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Synlett 2008(7): 1005-1008  
DOI: 10.1055/s-2008-1042923
LETTER
© Georg Thieme Verlag Stuttgart · New York

Selective β-Hydroxyethylation at the N-1 Position of a Pyrazolone: Synthesis of Benzyl 1-(β-Hydroxyethyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate

Aaron Siegmunda, Daniel Retza, Ning Xia, Celia Dominguezb, Roland Bürlia, Longbin Liu*a
a Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
b MRSSI/CHDI, Inc., 6080 Center Drive, Suite 100, Los Angeles, CA 90045, USA
e-Mail: lliu@amgen.com;
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Publication History

Received 11 December 2007
Publication Date:
17 March 2008 (online)

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Abstract

Selective 2-hydroxyethylation at the N-1 position of benzyl 5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate with epoxides was achieved using either AlMe3 or Mg(ClO4)2 under mild conditions. The epoxide ring opening was both regioselective and stereospecific. Moderate to excellent yields were obtained from mono- and disubstituted epoxides with the exception of cis-dimethyl-2-butene oxide that gave only a trace amount of the product.

Key words

pyrazolones - pyrazole - epoxide - hydroxyethyl - selective - trimethylaluminum - magnesium perchlorate

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16

The structure of 2 was confirmed based on an alternative synthesis in ca. 10% overall yield (Scheme [2] ).

Scheme 2

17

General Procedures for Method A
To a stirring suspension of 1 (15.0 g, 49 mmol) in dry MeCN (100 mL) at 0 °C was added Mg(ClO4)2 (33 g, 146 mmol) in 3 portions over 1 min. After the reaction temperature returned to 0 °C, the epoxide was added. The flask was equipped with a reflux condenser and was heated for the specified time and temperature. The solution was then concentrated under reduced pressure, dissolved in CHCl3 (100 mL), chilled to 10 °C, and quenched with ice-cold water (200 mL). The resulting biphasic solutions were stirred for 1 h and separated. The aqueous layer was extracted with CHCl3 (2 × 50 mL), and the combined organic layers were washed with NH4Cl (sat.), dried over MgSO4, and concentrated. The crude product was purified on SiO2 (120 g) chromatography eluting with a gradient of 1-2.5% of MeOH-CH2Cl2.
General Procedure for Method B
To a stirring suspension of 1 (5.0 g, 16 mmol) in chlorobenzene (25 mL) at 0 °C was added a solution of Me3Al (2.0 M in toluene, 24 mL, 49 mmol) under nitrogen. To the resulting clear solution was added the epoxide, and the mixture was stirred at 23 °C. The reaction was monitored by LCMS and more epoxide was added if the reaction stalled. Upon completion, the mixture was diluted with THF (100 mL), quenched with Na2SO4·10H2O (6 g), and stirred for 24 h. The salts were removed by filtration (glass frit) and washed with EtOAc (100 mL). The filtrate was washed with HCl (1 N, 20 mL) and NH4Cl (sat., 20 mL), dried over MgSO4, and concentrated. The crude product was purified on SiO2 (40 g) chromatography eluting with 25-75% of EtOAc in hexane.

18

All compounds were characterized by 1H NMR and LC-MS to be >95% pure except for 3 that was further derivatized via the mesylate. Selected 1H NMR [(400 MHz, CHCl3-d 1), δ in ppm] data are provided for compounds listed in Table [1] :
Compound 4: 0.95 (d, J = 6.26 Hz, 3 H), 2.65 (s, 3 H), 3.38 (dd, J = 14.87, 1.76 Hz, 1 H), 3.43 (s, 1 H), 3.65 (dd, J = 14.97, 9.88 Hz, 1 H), 3.94-4.05 (m, 1 H), 5.23 (s, 2 H), 7.20-7.39 (m, 5 H) 7.39-7.49 (m, 5 H).
Compounds 5 and 6: 0.74 (t, J = 7.43 Hz, 3 H), 1.18-1.37 (m, 2 H), 2.67 (s, 3 H), 3.55 (d, J = 13.30 Hz, 1 H), 3.61-3.77 (m, 2 H), 5.27 (d, J = 3.52 Hz, 2 H), 7.27-7.39 (m, 5 H), 7.41-7.51 (m, 5 H).
Compound 7: 2.68 (s, 3 H), 3.21-3.34 (m, 2 H), 3.65-3.78 (m, 1 H), 3.80-3.90 (m, 1 H), 4.02-4.12 (m, 1 H), 5.16-5.31 (m, 2 H), 5.73 (br s, 1 H), 7.28-7.35 (m, 5 H), 7.36-7.51 (m, 5 H).
Compound 8: 0.68 (d, J = 6.85 Hz, 3 H), 0.74 (d, J = 6.85 Hz, 3 H), 1.49 (dd, J = 12.81, 6.75 Hz, 1 H), 2.67 (s, 3 H), 3.25 (br s, 1 H), 3.46-3.53 (m, 1 H), 3.58-3.64 (m, 1 H), 3.70-3.80 (m, 1 H), 5.29 (q, J = 12.78 Hz, 2 H), 7.28-7.41 (m, 6 H), 7.42-7.50 (m, 4 H).
Compound 9: 0.95 (s, 6 H), 2.65 (s, 3 H), 3.77 (s, 2 H), 4.79 (s, 1 H), 5.21 (s, 2 H), 7.23 (d, J = 7.43 Hz, 2 H), 7.27-7.33 (m, 1 H), 7.37 (q, J = 7.50 Hz, 3 H), 7.42-7.47 (m, 2 H), 7.50 (t, J = 7.73 Hz, 2 H).
Compound 10: 0.74 (t, J = 7.53 Hz, 3 H), 0.82-0.93 (m, 1 H), 1.02 (s, 3 H), 1.23-1.43 (m, 2 H), 2.72 (s, 3 H), 3.68-3.89 (m, 2 H), 5.30-5.33 (m, 2 H), 7.21-7.27 (m, 3 H), 7.29-7.37 (m, 3 H), 7.42-7.53 (m, 4 H).
Compound 11: 1.05 (d, J = 6.1 Hz, 3 H), 1.41 (d, J = 7.2 Hz, 3 H), 2.12 (d, J = 3.3 Hz, 1 H), 3.75-3.85 (m, 1 H), 2.70 (s, 3 H), 3.87-3.97 (m, 1 H), 5.29 (s, 2 H), 7.22-7.29 (m, 3 H), 7.29-7.35 (m, 2 H), 7.35-7.42 (m, 1 H), 7.42-7.51 (m, 4 H).