Transformation of 2-(acetamido)-3-(4-chlorophenyl)acrylohydrazide into 1-arylideneamino-4-(4-chlorobenzylidene)-2-methyl-1H-imidazolin-5(4H)- ones and 4-aryl-1-[2-(acetamido)-3-(4-chlorophenyl) acryloyl]thiosemicarbazides

Vietnam Journal of Chemistry, International Edition, 54(4): 496-500, 2016 DOI: 10.15625/0866-7144.2016-00354 496 Transformation of 2-(acetamido)-3-(4-chlorophenyl)acrylohydrazide into 1-arylideneamino-4-(4-chlorobenzylidene)-2-methyl-1H-imidazolin-5(4H)- ones and 4-aryl-1-[2-(acetamido)-3-(4-chlorophenyl) acryloyl]thiosemicarbazides Nguyen Tien Cong * , Truong Ngoc Anh Luan Department of Chemistry, Ho Chi Minh City University of Education Received 2 June 2016; Accepted for publication 12 August 2016 Abstract Six 1-arylideneamino-4-(4-chlorobenzylidene)-2-methyl-1H-imidazolin-5(4H)-one compounds and two 4-aryl-1- [2-(acetamido)-3-(4-chlorophenyl)acryloyl]thiosemicarbazide compounds were synthesized by reaction of aromatic aldehydes or reaction of aryl isothiocyanates, respectively with 2-(acetamido)-3-(4-chlorophenyl)acrylohydrazide which was prepared starting from 4-chlorobenzaldehyde and acetylglycine via 4-(4-chlorobenzylidene)-2-methyloxazol- 5(4H)-one. The structures of the synthesized compounds were determined by IR, NMR and mass spectral data. Keywords. 2-(acetamido)-3-(4-chlorophenyl)acrylohydrazide, imidazolin-5(4H)-one, thiosemicarbazide. 1. INTRODUCTION 2-(Acetamido)-3-(4-chlorophenyl)acrylo hydrazide (1) was synthesized and then, transformed into some N-substituted hydrazide [1,2]. Some new compounds were synthesized and an unusual transformation was found out in the further research of transformations of the hydrazide (1). 2. EXPERIMENTAL General procedures: All chemicals and solvents were obtained from commercial sources and used without any further purification. Melting points were determined in open capillaries and the values are uncorrected. IR spectra were recorded in KBr discs on a Shimadzu FTIR 8400S spectrophotometer. NMR spectra were recorded on a Bruker Avance spectrometer (500 MHz for 1 H-NMR and 125 MHz for 13 C-NMR) using DMSO-d6 as solvent and tetramethylsilane (0.00 ppm) as an internal standard. MS spectra were recorded on a Bruker micrOTOF-Q 10187 spectrometer except two spectra of the (3a) and (3c) were recorded on an Agilent 6490 spectrometer. 2-(Acetamido)-3-(4-chlorophenyl)acrylo hydrazide (2) was synthesized from 4- chlorobenzaldehyde and acetylglycine via 4-(4- chlorobenzylidene)-2-methyloxazol-5(4H)-one (1) according to the method described in our earlier work [1, 2]. The hydrazide (2) was transformed further into compounds (3a-f) and (4a,b) as shown in the scheme 1. (Z)-4-(4-Chlorobenzylidene)-2-methyloxazol- 5(4H)-one (1): An equimolar mixture of 4- chlorobenzaldehyde (7.03 g, 0.05 mol) and acetylglycine (5.85 g, 0.05 mol) in freshly distilled acetic anhydride (25 mL) containing fused anhydrous sodium acetate (4.1 g) was refluxed for 3 hours and then cooled. The solid was triturated with cold saturated solution of sodium carbonate and filtered, washed with water, air dried and recrystallized from ethanol. Mp. 158-160 o C (literature [3]: 158-160 o C); yield 60%. IR ( , cm -1 ): 1800 and 1772 (C=O); 1661, 1605 and 1584 (C=N, C=C). 1 H-NMR ( , ppm): 8.19 (2H, d, J = 8.0 Hz, Ar-H), 7.57 (2H, d, J = 8.0 Hz, Ar-H), 7.23 (1H, s, -CH=C<), 2.39 (3H, s, CH3). 2-(Acetamido)-3-(4-chlorophenyl)acrylo hydrazide (2): 4-(4-Chlorobenzylidene)-2- methyloxazol-5-one (1) (2.22 g, 0.01 mol) was stirred with a solution of hydrazine hydrate 50 % (10.0 mL, 0.04 mol) in ethanol (50 mL) for 30 min. The deep yellow colour of the oxazolone immediately changed to a light yellow coloured solid, which was filtered, washed and purified by recrystallization from ethanol. Mp. 156-158 o C; yield 58 %. IR ( , cm -1 ): 3374 and 3217 cm -1 (N-H), 2990 cm -1 (C-H), 1672 cm -1 and 1653 cm -1 (C=O), 1624 cm -1 (C=C). 1 H-NMR ( , ppm): 9.40 (1H, s, VJC, 54(4) 2016 Nguyen Tien Cong, et al 497 N-H), 9.33 (1H, s, N-H), 7.53 (2H, d, J = 9.0 Hz, Ar-H), 7.43 (2H, d, J = 9.0 Hz, Ar-H), 6.99 (1H, s, -CH=C<), 4.36 (2H, s, NH2), 1.97 (3H, s, COCH3). General procedure for synthesis of 1- arylideneamino-4-(chlorobenzylidene)-2-methyl- 1H-imidazolin-5(4H)-one compounds (3a-f): Equimolar quantity of hydrazide (2) and a definite aldehyde was refluxed in ethanol for 4 hours. The reaction mixture was cooled down to room temperature and the obtained precipitate was filtered off and crystallized from dioxane. As the result, yellow crystals are obtained for all cases. Scheme 1: Pathway for synthesis 4-(4-chlorobenzylidene)-1-[(4- methoxybenzylidene)amino]-2-methyl-1H- imidazolin-5(4H)-one (3a). Yield 83%, mp. 176– 178 °C; IR (ν, cm-1): 3060, 2930, 1717, 1678, 1605; 1 H-NMR (δ, ppm and J, Hz): 9.44 (1H, s, -CH=N), 8.24 (2H, d, 3 J = 8.5, ArH), 7.79 (2H, d, 3 J = 8.0, ArH), 7.52 (2H, d, 3 J = 8.5, ArH), 7.08 (1H, s, -CH=C<), 7.05 (2H, d, 3 J = 8.0, ArH), 3.84 (3H, s, CH3O), 2.47 (3H, s, CH3-Hr); 13 C-NMR (δ, ppm): 165.6, 163.3, 161.8, 154.7, 137.2, 134.7, 133.3, 132.4, 129.2, 128.5, 125.8, 124.5, 114.3, 55.2, 14.8; MS: m/z 354 (M+H) + , calculated for C19H16ClN3O2: 353. 4-(4-chlorobenzylidene)-1-[(4- methylbenzylidene)amino]-2-methyl-1H- imidazolin-5(4H)-one (3b). Yield 68 %, mp. 182- 184 °C; IR (ν, cm-1): 3040, 2924, 1705, 1651, 1589; 1 H-NMR (δ, ppm and J, Hz): 9.52 (1H, s, -CH=N), 8.28 (2H, d, 3 J = 8.5, ArH), 7.75 (2H, d, 3 J = 8.0, ArH), 7.55 (2H, d, 3 J = 8.5, ArH), 7.32 (2H, d, 3 J = 8.0, ArH), 7.10 (1H, s, -CH=C<), 2.48 (3H, s, CH3Ar), 2.37 (3H, s, CH3-Hr); 13 C-NMR (δ, ppm): 165.9, 163.6, 154.6, 141.6, 137.3, 135.0, 133.7, 132.7, 130.9, 129.6, 128.9, 127.7, 124.9, 21.1, 15.2; HR-MS: m/z 360.0867 (M+Na) + , calculated for C19H16ClN3O: 337.0982. 1-(benzylideneamino)-4-(4- chlorobenzylidene)-2-methyl-1H-imidazolin- 5(4H)-one (3c). Yield 80 %, mp 173-174 °C; IR (ν, cm -1 ): 1713, 1651, 1589; 1 H-NMR (δ, ppm and J, Hz): 9.58 (1H, s, -CH=N), 8.28 (2H, d, 3 J = 8.5, ArH), 7.87 (2H, dd, 3 J = 8.0, 4 J = 2.0, ArH), 7.55 (5H, m, ArH), 7.12 (1H, s, -CH=C<), 2.49 (3H, s, CH3-Hr); 13 C-NMR (δ, ppm): 165.9, 163.6, 154.3, 137.2, 135.1, 133.7, 133.6, 132.6, 131.5, 129.0, 128.9, 127.7, 125.0, 15.2; MS: m/z 324 (M+H) + , calculated for C18H14ClN3O: 323. 4-(4-chlorobenzylidene)-1-[(4- fluorobenzylidene)amino]-2-methyl-1H- imidazolin-5(4H)-one (3d). Yield 73%, mp. 205- 207 °C; IR (ν, cm-1): 2946, 1713, 1651, 1589; 1H- NMR (δ, ppm and J, Hz): 9.59 (1H, s, -CH=N), 8.29 (2H, d, 3 J = 8.5, ArH), 7.95 (2H, d-d, 3 J = 8.0, 4 JH-F = 6.0, ArH), 7.56 (2H, d, 3 J = 8.5, ArH), 7.37 (2H, d-d, 3 J = 8.0, 3 JH-F = 8.0, ArH), 7.13 (1H, s, -CH=C<), 2.50 (3H, s, CH3-Hr); 13 C-NMR (δ, ppm): 165.9, 163.5, 163.0 (d, JC-F = 250 Hz), 153.1, 137.2, 135.1, 133.7, 132.6, 130.3, 130.1 (d, 3 JC-F = 8.8 Hz), VJC, 54(4) 2016 Transformation of 2-(acetamido)-3-(4-chlorophenyl) 498 128.9, 125.0, 116.1 (d, 2 JC-F = 21.3 Hz), 15.2; HR- MS: m/z 342.0818 (M+H) + , calculated for C18H13ClFN3O: 341.0731. 4-(4-chlorobenzylidene)-1-[(2- fluorobenzylidene)amino]-2-methyl-1H- imidazolin-5(4H)-one (3e). Yield 82%, mp. 196- 197 °C; IR (ν, cm-1): 3048, 1717, 1651, 1591; 1H- NMR (δ, ppm and J, Hz): 9.79 (1H, s, -CH=N), 8.22 (2H, d, 3 J = 8.5, ArH), 7.99 (1H, dd, 3 J1 = 3 J2 = 7.5, ArH), 7.58 (1H, m, ArH), 7.50 (2H, d, 3 J = 8.5, ArH), 7.33 (2H, m, ArH), 7.06 (1H, s, -CH=C<), 2.49 (3H, s, CH3-Hr); 13 C-NMR (δ, ppm): 165.6, 162.8, 161.0 (d, JC-F = 251 Hz), 146.6, 136.8, 134.8, 133.3, 133.0 (d, 3 JC-F = 8.8 Hz), 132.2, 128.4, 126.3, 124.9, 124.6 (d, 4 JC-F = 3.5 Hz), 120.9 (d, 3 JC-F = 9.8 Hz), 115.3 (d, 2 JC-F = 20.6 Hz), 14.5; HR-MS: m/z 342.0824 (M+H) + , calculated for C18H13ClFN3O: 341.0731. 4-(4-chlorobenzylidene)-1-[(4-hydroxy-3- methoxybenzylidene)amino]-2-methyl-1H- imidazolin-5(4H)-one (3f). Yield 64.5 %, mp. 221– 222 °C; IR (ν, cm-1): 3410, 2924, 1712, 1667, 1589; 1 H-NMR (δ, ppm and J, Hz): 9.78 (1H, br, OH), 9.35 (1H, s, -CH=N), 8.28 (2H, d, 3 J = 8.5, ArH), 7.55 (2H, d, 3 J = 8.5, ArH), 7.42 (1H, d, 4 J = 2.0, ArH), 7.28 (1H, d-d, 3 J = 8.0, 4 J = 2.0, ArH), 7.09 (1H, s, -CH=C<), 6.89 (1H, d, 3 J = 8.0, ArH), 3.84 (3H, s, CH3O), 2.49 (3H, s, CH3-Hr); 13 C-NMR (δ, ppm): 166.1, 164.1, 156.3, 150.5, 148.3, 137.6, 135.3, 133.9, 132.8, 129.1, 125.0, 124.9, 123.1, 115.8, 110.3, 55.9, 15.4; HR-MS: m/z 370.0975 (M+H) + , calculated for C19H16ClN3O3: 369.0880. Synthesis of 4-aryl-1-[2-(acetamido)-3-(4- chlorophenyl)acrylyl]thiosemicarbazide (4a,b): Equimolar quantity of hydrazide (3) and arylisothiocyanate were refluxed in ethanol for 1 hours. After cooling, the precipitate was filtered off, dried, and recrystallized from ethanol to give white crystals. 4-(4-methylphenyl)-1-[2-(acetamido)-3-(4- chlorophenyl)acryloyl] thiosemicarbazide (4a): yield 82%. M.p. 208-209 o C; IR ( , cm -1 ): 3379 and 3217 (N-H), 1667 (C=O), 1196 (C=S); 1 H-NMR ( , ppm and J, Hz): 10.41 (1H, s, N-H), 10.05 (1H, s, N-H), 9.73 (1H, s, N-H), 9.14 (1H, s, N-H), 7.61 (2H, d, J = 8,5 Hz, Ar-H), 7.54 (2H, d, J = 8.5, Ar-H), 7.48 (2H, d, J = 8.5, Ar-H), 7.13 (2H, d, J = 8.5, Ar-H), 6.90 (1H, s, =CH), 2.28 (3H, s, CH3), 2.08 (3H, s, CH3); 13 C-NMR: 181.3, 170.8, 164.1, 136.1, 133.9, 133.3, 132.4, 131.4, 128.9, 128.6, 128.5, 125.2, 123.8, 23.0, 20.5; HR-MS: m/z 403.0980 (M+H) + , calculated for C19H19ClN4O2S: 402.0917 . 4-phenyl-1-[2-(acetamido)-3-(4- chlorophenyl)acryloyl]thiosemicarbazide (4b): Yield 79%. M.p. 202-204 o C (literature [10]: 202- 204 o C); IR ( , cm -1 ): 3341 and 3287 (N-H), 1690 (C=O), 1651 (C=C), 1196 (C=S); 1 H-NMR ( , ppm and J, Hz): 10.45(1H, s, N-H), 10.10 (1H, s, N-H), 9.83 (1H, s, N-H), 9.22 (1H, s, N-H), 7.72 (2H, d, J = 7,5 Hz, Ar-H), 7.63 (2H, d, J = 8.5, Ar-H), 7.49 (2H, d, J = 8.5, Ar-H), 7.35 (2H, dd, J1 = J2 = 7.5, Ar-H), 7.16 (1H, dd, J1 = J2 = 7.5, Ar-H), 6.92 (1H, s, =CH), 2.11 (3H, s, CH3); 13 C-NMR: 180.0, 171.7, 164.0, 139.0, 133.3, 132.4, 131.4, 128.9, 128.6, 128.1, 125.2, 124.7, 123.7, 23.0; HR-MS: m/z 389.0855 (M+H) + , calculated for C18H17ClN4O2S: 388.0761. 3. RESULTS AND DISCUSSION Oxazolone (1) is an unsaturated lactone, so its IR spectrum shows two peaks related to the C=O stretching vibration. This phenomenon was explained by the Fermi resonance between the carbonyl stretching vibration and the overtones or combinations of other low-frequency vibrations [4]. Reaction of hydrazide and aldehydes normally gives N-substituted hydrazides and the formation of N-arylidene 2-(acetamido)-3-(4- chlorophenyl)acrylohydrazides was confirmed in our earlier reports [1, 2]. According to these reports, the hydrazide reacted with aldehydes for 1 hour to afford the corresponding N-substituted hydrazides. However, after 3 hours of the reaction, some products were not N-substituted hydrazides. In the IR spectra of the products, there was not only a lack of stretching bands for N-H bonds but also an appearance of the absorption signal of carbonyl group at a higher frequency in comparison with the IR spectra of the N-substituted hydrazides [1, 2]. The 1 H-NMR spectra of the products did not show any signals of active proton in N-H groups too. These phenomena may indicate that all of the NH groups in the molecule of hydrazide were transformed. Besides that, in the 1 H-NMR spectra of the products, the signals of methyl group (CH3) at 2.47-2.50 ppm are in downfield zone compared with signals of the methyl group in N-substituted hydrazide molecules at 2.01-2.03 ppm [1, 2]. At downfield zone, around 9.44-9.75 ppm in the 1 H- NMR spectra of each product, there was a singlet which in the HMBC spectra made cross peak with signal of carbon atom in the benzene ring of benzylidene moiety bonded to nitrogen. These singlets were assigned to protons of the azomethine groups and their chemical shifts were also similar to chemical shifts of the azomethine protons in the 1 H- NMR of 1-arylideneamino-4-arylidene-2-phenyl- 1H-imidazolin-5(4H)-one compounds [3]. VJC, 54(4) 2016 Nguyen Tien Cong, et al 499 Obviously, signals of these azomethine protons are in upfield zone in comparison with signals of corresponding protons in N-substituted hydrazide molecules at 8.34-8.51 ppm [1, 2]. Also, mass spectra of the products showed molecular ion peaks with mass reduced 18mu in comparison with molecular mass of the corresponding N-substituted hydrazides but these molecular ion peaks were absolutely conformed with molecular mass of the 1- arylideneamino-4-(4-chlorobenzylidene)-2-methyl- 1H-imidazolin-5(4H)-one compound. Formation of 1-arylideneamino-4-arylidene-2- methyl-1H-imidazolin-5(4H)-ones from N- arylidene-2-acetamido-4-arylacrylohydrazides on treatment with acetic acid has been described in literature [5]. However, in this reference, the structures of the imidazolin-5-(4H)-one compounds were only verified by elemental analysis and IR spectra without any other spectral data. Besides that, some 1-arylideneamino-4-arylidene-2-phenyl-1H- imidazolin-5(4H)-ones were also formed from corresponding arylidene-2-benzamido-4- arylacrylohydrazides by treatment with acetic acid [6, 7] or by hexamethyldisilazane [3]. It is possible that N-substituted hydrazide molecule formed in process of the reaction is transformed continuously to give 1,2,4-trisubstituted imidazole-5-one. It should be remarked that the first nitrogen atom in the hydrazino group possesses a pair of free electrons, so it may attack to carbon carbonyl in the acetamido group. A transformation may be continued as showing on the Scheme 2 to give 1- arylideneamino-4-arylidene-2-methyl-1H- imidazolin-5(4H)-one compounds. Cl N NH O O CH3 H N CHAr' Cl N N O H N CHAr' CH3 OH Cl N N O H N CHAr' CH3 OH2 H _ H2O Cl N N O H N CHAr' CH3 + _ H Cl N N O N CHAr' CH3 Scheme 2: Formation of the 1-arylideneamino-4-(4-chlorobenzylidene)-2-methyl-1H-imidazolin-5(4H)-ones The hydrazide (2) was refluxed with arylisothiocyanates in absolute ethanol to give corresponding 4-aryl-1-[2-(acetamido)-3-(4- chlorophenyl)acryloyl]thiosemicarbazides (4a,b). This is the conventional method to synthesize thiosemicarbazides reported previously [9-11] and the formation of the 4-phenyl-1-[2-(acetamido)-3-(4- chlorophenyl)acryloyl]thiosemicarbazide (4b) was also described in literature [11]. The IR spectra of (4a,b) exhibited a strong C=S absorption at 1196 cm -1 . The 13 C-NMR signal of this group was observed at δ = 180.0 – 181.3 ppm. The 1H-NMR of each compound displayed four singlets due to four different N-H groups above 9.0 ppm. Molecular ion peak of thiosemicarbazides (4a,b) was agreement with assumed structures. 4. CONCLUSION 1-Arylideneamino-4-(chlorobenzylidene)-2- methyl-1H-imidazolin-5(4H)-ones were formed as superseded products of the corresponding N- substituted hydrazides while treating 2-(acetamido)- 3-(4-chlorophenyl)acrylohydrazide with some aldehydes under condition of extended time. Besides that, two 4-aryl-1-[2-(acetamido)-3-(4- chlorophenyl)acryloyl]thiosemicarbazides were synthesized. The structures of the new compounds were confirmed by IR, 1 H-NMR, 13 C-NMR and mass spectral data. Acknowledgement. We would like to acknowledge HCMUE for financial support through project code CS.2015.19.78. VJC, 54(4) 2016 Transformation of 2-(acetamido)-3-(4-chlorophenyl) 500 REFERENCES 1. Nguyen Tien Cong, Nguyen Viet Doanh, Ta Thi Thanh Hoa, Hoang Tran Lan Phuong, Vuong Le Ai Thao. The synthesis and transformation of 2- (acetamido)-3-(4-chlorophenyl)acrylohydrazide. Journal of Sciences of Ho Chi Minh University of Education, 92, 20-26 (2014). 2. Nguyen Tien Cong, Nguyen Dang Dat, Truong Ngoc Anh Luan, Truong Thi Quynh Nhu. Synthesis and structures of N-arylidene 2-(acetamido)-4- (chlorophenyl)acrylohydrazide compounds, Vietnam Journal of Chemistry, 53(6e1,2), 315-319 (2015). 3. V. O. Topuzyan, L. G. Arutyunyan, A. A. Oganesyan, G. A. Panosyan. Derivatives of α,β- dehydro amino acids. 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Corresponding author: Nguyen Tien Cong Department of Chemistry Ho Chi Minh City University of Education 280, An Duong Vuong, 5 District, Ho Chi Minh City E-mail: congchemist@gmail.com; Tel.: 0908121866.