carbonyl group conjugated with a carbon-carbon double
bond . In addition , 1HNMR of compound (2a) showed OCH2CH3 (3H,
t) δ= 1.3 ppm , OCH2CH3 (2 H, q) δ= 4.1 ppm, cyclohexenone (3H, m)
δ =3.1-3.3 ppm, cyclohexenone (CH2, 2H, d) δ = 1.8 ppm and aromatic
(10H, m) δ = 6.8-8 ppm. UV spectra of compound (2a) mostly showed
intense maxima at 204 nm and 258 nm which belonged to (π-π*) and (nπ*) transition respectively. The values of IR and UV spectra of
compound (2b) are reported in table (1). The IR spectra of compound
(3a) carbohydrazide showed absorption band in the 3317 cm-1 (-NH2)
and 1668 cm-1 (-CO-NHNH2) group . In addition , 1HNMR of
compound (3a) showed in cyclohexenone (3H, m) δ= 2.7-2.9 ppm,
cyclohexenone (-CH2, 2H, d) δ= 2 ppm, -NH- (1H, S) δ= 6 ppm , -NH2
(2H, d) δ= 5.1-5.3 ppm and aromatic (10 H, m) δ =6.5-8 ppm. UV
spectra mostly showed intense maxima at 204 nm and 251 nm which
102
Al- Mustansiriyah J. Sci.
Vol. 23, No 7, 201٢
belonged to (π-π*) and (n-π*) transition respectively. The values of IR
and UV spectra of compound (3b) are reported in table (1).
The IR spectra of compound (4a) showed absorption band in the
3441 cm-1 (-NH) and the absorption band in the 1670 cm-1 for (-NHCO-) . In addition , 1HNMR of compound (4a) showed in
cyclohexenone (3H, m) δ= 3-3.2 ppm, cyclohexenone (-CH2, 2H, d) δ=
2.2 ppm, -NH- (1H, S) δ= 8.3 ppm , -NH-CO (1H, S) δ= 9 ppm, -COH
(1H, S) δ= 10.1 ppm and aromatic (10 H, m) δ =6.8-7.3 ppm . UV
spectra mostly showed intense maxima at 205 nm and 244 nm which
belonged to (π-π*) and (n-π*) transition respectively. The values of IR
and UV spectra of compound (4b) are reported in table (2).
The IR spectra of compound (5a) showed absorption bands in the
3431 cm-1 (-NH) and 1708 cm-1 (-NH-CO-) group . In addition ,
1
HNMR of compound (5a) showed in cyclohexenone (3H, m) δ= 3-3.1
ppm, cyclohexenone (-CH2, 2H, d) δ= 1.8 ppm, -CH3 (3H, S) δ= 2.3
ppm , -CONH (1H, S) δ= 10.3 ppm, -NHCOCH3 (1H, S) δ= 9.8 ppm
and aromatic (10 H, m) δ =6.9-7.8 ppm. UV spectra mostly showed
intense maxima at 204 nm and 247 nm which belonged to (π-π*) and (nπ*) transition respectively. The values of IR and UV spectra of
compound (5b) are reported in table (2).
The IR spectra of compound (6a) contain 3444-3240 cm-1 (-NH-CSNH-) and band at 1662 cm-1 (-C=O) group and 1039 cm-1 (C=S) and (CCl) at 756 cm-1. In addition , 1HNMR of compound (6a) showed in
cyclohexenone (3H, m) δ= 2.8.1 ppm, cyclohexenone (2H, d) δ= 1.8
ppm, -CONH (1H, S) δ= 9.8 ppm, -NHCS- (1H, S) δ= 8 ppm, -CSNH(1H, S) δ= 11.2 ppm and aromatic (14 H, m) δ =6.7-7.9 ppm . UV
spectra mostly showed intense maxima at 202 nm , 276 nm and 352 nm
which belonged to (π-π*) and (n-π*) transition respectively. The values
of IR and UV spectra of compound (6b) are reported in table (1).
The IR spectra of compound (7a) contains 3462 cm-1 (-NH-) and
absorption band in the (C=O) group function appeared at 1653 cm-1 and
(-C=O) ester function appeared at 1743 cm-1 and appearance of (C=N)
at 1612 cm-1. In addition , 1HNMR of compound (7a) showed in
cyclohexenone (3H, m) δ= 2.9-3.1 ppm, cyclohexenone (-CH2, 2H, d)
δ= 1.8 ppm, -CO-CH2CH3 (3H, t) δ= 1.5 ppm , --CO-CH2CH3 (2H, q)
δ= 4.2 ppm, -N=C-CH3 (3H, S) δ= 2.2 ppm, -N=C-CH2 (2H, S) δ= 3.8
ppm, -NH- (1H, S) δ= 10.8 ppm and aromatic (10 H, m) δ =6.9-7.8
ppm. UV spectra mostly showed intense maxima at 205 nm , 249 nm
and 365 nm due to (π-π*) and (n-π*) transition respectively. The values
of IR and UV spectra of compound (7b) are reported in table (2).
The IR spectra of compound (8a) contains 1656 cm-1 (C=O) carbonyl
group and absorption at 1597 cm-1 (-C=N) , 1220 cm-1 (C-N) and (CHal.) at 2918 cm-1. In addition , 1HNMR of compound (8a) showed in
103
Synthesis of Heterocyclic Compounds of Cyclohexenone Derived From Chalcone of Acetophenone
Nabil
cyclohexenone (3H, m) δ= 3 ppm, cyclohexenone (-CH2, 2H, d) δ= 2
ppm, -CH3 (3H, s) δ= 1.2 ppm , -CH3 (3H, S) δ= 4 ppm, -CH=C- (1H,
S) δ= 5.5 ppm, and aromatic (10 H, m) δ =6.8-7.6 ppm UV spectra
showed intense maxima at 208 nm , 249 nm and 357 nm due to (π-π*)
and (n-π*) transition respectively. The values of IR and UV spectra of
compound (8b) are reported in table (2).
Table -1 : physical properties and spectral data for compounds (1-3 a,b)
Comp.
R
M.P C٥
Yeild%
1a
H
170-172
82.7
1b
4-Cl
165-167
85
2a
H
138-140
72.2
2b
4-Cl
88-90
68.5
3a
H
95-97
60.3
3b
4-CI
100-102
63.5
UV λmax
357,249
208
258, 208
248, 204
327,251
204
251, 204
259, 204
Spectral data
IR ( cm-1 )
1654(C=O), 3030(CH)ar, 1610(C=C)
1670(C=O), 3050(CH)ar,
1600(C=C), 746(C-CI)
1660(C=O), 1730(C=O ester),
3064(CH)ar, 1590(C=C)
1670(C=O), 1745(C=Oester),
3050(CH)ar, 1600(C=C), 780(C-CI).
1656(C=O), 1668(-CONHNH2),
3059(CH)ar, 1595(C=C), 3317(3317)
1660(C=O), 1681(-CONHNH2),
3063(CH)ar, 1589(C=C),
3396(NH2), 829(C-CI)
Table-2 : physical properties and spectral data for compounds (4-8 a,b)
Comp
R
M.P C٥
Yeild%
4a
H
110-112
53
4b
4-CI
115-117
55.4
5a
H
116-118
68.2
5b
4-CI
128-130
58
6a
H
152-154
51
6b
4-CI
85-87
57
7a
H
135-137
67
7b
4-CI
144-146
69
8a
H
152-154
73
8b
4-CI
133-135
74
UV λmax
244,205
255,203
352,247
204
266, 205
352, 276
202
248, 265
365,249
205
258, 204
357, 249
208
320, 251
212
104
Spectral data
IR ( cm-1 )
1660(C=O), 1676(-NH-CO-),
3061(CH)ar, 1591(C=C), 3440(-NH-),
1630(C=O), 1670(-NH-CO-),
3030(C=C)ar, 3390(-NH-), 756(C-CI)
1670(C=O), 1708(-NH-CO-),
3059(CH)ar, 1593(C=C), 2922(CH)al,
3431(NH)
1672(C=O), 1713(-NH-CO-),
3070(CH)ar, 2930(CH)al, 1588(C=C),
3231(NH), 780(C-CI)
1662(C=O), 3055(CH)ar, 3444-3240(NH-CS-NH-), 1039(C=S), 1211(C-N),
852(C-CI)
1658(C=O), 3059(CH)ar, 3462-3300(NH-CS-NH-), 1039(C=S), 1217(C-N),
726(C-CI)
1653(C=O), 1743(C=O), 3061(CH)ar,
2931(CH)al, 3462(NH), 1612(C=N),
1589(C=C)
1657(C=O), 1710(C=O), 3076(CH)ar,
2910(CH)al,3381(NH),1629(C=N),
1601(C=C), 759(C-CI)
1656(C=O), 1597(C=C), 1492(C=N),
3059(CH)ar, 2854(CH)al, 1210(C-N)
1662(C=O), 1590(C=C), 1560(C=N),
756(C-CI),1219(C-N)
Al- Mustansiriyah J. Sci.
Vol. 23, No 7, 201٢
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