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- |
-C三C- | -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, Synthesis, 2006, 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., 2006, 8, 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., 2010, 12, 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. Chem, 2001, 66, 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., 2007, 72, 1271-1275.
High Temperature Metalation of Functionalized Aromatics and Heteroaromatics using (tmp)2Zn·2MgCl2·2LiCl and Microwave Irradiation
S. Wunderlich, P. Knochel, Org. Lett., 2008, 10, 4705-4707.
One-Pot Synthesis of Phthalazines and Pyridazino-aromatics: A Novel Strategy for Substituted Naphthalenes
S. N. Kessler, H. A. Wegner, Org. Lett., 2012, 14, 3268-3271.
【 J. Am. Chem. Soc. 1988, 110, 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
crystals. Yield 86%.
【Tetrahedron Lett.; EN; 39; 12; 1998; 1509-1512】
参考文献
一、Organic Chemistry Portal：http://www.organic-chemistry.org/namedreactions/directed-ortho-metalation.shtm
二、化学空间：https://cn.chem-station.com/reactions/%e5%8f%96%e4%bb%a3%e5%8f%8d%e5%ba%94/2014/06/%e9%82%bb%e4%bd%8d%e9%87%91%e5%b1%9e%e5%8c%96-directed-ortho-metalation.html
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