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Cleavage Reactions of Oxazolin-5-ones Reactions with 4-Substituted-2-aryl-2-oxazolin-5-ones Nazmi A. Kassab, Abdul Hammid Harhash, and Said A. Elbahaii Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt Z. Naturforsch. 33b, I145-U49 (1978); received April 7/June 22, 1978 Ring Cleavage, Triazolylcarbonyl Amino Acids, Nucleophilic Substitution, Grignard's Reaction, Ring Closure The oxazoline ring in 4-arylazo-2-aryl-2-oxazolin-5-ones (1) is converted to triazolyl-carbonyl amino acids 2, 4 and 6 by the nucleophiles glycine, anthranilic and p-aminobenzoic acids, respectively. The arylidene derivatives 3 of 2-triazolyl-2-oxazolin-5-one were obtained. Triazolylbenzoxazinones 5, were obtained by the ring closure of the amino acid 4.

Grignard's reagent effected ring cleavage of the oxazolinone ring in 4-cinnamylidene-2-aryl-2-oxazolin-5-ones yielding the carbinols 8, the latter cyclizes either in acidic or alkaline medium to afford either benzotropilidenes or oxazolines, respectively.

With the increasing interest in the chemistry of acylglycines as a precursor of the highly important oxazolinones [1-8], little attention has been paid to triazolylcarbonylglycines.

The triazolylcarbonylglycines 2 were prepared by the nucleophilic cleavage of 4-arylazo-2-aryl-2-oxazolin-5-ones ( la -d) with glycine in acetic acid solution, to afford the colourless N-(l,5-diaryl-l H-1.2.4-triazolyl-3-carbonyl)glycines (2a-d). The structure of 2 a-d was assigned from both analytical and infrared data. The N-triazolylcarbonylglycines (2a-d) were readily converted into 4-arylidene-2-(1.5-diaryl-l H-1.2.4-tiiazol-3-yl)-2-oxazolin-5-ones (3a-h) upon warming with the appropriate aro-matic aldehyde in the presence of acetic anhydride and anhydrous sodium acetate. The analytical and spectral data of compound 3 is in agreement with the proposed structure.

The rearrangement of 1 to 2 by the action of glycine prompted us to investigate the behaviour of 1 towards other amino acids, namely, anthranilic and p-aminobenzoic acids. Thus, when the highly coloured arylhydrazono-oxazolones (la-d), were refluxed with anthranilic acid in acetic acid, rear-rangement took place with the formation of the colourless N- (1,5-diaryl-1H-1,2,4-triazolyl-3-car-bonyl) anthranilic acids (4a-d). Authentic sample of 4 a was obtained by acylating anthranilic acid with l-o-chlorophenyl-5-phenyl-l H-l,2,4-triazolyl-3-carbonyl chloride in the presence of sodium

Requests for reprints should be sent to Dr. N. A. Kassab, Department of Chemistry, Faculty of Science, University of King Abdul-Aziz, P. O. Box 1540, Jeddah, Saudi Arabia.

hydroxide. The IR spectrum of 4a shows absorption characteristic for amide I band and for carboxylic group.

4 a-d was successfully cyclised upon refluxing with acetic anhydride to give 2-triazolyl-4H-3,l-benzoxazine-4-one derivatives (5a-d), respectively. The IR spectra of 5 a-d show absorption for vc=o at 1750 cm - 1 and for I>C=N at 1630 cm - 1 . Analogous rearrangement of l ( A r = A r = C6Hs) to the corre-sponding 2 and 4 has been reported [3].

Treatment of la-d with p-aminobenzoic acid, also effected rearrangement of the 2-oxazolin-5-one ring to afford the corresponding N-(l ,5-diaryl-lH-1,2,4- triazolyl - 3 - carbonyl) - p - amino benzoic acids (6 a-d).

The oxazolinone ring has been shown to be readily cleaved by the action of arylmagnesium halides. Thus, the 4-arylidene and the 4-arylazo derivatives of 2-aryl-2-oxazolin-5-ones suffer cleav-age to give l,l-diaryl-2-benzoylaminocinnamyl alcohols [9-13] and l,2,4-triazole-3-diphenylmethyl carbinols [14], respectively. On the other hand, treatment of the 4-arylidene derivatives with alkyl magnesium halides effects only 1,2-addition of the Grignard's reagent on the exocyclic double bond of the oxazolinone ring system [10, 15]. This change in behaviour prompted us to investigate the be-haviour of extended conjugation at the 4-position of the 2-oxazolin-5-one ring on the course of Grig-nard reaction. When the 4-cinnamylidene-2-aryl-2-oxazolin-5-ones (7 a-c) were treated with phenyl-magnesium bromide, addition of two molecules of the reagent to the lactone system took place with the formation of the carbinols 8 a-c. The structure of the Grignard products 8 a-c was inferred from

1146 N". A. Kassab et al. • Cleavage Reactions of Oxazolin-5-ones 1146

their correct analytical data, the isolation of benzo-phenone upon chromic acid oxidation of each of 8 a-c, and the exhibition of their IR spectra of absorption characteristic for -OH, -NH and amide I band.

When the Grignard products 8 a-c were refluxed with alcoholic potassium hydroxide solution, 4-cinn-amylidene-2-aryl-5,5-diphenyl-2-oxazolines (9 a-c) were formed. On the other hand, warming 8 a-c with acetic hydrochloric acid mixture led to the formation of 2-acylamino-l,l-diarylbenzotropilide-nes (10a-c). Cyclisation of 8 to either 9 or 10 depends on whether a nucleophilic anion (A) or an electro-philic carbonium ion (B) is formed as an inter-mediate in the reaction.

N=C-C0"NH CH COOH I I 2 -NN —

Ar 2a-d

Ar"CH=C—C-0 I I N 0 V I II Ar-N—CAr' 3a-h

Ar-N-N*C—C-0 N 0 Y

Ar' 1a-d

N=C-C0-NH I I Ar-N N H00C N=C-C' —- I I I Ar-N N 0, V Ar'

4a-d 5a-d

N=-C-CO-NH OVCOOH I I -N N

Ar' 1-6

a b c d

6a-d

Ar C6H5 C6H5 C6H4CH3-/> C6H4CH3-29

Ar C6H4Cl-o Ce^OCHg-p C6H4C1-O C6H40CH3-P

OH Ph-CH-CH-CH-C—C

©N

(A) Ar

Ph-CH-CH-CH-C—C-0 rll b PhMg Br V

OH Ph-CH=CH-CH=C—ZC

Ph-CH-CH-CH-C—C I I Ph N 0 Y Ar

9a-c

HOH Ar

7a-c

"X-O 1 Ar 8a-c

©,-Ph PhCH-CH-CH=C—C'™ 1 Ph H-N V'C-0 1 Ar (B) lOa-c

CI CH

A^NHCOAr

7-10 a b c

Ar C6H4C1-o C6H4OCH3-?> C6H5CH == CH—

The IR spectra of 9 a-c revealed no absorption characteristic for -OH, -NH or for C = 0 groups. The IR spectra of 10 a-c showed absorption for -NH and for amide I band absorption. In confirmation of structure 10 is the oxidation of 10 a with mercuric sulphate and sulphuric acid to give phthalic an-hydride. Also, o-chlorobenzoic acid was isolated upon hydrolysis of 10a with sulphuric acid. In favoui of structure 10 is the analogous cyclodehydra-tion of arylsubstituted tertiary carbinols into sub-stituted indenes by the action of acetic hydrochloric acid mixture [16-18].

Experimental Melting points are uncorrected. IR spectra were

obtained as a KBr disc with a Pye-Unicam SP 1100 spectrophotometer. UV spectra were measured in EtOH on a Pye-Unicam SP 8000 spectrophoto-meter.

N- (1,5-Diaryl-l H-1,2,4-triazolyl-3-carbonyl) amino acids 2a-d, 4a-d and 6a-d

General procedure: A suspension of each of la-d (2.5 g) and either glycine, anthranilic, or p-amino-benzoic acid (1.5 g) in glacial acetic acid (20 ml) was refluxed for 2 h and then poured into cold water. The crystals that separated were filtered off and re-crystallised from ethanol as colourless crystals. The amino acids 2a-d, 4a-d and 6a-d are listed in Table I.

IR spectrum of 2 a as an example of the N-(tri-azolyl-3-carbonyl) glycines 2a-d show absorption at vc=o 1670 cm - 1 , vc=o 1740 cm - 1 (carboxyl), I>OH 2580-2900 cm - 1 (carboxyl OH) and at van 3280 cm-1.

IR spectrum of 4 a as an example of the N-(tri-azolyl-3-carbonyl) anthranilic acids 4a-d show ab-sorption at VNH 3200 cm-1, VOH 2400-2900 cm"1 (OH dimer) and a broad band at 1680-1725 cm - 1 for vc=o.

IR spectrum of 6 a as an example of the N-(tri-azolyl-3-carbonyl) p-aminobenzoic acids 6a-d show absorption at vc=o 1650 cm - 1 , vc=o 1720 cm - 1

(carboxyl), VOH 2800-3050 cm - 1 for carboxyl group and at VNH 3180 cm - 1 .

4-Arylidene-2-( 1,5-diaryl-l H-l,2,4-triazol-3-yl )-2-oxazolin-5-ones (3a-h)

General procedure: A mixture of each of 2a-d (2.0 g), either benzaldehyde or anisaldehyde (1.0 g), acetic anhydride (5 ml) and sodium acetate (0.5 g) was warmed into solution. Heating was then con-tinued on a boiling water-bath for lh , cooled, then poured over water. The yellow solid product was filtered off and crystallised from ethanol. The ary-lidene derivatives 3a-h are listed in Table II.

IR spectrum of 3 a as an example of the 4-benzy-lidene derivatives 3a-d show absorption at vc=o

N". A. Kassab et al. • Cleavage Reactions of Oxazolin-5-ones 1147

Table I. Analytical data for 2a-d, 4a-d, and 6a-d.

Calcd. Compound m.p. Yield Formula Analysis (Found)

[°C] [%] (mol. wt.) C H N Cl

2a 173 70 CI7H13N403Cl 57.19 3.64 15.73 9.95 (386.8) (57.00) (3.52) (15.43) (9.88)

2b 235 70 CI8HI5N403C1 58.29 4.05 15.11 9.58 (370.8) (57.98) (3.96) (15.00) (9.48)

2c 176 75 C18HI6N404 61.36 4.58 15.90 (325.34) (61.21) (4.44) (15.63)

2d 179 68 C19H18N404 62.28 4.95 15.29 (366.37) (61.96) (4.62) (15.11)

4a 214 65 C22H15N4O3CI 63.08 3.58 13.38 8.48 (418.9) (62.58) (3.28) (13.02) (8.21)

4b 236 65 C23HI7N403C1 63.81 3.93 12.94 8.20 (432.9) (63.66) (3.63) (12.71) (7.95)

4c 265 60 C 2 3 H I 8 N 4 0 4 66.66 4.38 13.52 (414.4) (66.25) (4.11) (13.32)

4d 256 70 C24H20N4O4 67.28 4.71 13.08 (428.4) (66.91) (4.42) (12.86)

6a 212 75 C22HI5N403C1 63.08 3.58 13.38 8.48 (418.9) (62.77) (3.35) (13.00) (8.12)

6b 217 70 C23H17O3CI 63.81 3.93 12.94 -

(432.9) (63.42) (3.58) (12.62) -

6c 210 55 C23H18N4O4 66.66 4.38 13.52 (414.4) (66.37) (4.10) (13.11)

6d 252 60 C24H20N4O4 67.28 4.71 13.08 (428.4) (66.87) (4.41) (12.78)

Table II. Analytical data for 3a-h and 5 a-d.

Calcd. Compound m.p. Yield Formula Analysis (Found)

[°C] [%] (mol. wt.) C H N Cl

3 a 198 40 C24HI5N402C1 67.52 3.51 13.13 8.32 (426.9) (67.32) (3.22) (13.00) (8.11)

3b 202 55 C25HI8N403 71.08 4.30 13.26 (422.4) (70.80) (4.10) (12.98)

3c 148 65 C25HI7N402C1 68.10 3.85 12.71 -

(440.9) (68.00) (3.62) (12.48) -

3d 198 60 C26H2ON403 71.55 4.62 12.84 (436.4) (71.32) (4.31) (12.26)

3e 201 60 C25HI7N403C1 65.71 3.72 12.66 -

(456.9) (65.50) (3.56) (12.12) -

3f 188 70 C26H2ON404 69.01 4.46 12.38 (452.4) (68.78) (4.21) (12.11)

3g 199 45 C26HI9N403C1 66.31 4.03 11.92 7.54 (471.1) (66.19) (3.77) (11.63) (7.41)

3h 190 40 C27H22N4O4 69.52 4.75 12.01 (466.5) (69.21) (4.42) (11.88)

5a 202 70 C22H13N402C1 65.91 3.24 13.98 -

(400.8) (65.72) (3.10) (13.81) -

ob 215 65 C23H15N402C1 66.58 3.61 13.51 8.56 (414.9) (66.32) (3.18) (13.28) (8.21)

5c 242 75 C23HI6N 4 0 3 69.69 4.08 14.14 (396.4) (69.45) (3.76) (13.87)

od 259 70 C 2 4 H I 8 N 4 0 3 70.23 4.42 13.65 (410.4) (69.88) (4.18) (13.38)

1148 N". A. Kassab et al. • Cleavage Reactions of Oxazolin-5-ones 1148

1695 cm"1 and Vc=N 1630 cm - 1 . The UV spectrum of 3a showed Amax at 345 nm (e = 285 X 104).

IR spectrum of 3c as an example of the 4-anisy-lidene derivatives 3e-h show absorption at vc=o 1 6 9 0 c m - 1 a n d VC=N 1 6 2 5 c m - 1 .

2-(l,5-Diaryl-lH-l,2,4-triazol-3-yl)-4H-3,l-benzoxazin-4-ones (5a-d)

A suspension of each of 4a-d (2.0 g) in acetic anhydride (30 ml) was refluxed for 4 h, left overnight then poured into water (100 ml). The crystals that separated were filtered off and crystallised from ethanol. Compounds 5a-d are listed in Table II.

IR spectrum of 5 a as an example of 5a-d show absorption at vc=o 1750 cm - 1 and vc=n 1640 cm - 1 .

Reaction of 4-cinnamylidene-2-aryl-2-oxazolin-5-ones (7 a-c) with phenylmagnesium bromide to afford the carbinols 8 a -c

To a Grignard solution (prepared from 1.0 g of magnesium and 9.0 g of bromobenzene in 100 ml dry ether) was added to a suspension of 2.0 g of each of the cinnamylidene derivative of the 2-aryl-2-oxazolin-5-ones (7 a-c) in 100 ml of dry ether. The reaction mixture was refluxed for 30 min, left over-night at room temperature, and then decomposed with saturated aqueous ammonium chloride solu-tion. The resulting solid was filtered off, washed with water and crystallised from ethanol.

l,l-Diphenyl-2-o-chlorobenzoylaminocinnamyl alcohol (8a) formed colourless crystals, m.p. 182°C; yield 65%. CzoHztNOzCl

Found C 77.01 H 4.85 N 2.80 Cl 7.43, Calcd C 77.33 H 5.15 N 3.00 Cl 7.63.

1,1 -Diphenyl-2-p-methoxybenzoylaminocinnamyl alcohol (8b) formed colourless crystals, m.p. 175°C; yield 50%.

CsiHziNOs Found C 80 28 H 5.58 N 2.78, Calcd C 80.67 H 5.90 N 3.04.

l,l-Diphenyl-2-ciimamoylaminocinnamyl alcohol (8c) formed colourless crystals, m.p. 179 °C; yield 40%. C32H27NO2

Found C 83.42 H 5.45 N 2.77, Calcd C 84.00 H 5.95 N 3.06.

Action of chromic acid on 8 a-c A suspension of each of 8 a-c (1.0 g) and chromic

acid (1.0 g) in glacial acetic acid (30 ml) was heated on a boiling water-bath for 3h, then poured into ice-cooled water and extracted with ether. The oily residue, obtained upon evaporation of the ether layer, was treated with 2,4-dinitrophenylhydrazine. The resulting solid proved (m.p. and mixed m.p.) to be benzophenone 2,4-dinitrophenylhydrazone.

4-Cinnamylidene-5,5-diphenyl-2-aryl-2-oxazolines (9 a-c )

A suspension of each of 8 a-c (1.0 g) in 10 ml of ethanolic potassium hydroxide (10%) was refluxed for 30 min. The crystals, that separeted upon cooling the reaction mixture, were filtered off and recrystal-lised from ethanol. Compounds 9 a -c are all yellow coloured compounds and are listed in Table III.

2-Acylamino-1,1-diphenylbenzotropilidenes (10 a-c) To a suspension of each of 8 a - c (1.0 g) in acetic

acid (20 ml), 10 ml hydrochloric acid were added. The reaction mixture was warmed on a water-bath for 10 min and left at room temperature to cool. The crystals that separeted, were filtered off, washed with water and recrystallised from ethanol. Com-pounds lOa-c are all yellow in colour and listed in Table III.

Table III. Analytical data for 9a-c and lOa-c.

Compound m.p. [°C]

Yield [%] Formula (mol. wt.)

Analysis C H

Calcd. (Found) N Cl

9a 168 70 C 3 0 H 2 2 N O C I 80.44 4.92 3.13 7.93 (447.9) (80.21) (4.63) (2.78) (7.65)

9b 150 65 C 3 1 H 2 5 N O 0 83.94 5.65 3.16 (443.5) (83.52) (5.28) (2.81)

9c 157 60 C 3 2 H 2 5 N O 87.44 5.73 3.19 (439.5) (87.26) (5.41) (2.88)

10a 158 55 C 3 0 H 2 2 N O C I 80.44 4.92 3.13 7.93 (447.9) (80.21) (4.65) (2.90) (7.71)

10b 142 50 C 3 1 H 2 5 N O 2 83.94 5.65 3.16 (443.5) (83.65) (5.41) (2.99)

10 c 148 45 C 3 2 H 2 5 N O 87.44 5.73 3.19 (439.5) (86.90) (5.58) (2.86)

N". A. Kassab et al. • Cleavage Reactions of Oxazolin-5-ones 1149

IR spectrum of 10 a as an example of 10 a-c shows absorption at vc=o 1680 cm - 1 and VNH 3220 cm - 1 .

Oxidation of 10 a to phthalic anhydride A mixture of 10a (0.5 g), mercuric sulphate

(0.3 g) and concentrated sulphuric acid (4 ml) was placed in a 25 ml flask fitted with distilling head

and a short air condenser. The mixture was then heated in a metal bath for 10 min at 250 °C (bath temperature), then for 50 min at 300 °C. The colour-less crystals, that collected in the air condenser, were scratched and resublimed to give phthalic anhydride (m.p. and mixed m.p. and positive flu-orescene test).

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