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Directed ortho metalation ( DoM) is an adaptation of electrophilic aromatic substitution in which attach themselves exclusively to the ortho- position of a directing group or DMG through the intermediary of an aryllithium compound. The DMG interacts with lithium through a hetero atom. Examples of DMG's are the methoxy group, a tertiary amine group and an amide group. The compound can be produced by directed lithiation of anisole. (1979). 9780471264187 ISBN 9780471264187
The general principle is outlined in scheme 1. An aromatic ring system with a DMG group 1 interacts with an alkyllithium such as N-Butyllithium in its specific aggregation state (hence (R-Li)n) to intermediate 2 since the hetero atom on the DMG is a Lewis base and lithium the Lewis acid. The very basic alkyllithium then deprotonation the ring in the nearest ortho- position forming the aryllithium 3 all the while maintaining the acid-base interaction. An electrophile reacts in the next phase in an electrophilic aromatic substitution with a strong preference for the lithium ipso position replacing the lithium atom.
Ordinary electrophilic substitutions with an activating group show preference for both the ortho and para position, this reaction demonstrates increased regioselectivity because the ortho position alone is targeted.
This reaction type was reported independently by Henry Gilman and Georg Wittig around 1940. Relative Reactivities of Organometallic Compounds. XX.* Metalation Henry Gilman, Robert L. Bebb J. Am. Chem. Soc.; 1939; 61(1); 109-112. Georg Wittig et al. Chem. Ber. 1940, 73, 1197
The method has also been applied to the synthesis of enantiopure benzyl amines ortho-Metalation of Enantiopure Aromatic Sulfoxides and Stereocontrolled Addition to Imines Nicolas Le Fur, Ljubica Mojovic, Nelly Plé, Alain Turck, Vincent Reboul, and Patrick Metzner J. Org. Chem.; 2006; 71(7) pp 2609 - 2616; Abstract in scheme 3,Scheme 3. Reaction scheme: reaction of iodobenzene with N-Butyllithium and (S)-tert-butyl tert-butanethiosulfinate to enantiopure an sulfoxide followed by DOM reaction initiated again by n-butyllithium with electrophile N-tosylimine. The sulfoxide group is removed by hydrogenation with Raney nickel. ts is a tosyl group, ee stands for enantiomeric excess which involves ortho-lithiation of tert-butyl phenyl sulfoxide. On approach to the lithium intermediate, the bulky tosyl group on the imine electrophile is responsible for the asymmetric induction taking place.
In another application Contra-Friedel–Crafts tert-butylation of substituted aromatic rings via directed metallation and sulfinylation Jonathan Clayden, Christopher C. Stimson and Martine Keenan Chemical Communications, 2006, 1393 - 1394 Abstract DOM is applied in placing a bulky tert-butyl group in an ortho position ( scheme 4). The lithiation is a nucleophilic aromatic substitution and the subsequent reaction to the sulfoxide an electrophilic aromatic substitution. In the final step tert-butyllithium acts as a nucleophile in another nucleophilic aromatic substitution through an anionic intermediate.
D oM has also been applied combined with a Suzuki reaction in a one-pot synthesis:Directed ortho Metalation-Boronation and Suzuki-Miyaura Cross Coupling of Pyridine Derivatives: A One-Pot Protocol to Substituted Azabiaryls Manlio Alessi, Andrew L. Larkin, Kevin A. Ogilvie, Laine A. Green, Sunny Lai, Simon Lopez, and Victor Snieckus J. Org. Chem.; 2007; 72(5) pp 1588 - 1594. In this sequence the starting material nicotinamide is lithiated, then reacted with triisopropoxyborane to a boronate ester, then reacted with pinacol and finally reacted with iodobenzene and Tetrakis(triphenylphosphine)palladium(0)
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