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邻位金属化反应(Directed ortho Metalation)

烷基锂化合物和带有邻位导向基团 (Directed Metalation Group--DMG)的芳烃反应得到邻位金属中间体。好的邻位导向基团有很强的配位或螯合效应,导致邻位氢的酸性增强。

邻位金属中间体可以和各种亲电试剂反应,得到的产物的DMG可以复原,转化为其他基团,或直接除去。

一般情况下此类反应都是低温,强碱性条件,几乎完全的邻位选择性是此反应的特点。


反应机理

电子密度大的取代基与锂的相互作用,使得相邻的位置被选择性锂化。

DMG没必要必须是惰性基团:

强 DMGs:

-CON-R, -CONR2,

-N-COR, -N-CO2R


-OCONR2, -OMOM

-SO3R


-CH=NR

-SO2NR2


-CN

-SO2tBu

中等强度

-CF3

-NR2



-NC



-OMe



-F



-Cl

弱导向基团

-CH2O-

-O-


-CC-

-S-


Ph



反应实例


Efficient Two-Step Synthesis of Salicylaldehydes via Directed ortho-Lithiation of in situ N-Silylated O-Aryl N-Isopropylcarbamates
M. Kauch, D. Hoppe, Synthesis2006, 1575-1577.







Directed Ortho-Metalation of Unprotected Benzoic Acids. Methodology and Regioselective Synthesis of Useful Contiguously 3- and 6-Substituted 2-Methoxybenzoic Acid Building Blocks
T.-H. Nguyen, A.-S. Castanet, J. Mortier, Org. Lett.20068, 765-768.







Facile Double-Lithiation of a Transient Urea: Vicarious ortho-Metalation of Aniline Derivatives
C. E. Houlden, G. C. Lloyd-Jones, K. I. Brooker-Milburn, Org. Lett.201012, 3090-3092.







Selective Ortho and Benzylic Functionalization of Secondary and Tertiary p-Tolylsulfonamides. Ipso-Bromo Desilylation and Suzuki Cross Coupling Reactions
S. L. MacNeil, O. B. Familoni, V. Snieckus, J. Org. Chem200166, 3662-3670.







Palladium-Catalyzed Aryl-Aryl Cross-Coupling Reaction Using ortho-Substituted Arylindium Reagents
M. A. Pena, J. P. Sestelo, L. A. Sarandeses, J. Org. Chem.200772, 1271-1275.







High Temperature Metalation of Functionalized Aromatics and Heteroaromatics using (tmp)2Zn·2MgCl2·2LiCl and Microwave Irradiation
S. Wunderlich, P. Knochel, Org. Lett.200810, 4705-4707.







One-Pot Synthesis of Phthalazines and Pyridazino-aromatics: A Novel Strategy for Substituted Naphthalenes
S. N. Kessler, H. A. Wegner, Org. Lett.201214, 3268-3271.






【 J. Am. Chem. Soc. 1988110, 7178】






J. Org. Chem. 1984, 49, 1078】






J. Am. Chem. Soc. 1992, 114, 10971】





To a stirred solution of 3-phenylsydnone (1) (0.25 g, 1.54 mmol) in dry THF (100 ml) at

-78℃ under an atmosphere of dry nitrogen gas was added N, N, N’,

N’-tetramethylethylenediamine (0.29 ml, 1.93 mmol) then n-butyllithium (2.31 ml, 3.47

mmol, 15 M in pentane) dropwise. After 0.5 h, the appropriate

2-chloro-N-methoxy-N-methylacetamide (1.93 mmol) was added to the golden yellow

solution and, after a additional 1h, the mixture was quenched with aqueous hydrochloric acid

(100ml, 10% v/v) then extracted with dichloromethane (3*100 ml). the combined organic

layers were dried (MgSO4) and the solvent removed in vacuo to afford the corresponding

o-acylated sydnone 4as an oil which was puriied by colum chromatography to afford colorless

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