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Construction of a Library of Arylpiperazinyl 1,2,3-Triazole Derivatives as Ligands for Dopamine D<sub>3</sub>/D<sub>4</sub> Receptor
Construction of a Library of Arylpiperazinyl 1,2,3-Triazole Derivatives as Ligands for Dopamine D3/D4 Receptor
Bulletin of the Korean Chemical Society. 2013. Nov, 34(11): 3467-3470
Copyright © 2013, Korea Chemical Society
  • Received : August 05, 2013
  • Accepted : August 06, 2013
  • Published : November 20, 2013
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About the Authors
Ju Myung Kwak
Ji Soo Moon
Jea I Choi
Ravichandran N. Murugan
Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea
Woo Kyu Park
Pharmaceutical Screening Research Team, Korea Research Institute of Chemical Technology, Daejeon 305-343, Korea
Jae Yang Gong
College of Pharmacy, Keimyung Univeristy, 1095 dalgubeol-daegu 704-701, Korea
Hee Yoon Lee
Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea
Hun Yeong Koh

Abstract
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Experimental
General Procedure for the Synthesis of 3-Azido Propanol 2. A solution of alcohol (1) (where, n = 3 and 5 g, 36.0 mmol) and NaN 3 (4.67 g, 71.9 mmol) in DMF (50 mL) under a nitrogen atmosphere was stirred well at 50 ℃ for 15 h. The progress of reaction was monitored by TLC. The reaction mixture was filtered after 15 h and the solvent was evaporated. The product obtained was washed with water and extracted with ethyl acetate (3 × 50 m). The collected organic layer was dried over NaSO 4 and filtered. The product was isolated after evaporating the solvent using a rotary evaporator as a slightly brown colored liquid with 90% yield.
1 H NMR (200 MHz, CDCl 3 ) δ 3.76 (t, 2H, J = 5.8 Hz), 3.45 (t, 2H, J = 6.2 Hz), 1.87-1.78 (m, 2H).
General Procedure for the Synthesis of 3-(5-o-tolyl-1H-1,2,3-triazole-1-yl)-propan-1-ol (4a) and 3-(4-o-tolyl-1H-1,2,3-triazole-1-yl)-propan-1-ol (4b). A solution of azido alcohol 2 (where, n = 3, 500 mg, 4.9 mmol) and 2-ethynyl toluene (573.8 mg, 5.0 mmol) was reacted using a microwave reactor at 150 W, 150 ℃ for 1 h. The progress of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was washed with water and the product was extracted with ethyl acetate (3 × 25 mL). The crude product thus obtained was purified by column chromatography (EA: n -Hex = 4:6) to give a liquid containing 4a and 4b in 40% and 50% yields, respectively.
1 H NMR of compound 4a (200 MHz, CDCl 3 ) δ 7.70 (s, 1H), 7.49-7.38(m, 4H), 4.35 (t, 2H, J = 7.0 Hz), 3.65 (t, 2H, 6.0 Hz), 2.19 (s, 3H), 2.09-1.95 (m, 3H).
1 H NMR of 4b (200 MHz, CDCl 3 ) δ 7.78-7.73 (m, 1H), 7.69 (s, 1H), 7.38-7.18 (m, 3H), 4.59 (t, 2H, J = 7.0 Hz), 3.70 (t, 2H, J = 6.0 Hz), 2.46 (s, 3H), 2.25-2.12 (m, 2H), 2.00 (br s, 1H).
Other aryl alcohol 1,2,3-triazole derivatives were synthesized similarly and characterized by 1 H NMR.
General Procedure for Synthesis of 3-(5-o-tolyl-1H-1,2,3-triazole-1-yl)-propan-1-al (5a). A solution of oxalyl chloride (0.26 mL, 2.9 mmol) in 4 mL of methylene chloride was stirred at −78 ℃ and then DMSO (0.4 mL, 5.8 mmol) in 2 mL of methylene chloride was added over 10 min. Next, a solution of 3-(5-o-tolyl-1H-1,2,3-triazole-1-yl)-propan-1-ol ( 4a ) in 2 mL of methylene chloride was added to the reaction mixture over 30 min using a dropping funnel. Next, Et 3 N (1.3 mL, 9.7 mmol) was added to the reaction mixture and stirred for 5 min. The temperature of the reaction mixture was then raised to room temperature, and then stirred for 1 h. The progress of reaction was monitored by TLC (EA:n-Hex = 1:2). Water (10 mL) was added to the reaction mixture and the organic layer was separated and dried over MgSO 4 . The reaction mixture filtrated to remove MgSO 4 and then the solvent was removed. The product was purified over column chromatography (EA:n-Hex = 1:4) to give a liquid with 53% yield.
1 H NMR of ( 5a ) δ 9.78 (s, 1H), 7.67 (s, 1H), 7.45-7.22 (m, 4H), 4.42 (t, 2H, J = 7.0 Hz), 3.18 (t, 2H, J = 7.0 Hz), 2.19 (s, 3H).
Other aryl aldehyde 1,2,3-triazole derivatives were synthesized similarly and characterized by 1 H NMR.
General Procedure for Synthesis of 1-(2-Chlorophen-yl)-4-(3-5-phenyl-1H-1,2,3-triazole-1-yl)propyl)piperazine (7a). A solution of 3-(5- o -tolyl-1 H -1,2,3-triazole-1-yl)-propan- 1-al ( 5a ) (50 mg, 0.22 mmol) and 1-(2-chlorophenyl)- piperazine (67.9 mg, 0.3 mmol) in 5 mL of methylene chloride was stirred at room temperature for 10 min. Molecular sieve (0.6 g, 4 Å) and DIPEA (0.12 mL, 0.7 mmol) were added slowly. After 30 min, NaBH(OAc) 3 (146.2 mg, 0.7 mmol) was added and stirred for 12 h. The progress of reaction was monitored by TLC. After completion of the reaction, water was added and the organic layer was separated. The organic layer was dried over MgSO 4 and then filtered to remove MgSO 4 . Finally, the product was purified by flash column chromatography (EA:n-Hex = 4:1) to give the product in 87% yield.
1 H NMR (Entry 1) (400 MHz, MeOH- d 4 ) δ 7.77 (s, 1H), 7.47-7.33 (m, 4H), 7.29-7.22 (m, 3H), 7.09-7.03 (m, 2H), 4.37 (t, 2H, J = 6.4 Hz), 3.63-3.57 (m, 4H), 3.39 (d, 2H, J = 6.4 Hz), 3.36 (br s, 2H), 3.10-3.06 (m, 2H), 2.58 (br s, 2H), 2.16 (s, 3H). ESI-MS m/z calcd for C 22 H 26 ClN 5 [M + H] + 396.1955, found 396.1618.
Other arylpiperazinyl 1,2,3-triazole derivatives were synthesized similarly and characterized 1 H NMR.
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