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DOI: 10.1055/s-2005-865208
A Practical Synthesis of Piperidine-/Tropane-Substituted 1,2,4-Triazoles
Publication History
Publication Date:
14 April 2005 (online)
Abstract
A robust synthesis of 1,2,4-triazoles is disclosed with a particular focus on developing methodology capable of delivering gram quantities and minimising hazardous waste.
Key words
heterocycles - triazoles - isostere - tropane - piperidine
-
1a
Wermuth CG. In The Practice of Medicinal ChemistryWermuth CG. Academic Press; San Diego: 2001. -
1b
Patani GA.LaVoie EJ. Chem. Rev. 1996, 96: 3147 - 2
Wadsworth HJ.Jenkins SM.Orlek BS.Cassidy F.Clark MSG.Brown F.Riley GJ.Graves D.Hawkins J.Naylor CB. J. Med. Chem. 1992, 35: 1280 - 3
Stocks MJ.Cheshire DR.Reynolds R. Org. Lett. 2004, 6: 2969 -
4a
Boeglin D.Cantel S.Heitz A.Martinez J.Fehrentz JA. Org. Lett. 2003, 5: 4465 -
4b
Jagodzinski TS. Chem. Rev. 2003, 103: 197 -
5a
Clausen K.Thorsen M.Lawesson SO. Tetrahedron 1981, 37: 3635 -
5b
Voss J. In Encyclopedia of Reagents for Organic Synthesis Vol. 1:Paquette LA. John Wiley and Sons; Chichester: 1995. - 6
Barrett AGM.Lee AC. J. Org. Chem. 1992, 57: 2818 -
7a
Klingsberg E. J. Am. Chem. Soc. 1958, 80: 5786 - 7b inventors; patent GB670,480 . See examples contained within
-
7c
Garrat PJ. In Comprehensive Heterocyclic Chemistry II Vol. 4:Storr RC. Elsevier; Oxford: 1996. - 8
Atkinson MR.Polya JB. J. Chem. Soc. 1954, 141 -
9a
Protective Groups in Organic Synthesis
3rd ed.:
Greene TW.Wuts PGM. John Wiley and Sons; Chichester: 1999. -
9b
Ram S.Spicer LD. Tetrahedron Lett. 1987, 28: 515
References
Preparation of Entry 1.
PCl5 (20.5 g, 98 mmol) was added portionwise to a stirred CH2Cl2 (200 mL) solution of the amide (19.7 g, 76 mmol) at 0 °C. After 2 h stirring at 0 °C acetic hydrazide (16.8 g, 227 mmol) and t-amylalcohol (195 mL) were added and the reaction was stirred for 12 h and then allowed to warm to r.t. The solvent was removed in vacuo and toluene (200 mL) and p-TsOH (474 mg, 2.5 mmol) were added and the reaction was heated under reflux for 6 h. The reaction was cooled to r.t., the solvent was decanted, and CH2Cl2 (200 mL) and H2O (200 mL) were added with stirring; 1 N aq NaOH was slowly added to take the pH to >9. The organic layer was separated and the aqueous was washed with CH2Cl2 (2 × 100 mL), the organics were combined and washed with H2O (2 × 200 mL), brine (200 mL) and dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 10% MeOH in EtOAc to give the product of entry 1 (11.0 g, 50%) as a white solid. 1H NMR (400 MHz, CD3OD): δ = 7.30 (5 H, m), 4.13 (1 H, m), 3.58 (2 H, s), 3.23 (1 H, sept, J = 7.0 Hz), 3.08 (2 H, m), 2.54 (3 H, s), 2.23 (4 H, m), 1.84 (2 H, m), 1.38 (6 H, d, J = 7.0 Hz). LRMS: m/z = 299 [MH+].