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.

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

1b Katritzky AR. Maine FW. Tetrahedron  1964,  20:  299 

For the synthesis of 4-acyl/carboxyl pyrazolones, see:

2a Jensen BS. Acta Chem. Scand.  1959,  13:  1668 

2b Lopez R. León G. Oliva A. J. Heterocycl. Chem.  1995,  32:  1377 

For examples of reactions at C-4, see:

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 

4a Holzer W. Plagens B. Lorenz K. Heterocycles  1997,  45:  309 

4b Subasinghe NL. Ali F. Illig CR. Rudolph MJ. Lein S. Khalil E. Soll RM. Bone RF. Spurlino JC. Des Jarlais RL. Crysler CS. Cummings MD. Morris PE. Kilpatrick JM. Babu YS. Bioorg. Med. Chem. Lett.  2004,  14:  3043 

O-Methylation was assigned based on ¹H NMR chemical shifts:

5a Ogawa K. Terada T. Honna T. Chem. Pharm. Bull.  1984,  32:  930 

5b Bregant N. Perina I. Malnar M. Croat. Chim. Acta  1977,  49:  813 

6a Holzer W. Plagens B. Sci. Pharm.  1996,  64:  455 ; and references cited therein

6b Holzer W. Schmid E. J. Heterocycl. Chem.  1995,  32:  1341 

7a Terebenina A. Dimitrova K. Iordanov B. Chervenakov P. Borisov G. Izv. Khim.  1985,  18:  31 ; Chem. Abstr. 1986, 104, 148787

7b inventors; JP  59181259.  ; Chem. Abstr. 1985, 102, 113480

8a Khan MA. Ellis GP. Pagotto MC. J. Heterocycl. Chem.  2001,  38:  193 

8b Rachedi Y. Hamdi M. Sakellariou R. Speziale V. Synth. Commun.  1991,  21:  1189 

8c Wise LD. Butler DE. DeWald HA. Lustgarten DM. Pattison IC. Schweiss DN. Coughenour LL. Downs DA. Heffner TG. Pugsley TA. J. Med. Chem.  1987,  30:  1807 

9 Holzer W. Hahn K. J. Heterocycl. Chem.  2003,  40:  303 

10a Juršić B. Bregant N. Synth. Commun.  1989,  19:  2087 

10b Holzer W. Hahn K. Brehmer T. Claramunt RM. Pérez-Torralba M. Eur. J. Org. Chem.  2003,  1209 

11a Sanghvi YS. Upadhya KG. Dalley NK. Ronibs RK. Revankar GR. Nucleosides Nucleotides  1987,  6:  737 

11b Anderson J. Cottam HB. Larson SB. J. Heterocycl. Chem.  1989,  27:  439 

11c Esanu A. inventors; BE  902231.  ; Chem. Abstr. 1986, 104, 110121

12a Alberty JE. Hukki J. Laitinen P. Myry J. Arzneim. Forsch.  1967,  17:  214 ; Chem. Abstr., 1967, 67, 43734

12b Sammour A. Raouf AA.-E. Elkasaby M. Hassan MA. Egypt. J. Chem.  1972,  15:  429 

13 Chiba P. Holzer W. Landau M. Bechmann G. Lorenz K. Plagens B. Hitzler M. Richter E. Ecker G. J. Med. Chem.  1998,  41:  4001 

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 

15 Duprez V. Heumann A. Tetrahedron Lett.  2004,  45:  5697 

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).

19 Overman LE. Flippin LA. Tetrahedron Lett.  1981,  22:  195 

20 For an example of epoxide activation with AlMe₃, see: Schreiber SL. J. Am. Chem. Soc.  1980,  102:  6163 

21a Chini M. Croti P. Macchia F. Tetrahedron Lett.  1990,  31:  4661 

21b Schoffers E. Tran SD. Mace K. Heterocycles  2003,  60:  769 

21c Saladino R. Ciambecchini U. Hanessian S. Eur. J. Org. Chem.  2003,  4401