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Article

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

Supporting Info

Yoshinori Kondo,^† James V. Morey,^‡ Jacqueline C. Morgan,^‡ Hiroshi Naka,^†^§ Daisuke Nobuto,^# Paul R. Raithby, Masanobu Uchiyama,*^#^§ and Andrew E. H. Wheatley*^‡;

Contribution from the Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki Aza Aoba 6-3, Aoba-ku, Sendai 980-8578, Japan, Department of Chemistry, Cambridge University, Lensfield Road, Cambridge, CB2 1EW, U.K., Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan, Advanced Elements Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan, Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, U.K., and PRESTO, Japan Science and Technology Agency (JST)

J. Am. Chem. Soc., 2007, 129 (42), pp 12734–12738

DOI: 10.1021/ja072118m

Publication Date (Web): October 2, 2007

†

Tohoku University.

‡

Cambridge University.

PRESTO, JST.

The University of Tokyo.

RIKEN.

University of Bath.

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, uchi_yama@riken.jp, ; , aehw2@cam.ac.uk

Abstract

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.