Page  1 General Papers ARKIVOC 2006 (xiv) 1-9 New intermediates for the selective synthesis of 1-methyl-3phenylpiperazine and some phenylpiperazine derivatives Divvela V. N. Srinivasa Rao, a Ramesh Dandala,a* Vijay Kumar Handa,a Meenakshisunderam Sivakumaran,a and Andra Naidub aChemical Research Department, APL Research Centre, Hyderabad-500 072, India bJ. N. T. University, Kukatpally, Hyderabad-500 072, Andhra pradesh, India E-mail: rdandala@aurobindo.com Abstract New intermediates, 4-protected-1-alkyl-2-oxo-3-phenylpiperazines (3a-e) and 1-alkyl-2-oxo-3phenylpiperazines (6a-d) for the selective synthesis of 1-alkyl-3-phenylpiperazines (5a-e) are described. First method involves the reduction of the 4-protected-1-alkyl-2-oxo-3phenylpiperazine (3a-e) followed by deprotection giving the 1-alkyl-3-phenylpiperazine (5a-e). Second method involves the deprotection of 4-protected-1-alkyl-2-oxo-3-phenylpiperazine (3ae) followed by reduction giving the 1-alkyl-3-phenylpiperazine (5a-e). Keywords: 3-Phenylpiperazin-2-one, 4-benzyl-1-methyl-2-oxo-3-phenylpiperazine, 1-methyl-2oxo- 3-phenylpiperazine, protection, deprotection Introduction 1-Methyl-3-phenylpiperazine is an intermediate for the preparation of Mirtazapine, an antidepressant drug.1 Several methods have been reported for the preparation of 1-methyl-3phenylpiperazine. They have been prepared from 2-phenylpiperazine,2 N- (2-chloroethyl)-Nmethyl- ß-chloro-ß-phenylethylamine,3 2-chloroacetamide-N-methyl-2-phenylacetamide,4 1benzyl- 2-phenylpiperazine.5,6 Our present work describes new intermediates such as 4-benzyl-1methyl- 2-oxo-3-phenylpiperazine 7 and 1-methyl-2-oxo-3-phenylpiperazine7 for the preparation of 1-methyl-3-phenylpiperazine and some phenylpiperazine derivatives. Results and Discussion The method described by Roderick,2 involves the methylation of 2-phenylpiperazine and this step afforded low yields because it was not selective and produces unwanted product 1,4- ISSN 1424-6376 Page 1 ©ARKAT

Page  2 General Papers ARKIVOC 2006 (xiv) 1-9 dimethylpiperazine. By the route of Dolitzky,3 the piperazine was made from N- (2-chloroethyl)N- methyl-ß-chloro-ß-phenylethylamine and this method afforded by product 1-methyl-2phenylpiperazine. This may be because of the non-selectivity in the reaction of starting material preparation. The method described by Guo,5 involves the use of excess of lithium aluminum hydride,7 for the unsubstituted amide reduction. We wish to report herein an improved procedure using new intermediates, which circumvents these problems. Different 1-alkyl-3phenylpiperazines were prepared in two methods by simply changing the sequence of reduction and deprotection of the phenylpiperazine derivatives. First method involves the reduction of 3a-e followed by the deprotection of 4a-e to get 1-alkyl-3-phenylpiperazine 5a-e (Scheme 1). P P H N N C6H5 N C6H5 C6H5 iii i ii NO NO NO HH R 3a P=CH2C6H5; R=CH3 2a P=CH2C6H5 1 3b P=CH2C6H5; R=CH2CH3 2b P=OCOC(CH3)3 3c P=OCOC(CH3)3; R=CH2CH=CH2 3d P=CH2C6H5; R=CH2CH=CH2 3e P=OCOC(CH3)3; R=CH2C6H5 P H N C6H5 N C6H5 iv NN RR 4a P=CH2C6H5; R=CH3 5a R=CH34b P=CH2C6H5; R=CH2CH3 5b R=CH2CH34c P=OCOC(CH3)3; R=CH2CH=CH2 5c R=CH2CH=CH24d P=CH2C6H5; R=CH2CH=CH2 5d R=CH2CH2CH34e P=OCOC(CH3)3; R=CH2C6H5 5e R=CH2C6H5 Scheme 1. i. Protection: for benzyl; C6H5CH2Cl, NaHCO3, DMF, 100 °C; for Boc. di-tert-butyl dicarbonate, (C2H5)3N, CH2Cl2, rt. ii. RI, NaH, DMF, 25 °C. iii. LiAlH4, THF, reflux. iv. deprotection: for benzyl; H2, Pd-C, CH3OH, CH3COOH, rt; for Boc; 6N HCl, rt. Second method involves the deprotection of 3a-c, e followed by reduction of 1-alkyl-2oxo- 3-phenylpiperazines 6a-d giving the 1-alkyl-3-phenylpiperazines 5a-c, e (Scheme 2). ISSN 1424-6376 Page 2 ©ARKAT

Page  3 General Papers ARKIVOC 2006 (xiv) 1-9 N N O C6H5 P R iiiN H N C6H5 R N H N C6H5 R O 3a P=CH2C6H5; R=CH3 6a R=CH3 5a R=CH33b P=CH2C6H5; R=CH2CH3 6b R=CH2CH3 5b R=CH2CH33c P=OCOC(CH3)3; R=CH2CH=CH2 6c R=CH2CH=CH2 5c R=CH2CH=CH23e P=OCOC(CH3)3; R=CH2C6H5 6d R=CH2C6H5 5e R=CH2C6H5 Scheme 2. i. deprotection: for benzyl; H2, Pd-C, acetic acid, rt. for Boc; 6N HCl, rt, ii. LiAlH4, THF, reflux. In summary, we report two different sequences of reactions, viz. lactam reduction and N4deprotection, or, initial N4-deprotection followed by lactam reduction, provided the title compounds in good overall yield. However, the intermediates (6a-d) obtained by following the second method may be useful for making some biological important compounds owing to the available free NH group. Experimental Section General Procedures. All melting points were determined with Palmon melting point apparatus. 1H-NMR spectra were recorded on a Bruker 300 spectrometer. Chemical shifts are reported in ppm downfield from TMS as internal standard. Mass spectra were measured on Perkin Elmer PE SCIEX-API 2000 mass spectrometer. Elemental analyses were performed using a Heraeus CHNO- Rapid instrument. Analytical HPLC8 were run with Hypersil ODS Rx-C18 column at 210nm. “RT” denotes room temperature. 4-Benzyl-2-oxo-3-phenylpiperazine (2a). Benzyl chloride (75.0 g, 0.593 mol) was added to a suspension of 1 (100.0 g, 0.568 mol) obtained by the reported method (lit.2 mp 138-140 °C) and sodium bicarbonate (100.0 g, 1.19 mol) in DMF (250 mL) and heated to 100 °C for 2 h. Cooled the mixture to 75 °C and water (500 ml) was added. Filtered the product and washed with water, dried, to yield 2a (135.0 g, 89%) as a white solid; purity 99% (by HPLC); mp 225-226 °C (lit,5 >210 °C); IR (KBr, cm-1) 3181, 2891, 1678, 1602, 742, 698; 1H-NMR (300 MHz, CDCl3) d 2.48-2.54 (m, 1H), 2.98-3.00 (m, 1H), 3.17 (d, 1H, J=13.5 Hz), 3.26-3.28 (m, 1H), 3.52-3.44 (m, 1H), 3.75 (d, 1H, J=13.5 Hz), 4.07 (s, 1H), 6.41 (bs, 1H), 7.20-7.30 (m, 5H), 7.32-7.41 (m, 3H), 7.54-7.55 (m, 2H); 13C-NMR (300 MHz, CDCl3) d 46.1, 51.7, 63.7, 76.0, 132.3, 133.8, 132.8, 133.5, 134.3, 143.2, 144.6, 174.9; MS (ESI, m/z): 267.4 [M+H]+. Anal. Calcd. For C17H18N2O (266.34): C, 76.66; H, 6.81; N, 10.52. Found: C, 76.70; H, 6.74; N, 10.45. 4-tert-Butoxycarbonyl-2-oxo-3-phenylpiperazine (2b). Di-tert-butyl dicarbonate (126.4 g, 0.58 mol) was added to a suspension 1 (100.0 g, 0.568 mol) and triethylamine (72.72 g, 0.72 mol) in dichloromethane (1000 mL) at 10°C and stirred at RT for 15 h. The reaction mixture was washed ISSN 1424-6376 Page 3 ©ARKAT

Page  4 General Papers ARKIVOC 2006 (xiv) 1-9 with water and evaporated. The residue was treated with cyclohexane (500 mL). Filtered the product and washed with cyclohexane, dried, to yield 2b (125.0 g, 80%) as a white solid; mp 152-153 °C; IR (KBr, cm-1) 3197, 2986, 1690, 1674, 1602, 1395, 737, 699; 1H-NMR (300 MHz, CDCl3) d 1.45 (s, 9H), 3.27-3.34 (m, 2H), 3.48-3.52 (m, 1H), 3.92-4.04 (m, 1H), 5.71 (s, 1H), 6.65 (bs, 1H), 7.28-7.44 (m, 5H); 13C-NMR (300 MHz, CDCl3) d 28.8, 37.9, 41.1, 60.7, 81.4, 127.5, 128.3, 129.0, 137.9, 154.3, 170.1; MS (ESI, m/z): 277.2 [M+H]+. Anal. Calcd. For C15H20N2O3 (276.33): C, 65.20; H, 7.30; N, 10.14. Found: C, 65.12; H, 7.34; N, 10.18. General procedure for alkylation of 4-protected-2-oxo-3-phenylpiperazines (2a-b). 4Benzyl- 1-methyl-2-oxo-3-phenylpiperazine (3a). Under N2 atmosphere, 2a (100.0 g, 0.376 mol) was added portion wise to a suspension of sodium hydride (15.3 g, 65% dispersed in mineral oil, 0.41 mol) in anhydrous DMF (250 mL) at 10-15 °C over a period of 1 h. A solution of methyl iodide (64.0 g, 0.45 mol) in anhydrous DMF (65 mL) was added slowly by maintaining the temperature below 25 °C and the stirring was continued for 1 h. The reaction mass was poured slowly into cold water (1000 mL) and product was extracted with toluene (800mL), the combined organic solution was washed with water and concentrated. The residue was treated with cyclohexane (200mL) at 10 °C for 1 h. Filtered the product to yield 3a (98.5 g, 94%) as a light yellow solid; purity 99% (by HPLC); mp 101-102 °C; IR (KBr, cm-1) 2935, 2805, 1646, 1602, 733, 697; 1H-NMR (300 MHz, CDCl3) d 2.54-2.58 (m, 1H), 2.99 (s, 3H), 3.03-3.05 (m, 1H), 3.17 (d, 1H, J=13.5 Hz), 3.15-3.20 (m, 1H), 3.22-3.60 (m, 1H), 3.75 (d, 1H, J=13.4 Hz), 4.08 (s, 1H), 7.26-7.32 (m, 6H), 7.35-7.40 (m, 2H), 7.55 (d, 2H, J=7.4 Hz); 13C- NMR (300 MHz, CDCl3) d 35.1, 46.9, 48.9, 59.3, 71.5, 127.7, 128.2, 128.8, 129.2, 129.5, 138.4, 139.7, 168.7; MS (ESI, m/z): 281.2 [M+H]+. Anal. Calcd. For C18H20N2O (280.36): C, 77.11; H, 7.19; N, 9.99. Found: C, 77.03; H, 7.22; N, 9.96. 4-Benzyl-1-ethyl-2-oxo-3-phenylpiperazine (3b). This compound was prepared in a similar way to 3a, using compound 2a (8.0 g, 30.07 mmol) and ethyl bromide, as a light yellow solid (8.13 g, 92%); mp 88-89 °C; IR (KBr, cm-1) 2937, 2818, 1648, 1602, 742, 699; 1H-NMR (300 MHz, CDCl3) d 1.13 (t, 3H, J=7.2 Hz), 2.50-2.54 (m, 1H), 3.03-3.13 (m, 1H), 3.15-3.18 (m, 2H), 3.34-3.38 (m, 1H), 3.46-3.53 (m, 2H), 3.72-3.77 (d, 1H, J=13.4 Hz), 4.04 (s, 1H), 7.21-7.38 (m, 8H), 7.52 (d, 2H, J=7.4 Hz); 13C-NMR (300 MHz, CDCl3) d 12.1, 41.8, 45.7, 46.6, 58.8, 71.0, 127.2, 127.7, 128.3, 128.7, 129.0, 137.9, 139.5, 167.6; MS (ESI, m/z): 295.3 [M+H]+. Anal. Calcd. For C19H22N2O (294.39): C, 77.52; H, 7.53; N, 9.52. Found: C, 77.46; H, 7.50; N, 9.56. 1-Allyl-4-tert-butoxycarbonyl -2-oxo-3-phenylpiperazine (3c). This compound was prepared in a similar way to 3a, using compound 2b (8.0 g, 28.98 mmol) and allyl bromide, as a light yellow liquid (8.2 g, 92%); IR (neat, cm-1) 3083, 1698, 1658, 1392, 721, 698; 1H-NMR (300 MHz, CDCl3) d 1.44 (s, 9H), 3.23-3.28 (m, 2H), 3.32-3.36 (m, 1H), 3.85-3.97 (m, 2H), 4.19-4.21 (m, 1H), 5.15-5.21(m, 2H), 5.71-5.79 (m, 2H), 7.29-7.38 (m, 5H); 13C-NMR (300 MHz, CDCl3) d 28.1, 37.7, 44.8, 49.0, 60.6, 80.7, 118.0, 125.2, 126.6, 127.5, 127.9, 128.3, 133.1, 137.4, 153.7, 166.3; MS (ESI, m/z): 317.3 [M+H]+. Anal. Calcd. For C18H24N2O3 (316.39): C, 68.33; H, 7.65; N, 8.85. Found: C, 68.40; H, 7.58; N, 8.82. ISSN 1424-6376 Page 4 ©ARKAT

Page  5 General Papers ARKIVOC 2006 (xiv) 1-9 1-Allyl-4-benzyl-2-oxo-3-phenylpiperazine (3d). This compound was prepared in a similar way to 3a, using compound 2a (8.0 g, 30.07 mmol) and allyl bromide, as a yellow oil (8.37 g, 91%); IR (neat, cm-1) 3084, 2804, 1649, 1603, 754, 700; 1H-NMR (300 MHz, CDCl3) d 2.51-2.53 (m, 1H), 3.01-3.14 (m, 1H), 3.16-3.20 (m, 2H), 3.48-3.52 (m, 1H), 3.75-3.80 (d, 1H, J=13.4 Hz), 3.98-4.05 (m, 2H), 4.10 (s, 1H), 5.17-5.23 (m, 2H), 5.71-5.84 (m, 1H), 7.28-7.41 (m, 8H), 7.57(m, 2H); 13C-NMR (300 MHz, CDCl3) d 45.8, 46.6, 49.3, 58.8, 71.0, 117.8, 127.2, 127.8, 128.3, 128.7, 129.0, 132.3, 137.8, 139.2, 162.5, 168.0; MS (ESI, m/z): 307.5 [M+H]+. Anal. Calcd. For C20H22N2O (306.40): C, 78.40; H, 7.24; N, 9.14. Found: C, 78.51; H, 7.22; N, 9.10. 1-Benzyl-4-tert-butoxycarbonyl-2-oxo-3-phenylpiperazine (3e). This compound was prepared in a similar way to 3a, using compound 2b (8.0 g, 28.98 mmol) and benzyl bromide, as a light brown oil (9.75 g, 92%); IR (neat, cm-1) 3062, 2877, 1676, 1603, 1389, 729, 702; 1H-NMR (300 MHz, CDCl3) d 1.45 (s, 9H), 3.20-3.23 (m, 1H), 3.32-3.36 (m, 2H), 3.93 (m, 1H), 4.49 (d, 1H, J=14.5 Hz), 4.85 (d, 1H, J=14.5 Hz), 5.78 (s, 1H), 7.27-7.41 (m, 10H); 13C-NMR (300 MHz, CDCl3) d 28.6, 38.8, 45.3, 50.4, 60.9, 81.3, 127.9, 128.1, 128.4, 128.6, 128.7, 128.9, 129.1, 129.4, 129.5, 138.1, 154.3, 162.8, 167.2; MS (ESI, m/z): 367.2 [M+H]+. Anal. Calcd. For C22H26N2O3 (366.45): C, 72.11; H, 7.15; N, 7.64. Found: C, 72.18; H, 7.18; N, 7.61. General procedure for reduction of 4-protected-1-alkyl-3-phenylpiperazines (3a-e). 4Benzyl- 1-methyl-3-phenylpiperazine (4a). Under N2 atmosphere, 3a (90.0 g, 0.321 mol) was added slowly to a suspension of LiAlH49 (14.6 g, 0.384 mol) in anhydrous THF (450 mL) at 1015 °C over a period of 1 h and refluxed for 6 h. The excess LiAlH4 was destroyed at 0 °C with water (14.6 mL), 15% NaOH (14.6 mL) and water (42.8 mL). After filtration, the filtrate was evaporated to dryness and water (300 mL) was added. Filtered the product to yield 4a (80.0 g, 94%) as a light yellow solid; purity 98% (by HPLC); mp 79-80 °C; IR (KBr, cm-1) 2932, 2788, 1599, 740, 698; 1H-NMR (300 MHz, CDCl3) d 2.15-2.22 (m, 2H), 2.23-2.28 (m, 1H), 2.99 (s, 3H), 2.80-2.85 (m, 2H), 2.86 (d, 2H, J=13.4 Hz), 3.44 (dd, 1H, J=10.5, 2.9 Hz), 3.82 (d, 1H, J=13.4 Hz), 7.19-7.30 (m, 6H), 7.40-7.38 (m, 2H), 7.50-7.52 (m, 2H); 13C-NMR (300 MHz, CDCl3) d 46.3, 52.3, 55.7, 59.4, 64.6, 67.9, 127.2, 127.9, 128.4, 128.5, 129.0, 129.2, 139.5, 142.5; MS (ESI, m/z): 267.4 [M+H]+. Anal. Calcd. For C18H22N2 (266.38): C, 81.16; H, 8.32; N, 10.52. Found: C, 81.02; H, 8.44; N, 10.54. 4-Benzyl-1-ethyl-3-phenylpiperazine (4b). This compound was prepared in a similar way to 4a, using compound 3b (5.0 g, 17.0 mmol), as a light yellow oil (4.52 g, 95%); IR (neat, cm-1) 2945, 2805, 1603, 1470, 736, 700; 1H-NMR (300 MHz, CDCl3) d 1.06 (t, 3H, J=7.2 Hz), 2.052.19 (m, 2H), 2.23-2.31 (m, 1H), 2.36-2.44 (m, 2H), 2.84-2.92 (m, 4H), 3.41-3.44 (m, 1H), 3.78 (d, 1H, J=13.4 Hz), 7.19-7.37 (m, 8H), 7.49-7.51 (m, 2H); 13C-NMR (300 MHz, CDCl3) d 12.4, 52.3, 52.6, 53.3, 59.5, 62.4, 67.8, 127.1, 127.9, 128.4, 128.5, 128.8, 129.0, 129.2, 139.5, 142.7; MS (ESI, m/z): 281.3 [M+H]+. Anal. Calcd. For C19H24N2 (280.41): C, 81.38; H, 8.63; N, 9.99. Found: C, 81.24; H, 8.62; N, 10.14. 1-Allyl-4-tert-butoxycarbonyl-3-phenylpiperazine (4c). This compound was prepared in a similar way to 4a, using compound 3c (5.0 g, 15.82 mmol), as a light yellow oil (3.72 g, 78%) after purification by silica gel (100-200 mesh) column chromatography [AcOEt-hexane (1:9)]; ISSN 1424-6376 Page 5 ©ARKAT

Page  6 General Papers ARKIVOC 2006 (xiv) 1-9 IR (neat, cm-1) 3063, 1694, 1603, 1392, 1300, 722, 700; 1H-NMR (300 MHz, CDCl3) d 1.48 (s, 9H), 2.13-2.14 (m, 1H), 2.31-2.37 (m, 1H), 2.79-2.83 (m, 2H), 3.03-3.08 (m, 2H), 3.39-3.43 (m, 1H), 3.92-3.96 (m, 1H), 5.17-5.26 (m, 3H), 5.86-5.88 (m, 1H), 7.24-7.43 (m, 3H), 7.46 (m, 2H); 13C-NMR (300 MHz, CDCl3) d 28.8, 40.4, 53.7, 53.8, 55.2, 62.2, 80.3, 118.6, 127.2, 127.8, 128.7, 135.2, 140.8, 155.4; MS (ESI, m/z): 303.3 [M+H]+. Anal. Calcd. For C18H26N2O2 (302.41): C, 71.49; H, 8.67; N, 9.26. Found: C, 71.28; H, 8.79; N, 9.29. 1-Allyl-4-benzyl -3-phenylpiperazine (4d). This compound was prepared in a similar way to 4a, using compound 3d (5.0 g, 16.33 mmol), as a light yellow solid (4.20 g, 88%); mp 86-88 °C. IR (KBr, cm-1) 3062, 2795, 1603, 741, 701; 1H-NMR (300 MHz, CDCl3) d 2.07-2.14 (m, 1H), 2.18-2.30 (m, 2H), 2.81-2.90 (m, 4H), 2.97-2.99 (m, 2H), 3.40 (dd, 1H, J=10.4, 2.7 Hz), 3.79 (dd, 1H, J=13.4 Hz), 5.10-5.16 (m, 2H), 5.73-5.84 (m, 1H), 7.21-7.36 (m, 8H), 7.49 (d, 2H, J=7.4 Hz); 13C-NMR (300 MHz, CDCl3) d 52.2, 53.6, 59.4, 62.1, 62.4, 67.8, 118.7, 127.2, 127.9, 128.4, 128.5, 128.8, 129.0, 129.2, 135.1, 139.4, 142.6; MS (ESI, m/z): 293.1 [M+H]+. Anal. Calcd. For C20H24N2 (292.42): C, 82.15; H, 8.27; N, 9.58. Found: C, 82.04; H, 8.30; N, 9.66. 1-Benzyl-4-tert-butoxycarbonyl -3-phenylpiperazine (4e). This compound was prepared in a similar way to 4a, using compound 3e (5.0 g, 13.66 mmol), as a light yellow oil (3.82 g, 79%) after purification by silica gel (100-200 mesh) column chromatography [AcOEt-hexane (1:9)]; IR (neat, cm-1) 2809, 1682, 1602, 1392, 737, 698; 1H-NMR (300 MHz, CDCl3) d 1.47 (s, 9H), 2.15-2.19 (m, 1H), 2.38-2.43 (m, 1H), 2.78-2.82 (m, 1H), 2.99-3.06 (m, 1H), 3.26-3.30 (m, 1H), 3.44 (d, 1H, J=13.2 Hz), 3.57 (d, 1H, J=13.2 Hz), 3.88-3.93 (m, 1H), 5.23 (s, 1H), 7.21-7.36 (m, 8H), 7.41 (d, 2H, J=7.4 Hz); 13C-NMR (300 MHz, CDCl3) d 28.9, 31.7, 40.3, 53.8, 55.4, 63.6, 80.3, 127.2, 127.6, 128.1, 128.5, 128.7, 129.6, 138.3, 140.9, 155.4; MS (ESI, m/z): 353.3 [M+H]+. Anal. Calcd. For C22H28N2O2 (352.47): C, 74.97; H, 8.01; N, 7.95. Found: C, 74.80; H, 8.15; N, 7.98. 1-Methyl-3-phenylpiperazine (5a). The mixture of 4a (60.0 g, 0.226 mol), 5% Pd-C (3.0 g, 50% wet),10 methanol (300 mL) and acetic acid (50 mL) was hydrogenated with H2 (100 psi.) at 25-30 °C for 5 h, filtered and the filtrate was evaporated to dryness. Dissolved the residue in water (150 mL), pH adjusted to 11.5 with 40% NaOH and extracted with toluene (240 mL). Combined organic solution was concentrated to dryness and the product was precipitated with cyclohexane. Filtered to yield 5a (36.2 g, 91%) as a light yellow solid; purity 99.9% (by HPLC); mp 58-60 °C (lit,6 53-55°C); IR (KBr, cm-1) 3253, 2942, 2816, 2792, 1603, 761, 703; 1H-NMR (300 MHz, CDCl3) d 1.76 (bs, 1H), 1.92-1.99 (m, 1H), 2.10-2.15 (m, 1H), 2.31 (s, 3H), 2.802.89 (m, 2H), 3.01-3.11 (m, 2H), 3.87 (dd, 1H, J=10.6, 2.7 Hz), 7.27-7.41 (m, 5H); 13C-NMR (300 MHz, CDCl3) d 46.6, 46.7, 55.6, 60.8, 63.7, 127.3, 127.9, 128.8, 142.9; MS (ESI, m/z): 177.0 [M+H]+. Anal. Calcd. For C11H16N2 (176.26): C, 74.96; H, 9.15; N, 15.89. Found: C, 74.90; H, 9.22; N, 15.88. 1-Ethyl-3-phenylpiperazine (5b). This compound was prepared in a similar way to 5a, using compound 4b (3.0 g, 10.71 mmol), as a light yellow liquid (1.83 g, 90%); IR (neat, cm-1) 3268, 2944, 2809, 1603, 1470, 756, 700; 1H-NMR (300 MHz, CDCl3) d 1.10 (t, 3H, J=7.2 Hz), 1.951.98 (m, 1H), 2.02-2.13 (m, 1H), 2.45 (q, 2H, J=7.2Hz), 2.91-2.97 (m, 2H), 3.06-3.10 (m, 2H), ISSN 1424-6376 Page 6 ©ARKAT

Page  7 General Papers ARKIVOC 2006 (xiv) 1-9 3.87-3.91 (dd, 1H, J=10.4, 2.7 Hz), 7.20-7.32 (m, 3H), 7.34-7.41 (m, 2H); 13C-NMR (300 MHz, CDCl3) d 12.2, 46.5, 52.9, 53.1, 60.7, 61.4, 127.4, 127.8, 128.0, 128.6, 128.7, 128.9, 142.9; MS (ESI, m/z): 191.2 [M+H]+. Anal. Calcd. For C12H18N2 (190.28): C, 75.74; H, 9.53; N, 14.72. Found: C, 75.60; H, 9.61; N, 14.79. 1-Allyl-3-phenylpiperazine (5c). Compound 4c (3.0 g, 9.93 mmol) was treated with 6N HCl (12 mL) at 25-30°C for 4 h. Adjusted the pH to 11.5 with 40% NaOH and the aqueous solution was extracted with dichloromethane (30 mL), evaporated to dryness to yield 5c as a light yellow liquid (1.76 g, 88%); IR (neat, cm-1) 3069, 2886, 1603, 1471, 761, 698; 1H-NMR (300 MHz, CDCl3) d 1.98 (br, 1H), 3.56-3.68 (m, 6H), 3.72-3.84 (m, 2H), 4.85-4.88 (m, 1H), 5.51-5.63 (m, 2H), 5.95-6.09 (m, 1H), 7.49-7.54 (m, 3H), 7.69-7.71(m, 2H); 13C-NMR (300 MHz, CDCl3) d 41.8, 47.0, 52.5, 57.1, 59.7, 125.6, 127.4, 128.7, 129.8, 130.8, 132.0; MS (ESI, m/z): 203.3 [M+H]+. Anal. Calcd. For C13H18N2 (202.30): C, 77.18; H, 8.97; N, 13.85. Found: C, 77.31; H, 8.88; N, 13.81. 1-Propyl-3-phenylpiperazine (5d). This compound was prepared in a similar way to 5a, using compound 4d (3.0 g, 10.27 mmol), as a light yellow liquid (1.92 g, 92%); IR (neat, cm-1) 3257, 2935, 2807, 1603, 755, 700; 1H-NMR (300 MHz, CDCl3) d 0.90 (t, 3H, J=7.2 Hz), 1.50-1.53 (m, 2H), 1.95-2.11 (m, 2H), 2.29-2.34(m, 2H), 2.85-2.93 (m, 2H) 3.04-3.09 (m, 2H), 3.85 (dd, 1H, J=10.4, 2.7 Hz), 7.24-7.33 (m, 3H), 7.37-7.40 (m, 2H); 13C-NMR (300 MHz, CDCl3) d 12.4, 20.2, 46.6, 53.6, 60.8, 61.3, 61.9, 127.2, 127.4, 127.8, 128.4, 128.7, 143.0; MS (ESI, m/z): 205.2 [M+H]+. Anal. Calcd. For C13H20N2 (204.31): C, 76.42; H, 9.87; N, 13.71. Found: C, 76.58; H, 9.90; N, 13.52. 1-Benzyl-3-phenylpiperazine (5e). This compound was prepared in a similar way to 5c, using compound 4e (3.0 g, 8.52 mol), as a light yellow solid (1.93 g, 90%); mp 55-56 °C (lit,2 55-63 °C); IR (KBr, cm-1) 3244, 2802, 1602, 761, 741, 701, 696; 1H-NMR (300 MHz, CDCl3) d 1.99 (bs, 1H), 2.05-2.13 (m, 1H), 2.21-2.26 (m, 1H), 2.84-2.94 (m, 2H), 3.07-3.11 (m, 2H), 3.57 (s, 2H), 3.91 (dd, 1H, J=10.4, 2.7 Hz), 7.24-7.38 (m, 10H); 13C-NMR (300 MHz, CDCl3) d 46.6, 53.6, 60.8, 61.6, 63.8, 127.5, 127.9, 128.7, 128.8, 129.7, 138.3, 143.0; MS (ESI, m/z): 253.1 [M+H]+. Anal. Calcd. For C17H20N2 (252.35): C, 80.91; H, 7.99; N, 11.10. Found: C, 80.98; H, 7.96; N, 11.06. 1-Methyl-2-oxo-3-phenylpiperazine (6a). The mixture of 3a (15.0 g, 53.57 mmol), 5% Pd-C (3.0 g, 50% wet) and acetic acid (90 mL) was hydrogenated with H2 (100 psi.) at 25-30 °C for 5 h, filtered and the filtrate was evaporated to dryness. Dissolved the residue in water (75 mL), pH adjusted to 10.5 with 20% NaOH and extracted with dichloromethane (150 mL). Combined organic solution was concentrated to dryness to yield 6a (10.0 g, 98%) as light yellow oil; IR (neat, cm-1) 3301, 2925, 2865, 1640, 1588, 738, 699; 1H-NMR (300 MHz, CDCl3) d 1.99 (bs, 1H), 3.03 (s, 3H), 3.05-3.19 (m, 2H), 3.31-3.55 (m, 2H), 4.58 (s, 1H), 7.27-7.42 (m, 5H); 13C- NMR (300 MHz, CDCl3) d 35.1, 41.5, 50.6, 64.2, 128.0, 128.7, 140.3, 169.1; MS (ESI, m/z): 191.0 [M+H]+. Anal. Calcd. For C11H14N2O (190.24): C, 69.45; H, 7.42; N, 14.73. Found: C, 69.54; H, 7.35; N, 14.75. ISSN 1424-6376 Page 7 ©ARKAT

Page  8 General Papers ARKIVOC 2006 (xiv) 1-9 1-Ethyl-2-oxo-3-phenylpiperazine (6b). This compound was prepared in a similar way to 6a, using compound 3b (2.5 g, 8.50 mmol), as a light yellow oil (1.64 g, 95%); IR (neat, cm-1) 3312, 2934, 2873, 1639, 1451, 752, 698; 1H-NMR (300 MHz, CDCl3) d 1.19 (t, 3H, J=7.2 Hz), 2.10 (bs, 1H), 3.02-3.10 (m, 1H), 3.13-3.20 (m, 1H), 3.27-3.37 (m, 1H), 3.39-3.44 (m, 1H), 3.47-3.58 (m, 2H), 4.55 (s, 1H), 7.27-7.40 (m, 5H); 13C-NMR (300 MHz, CDCl3) d 12.6, 41.5, 42.4, 47.7, 64.1, 128.4, 128.6, 128.7, 128.8, 129.3, 140.4, 168.5; MS (ESI, m/z): 205.2 [M+H]+. Anal. Calcd. For C12H16N2O (204.27): C, 70.56; H, 7.90; N, 13.71. Found: C, 70.34; H, 7.92; N, 13.74. 1-Allyl-2-oxo-3-phenylpiperazine (6c). This compound was prepared in a similar way to 5c, using compound 3c (2.5 g, 7.91 mmol), as a light yellow oil (1.53 g, 90%); IR (neat, cm-1) 3309, 3083, 2865, 1638, 1490, 751, 700; 1H-NMR (300 MHz, CDCl3) d 1.99 (bs, 1H), 2.88-2.95 (m, 1H), 3.09-3.17 (m, 1H), 3.19-3.22 (m, 1H), 3.32-3.49 (m, 1H), 4.07 (d, 2H, J=6.0 Hz), 4.61 (s, 1H), 5.20-5.26 (m, 2H), 5.81-5.97 (m, 1H), 7.28-7.40 (m, 5H); 13C-NMR (300 MHz, CDCl3) d 41.6, 47.9, 49.7, 64.3, 118.2, 128.0, 128.7, 132.9, 140.3, 168.8; MS (ESI, m/z): 217.2 [M+H]+. Anal. Calcd. For C13H16N2O (216.28): C, 72.19; H, 7.46; N, 12.95. Found: C, 72.06; H, 7.58; N, 12.98. 1-Benzyl-2-oxo-3-phenylpiperazine (6d). This compound was prepared in a similar way to 5c, using compound 3e (2.5 g, 6.83 mmol), as a light yellow oil (1.59 g, 88%); IR (neat, cm-1) 3313, 2862, 1645, 753, 700; 1H-NMR (300 MHz, CDCl3) d 1.91 (bs, 1H), 2.96-3.00 (m, 1H), 3.20-3.24 (m, 1H), 3.42-3.46 (m, 1H), 3.69-3.72 (m, 1H), 4.67 (s, 2H), 5.31 (s, 1H), 7.20-7.49 (m, 10H); 13C-NMR (300 MHz, CDCl3) d 41.6, 47.5, 50.7, 64.2, 127.9, 128.0, 128.4, 128.6, 128.7, 128.9, 129.0, 129.1, 129.3, 129.4, 137.1, 139.7, 168.7; MS (ESI, m/z): 267.1 [M+H]+. Anal. Calcd. For C17H18N2O (266.34): C, 76.66; H, 6.81; N, 10.52. Found: C, 76.50; H, 6.83; N, 10.54. General method for the preparation of 1-alky-3-phenylpiperazine (5a-c, e) by the reduction of 1-alkyl-2-oxo-3-phenylpiperazines (6a-d). 1-Methyl-3-phenylpiperazine (5a). Under N2 atmosphere, 6a (9.0 g, 47.36 mmol) was added slowly to a suspension of LiAlH4 (3.1 g, 81.58mmol) in anhydrous THF (100 mL) at 10-15 °C over a period of 1 h and then refluxed for 6 h. The excess LiAlH4 was destroyed at 0 °C with water (3.1 mL), 15% NaOH (3.1 mL) and water (9.3 mL). After filtration, the filtrate was evaporated to dryness and dissolved the residue in water (25 mL). Acidified the solution to pH 2.0 with 15% HCl and washed the solution with toluene (20 mL). Basified to pH 10.5 with 20% NaOH. The aqueous solution was extracted with dichloromethane (100 mL); the combined organic solution was evaporated. The residue was treated with cyclohexane (20 mL) to yield 5a (7.4 g, 84%) as a light yellow solid; purity 99.5% (by HPLC), mp 58-59 °C; 1H-NMR (300 MHz, CDCl3) d 1,80 (bs, 1H), 1.96-2.03 (m, 1H), 2.132.18 (m, 1H), 2.31 (s, 3H), 2.80-2.89 (m, 2H), 3.06-3.10 (m, 2H), 3.86 (dd, 1H, J=10.6, 2.7 Hz), 7.23-7.40 (m, 5H); MS (ESI, m/z): 177.0 [M+H]+. Similarly, by following the same procedure 5b, 5c and 5e can be prepared. ISSN 1424-6376 Page 8 ©ARKAT

Page  9 General Papers ARKIVOC 2006 (xiv) 1-9 Acknowledgements Authors thank the management of Aurobindo Pharma Limited, Hyderabad for permission to publish this work. Authors also thank the Analytical Research Department for their valuable contribution to this work. References and Footnotes 1. Van der Burg, W. J. Ger. Offen. 2, 614, 406, 1975; Chem. Abstr. 1977, 86, 29883. 2. Roderick, W. R.; Platte, H. J.; Pollard, C. B. J. Med. Chem. 1966, 9, 181-185. 3. Dolitzky, Ben-Zion. PCT Int. Appl. WO 00/63, 185: Chem. Abstr. 2000, 133, 321901. 4. Bosch i Llado, J.; Camps Garcia, P.; Contreras Lascorz, J.; Onrubia Miguel, M. PCT Int. Appl. WO 03/024, 918; Chem. Abstr. 2003, 138, 254962. 5. Guo, B. S.; Yang, Y. S.; Ji, R. Y. Chinese Chemical Lett. 2003, 14, 365. 6. Ramamohan Rao, D.; Sankara Rao, Ch.; Sreenivasulu, P. PCT Int. Appl. WO 02 090, 339, 2002; Chem. Abstr. 2002, 137, 370108. 7. Handa, V. K.; Srinivasarao D. V. N.; Sivakumaran, M. US. Pat. Appl. 242, 879, 2004: Chem. Abstr. 2005, 142, 23309. 8. HPLC analyses were carried out only for compounds 2a, 3a, 4a and 5a. Retention times were 12.1, 13.1, 10.3 and 6.5 respectively (CH3CN: 0.05 M KH2PO4). 9. Lithium aluminum hydride reacts violently with water, liberating hydrogen, incompatible with strong oxidizing agents. Reactions to be carried out in anhydrous conditions. 10. Palladium on carbon is flammable, pyrophoric after activation with hydrogen. It should always be kept at inert atmosphere. ISSN 1424-6376 Page 9 ©ARKAT