http://www.chemistrymag.org/cji/2000/024022ne.htm |
Apr.24, 2000 Vol.2 No.4 P.22 Copyright |
Chen Hu, Cao Ruzhen, Liu Lunzu
(National Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, China)
Received
Jan. 17, 2000; Supported by the Natural Science Foundation of China. (29972024)Abstract The benzylation of 3(5)-methyl-5(3)-phenylpyrazole under the influence of KOH-Al2O3 or KF- Al2O3 has been investigated.
Keywords benzylation, pyrazoles, alkylation, regioselectivity
In general, both nitrogen atoms of pyrazole
ring could be alkylated to provide a mixture of isomers. Depending on the temperature and
the base used, the mixture with different proportions of N-alkylated products are
obtained, thus, the alkylation of pyrazoles with alkyl halides in the presence of
inorganic base is non-selective.[1,2] The benzylation of some pyrazoles bearing
bulky substituents under the influence of bases supported by inorganic solid, such as
KOH-Al2O3, KF-Al2O3 and CsF-Al2O3
has been investigated. The results showed good regioselectivity[3] and prompted
us to explore the benzylation of sterically less shielded pyrazoles.
The first target of our investigation was the benzylation of
3(5)-methyl-5(3)-phenylpyrazole in the presence of different bases supported by Al2O3
in different solvents, and a general, simple and cheap method was found for regioselective
benzylation of pyrazoles. In order to judge the regioselectivity, the products also have
been prepared in the presence of bases without support. We have run the following reaction
in the presence of KOH and ethyl acetate to lead to the formation of both isomers 2 and 3
in a ratio of 65:35. If Et3N was used and 1,4-dioxane as solvent, the reaction
mixture was heated at 80°C for 10h, the total yield of 2 and 3 was 75%, the ratios of 2
and 3 was 73:27. Under the same reaction conditions, when KF and 1,4-dioxane was used, the
total yield of 2 and 3 was 51%, the ratio was 75:25. In contrast, when KOH or KF supported
by aluminum oxide was used, the regioselectivity is increased significantly. As shown in
the Table, the order of efficiency of the bases was KOH-Al2O3>KF-Al2O3
>KOH, and the solvent effect order was 1,4-dioxane>DMF, acetone>THF>ethyl
acetate; while acetonitrile was used decomposition might happen.
Table 1. Benzylation of 3(5)-methyl-5(3)-phenylpyrazole in the presence of different bases and solvents
Base |
Solvent (ml) |
Ratio of 2:3 a |
Yield b(%) |
KOH |
Ethyl acetate(30) |
65:35 |
98 |
KOH |
DMF(20) |
70:30 |
99 |
KOH |
1,4-Dioxane(15) |
77:23 |
99 |
KF |
1,4-Dioxane(15) |
75:25 |
51 |
Et3N |
1,4-Dioxane(15) |
73:27 |
75 |
KF-Al2O3 |
Ethyl acetate(30) |
77:23 |
98 |
KF-Al2O3 |
Acetone(30) |
81:19 |
99 |
KF-Al2O3 |
THF(20) |
76:24 |
98 |
KF-Al2O3 |
DMF(20) |
91:9 |
100 |
KF-Al2O3 |
1,4-Dioxane(15) |
90:10 |
100 |
KOH-Al2O3 |
Ethyl acetate(30) |
86:14 |
99 |
KOH-Al2O3 |
Acetone(30) |
93:7 |
99 |
KOH-Al2O3 |
THF(20) |
83:16 |
98 |
KOH-Al2O3 |
DMF(20) |
88:12 |
100 |
KOH-Al2O3 |
1,4-Dioxane(15) |
100:0 |
100 |
of pyrazole rings in the 1H NMR spectra (CDCl3);
b Total yield of isomers 2 and 3.
The observed regioselectivity could be rationalized by an adsorptive substrate mechanism. While the aryl substituent is adsorbed on the Al2O3-surface, the pyrazole ring twists out of the plane of the aryl group, the alkylation takes place at the nitrogen of the ortho-position of the methyl group (Scheme).
On the other hand, this reaction showed an obvious solvent effect. 1,4-Dioxane, DMF and acetone support the selectivity owing to their strong polarity.
Scheme: Mechanism of alkylation on inorganic solid supported bases
1 EXPERIMENTAL1H NMR, NOE spectra were taken on a Bruker AC-P 200 spectrometer. Elemental analyses were run on a Yana MT-3 instrument.Pyrazole 1[4], KOH-Al2O3[5], KF-Al2O3[6] were prepared according to the literatures.
1.1 General Procedure of N-benzylation of Pyrazole 1.
Pyrazole 1 (0.079g, 0.5mmol) was placed in a 50ml flask in which the solvent as indicated in the Table was used. Then 12-fold excess of inorganic solid supported base (6mmol, KOH: 0.34g, KF-Al2O3: 1.57g, KOH-Al2O3: 1.16g) was added. After stirring at room temperature for 5 min., 0.2ml (0.28g, 1.6mmol) of benzyl bromide was added with a syringe. The mixture was stirred at room temperature for 10~20h. Then it was filtered and the filter cake was washed with 15ml solvent. The solvent was then removed from the filtrate and the oily residue was dissolved in 50ml of ethyl acetate. Then 50ml of water and 5ml of triethylamine were added and the mixture was stirred vigorously for 1h. The two layers were separated and the organic layer was washed with water (30ml´ 3) and then dried over anhydrous MgSO4. After removal of the solvent, the product was dried under vacuum for 0.5h and then investigated by 1H NMR (CDCl3) (See Table).
Each pure isomer was obtained by preparative chromatography (eluent: CH2Cl2-Petr.ether-Et2O 30:30:1) and identified by 1H NMR, NOE, elemental analysis.
Compound 2, mp. 88-89°C. 1H NMR (CDCl3): d 2.21(s, 3H, CH3), 5.34(s, 2H, CH2), 6.38(s, 1H, 4-C-H), 7.11~7.83(m, 10H, C6H5). (Found: C, 81.95; H, 6.33; N, 11.40. C17H16N2 calcd. C, 82.26; H, 6.45; N, 11.29.)
Compound 3, mp. 74-75°C. 1H NMR (CDCl3): d 2.34(s, 3H, CH3), 5.29(s, 2H, CH2), 6.15(s, 1H, 4-C-H), 7.03~7.38(m, 10H, C6H5). (Found: C, 81.71; H, 6.70; N, 11.10. C17H16N2 calcd. C, 82.26; H, 6.45; N, 11.29.)
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