organic727_130127151853 (1)
TRANSCRIPT
Copyright © 2013 by Modern Scientific Press Company, Florida, USA
International Journal of Modern Organic Chemistry, 2013, 2(1): 11-25
International Journal of Modern Organic Chemistry
Journal homepage: www.ModernScientificPress.com/Journals/ijorgchem.aspx
ISSN: 2166-0174
Florida, USA
Article
Reactivity of Oxazolone Derivative towards Nitrogen and
Carbon Nucleophilic Reagents: Applications to the Synthesis of
New Heterocycles
Osman M. O. Habib, Hussein M. Hassan, Evelin B. Moawad and Ahmed El-Mekabaty*
Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
* Author to whom correspondence should be addressed; E-Mail: [email protected];
[email protected]; Tel: (+2010)03677361.
Article history: Received 7 January 2013, Received in revised form 23 January 2013, Accepted 25
January 2013, Published 28 January 2013.
Abstract: Oxazolone derivative 2 was utilized as a key intermediate for the synthesis of
some new oxazolone and imidazolone derivatives. Reaction of 2 with diamines under
different conditions gives the corresponding imidazolone derivatives 3-8, respectively. In
addition, its reaction with some heterocyclic amines in glacial acetic acid gives the
corresponding imidazolone derivatives 9-14, respectively. Moreover, cyclocondensation of
thiosemicarbazide with 2 in dry pyridine afforded 15. Furthermore, addition of secondary
amines to the olefinic double bond of compound 2 gives the corresponding addition
products 16-19, respectively. Finally, Michael addition of oxazolone 2 with some active
methylene compounds afforded oxazolone derivatives 20-23, respectively.
Keywords: Oxazolone; Imidazolone; Pyrazole; Benzoimidazole.
1. Introduction
The Erlenmeyer reaction was first described in 1893 by Friedrich Gustav Carl Emil
Erlenmeyer1 who condensed benzaldehyde with N-acetyl glycine in the presence of acetic anhydride
and sodium acetate. The reaction goes via a Perkin condensation following the initial cyclization of the
N-acetylglycine yielding the so-called Erlenmeyer azlactones. Erlenmeyer azlactones have been used
in a wide variety of reactions as precursors for biologically active peptides, herbicides, fungicides, and
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as drugs, pesticides and agrochemical intermediates. Oxazol-5-ones inhibit the activity of tyrosinase
enzyme with a maximum inhibition by the derivative which bears a cinnamoyl residue at C-4 of
oxazolone moiety. Some prepared 3,4-diaryloxazolones showed inhibition of cyclooxygenase-2 (COX-
2), in vivo anti-inflammatory and excellent activities of arthritis and hyperalgesia [1-5]. Several
imidazolidine derivatives are proved as insecticides such as imidazolidin-2-one and imidaclopride;
herbicides as imazamethabenz-methyl and oxadiargyl and fungicides as iprodione that controlled the
brown patch (Rhizoctonia solani) [6]. Great fungitoxic effect was exhibited by imidazole derivatives
that posses an electron-attracting moietysubstituted on the imine nitrogen atom [7]. On the other hand,
it has been stated that compounds containing aromatic sulfonate or sulfonamide moieties possess high
acaricidal as well as insecticidal activity [8-9]. In view of the aforementioned facts, taking these
structural features into consideration and as a continuation of our previous work on the chemistry of
heterocyclic compounds [10-12], we report herein the synthesis of some heterocyclic systems bearing
both aryl sulfonate, oxazolone and imidazolone moieties in the same molecule, as new compounds in
this field, of anticipated biological activities.
2. Materials and Methods
2.1. Instruments
All melting points (uncorrected) were determined on Gallenkamp electric melting point
apparatus, FTIR spectra (KBr disk) were recorded on a Nicolet Magna. IR model 550
spectrophotometers, 1H-NMR spectra, were determined on Brucker Wpsy 300 MHZ spectrometer with
TMS as internal standard and the chemical shifts are in σ ppm. Mass spectra were recorded at 70 ev
with a varian MAT 311. Elemental analyses are satisfactory for all synthesized compounds (2-23), all
analyses were carried out in Faculty of Science, Cairo University, Egypt. (Z)-4-((5–oxo-2-
phenyloxazol-4(5H)–ylidene)methyl)phenyl-4-methylbenzene sulfonate 2 was prepared previously as
shown in literature [13].
2.2. Synthesis
2.2.1. Reaction of oxazolone (2) with o-phenylenediamine
a) By fusion at 140 ºC and 190 ºC
A mixture of oxazolone 2 (0.003 mol), o-phenylenediamine (0.003 mol) and freshly fused
sodium acetate (0.2 gm) was fused at 140 C and/or 190 C for 3 h. In each case, the reaction mixture
was cooled, washed with dil. HCl, and the separated solid product was dried and recrystallized from
methanol to give 3 and 4, respectively.
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4-(2-benzamido-2-(1H-benzo[d]imidazol-2-yl)vinyl)phenyl4-methylbenzenesulfonate (3):
Gray powder; Yield 53%; m.p. 149-151oC. IR (KBr): ν/cm
-1: 1680 (CO, amidic), 3174-3289 (2NH),
1360 (SO3), 1600 (C=N), 1590 (C=C). EIMS (m/z) (%): 509 (M+, 20), 422 (54), 353 (23), 268 (11),
263 (16), 191 (32), 104 (100), 77 (37). Anal. for C29H23N3O4S (509.5): Calcd.: C, 68.35%; H, 4.55%;
N, 8.25 %. Found: C, 68.31%; H, 4.50%; N, 8.15 %.
(Z)-4-((1-phenyl-3H-benzo[d]imidazo[1,5-a]imidazol-3-ylidene)methyl)phenyl-4-methylbenzene
sulfonate (4):
Brown powder; Yield 63%; m.p. 238-240oC. IR (KBr): ν/cm
-1: 1360 (SO3), 1620 (C=N). EIMS (m/z)
(%): 489 (M+-2, 18), 341 (38), 295 (25), 213 (40), 193 (48), 147 (73), 91 (38), 44 (100).
1H NMR
(DMSO) (δ, ppm), 2.4 (s, 3H, CH3), 7.1-8.2 (m, 18H, Ar-H, CH=C). Anal. for C29H21N3O3S (491.5):
Calcd.: C, 70.86%; H, 4.31%; N, 8.55%. Found: C, 70.81%; H, 4.30%; N, 8.45%.
b) By refluxing in ethyl alcohol
(Z)-4-(3-((2-aminophenyl)amino)-2-benzamido-3-oxoprop-1-en-1-yl)phenyl-4-methylbenzene
sulfonate (5)
A mixture of oxazolone 2 (0.003 mol) and o-phenylenediamine (0.003 mol) in absolute ethanol
(20 mL) was refluxed for 6 h. The solid product that separated on cooling was filtered off and
recrystallized from ethanol to give 5:
Grey powder; Yield 65%; m.p. 218-220oC. IR (KBr): ν/cm
-1: 1680 (CO, amidic), 3430, 3490 (2NH),
3225-3370 (NH2), 1360 (SO3), 1620 (C=N). EIMS (m/z) (%) : 527 (M+, 30), 495 (11), 480 (14), 422
(27), 380 (56), 268 (16), 253 (100), 105 (52). 1H NMR (DMSO) (δ, ppm), 2.4 (s, 3H, CH3), 4.5 (br,
2H, NH2), 6.9-8.3 (m, 20H, Ar-H, CH=C, 2NHCO). Anal. for C29H25N3O5S (527.5): Calcd.: C,
66.02%; H, 4.78%; N, 7.96%. Found: C, 66.01%; H, 4.80%; N, 7.86%.
c) By refluxing in glacial acetic acid
(Z)-4-((1-(2-acetamidophenyl)-5-oxo-2-phenyl-1H-imidazol-4(5H)-ylidene)methyl)phenyl-4-methyl
benzenesulfonate (6)
A mixture of oxazolone 2 (0.003 mol) and o- phenylenediamine (0.003 mol) in glacial acetic
acid (20 mL) containing freshly fused sodium acetate (0.2 gm) was heated under reflux for 7 h. The
reaction mixture was left to cool, and then poured over ice; the solid that separated out was filtered off,
dried and recrystallized from ethanol-ether affording 6:
Yellow powder; Yield 65%; m.p. 180-182oC. IR (KBr): ν/cm
-1: 1698 (CO, amidic), 1665 (CONH),
3133 (NH), 1360 (SO3), 1610 (C=N). EIMS (m/z) (%): 551 (M+, 45), 451 (42), 368 (25), 282 (26), 197
(19), 148 (40), 78 (51), 63 (100). 1H NMR (DMSO) (δ, ppm), 2.4 (s, 3H, CH3), 2.2 (s, 3H, CH3CO),
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14
7.1-8.2 (m, 19H, Ar-H, CH=C, NH). Anal. for C31H25N3O5S (551.6): Calcd.: C, 67.5%; H, 4.57%; N,
7.62%. Found: C, 67.4%; H, 4.50%; N, 7.65%.
2.2.2. Synthesis of (Z)-4-((1-(4-acetamidophenyl)-5-oxo-2-phenyl-1H-imidaz-ol-4(5H)-ylidene)
methyl)phenyl-4-methylbenzenesulfonate (7)
A mixture of oxazolone 2 (0.003 mol) and p- phenylenediamine (0.003 mol) in glacial acetic
acid (30 mL) containing freshly fused sodium acetate (0.2 gm) was heated under reflux for 5 h. The
reaction mixture was left to cool; the solid that separated was filtered off, dried and recrystallized from
acetic acid affording 7:
Yellow powder; Yield 80%; m.p. 225-227oC. IR (KBr): ν/cm
-1: 1700 (CO, amidic), 1660 (CON), 3350
(NH), 1360 (SO3), 1640 (C=N). EIMS (m/z) (%): 552 (M+, 15), 446 (12), 342 (15), 256 (25), 157 (16),
109 (35), 84 (63), 40 (100). 1H NMR (DMSO) (δ, ppm), 2.4 (s, 3H, CH3), 2.6 (s, 3H, CH3CO), 7.1-8.4
(m, 19H, Ar-H, CH=C, NH). Anal. for C31H25N3O5S (551.6): Calcd.: C, 67.5%; H, 4.57%; N, 7.61%.
Found: C, 67.1%; H, 4.49%; N, 5.62%.
2.2.3. Synthesis of ((1Z,1'Z)-(1,1'-(1,4-phenylene)bis(5-oxo-2-phenyl-1H-imidazole-1(5H)-yl-4-(5H)-
yli dene))bis(methanylylidene))bis(4,1-phenylen- e)bis(4-methylbenzenesulfonate) (8)
A mixture of oxazolone 2 (0.006 mol) and p- phenylenediamine (0.003 mol) in glacial acetic
acid (30 mL) containing freshly fused sodium acetate (0.5 gm) was heated under reflux for 8 h. The
reaction mixture was left to cool, and then poured over ice, the solid that separated out was filtered off,
dried and recrystallized from dimethylformamide affording the bis imidazolone 8:
Grey powder; Yield 75%; m.p. 271-273oC. IR (KBr): ν/cm
-1: 1675 -1688 (2CON), 1360 (SO3), 1620
(C=N). EIMS (m/z) (%): 911 (M+, 22), 788 (33), 540 (11), 382 (100), 364 (44), 301 (8), 285 (53), 218
(17), 155 (25), 75 (33). 1H NMR (DMSO) (δ, ppm), 2.4 (br, 6H, 2CH3), 6.9-8.3 (m, 32H, Ar-H,
2CH=C). Anal. for C52H38N4O8S2 (911): Calcd.: C, 68.56%; H, 4.2%; N, 6.15%. Found: C, 68.48%; H,
4.1%; N, 6.11%.
2.2.4. Reaction of oxazolone (2) with heterocyclic amines
A mixture of 2 (0.01 mol) and the appropriate heterocyclic amines namely 2-aminopyridine, 3-
aminopyridine, 2-aminothiazole, 2-amino benzothiazole, 4-aminoantipyrine and 3-amino-4-
(phenyldiazenyl)-1H-pyrazol-5(4H)-one (0.01 mol) and freshly fused sodium acetate (0.5 gm) in
glacial acetic acid (40 mL) was refluxed for 5-8 h, then cooled and the reaction mixture was poured
onto ice-water. The solids separated were filtered off and recrystallized from methanol to give
imidazolone derivatives 9-14.
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(Z)-4-((5-oxo-2-phenyl-1-(pyridin-2-yl)-1H-imidazol-4(5H)-ylidene)methyl)phenyl-4-methylbenzene
sulfonate (9):
Yellow crystals; Yield 62%; m.p. 158-160oC. IR (KBr): ν/cm
-1: 1680 (CO, amidic), 1360 (SO3), 1620
(C=N). EIMS (m/z) (%): 496 (M++1, 16), 267 (14), 232 (13), 195 (18), 153 (14), 101 (12), 86 (47), 74
(100). Anal. for C28H21N3O4S (495.5): Calcd.: C, 67.86%; H, 4.27%; N, 8.48 %. Found: C, 67.81%; H,
4.20%; N, 8.35 %.
(Z)-4-((5-oxo-2-phenyl-1-(pyridin-3-yl)-1H-imidazol-4(5H)-ylidene)methyl)phenyl-4-methylbenzene
sulfonate (10):
Yellow powder; Yield 72%; m.p. 166-168oC. IR (KBr): ν/cm
-1: 1680 (CO, amidic), 1360 (SO3), 1620
(C=N). EIMS (m/z) (%): 495 (M+, 24), 378 (23), 256 (41), 202 (37), 184 (12), 126 (15), 88 (43), 58
(100). Anal. for C28H21N3O4S (495.5): Calcd.: C, 67.86%; H, 4.27%; N, 8.48%. Found: C, 67.78%; H,
4.25%; N, 8.49%.
(Z)-4-((5-oxo-2-phenyl-1-(thiazol-2-yl)-1H-imidazol-4(5H)-ylidene)methyl)phenyl-4-methylbenzene
sulfonate (11):
Yellow powder; Yield 52%; m.p. 181-183oC. IR (KBr): ν/cm
-1: 1680 (CO, amidic), 1360 (SO3), 1620
(C=N). EIMS (m/z) (%): 501 (M+, 41), 445 (38), 404 (48), 388 (71), 347 (41), 294 (66), 263 (33), 191
(11), 105 (81), 58 (100). Anal. for C26H19N3O4S2 (501.5): Calcd.: C, 62.26%; H, 3.82%; N, 8.38%.
Found: C, 62.28%; H, 3.80%; N, 8.28%.
(Z)-4-((1-(benzo[d]thiazol-2-yl)-5-oxo-2-phenyl-1H-imidazol-4(5H)-ylidene)methyl)-phenyl-4-
methylbenzenesulfonate (12):
Grey powder; Yield 60%; m.p. 163-165oC. IR (KBr): ν/cm
-1: 1680 (CO, amidic), 1360 (SO3), 1620
(C=N). EIMS (m/z) (%): 553 (M++2, 20), 423 (20), 383 (41), 305 (59), 256 (25), 227 (48), 186 (11),
156 (10), 122 (15), 75 (100). Anal. for C30H21N3O4S2 (551.6): Calcd.: C, 65.32%; H, 3.84%; N, 7.62
%. Found: C, 65.28%; H, 3.80%; N, 7.55 %.
(Z)-4-((1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-5-oxo-2-phenyl-1H-imidazol-
4(5H)-ylidene)methyl)phenyl 4-methylbenzenesulfonate (13):
Yellow powder; Yield 42%; m.p. 194-196oC. IR (KBr): ν/cm
-1: 1680 (CO, amidic), 1360 (SO3), 1620
(C=N). EIMS (m/z) (%): 604 (M+, 32), 450 (13), 347 (26), 290 (11), 263 (16), 231 (39), 156 (62), 105
(100). Anal. for C34H28N4O5S (604.6): Calcd.: C, 67.53%; H, 4.67%; N, 9.27%. Found: C, 67.58%; H,
4.60%; N, 9.24%.
4-((1Z)-(5-oxo-1-(5-oxo-4-(phenyldiazenyl)-4,5-dihydro-1H-pyrazol-3-yl)-2-phenyl-1H-imidazol-4
(5H)-ylidene)methyl)phenyl 4-methylbenzenesulfonate (14):
Yellow powder; Yield 46%; m.p. 172-174oC. IR (KBr): ν/cm
-1: 1680 (CO, amidic), 3320 (NH), 1360
(SO3), 1620 (C=N). EIMS (m/z) (%): 605 (M+, 21), 495 (16), 449 (12), 369 (23), 255 (12), 196 (16),
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104 (73), 91 (100). Anal. for C32H24N6O5S (604.6): Calcd.: C, 63.57%; H, 4.0%; N, 13.90%. Found: C,
63.58%; H, 3.80%; N, 13.88%.
2.2.5. Synthesis of (Z)-4-((5-phenyl-2-thioxo-2H-imidazo[1,5-b][1,2,4]triazol-7(3H)-ylidene)methyl)
phenyl-4-methylbenzenesulfonate (15)
To a solution of 2 (0.01 mol) in 30 ml dry pyridine, thiosemicarbazide (0.03 mol) was added
and the reaction mixture was heated under reflux for 8 h, left to cool, poured onto cold water with
stirring. The solid product was filtered off, washed with water several times and recrystallized from
dimethylformamide to give 15:
Grey powder; Yield 41%; m.p. 181-183oC. IR (KBr): ν/cm
-1: 1376 (C=S), 3442 (NH), 1340 (SO3),
1640 (C=N). EIMS (m/z) (%): 475 (M+, 42), 411 (75), 320 (18), 275 (53), 167 (57), 139 (27), 91 (100),
50 (49). 1H NMR (DMSO) (δ, ppm), 2.4 (s, 3H, CH3), 9.8 (s, 1H, NH), 7.2-8.3 (m, 14H, Ar-H,
CH=C). Anal. for C24H18N4O3S2 (474.5): Calcd.: C, 60.74%; H, 3.82%; N, 11.81 %. Found: C,
60.71%; H, 3.79%; N, 11.78 %.
2.2.6. Reaction of oxazolone (2) with secondary amines and thiophenol
A mixture of oxazolone 2 (0.05 mol) and the appropriate reagent namely piperidine,
morpholine, piperazine, and thiophenol (0.05 mol) in dry benzene (30 mL) was heated at 60ºC with
stirring for 3-5 h. The reaction mixture were left to stand overnight at room temperature, then
petroleum ether (40-60ºC) was added and the precipitated solid products were filtered off and
recrystallized from benzene-hexane (2:1) to give 16-19 respectively.
4-((5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)(piperidin-1-yl)methyl)phenyl-4-methylbenzene sulfonate
(16):
Yellow powder; Yield 25%; m.p. 186-188oC. IR (KBr)νmax. cm
-1: 1770 (CO, lactone), 1644 (C=N),
1360 (SO3). EIMS (m/z) (%): 504 (M+, 12), 478 (7.1), 365 (58), 282 (10), 161 (14), 85 (100), 72 (28).
1H NMR (DMSO) (δ, ppm), 2.4 (s, 3H, CH3), 2.46-2.47 (t, 4H, N(CH2)2), 1.48-1.49 (m, 6H, 3CH2 of
piperidine), 4.51-4.52 (m, 2H, N-CH, CH of oxazolone), 6.9-8.1 (m, 14H, Ar-H, CH=C). Anal. for
C28H28N2O5S (504.6): Calcd.: C, 66.65%; H, 5.59%; N, 5.55%. Found: C, 66.55%; H, 5.55%; N,
5.54%.
4-(morpholino(5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)methyl)phenyl-4-methylbenzenesulfonate
(17):
Yellow powder; Yield 31%; m.p. 160-162oC. IR (KBr)νmax. cm
-1: 1780 (CO, lactone), 1640 (C=N),
1360 (SO3). EIMS (m/z) (%): 506 (M+, 16), 420 (16), 265 (19), 161 (100), 117 (45), 93 (46), 57 (18).
1H NMR (DMSO) (δ, ppm), 2.4 (s, 3H, CH3), 2.67-2.68 (t, 4H, N(CH2)2), 3.58-3.59 (t, 4H, O(CH2)2),
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4.51-4.52 (m, 2H, N-CH, CH of oxazolone), 6.9-8.1 (m, 14H, Ar-H, CH=C). Anal. for C27H26N2O6S
(506.5): Calcd.: C, 64.02%; H, 5.17%; N, 5.53%. Found: C, 64.0%; H, 5.15%; N, 5.53%.
4-((5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)(piperazin-1-yl)methyl)phenyl-4-methylbenzene
sulfonate (18):
Yellow powder; Yield 34%; m.p. 221-223oC. IR (KBr)νmax. cm
-1: 1780 (CO, lactone), 3423 (NH),
1638 (C=N), 1360 (SO3). EIMS (m/z) (%): 505 (M+, 22), 441 (26), 395 (52), 315 (12), 277 (53), 200
(61), 148 (79), 105 (100), 48 (61). 1H NMR (DMSO) (δ, ppm), 2.4 (s, 3H, CH3), 2.65-2.66 (m, 8H,
N(CH2)4), 4.51-4.52 (m, 2H, N-CH, CH of oxazolone), 6.9-8.1 (m, 15H, Ar-H, CH=C, NH). Anal. for
C27H27N3O5S (505.5): Calcd.: C, 64.14%; H, 5.38%; N, 8.31%. Found: C, 64.13%; H, 5.35%; N,
8.24%.
4-((5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)(phenylthio)methyl)phenyl-4-methylbenzenesulfonate
(19):
Yellow powder; Yield 41%; m.p. 196-198oC. IR (KBr)νmax. cm
-1: 1780 (CO, lactone), 1640 (C=N),
1360 (SO3). EIMS (m/z) (%): 529 (M+, 25), 401 (19), 316 (47), 257 (29), 213 (37), 188 (15), 101 (12),
77 (20), 43 (100). Anal. for C29H23NO5S2 (529.6): Calcd.: C, 65.77%; H, 4.38%; N, 2.64%. Found: C,
65.73%; H, 4.35%; N, 2.54%.
2.2.7. Synthesis of ethyl2-cyano-3-(5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)-3-(4-(tosyloxy)phenyl)
propanoate (20)
A mixture of oxazolone 2 (0.03 mol), ethylcyanoacetate (0.05 mol) and few drops of piperidine
in dry chloroform (50 mL) was heated under reflux for 8 hours. The solvent was evaporated under
reduced pressure; the obtained solid product was filtered off, and recrystallized from methanol to
furnish 20:
Yellow powder; Yield 28%; m.p. 297-299oC. IR (KBr)νmax. cm
-1: 1780 (CO, lactone), 1730 (CO,
ester), 2110 (CN), 1640 (C=N), 1360 (SO3). EIMS (m/z) (%): 533 (M+, 10), 413 (19), 341 (42), 304
(25), 280 (14), 189 (17), 168 (42), 105 (44), 77 (59), 43 (100). 1H NMR (DMSO) (δ, ppm), 2.4 (s, 3H,
CH3), 1.29-1.30 (t, 3H, CH3CH2), 4.37-4.43 (q, 2H, CH3CH2), 4.31-4.32 (m, 3H, CH-CH, CH of
oxazolone), 6.9-8.1 (m, 14H, Ar-H, CH=C). Anal. for C28H24N2O7S (532.5): Calcd.: C, 63.15%; H,
4.54%; N, 5.25%. Found: C, 63.13%; H, 5.55%; N, 5.21%.
2.2.8. Synthesis of 2-acetyl-4-benzamido-3-(4-(tosyloxy)phenyl)pentanedioic acid (21)
A mixture of 2 (0.005 mol) and ethylacetoacetate (0.01 mol) in 30ml ethanol was added
dropwise to 10 mL sodium hydroxide (10%), the mixture was stirred at room temperature for 24 h then
poured onto 5ml of 5% HCl. The formed solid was filtered, washed with water and recrystallized from
ethanol to give 21:
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White powder; Yield 51%; m.p. 285-287oC. IR (KBr)νmax. cm
-1: 1670 (CO, amidic), 1700 (CO), 3400
(OH), 3300 (NH), 1640 (C=N), 1360 (SO3). EIMS (m/z) (%): 539 (M+, 46), 457 (10), 382 (100), 298
(10), 254 (35), 181 (27), 147 (16), 111 (15), 91 (56). Anal. for C27H25NO9S (539.5): Calcd.: C,
60.10%; H, 4.67%; N, 2.60 %. Found: C, 60.13%; H, 4.65%; N, 2.54 %.
2.2.9. Synthesis of 4-(2-nitro-1-(5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)alkyl)phenyl-4-methyl
benzenesulfonate (22 and 23)
A mixture of compound 2 (0.005 mol) , the appropriate nitroalkane namely, nitromethane
and/or nitroethane (0.01 mol) and few drops of triethylamine in ethanol (30 mL) was refluxed with
stirring for 12 h, then poured onto ice-water, The solid that separated was filtered off and recrystallized
from ethanol to give 22, 23.
4-(2-nitro-1-(5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)ethyl)phenyl-4-methylbenzenesulfonate (22):
Yellow crystal; Yield 38%; m.p. 205-207oC. IR (KBr)νmax. cm
-1: 1770 (CO, lactone), 1350 (NO2),
1640 (C=N), 1360 (SO3). EIMS (m/z) (%): 482 (M++2, 19), 411 (28), 344 (36), 218 (55), 275 (100),
197 (45), 155 (47), 129 (46), 91 (67). Anal. for C24H20N2O7S (480.4): Calcd.: C, 59.99%; H, 4.20%; N,
5.83%. Found: C, 60.03%; H, 4.25%; N, 5.84%.
4-(2-nitro-1-(5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)propyl)phenyl-4-methylbenzene sulfonate (23):
Yellow crystal; Yield 25%; m.p. 165-167oC. IR (KBr)νmax. cm
-1: 1770 (CO, lactone), 1350 (NO2),
1640 (C=N), 1360 (SO3). EIMS (m/z) (%): 495 (M+, 23), 455 (16), 419 (80), 384 (46), 350 (63), 334
(12), 295 (60), 238 (100), 155 (36). 1
H NMR (DMSO) (δ, ppm), 2.4 (s, 3H, CH3), 1.7 (d, 3H, CH3-
CH), 3.3 (t, 1H, CH), 4.31-4.32 (m, 2H, O2NCH-, CH of oxazolone), 6.9-8.1 (m, 14H, Ar-H, CH=C).
Anal. for C25H22N2O7S (494.5): Calcd.: C, 60.72%; H, 4.48%; N, 5.66%. Found: C, 60.73%; H,
4.45%; N, 5.56%.
3. Results and Discussion
3.1. Synthesis
The required (Z)-4-((5–oxo-2-phenyloxazol-4(5H)–ylidene)methyl)phenyl-4-methyl benzene
sulfonate 2, was prepared by means of the reaction of 4-toluenesulfonyloxy benzaldehyde 1 with
hippuric acid and acetic anhydride in the presence of freshly fused sodium acetate according to the
method reported in literature [13] (Scheme 1).
Int. J. Modern Org. Chem. 2013, 2(1): 11-25
Copyright © 2013 by Modern Scientific Press Company, Florida, USA
19
Scheme 1. Synthesis of oxazolone derivative 2
Synthesis of benzimidazole ring is an important pharmacophore in modern drug discovery [14].
Benzimidazole derivatives exhibit significant activity against several viruses such as HIV [15-16],
herps (HSV-1) [17], RNA [18] and influenza [19]. Therefore, a part of this program was to synthesize
these compounds starting with oxazolone derivative 2. Fusion of 2 with o-phenylenediamine in the
presence of freshly fused sodium acetate at 140 oC and 190
oC gives different products. When fusion
was carried out at 140oC, compound 3 was obtained, while fusion at 190
oC leads to the formation of 4.
Structures 3 and 4 were based on correct analytical results. The IR spectrum of 3 showed stretching
frequencies at 1680, 3174-3289, and 1590 cm-1
attributable to the amidic (CO), (2NHCO), and (C=C)
groups, respectively, the IR spectrum of 4 revealed absorption bands at 1620 cm-1
attributable for
(C=N), group. The bands characteristic for the C=O and –NH2 groups disappeared. Next, reaction of
oxazolone 2 with o-phenylenediamine in absolute ethanol under reflux afforded 5. The IR spectrum
showed stretching frequencies at 3225-3370 and 1680 cm-1
attributable to the (–NH2), amidic (CO),
groups, respectively. 1H-NMR showed signals at δ 2.4 (s, 3H, CH3), 4.5 (br, 2H, NH2), 6.9-8.3 (m,
20H, Ar-H, CH=C, 2NHCO). In the context of this program and because of increased interest in
imidazolone derivatives, some new imidazolone derivatives were required for the study of their
efficiency as anticipated biological activities. Oxazolone derivative 2 seemed to be a good precursor to
fulfill this objective via its reactions with some nucleophilic reagents. Treatment of 2 with o-
phenylenediamine in glacial acetic acid under reflux in the presence of fused sodium acetate gives
imidazolone derivative 6. The IR spectrum of compound 6 showed absorption bands at 3133 and 1698
cm-1
due to (NH) and (CONH) groups. The 1H-NMR spectrum revealed singlet signals at δ 8.2 and 2.2
characteristic for (NHCO) and (COCH3) protons, respectively. Besides, the mass spectrum showed the
molecular ion peak at m/e 551(M+) (Scheme 2).
Int. J. Modern Org. Chem. 2013, 2(1): 11-25
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20
NN
Ph
CHAr
Ar =4
N
N
NH
CCH
NH
Ar
3
O
Ph
ON
O
Ph
CHAr
2
+
H2N
H2N
5
HN
O
HN
OPh
Ar
6
140oC
190oCAcOH
S
O
O
H3C
H2N
HN COCH3
NN
O
Ph
CHAr
O
EtOH
Scheme 2. Reaction of oxazolone 2 with o-phenylenediamine under different conditions
On the other hand, refluxing of one mol of oxazolone 2 with one mol of p-phenylenediamine in
the presence of glacial acetic acid and fused sodium acetate, afforded 7. However, using two mol of
compound 2 to one mol of the other gives bis imidazolone 8. The structure of compounds 7 and 8 was
confirmed by analytical as well as spectral data. The IR spectrum of 7 showed absorption bands at
3350 and 1700 cm-1
due to (NH) and (CONH) groups. The IR spectrum of 8 showed absorption bands
at 1675 and 1688 cm-1
due to two (CON) groups. The 1H-NMR spectrum of 7 revealed singlet signals
at δ 8.2 and 2.6 characteristic for (NHCO) and (COCH3) protons, respectively. In addition, the mass
spectrum of compounds 7 and 8 showed the molecular ion peak at m/e 552 (M+) and 911 (M
+),
respectively (Scheme 3).
Scheme 3. Reaction of oxazolone 2 with p-phenylenediamine under different moles
Pyridine, thiazole, benzothiazole and pyrazole derivatives are biologically interesting molecules
that have established utility in the pharmaceutical and the agrochemical industries. Compounds with
these ring systems have diverse pharmacological activity such as antitumor, anticonvulsant, antiviral,
antimicrobial and fungicidal activities [19-20]. Encouraged by the above observations, it was planned
Int. J. Modern Org. Chem. 2013, 2(1): 11-25
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21
to study structure variation by attaching some biologically active heterocycles such as Pyridine,
thiazole, benzothiazole and pyrazole rings at position 1 of the main oxazolone moiety. These
combinations were suggested in an attempt to investigate the possible synergistic influence of such
structure hybridizations on the anticipated activity, hoping to discover a new lead structure that would
have a significant antimicrobial activity at very small concentration.
As a result, imidazolone derivatives 9-14, respectively could be achieved on treatment of 2 with
some heterocyclic amines namely; 2-aminopyridine, 3–aminopyridine, 2-aminothiazole, 2-
aminobenzothiazole, 4–amino antipyrine and 5-amino-4-phenylazo-2,4-dihydropyrazol-3-one in
glacial acetic acid and fused sodium acetate. The IR spectrum in general showed absorption bands at
1680 cm-1
due to CON group and the disappearance of the band characteristic for carbonyl of lactone
group (Scheme 4).
Scheme 4. Reaction of oxazolone 2 with different heterocyclic amines
On the other hand, synthesis of 1,2,4-triazoles fused to another heterocyclic ring has attracted
wide spread attention due to their diverse applications as antibacterial-, antidepressant-, antiviral-,
antitumorial- and anti-inflammatory agents, pesticides, herbicides dyes, lubricant and analytical
reagents [21-23]. Among these, the commonly known systems are generally triazoles fused to
imidazoles. In the present study Cyclocondensation of thiosemicarbazide with oxazolone 2 in dry
pyridine afforded (Z)-4-((5-phenyl-2-thioxo-2H-imidazo[1,5-b][1,2,4]triazol-(3H)-ylidene)methyl)
phenyl-4-methyl benzenesulfonate 15. Structure 15 was inferred by its correct elemental analysis and
spectroscopic data. The IR spectrum showed stretching frequencies at 3442 and 1376 cm-1
attributable
to the (NH) and (C=S) groups, respectively. 1H-NMR showed signals at δ 2.4 (s, 3H, CH3), 9.8 (s, 1H,
NH), 7.2-8.3 (m, 14H, Ar-H, CH=C). Beside, the mass spectrum revealed molecular ion peak at m/e
475 (M+) with relative abundance corresponding to the molecular formula C24H18N4O3S2 (Scheme 5).
Int. J. Modern Org. Chem. 2013, 2(1): 11-25
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22
Scheme 5. Reaction of oxazolone 2 with thiosemicarbazide
The reactivity of the exocyclic (C=C) bond in the four position of the oxazolone ring is due to
conjugation with the adjacent carbonyl group [8]. In the present work, the addition of piperidine,
morpholine, piperazine and thiophenol to the olefinic double bond in the four position of compound 2
gives the corresponding addition products 16-19, respectively (Scheme 6).
ON
O
Ph
Ar
N
ON
O
Ph
Ar
N
O
16
17
ON
O
Ph
Ar
N
HN
ON
O
Ph
Ar
S
18
19
Ar =
2
S
O
O
OH3C
HN
HN O
NHHN
HS
Dry Benzene
Dry Benzene
Dry Benzene
Dry Benzene
600C
600C
600C
600C
Scheme 6. Reaction of oxazolone 2 with secondary amines and thiophenol
The present investigation deals also with the Michael addition on the exocyclic double bond in
compound 2. Thus addition of ethylcyanoacetate to compound 2 in chloroform afforded oxazolone
derivative 20 but the addition of ethylacetoacetate in the presence of sodium hydroxide afforded
compound 21. On the other hand, the nitroalkanes are known to add to the (C=C) bond in the α,β-
unsaturated carbonyl compounds in the presence of a base catalyst. So, addition of nitro methane and
nitro ethane to oxazolone 2 leads to the formation of compounds 22 and 23, respectively. The structure
of compounds 22 and 23 were confirmed by analytical as well as spectral data. The IR spectrum in
general showed absorption bands at 1770, 1350 and 1640 cm-1
due to carbonyl of lactone, NO2 and
Int. J. Modern Org. Chem. 2013, 2(1): 11-25
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23
C=N groups. The 1H-NMR spectrum of 23 revealed 2.4 (s, 3H, CH3), 1.7 (d, 3H, CH3-CH), 3.3 (t, 1H,
CH), 4.31-4.32 (m, 2H, O2NCH-, CH of oxazolone), 6.9-8.1 (m, 14H, Ar-H, CH=C). In addition, the
mass spectrum of compounds 22 and 23 showed the molecular ion peak at m/e 482 (M++2) and 495
(M+), respectively (Scheme 7).
Ar =
2
S
O
O
OH3C
20
21
ON
O
Ph
Ar
NO2H3C
ON
O
Ph
Ar
NO2H
22
23
ON
O
Ph
Ar
CNEtOOC
O
COOH
HN
Ph
Ar
COMeHOOC
CH3CH2NO2
CH3NO2NCCH2COOEt
CH3COCH2COOEt
Dry Chloroform
Ethanol/NaOH (10%)
Ethanol/Et3N
Ethanol/Et3N
Scheme 7. Reaction of oxazolone 2 with active methylene compounds
4. Conclusions
We reported herein the synthesis of some heterocyclic systems bearing both aryl sulfonate,
oxazolone or imidazolone moieties in the same molecule as new compounds in this field of anticipated
biological activities. Oxazolone derivative 2 was utilized as a key intermediate for the synthesis of
some new oxazolone and imidazolone derivatives. It was prepared by means of the reaction of 4-
toluenesulfonyloxy benzaldehyde 1 with hippuric acid and acetic anhydride in the presence of freshly
fused sodium acetate. Reaction of 2 with diamines and heterocyclic amines under different conditions
gives the corresponding imidazolone derivatives 3-14, respectively. In addition, cyclocondensation of
thiosemicarbazide with compound 2 in dry pyridine afforded 15. Moreover, the addition of secondary
amines to the olefinic double bond of compound 2 gives the corresponding addition products 16-19,
respectively. Finally, Michael addition of compound 2 with some active methylene compounds
afforded oxazolone derivatives 20-23, respectively.
Potential Conflicts of Interest
The authors declare no conflict of interest.
Int. J. Modern Org. Chem. 2013, 2(1): 11-25
Copyright © 2013 by Modern Scientific Press Company, Florida, USA
24
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