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

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

References and Notes

• For a detailed discussion on the tautomerism of pyrazolones, see:
• 1a Holzer W. Kautsch C. Laggner C. Claramunt RM. Pérez-Torralba M. Alkorta I. Elguero J. Tetrahedron  2004,  60:  6791 ; and references cited therein
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• 2a Jensen BS. Acta Chem. Scand.  1959,  13:  1668 
• 2b Lopez R. León G. Oliva A. J. Heterocycl. Chem.  1995,  32:  1377 
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• 3a Bromination/nitration: Das S. Mittra AS. J. Indian Chem. Soc.  1978,  55:  520 
• 3b Azirine formation: Holzer W. Claramunt RM. Pérez-Torralba M. Guggi D. Brehmer TH. J. Org. Chem.  2003,  68:  7943 
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• O-Methylation was assigned based on ¹H NMR chemical shifts:
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• 14 The only other example relevant to epoxide opening is found in the reaction of pyrazolone with the intermediate derived from pyrimidone and epichlorohydrin under basic conditions, possibly proceeded via an epoxide intermediate formed in situ: Krivonogov VP. Kozlova GG. Sivkova GA. Spirikhin LV. Abdrakhmanov IB. Murinov YuI. Tolstikov GA. Russ. J. Org. Chem.  2003,  39:  257 
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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).