Isoprene-mediated lithiation of 1-alkylimidazoles: Chiral induction of the alkyl substituent

Letters in Organic Chemistry

Volumn 7, Issue 5, 2010, Pages 373-376

  Pastor, Isidro M ^a   Torregrosa, Rosario ^a   Yus, Miguel ^a  

^a UNIVERSITY OF ALICANTE   (Spain)

Author keywords

Imidazole derivatives; Isoprene mediated lithiation; Lithium; Nucleophilic addition

Indexed keywords

EID: 77955967495     PISSN: 15701786     EISSN: None     Source Type: Journal    
DOI: 10.2174/157017810791514850     Document Type: Article

References (31)

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22. Torregrosa, R.; Pastor, I. M.; Yus, M. Isoprene-catalyzed lithiation of imidazole: synthesis of 2-(hydroxyalkyl)-and 2-(aminoalkyl)imidazoles. Tetrahedron, 2005, 61, 11148-11155.
23. Torregrosa, R.; Pastor, I. M.; Yus, M. Isoprene-promoted lithiation of 1-phenylimidazole. ARKIVOC, 2008, vii, 8-15.
24. Torregrosa, R.; Pastor, I. M.; Yus, M. Isoprene-catalysed lithiation: deprotection and functionalisation of imidazole derivatives. Tetrahedron, 2007, 63, 947-952.
25. A part of this study was preliminary presented: Torregrosa, R.; Pastor, I. M.; Yus, M. Isoprene-mediated lithiation of chiral Nalkylimidazoles. ECSOC-11, 2007, communication [a005] (http://www.mdpi.org/ecsoc-11).
26. General procedure for preparation of imidazoles: A solution of the corresponding amine (10 mmol) and ammonia (25% aq., 10 mmol, 0.75 mL) in MeOH (4 mL) and a solution of glyoxal (trimer dihydrate, 10 mmol, 0.70 g) and formaldehyde (36% aq., 10 mmol, 0.77 mL) in MeOH (4 mL) and water (4 mL) were slowly and simultaneously added to a round bottom flask with MeOH (7 mL) heated to 50 °C. After the addition was finished, the reaction mixture was heated to 75 °C during 3 h. The reaction mixture was cooled down, diethyl ether and water were added in equal portions until two phases were observed and the aqueous phase was extracted with Et2O (3×10 mL). All the organic phases were dried over anhydrous magnesium sulphate. The solvents were evaporated under reduced pressure and the corresponding imidazoles were purified by column chromatography (silica gel, mixtures of hexane and ethyl acetate).
27. Different amounts of isoprene have been used depending on the substrate, see ref. 6-8. For these cases it was observed and improvement of the yield in the final product by increasing the isoprene amount up to 200% molar, so this amount has been employed for all the reactions.
28. General procedure for the isoprene-mediated lithiation: The corresponding imidazole (2 mmol) was added to a suspension of lithium powder (6 mmol, 0.042 g) and isoprene (4 mmol, 0.404 mL) in THF (5 mL) at room temperature. The mixture was stirred for 1 hour and then the corresponding electrophile (2.2 mmol) was added, continuing the stirring during 45 min at the same temperature. The reaction mixture was hydrolyzed with water (10 mL), extracted with ethyl acetate (3×10 mL), and the resulting organic phase was dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure (15 Torr), the resulting crude was purified by column chromatography (silica gel, mixtures of hexane and ethyl acetate) or by recrystallization.
29. Imidazoles 12 and 13 were respectively isolated with 70% and 44% yield after column chromatography (silica gel, hexane/ethyl acetate mixtures).
30. The N-benzyl substituent is not stable under isoprene-mediated lithiation reaction: for the stability of N-substituted imidazoles under these conditions see ref. 8.
31. 1-[1-(1-Cyclohexylethyl)-1H-imidazol-2-yl]-2,2-dimethylpropan-1-ol (14). [Diastereoisomer 1]: Colorless solid; m.p. 72-74 °C; [α]D20 = +3.6 (c 2.4, CH2Cl2); tr 15.33; Rf 0.35 (hexane/EtOAc 2:1); ν (KBr) 3660-3019 (OH); δH (400 MHz, CDCl3): 0.84-0.92, 0.98, 1.07, 1.20-1.26, 1.42-1.44, 1.65, 1.76-1.80, 1.84-1.88 [1H, 10H, 3H, 1H, 4H, 2H, 1H and 1H, 8m, 5×Ch2 and CH, CH3CH and C(CH3)3], 3.42 (1H, br s, OH), 3.88-3.92 (1H, m, CHCH3), 4.36 (1H, s, CHOH), 6.85, 7.03 (1H and 1H, 2s, NCHCHN); δC (100 MHz, CDCl3): 18.8 (CH3CH), 25.6 [3C, C(CH3)3], 25.8, 25.9, 25.9, 29.3, 30.0 (5×CH2), 37.0 [C(CH3)3], 45.3 (CH), 56.7 (CHCH3), 73.2 (CHOH), 115.5, 127.3 (NCHCHN), 149.1 (NCN); m/z 265 (M++1, 1%), 264 (4), 208 (12), 207 (76), 97 (100), 69 (20). HRMS calculated for C16H28N2O 264.2202, found 264.2210. [Diastereoisomer 2]: Colorless solid; m.p. 30-35 °C; [α]D20 = +10.5 (c 2.9, CH2Cl2); tr 15.44; Rf 0.29 (hexane/EtOAc 2:1); ν (KBr) 3800-3024 (OH); δH (400 MHz, CDCl3): 0.82-0.91, 1.07, 1.14, 1.26, 1.33-1.34, 1.46-1.49, 1.68, 1.81-1.84, 1.91-1.94 [1H, 10H, 2H, 1H, 3H, 1H, 3H, 1H and 1H, 9m, 5×CH2 y CH, CH3CH and C(CH3)3], 2.58 (1H, br s, OH), 4.00-4.07 (1H, m, CHCH3), 4,37 (1H, s, CHOH), 6.87, 7.02 (1H and 1H, 2s, NCHCHN); δC (100 MHz, CDCl3): 20.7 (CH3CH), 26.0, 26.1, 26.1, 30.0, 30.4 (5×CH2), 26.2 [3C, C(CH3)3], 36.5 [C(CH3)3], 43.7 (CH), 56.9 (CHCH3), 73.6 (CHOH), 115.7, 127.5 (NCHCHN), 148.4 (NCN); m/z 264 (M+, 4%), 208 (12), 207 (69), 99 (10), 97 (100), 69 (24), 55 (10). HRMS calculated for C16H28N2O 264.2202, found 264.2192.