Organic727_130127151853 (1)

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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Int. J. Modern Org. Chem. 2013, 2(1): 11-25


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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.



13

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),



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


reaction mixture was left to cool; the solid that separated was filtered off, dried and recrystallized from

acetic acid affording 7:


-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


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:


-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.



15

(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):


-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):


-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):


-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):


-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):


-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),



16

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:


-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):


-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),



17

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):


-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):


-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:


-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:



18

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).



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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).



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



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).



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



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.



24

References

[1] Khan KM, Mughal UR, Khan MT, Zia US, Choudhary MI., Oxazolones: new tyrosinase

inhibitors; synthesis and their structure-activity relationships. Bioorganic and Medicinal

Chemistry. 2006, 14: 6027-6033.

[2] Mistry RN, Desai KR., Studies on Synthesis of Some Novel Heterocyclic Azlactone Derivatives

and Imidazolinone Derivatives and their Antimicrobial Activity. E-Journal of Chem., 2005, 2:

42-51.

[3] Aaglawe M J; Dhule SS, Bahekar SS, Wakte P S, shinde DB., Synthesis and Antibacterial

Activity of Some Oxazolone Derivatives. J. Korean Chem. Soc., 2003, 47: 133-136.

[4] Joshi H, Upadhyay P, Karia D, Baxi AJ., Synthesis of Some Novel Imidazolinones as Potent

Anticonvulsant Agents. European Journal of Medicinal Chemistry, 2003, 38: 837-840.

[5] Siddiqui SA, Bhusare SR, Jarikote DV, Pawar R, Vibhute PYB., New Novel Synthesis and

Antibacterial Activity of 1-(Substituted phenyl)-2-phenyl-4-(3-halo, 4-hydroxy 5-methoxy

benzylidene)-imidazole-5-ones. Bull. Korean Chem. Soc., 2001, 22: 1033-1036.

[6] Fidanza MA, Dernoeden PH., Brown patch in perennial ryegrass as influenced by irrigation,

fungicide and fertilizers.Crop Sci., 1996, 36: 1631-1638.

[7] Ahmed SA., Pesticidal Effects of Some Imidazolidine and Oxazolone Derivatives. World Journal

of Agricultural Sciences., 2009, 5: 105-113.

[8] Habib OMO, Moawad EB, El-Morsy SS., Synthesis of Some New Heterocyclic Conpounds with

Expected Potential Biological Activity. Journal of Islamic Academy of Sciences., 1989, 2: 135-

138.

[9] Habib OMO, Girges MM, Moawad EB, El-Shafei AM., Synthetic approaches and biological

evaluation of some new sulfonate ester-containing quinazoline derivatives as potentially active

antimicrobial agents. Boll. Chim. Farmaceutico., 1995, 134: 209-215.

[10] Habib OMO, Hassan HM, El-Mekabaty A., Novel quinazolinone derivatives: synthesis and

antimicrobial activity. Med Chem. Res, 2012, DOI 10.1007/s00044-012-0079-x.

[11] El-Mekabaty A. Improvement of lubricating oils characters using novel additives. International

Journal of Modern Organic Chemistry, 2012, 1: 72-95.

[12] Habib OMO, Hassan HM, El-Mekabaty A., Studies on Some Benzoxazine-4-one Derivatives

with Potential Biological Activity. American Journal of Organic Chemistry, 2012, 2: 45-51.

[13] Girges MM, Abou El-Zahab MM, Hanna MA., Facile Synthesis and Biological Activity of

Sulfonate Ester-Containing ImidazolylpyridineImidazo(4,5-b)Pyridine and Imidazo(5,1:2,3)

Imidazo(4,5-b)Pyridine Derivatives. Collect Czech. Chem. Commun., 1989, 54: 1096-1103.



25

[14] Tobbe M, Spitzer W, Victor F, Miller S, Lee C, Sattelberg T, Mckinney E, Tang C.,

Antirhino/Enteroviral Vinylacetylene Benzimidazoles: A Study of Their Activity and Oral

Plasma Levels in Mice. J. Med. Chem., 1997, 40: 3937–3946.

[15] Porcari A, Devivar R, Kučera L, Drach J, Townsend L., Design, Synthesis and Antiviral

Evaluations of 1-(Substitutedbenzyl)-2-Substituted-5,6-dichlorobenzimidazoles as

Nonnucleoside Analogues of 2,5,6-Trichloro-1-(β-D-ribofuranosyl)benzimidazole. J. Med.

Chem., 1998, 41: 1252–1262.

[16] Roth M, Morningstar M, Boyer P, Hughes S, Bukheit R, Michejda C., Synthesis and Biological

Activity of Novel Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase. 2-Aryl-Substituted

Benzimidazoles. J. Med. Chem., 1997, 40: 4199–4207.

[17] Mrgawa M, Girardet J, Walker J, Koszalka G, Chamberlain S, Drach J, Townsend L., Design,

Synthesis, and Antiviral Activity of α-Nucleosides: D- and L-Isomers of Lyxofuranosyl and (5-

Deoxylyxofuranosyl)benzimidazoles. J. Med. Chem.,1998, 41: 1242–1251.

[18] Tamm I, Sehgal P., Halobenzimidazole Ribosides and RNA Synthesis of Cells and Viruses. Adv.

Virus Res., 1979, 22: 187–192.

[19] Baltork M, Moghadam M, Tangestaninejad S, Mirkhani V, Zolfigol M, Hojati S., Silica Sulfuric

Acid Catalyzed Synthesis of Benzoxazole, Benzimidazoles and Oxazolo [4,5-b]pyridines Under

Heterogeneous and Solvent-Free Conditions. J. Iran. Chem. Soc., 2008, 5: S65-S70.

[20] Bondock S, Fadaly W, Metwally MA., Synthesis and antimicrobial activity of some new

thiazole, thiophene and pyrazole derivatives containing benzothiazole moiety. Eur. J. Med.

Chem., 2010, 45: 3692-3701.

[21] Bondock S, Fadaly W, Metwally MA. Enaminonitrile in heterocyclic synthesis: Synthesis and

antimicrobial evaluation of some new pyrazole, isoxazole and pyrimidine derivatives

incorporating a benzothiazole moiety. Eur. J. Med. Chem., 2009, 43: 2342-2349.

[22] Holla BS, Poorjary NK, Rao SB, Shivananda MK. New bis-aminomercaptotriazoles and bis-

triazolothiadiazoles as possible anticancer agents. Eur. J. Med. Chem., 2002, 37: 511–517.

[23] Holla BS, Akberali PM, Shivananda MK. Studies on nitrophenylfuran derivatives-Part XII.

Synthesis, characterization, antibacterial and antiviral activities of some

nitrophenylfurfurylidene- 1,2,4-triazolo[3,4-b]-1,3,4 thiadiazines. II Farmaco., 2001, 56: 919–

927.

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