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On the Kinetic and Thermodynamic Reactivity of Lithium Di(alkyl)amidozincate Bases in Directed Ortho Metalation

2007; American Chemical Society; Volume: 129; Issue: 42 Linguagem: Inglês

10.1021/ja072118m

1943-2984

Yoshinori Kondo, J. V. Morey, Jacqueline C. Morgan, Hiroshi Naka, Daisuke Nobuto, Paul R. Raithby, Masanobu Uchiyama, Andrew E. H. Wheatley,

Synthesis of heterocyclic compounds

Sequential reaction of HTMP (= 2,2,6,6-tetramethylpiperidine) with nBuLi and Et2Zn affords unsolvated polymer chains of EtZn(μ-Et)(μ-TMP)Li 6. The scope of this reagent in directed ortho metalation (DoM) chemistry has been tested by its reaction with N,N-diisopropylnaphthamide in THF to give EtZn(μ-C10H6C(O)NiPr2-2)2Li·2THF 7. Data reveal that 6 has undergone reaction with 2 equiv of aromatic tertiary amide and imply that it exhibits dual alkyl/amido basicity. DFT calculations reveal that direct alkyl basicity is kinetically disfavored and instead point to a stepwise mechanism whereby 6 acts as an amido base, liberating HTMP during the first DoM event. Re-coordination of the amine at lithium then incurs the elimination of EtH. Reaction of the resulting alkyl(amido)(arylamido)zincate with a second equivalent of N,N-diisopropylnaphthamide eliminates HTMP and affords 7. Both DoM steps involve the exhibition of amido basicity and each reveals a low kinetic barrier to reaction. Understanding of this reaction sequence is tested by treating 6 with N,N-diisopropylbenzamide in THF. On the basis of theory and experiment, the presence of THF solvent (in place of stronger Lewis bases) combined with the use of a sterically less congested aromatic amide is expected to encourage threefold, stepwise reaction. Isolation and characterization of the resulting tripodal zincate Zn(μ-C6H4C(O)NiPr2-2)3Li·THF 8 bears this out and suggests a significant new level of control in zincate-induced DoM chemistry through the combination of experiment and DFT studies.