Regioselective synthesis of 4-(2-alkyl-5-methyl-2H-pyrazol-3-yl)- piperidines

Tetrahedron Letters

Volumn 47, Issue 11, 2006, Pages 1729-1731

  Dirat, Olivier ^a   Clipson, Alex ^a   Elliott, Jason M ^a   Garrett, Sasha ^a   Brian Jones, A ^a   Reader, Michael ^a   Shaw, Duncan ^a  

^a NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

PIPERIDINE DERIVATIVE; PYRAZOLE DERIVATIVE;

ARTICLE; CHEMICAL REACTION; CHEMICAL STRUCTURE; CRYSTALLIZATION; POLYMERIZATION; SYNTHESIS;

EID: 32244449191     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2006.01.044     Document Type: Article

References (14)

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2. J. Elguero A.R. Katritzky C.W. Rees E.F.V. Scriven Comprehensive Heterocyclic Chemistry II Vol. 3 1996 Pergamon Oxford 1
3. S. Bourrain, M. Ridgill, and I. Collins Synlett 2004 795
4. C.A. Dvorak, D.A. Rudolph, S. Ma, and N.I. Carruthers J. Org. Chem. 70 2005 4188
5. M. Calle, P. Cuadrado, A.M. Gonzalez-Nogal, and R. Valero Synthesis 2001 1949
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7. B.C. Raimundo, J.D. Oslob, A.C. Braisted, J. Hyde, R.S. McDowell, M. Randal, N.D. Waal, J. Wilkinson, C.H. Yu, and M. Arkin J. Med. Chem. 47 2004 3111
8. 3OD): δ 5.97 (s, 1 H); 3.18-3.08 (m, 3H); 2.72-2.64 (m, 2H); 2.15 (s, 3H); 1.82 (m, 2H); 1.61 (m, 11H); 1,45 (s, 9H).
9. Structure of 7 and 8 assigned by NOE experiments.
10. Separation of the regioisomers proved impossible by crystallisation at any stage of the sequence.
11. G.J. Roth, B. Liepold, S.G. Mueller, and H.J. Bestmann Synthesis 2004 59
12. Dimethyl (2-oxopropyl)phosphonate (50 g, 0.30 mol), THF (270 mL) and toluene (1.3 L) were charged to a reaction vessel with stirring under nitrogen. Ice cooling was applied, and sodium hydride (60% in mineral oil) (13.25 g, 0.33 mol) was added over 10 min. The turbid yellow mixture was stirred for one hour with ice water cooling. 4-Acetamidobenzenesulfonyl azide (80 g, 0.33 mol) was then added over 10 min. The turbid orange mixture was stirred overnight at room temperature under nitrogen. The orange mixture was filtered on a Celite pad, the resulting cake was washed with toluene (250 mL), EtOAc (500 mL) and the filtrate was concentrated in vacuo. Compound 16 (57 g) was isolated pure as a clear liquid after a filtration on silica gel (EtOAc) in 98% yield.
13. When the hydrazine addition is performed at 60°C, hydrazone 19 is isolated in 50% yield, alongside less than 10% of pyrazole 18. A variety of acidic and basic conditions were screened to transform 19 into the pyrazole 18 presumably through a trans to cis isomerisation of the hydrazone. Three equivalents of acetic acid in refluxing ethanol gave the best reaction profile (with fewer side products), yielding 18 as a single regioisomer in 25% yield.
14. Microwave heating performed in a SmithSynthesizer in 20 mL vials.