Myers Directed Ortho Metalation Chem 115 Reviews: Snieckus, V Chem Rev 1990, 879 Clayden, J In Chemistry of Organolithium Compounds; Rappoport, Z., Marek, I., Eds.; Wiley: Chichester, 2004; Vol 1, pp 495–646 DMG DMG RLi Relative Rates of Directed Metalation: SO2NR2, CONR, CH2NR2 > OCH3 > CH2CH2NR2, CF3, F, NR2 DMG E Li Slocum, D W.; Jennings, C A J Org Chem 1976, 41, 3653 E Gliman, H.; Bebb, R L J Am Chem Soc 1939, 61, 109 Wittig, G.; Fuhrman, G Chem Ber 1940, 73, 1197 O CONR > CONR2 > N Ar CH3 CH3 > SO2NR2, SO2NR, CH2NR, OCH3, Cl Directed metalation of anisole with n-BuLi was discovered independently in 1939–1940 by Gilman and Wittig This led to the discovery of more than 40 directing groups Beak, P.; Brown, R A J Org Chem 1982, 47, 34 Beak, P.; Tse, A.; Hawkins, J.; Chen, C.; Mills, S Tetrahedron 1983, 39, 1983 O Ar O N R N R ArO R ArN N CH3 CH3 Ar N O Ot-Bu R O Ar R O Ar Ar N R Protective groups that also serve as strong directing groups are especially useful: OR N OR N R Ar ArOCH2OCH3 Ar OR OR H O Ar O NR2 Ar N CH3 CH3 Meta oriented directing groups almost always direct metalation to the position ortho to both groups O P NR2 ArO NR2 O O S t-Bu Ar ArCF3 H O Ar CH3 CH3 NR2 O ArOCH2OCH3 ArOCH3 ArO– N ArCH2O– THF, −78 °C ~100% Cl ArF ArCl ArCH2N(CH3)2 3.0 eq n-BuLi MeI CH3 CH3 O N CH3 Cl ArN(CH3)2 Pansegrau, P D.; Rieker, W F.; Meyers , A I J Am Chem Soc 1988, 110, 7178 Dionicio Siegel, Jonathan William Medley Myers Directed Ortho Metalation Lithiation occurs ortho to the stronger directing group in cases where two lithiation sites are possible O N CH3 CH3 H3CO Ortho tolyl anion formation is facile by directed metalation Cl CH3 O sec-BuLi, TMEDA MeI THF, −78 °C Chem 115 N CH3 H3CO NR2 CH3 H3CO H3CO O THF, −78 °C CH3 97% H3CO O s-BuLi, LDA OCH3 NR2 O NHR2 THF, −78 °C CH2Li Mills, R J.; Snieckus, V J Org Chem 1989, 54, 4386 OCH3 Reitz, D B.; Massey, S M J Org Chem 1990, 55, 1375 Ethoxyvinyllithium (EVL) with HMPA shows a reversal in selectivity; the proton ortho to the methoxyl group is removed 74% Heterocycle and Vinyl Ether Metalation: Metalation of vinyl ethers and heterocycles occurs readily at the indicated positions OEt O N(i-Pr)2 MeI OCH3 N(i-Pr)2 THF, −78 → −30 °C CH3O O HMPA Li O H H CH3 Aldehydes can be transiently protected and, at the same time, transformed into a directing group by amide anion addition CHO N Li H3C H LiO OCH3 t-BuLi, −65 to °C cyclopentanone, −65 °C THF O H3CO HO HCl HO CH3 88% 98% CH3 CH3 Baldwin, J E.; Hofle, G A.; Lever, O W., Jr J Am Chem Soc 1974, 96, 7125 n-BuLi MeI Directed lithiation of a tryptamine derivative has been employed in the total synthesis of (+)-minfiensine CHO CH3 THF, −20 °C THF, −20 °C Cl N N H S Vinyl ether anions provide an acyl anion equivalent Shimano, M.; Meyers, A I J Am Chem Soc 1994, 116, 10815 H3C H N CH3 H CH3O 93% CH3 H3C N O Cl NHBoc Cl 80% N PMB n-BuLi (4 equiv) 1,2-DME −78 → 23 °C; DMF 78% Comins, D L.; Brown, J D J Org Chem 1984, 49, 1078 OH NHBoc CHO N PMB N N H H3C (+)-minfiensine Jones, S B.; Simmons, B S.; MacMillan, D W C J Am Chem Soc 2009, 131, 13606 Dionicio Siegel, Jonathan William Medley Myers Directed Ortho Metalation Chem 115 The highly hindered amide base TMPMgCl•LiCl has been shown to effect efficient directed metallation of electron-poor heteroarenes and arenes containing sensitive functional groups Metalation of pyridine is complicated by 1,2-addition of the organometallic into the pyridine ring H3C CH NH H3C CH i-PrMgCl•LiCl N MgCl•LiCl THF, °C H3C CH3 H3C CH3 BuLi H Bu N Li N R R Br R = CO2Et TMPMgCl•LiCl R −25 °C, 30 THF Br R TMPMgCl•LiCl ca.1.2 M in THF I2 88% MgCl•LiCl R R Br I Krasovskiy, A.; Krasovskaya, V.; Knochel, P Angew Chem., Int Ed 2006, 45, 2958 With appropriate directing groups, lithiation of the pyridine ring can be efficient O O OEt sec-BuLi, TMEDA I2 N OCONEt2 THF, −78 °C I N TMPMgCl•LiCl OEt °C, h THF; TsCN Cl CN Cl 76% OCONEt2 Lin, W.; Baron, O.; Knochel, P Org Lett 2006, 8, 5673 OCONEt2 N sec-BuLi, TMEDA Me3SnCl THF, −78 °C SnMe3 OCONEt2 This metallation technology has been employed iteratively in the synthesis of a fully substituted pyrimidine derivative N N TMPMgCl•LiCl Br H3CS N −55 °C, 1.5 h, THF; CH3SSO2CH3 N Br N TMPMgCl•LiCl 20 °C, min, THF; FCl2CCClF2 76% 81% H3CS N Ph Miah, M A.; Snieckus, V J Org Chem 1985, 50, 5436 Br N O Cl TMPMgCl•LiCl H3CS 20 °C, 20 min, THF; CuCN•2LiCl; PhCOCl 81% N Br N Cl Mosrin, M.; Knochel, P Org Lett 2008, 10, 2497 Dionicio Siegel, Jonathan William Medley Myers Directed Ortho Metalation Chem 115 Examples of Directed Ortho Metalation in Synthesis: t-BuLi, −78 °C H3C H3CO O H3C eq (n-BuLi-KOt-Bu) Bu3SnCl H CH3 O H3C H3CO THF, −78 °C O H CH3 O N Cl SnBu3 H3C CH3 N N CH3 N Li CHO N H OLi CH3 OCH3 N Cl n-BuLi, −23 °C THF ~100% CH3 OCH3 I2 H3C H3CO O OTBS H CH3 70% 1 eq n-BuLi −78 → °C THF CH3 CHO N CH3 N OTBDPS Br I O OTBDPS O O Et HO N Cl 78% OTBS HMPA → 23 oC H3C H O O O (S)-camptothecin Lithiation adjacent to the methoxyl group followed by trapping with the formamide shown provides an α-amino alkoxide to direct a second metalation reaction Comins, D L.; Baevsky, M F.; Hong, H J Am Chem Soc 1992, 114, 10971 CH3 H3C Carbamate directing groups can rearrange upon warming after lithiation The resulting amide can be used for a second metalation reaction CH3 O NH OCH3 O OCONEt2 N HO2C O NHCH3 sec-BuLi, TMEDA warm to 23 °C TBSCl, imidazole TBSO O O 50% OH O O Boeckman, R K., Jr.; Charette, A B.; Asberom, T.; Johnston, B H J Am Chem Soc 1987, 109, 7553 NEt2 O Calcimycin Note that treatment with t-BuLi alone failed to provide the desired anion Trapping the anion under LICKOR conditions with tin provided a substrate that could be readily converted to the corresponding organolithium reagent O O TBSO NH H HO OH O OH O OH O NEt2 sec-BuLi, TMEDA DMF THF, −78 °C CHO 70% Pancratistatin Danishefsky, S.; Lee, J Y J Am Chem Soc 1989, 111, 4829 Dionicio Siegel, Jonathan William Medley ... Myers Directed Ortho Metalation Chem 115 Examples of Directed Ortho Metalation in Synthesis: t-BuLi, −78 °C H3C H3CO O H3C eq (n-BuLi-KOt-Bu) Bu3SnCl H CH3 O H3C H3CO THF, −78 °C O H CH3 O N... °C O H CH3 O N Cl SnBu3 H3C CH3 N N CH3 N Li CHO N H OLi CH3 OCH3 N Cl n-BuLi, − 23 °C THF ~100% CH3 OCH3 I2 H3C H3CO O OTBS H CH3 70% 1 eq n-BuLi −78 → °C THF CH3 CHO N CH3 N OTBDPS Br I O OTBDPS... formation is facile by directed metalation Cl CH3 O sec-BuLi, TMEDA MeI THF, −78 °C Chem 115 N CH3 H3CO NR2 CH3 H3CO H3CO O THF, −78 °C CH3 97% H3CO O s-BuLi, LDA OCH3 NR2 O NHR2 THF, −78 °C CH2Li