A Practical Synthesis of Piperidine-/Tropane-Substituted 1,2,4-Triazoles

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.

heterocycles - triazoles - isostere - tropane - piperidine

References

1a Wermuth CG. In The Practice of Medicinal Chemistry   Wermuth 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 

10

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⁺].