Directed ortho metalation

Examples

DOM has traditionally been applied to tertiary anilines and benzyl amines.

The method has also been applied to the synthesis of enantiopure benzyl amines in scheme 3, 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 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.

DoM has also been applied combined with a Suzuki reaction in a one-pot synthesis:

Thiophenol derivatives

DOM has also been used with thiophenols to prepare compounds that are useful as hindered ligands.

Related reaction

Directed metallation is not limited to lithium intermediates or even to an ortho preference. In one study *Directed meta-Metalation Using Alkali-Metal-Mediated Zincation * David R. Armstrong, William Clegg, Sophie H. Dale, Eva Hevia, Lorna M. Hogg, Gordon W. Honeyman, Robert E. Mulvey Angewandte Chemie International Edition Volume 45, Issue 23, Pages 3775 - 3778 2006 it is found that the reaction product of N,N-dimethylaniline with a complex of TMEDA, sodium salt of TMP and di-tert-butylzinc is a meta zincated complex as a stable crystalline compound. This complex reacts with electrophilic iodine to N,N-dimethyl-3-iodoaniline:

References

References

1. (September 1990). "Directed ortho metalation. Tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics". Chemical Reviews.
2. (1979). "Organic Reactions".
3. ''Relative Reactivities of Organometallic Compounds. XX.* Metalation'' [[Henry Gilman]], Robert L. Bebb [[J. Am. Chem. Soc.]]; '''1939'''; 61(1); 109-112. {{doi. 10.1021/ja01870a037
4. [[Georg Wittig. G. Wittig]] et al. [[Chem. Ber.]] '''1940''', 73, 1197
5. (2015). "Directed lithiation of simple aromatics and heterocycles for synthesis of substituted derivatives". Arkivoc.
6. J. V. Hay And T. M. Harris "Dimethylamino-5-methylphenyl)diphenylcarbinol" Org. Synth. 1973, volume 53, 56. {{doi. 10.15227/orgsyn.053.0056
7. ''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; [https://dx.doi.org/10.1021/jo052358p Abstract]
8. Scheme 3. Reaction scheme: reaction of [[iodobenzene]] with [[N-Butyllithium. ''n''-butyllithium]] and (S)-tert-butyl tert-butanethiosulfinate to enantiopure an [[sulfoxide]] followed by DOM reaction initiated again by n-butyllithium with [[electrophile. electrophilic]] N-tosylimine. The sulfoxide group is removed by [[hydrogenation]] with [[Raney nickel]]. ts is a [[tosyl]] group, ee stands for [[enantiomeric excess]]
9. ''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 [https://dx.doi.org/10.1039/b600181e Abstract]
10. 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. {{doi. 10.1021/jo0620359
11. 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)]]
12. Directed ortho-lithiation of lithium thiophenolate. New methodology for the preparation of ortho-substituted thiophenols and related compounds Garret D. Figuly, Cynthia K. Loop, J. C. Martin [[J. Am. Chem. Soc.]]; '''1989'''; 111 pp 654-658 {{doi. 10.1021/ja00184a038. Ortho-Lithiothiophenol Equivalents: Generation, Reactions and Applications in Synthesis of Hindered Thiolate Ligands Eric Block, Venkatachalam Eswarakrishnan, Michael Gernon, Gabriel Ofori-Okai, Chantu Saha, Kaluo Tang, Jon Zubieta [[J. Am. Chem. Soc.]]; '''1989'''; 111 pp 658-665. {{doi. 10.1021/ja00184a039. Directed lithiation of arenethiols Keith Smith, Charles M. Lindsay, Gareth J. Pritchard [[J. Am. Chem. Soc.]]; '''1989'''; 111 pp 665-669; {{doi. 10.1021/ja00184a040. 2-Phosphino- and 2-Phosphinyl-benzenethiols: New Ligand Types Eric Block, Gabriel Ofori-Okai and Jon Zubieta [[J. Am. Chem. Soc.]]; '''1989'''; 111 pp 2327-2329; {{doi. 10.1039/B511827A
13. Solvent [[hexane]] reaction at [[room temperature]]. Selected bond lengths in 2: Zn-C bond 203.5 pm in plane with aryl plane, Na-C bond 269 pm at 76° to aryl plane