A one-pot process for the regioselective synthesis of 1,3,4-trisubstituted-1H-pyrazoles

Tetrahedron Letters

Volumn 50, Issue 6, 2009, Pages 696-699

  Raw, Steven A ^a   Turner, Andrew T ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

PYRAZOLE DERIVATIVE;

ARTICLE; CHEMICAL BOND; CHEMICAL REACTION; CHEMICAL STRUCTURE; CYCLIZATION; ONE POT SYNTHESIS;

EID: 57849149906     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2008.11.099     Document Type: Article

References (31)

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16. Wijnberger C., and Habraken C.L. J. Heterocycl. Chem. 6 (1969) 545
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23. We found some precedence for this type of cyclisation in the production of pyrazolo[1,5-a]indole and quinoline systems, in which the N-carbonyl and N-alkyl substituents of the hydrazone are contained in a cyclic motif, see:. Winters G., Odasso G., Conti M., Tarzia G., and Galliani G. Eur. J. Med. Chem. 19 (1984) 215-218
24. A similar mechanism has also been implicated in the production of a minor pyrazolo[5,1,a]indole by-product, see:. Toja E., Omodei-Sale A., and Nathansohn G. Tetrahedron Lett. 31 (1979) 2921-2924
25. Pedersen C.T. Acta Chem. Scand. 18 (1964) 2199-2200
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27. For example, see:. Heller S.T., and Natarajan S.R. Org. Lett. 8 (2006) 2675 It should be noted that, even in this methodology, the use of methylhydrazine gives poor regioselectivity at best
28. Typical laboratory-scale procedure for 2: To a cooled solution (0-5 °C) of methylhydrazine (660 mmol, 35.0 mL) in IMS (215 mL) was added ethyl formate (688 mmol, 55.5 mL) dropwise so that the temperature remained below 10 °C. Once the addition was complete, the solution was heated to reflux for 4 h. To the colourless solution was then added ethyl acetoacetate (550 mmol, 70.0 mL) and reflux continued for a further 4 h. The resulting yellow solution was cooled to ∼55 °C and a solution of 21 wt % sodium ethoxide in IMS (550 mmol, 205.4 mL) was added dropwise so that a gentle reflux was maintained. Once addition was complete, reflux was maintained for 45 min. The suspension was then cooled to rt and diluted with 3 M ammonium chloride (360 mL) and brine (360 mL). The resulting solution was extracted with MTBE (2 × 360 and 1 × 180 mL). The combined organics were washed with saturated brine (180 mL) diluted with water (180 mL). The MTBE solution was concentrated by distillation to ∼400 mL, then n-heptane (1200 mL) was added. Distillation was continued until the head temperature was constant at 97-99 °C and the volume in the vessel was 380 mL. The solution was allowed to cool to ambient temperature, then in an ice/water bath to 3-5 °C. The precipitated solid was collected by filtration, washed with cold n-heptane (2 × 80 mL) and dried in vacuo at ambient temperature to give the desired pyrazole ester 2 (38.32 g, 98 wt %, 223 mmol, 41% yield), as an off-white crystalline solid. The spectroscopic data for this material match those reported, see Ref. 4c.
29. Acid 10 has been shown to undergo the reduction-oxidation chemistry applied to ester 2 equally well.
30. All compounds gave satisfactory spectroscopic data.
31. 4 in THF (204 mmol, 102 mL) dropwise so that the temperature remained below 10 °C. Once the addition was complete, the mixture was stirred at 0-3 °C for 1 h, then warmed to ambient temperature. After a total of 3 h, the mixture was cooled in a water bath, and water (7.0 mL) was added dropwise [CAUTION-vigorous effervescence!] over 10 min. This was followed by dropwise addition of 1 M sodium hydroxide (7.0 mL) over 10 min, then more water (7.0 mL) over 1 min. Vigorous stirring was employed to maintain mobility. Harborlite-800 filter aid (30 g) was added to the mixture and the solid residues were removed by filtration. The cake was washed with THF (3 × 70 mL). To the combined organic solution (containing 3) was added manganese dioxide [85%, activated <5 μm, Aldrich cat. 217646] (1020 mmol, 102.3 g) and the mixture heated to reflux. After 6 h, the mixture was cooled to room temperature and the solid residues were removed by filtration (double-thickness of Whatman GF/B paper in a split Buchner funnel). The cake was washed with THF (3 × 80 mL). The combined THF solution was concentrated by distillation to ∼100 mL, then n-heptane (200 mL) was added. Distillation was continued until the head temperature was constant at 97-99 °C and the volume in the vessel was 160 mL. The solution was allowed to cool to 45 °C, which caused precipitation of the product as an oil which then crystallised. The mixture was then cooled in an ice/water bath to 3-5 °C. The solid was collected by filtration, washed with cold n-heptane (2 × 30 mL) and dried in vacuo at ambient temperature to give the desired pyrazole aldehyde 1 (19.82 g, 99 wt %, 158 mmol, 78% yield), as a white crystalline solid. The spectroscopic data for this material match those reported, see Ref. 3e.