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Directed ortho Metalation (DOM)

The reaction of an alkyllithium compound with an arene bearing a "Directed Metalation Group" (DMG) normally leads to an ortho-metalated intermediate. Good DMG's are strong complexing or chelating groups that have the effect of increasing the kinetic acidity of protons in the ortho-position.

The ortho-metalated intermediate can be reacted with a variety of electrophiles, after which the DMG can be retained if desired, converted to a different functional group, or in some cases removed.


Mechanism of Directed Ortho Metalation

The DMG does not necessarily have to be inert:

strong DMGs: -CON-R, -CONR2 -N-COR, -N-CO2R
-OCONR2, -OMOM
-SO3R
-CH=NR -SO2NR2
-CN -SO2tBu
moderate -CF3 -NR2
-NC
-OMe
-F
-Cl
weak -CH2O- -O-
-CC- -S-
Ph

Recent Literature


The Tetraethylphosphorodiamidate (OP(O)(NEt2)2) Directed Metalation Group (DMG). Directed ortho and Lateral Metalation and the Phospha Anionic Fries Rearrangement
M. Alessi, J. J. Patel, K. Zumbansen, V. Snieckus, Org. Lett., 2020, 22, 2147-2151.


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.


Redox Cyclization of Amides and Sulfonamides with Nitrous Oxide for Direct Synthesis of Heterocycles
Z. Lai, C. Wang, J. Li, S. Cui, Org. Lett., 2020, 22, 2017-2021.