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Soluble polymer-supported synthesis of pyrazoles via 1,3-dipolar cycloaddition strategy
Xu-Feng Lin,
Yan-Guang Wang,
Han-Feng Ding,
Xu-Feng Lin
Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, China
Search for more papers by this authorYan-Guang Wang
Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, China
Search for more papers by this authorHan-Feng Ding
Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, China
Search for more papers by this authorXu-Feng Lin,
Yan-Guang Wang,
Han-Feng Ding,
Xu-Feng Lin
Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, China
Search for more papers by this authorYan-Guang Wang
Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, China
Search for more papers by this authorHan-Feng Ding
Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, China
Search for more papers by this authorAbstract
Rapid parallel liquid-phase synthesis of pyrazoles has first been developed. The 1,3-dipolar cycloaddition between nitrilimines generated in situ and soluble polymer-supported alkynyl or alkenyl dipolarophiles in parallel one-pot fashion gave the corresponding PEG-supported regioisomeric pyrazoles or regiospecific pyrazolines. The latter was assuredly oxidated by DDQ to PEG-supported regiospecific pyrazoles. Cleavage from the support under mild conditions afforded pyrazoles in good yields and high purity.
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- 12 Typical procedure for synthesis of pyrazole 9a: after combining 1 mmol of benzaldehyde, 1 mmol of 4-fluorophenylhydraxine hydrochloride and 1 mmol of trioctylamine in 8 mL of toluene at room temperature for 30 min under N2+ 1 mmol of N-bromosuccinimide was partly added at 0 °C and the mixture was stirred for 30 min at the same temperature. Then, 0.25 mmol of PEG-supported acry late 6 and 1 mmol of moctylamine were added in one pornon, and the mixture was stu-red for 24 h at 100 °C. Upon compfetion of the reaction, 30 mL of cold diethyl ether was slowly added to the reaction mixture to precipitate the PEG-bound pyrazoline 7a. 1H NMR (500 MHz, CDCl3) S : 3.50–3.80 (m, pyrazoline cyclic-4-H and PEG backbone), 4.33 (t, J=5 Hz, 2H, PEG-O-CH2OCO), 4.80 (dd, J = 6.9, 12.7 Hz, lH), 6.98 (t, J=6.8 Hz, 2H), 7.07–7–.10 (m, 2H), 735–7.41 (m, 3H), 7.70 (d, J=7.3 Hz, 2H). 0.75 mmol of DDQ was added to 7a in 5 mL of CH2C12 under N2 and the mixture was stirred at room temperature for 24 h. Upon completion of the reaction, 40 mL of cold diethyl ether was slowly added to the reaction mixture to precipitate the PEG-bound pyrazole 8a. 1H NMR (500 MHz, CDC13) Δ: 3.50–3–.80 (m, PEG backbone, OCH2CH2O), 4.37 (f, J=5 Hz, 2H, PEG-O-CH2OCO), 7.17 (t, J=8.4 Hz, 2H), 7.32–7–.36 (m, 2H), 7.43 (t, J=8.7 Hz, 2H), 7.46–7–.49 (m, 2H), 7.86 (d, J=7.3 Hz, 2H), 8a was treated with 0.1 N MeONa in anhydrous methanol (5 mL) at room temperature. After 6 h of reaction, the detached PEG-OH was precipitated by adding cold diethyl ether (30 mL). The polymer was filtered, and the combined filtrate was flash passed through a short column to remove a trace amount of PEG and MeONa The final compound was dried to offer the corresponding crude product 9a. Spetwal data of representative compound 9a are as follows: 1H NMR (500 MHz, CDC13) Δ: 3.83 (s, 3H). 7.18 (t, J=8.4 Hz, 2H), 7.32 (s, lH), 7.36 (t, J=7.2 Hz. lH), 7.43 (t, J=8.7 Hz. 2H), 7.46–7–.49 (m, 2H), 7.86 (d, J =7.3 Hz, 2H);13C NMR (125 MHz. CDC13) Δ: 52.4, 109.8, 115.7, 115.9, 126.0, 128.2, 128.3, 128.8, 129.0, 132.2, 134.5, 136.6, 151.9, 159.7, 163.8; EMS (m/z): 296; HRMS calcd for C17H14FN2O2 ([M+H]+) 297.0961, found 297.0965.
