Mixed alkylamido aluminate as a kinetically controlled base.
The mechanisms by which directed ortho metalation (DoM) and postmetalation processes occur when aromatic compounds are treated with mixed alkylamido aluminate i-Bu3Al(TMP)Li (TMP-aluminate 1; TMP = 2,2,6,6-tetramethylpiperidide) have been investigated by computation and X-ray diffraction. Sequential reaction of ArC(=O)N(i-Pr)2 (Ar = phenyl, 1-naphthyl) with t-BuLi and i-Bu3Al in tetrahydrofuran affords [2-(i-Bu3Al)C(m)H(n)C(=O)N(i-Pr)2]Li x 3 THF (m = 6, n = 4, 7; m = 10, n = 6, 8). These data advance the structural evidence for ortho-aluminated functionalized aromatics and represent model intermediates in DoM chemistry. Both 7 and 8 are found to resist reaction with HTMP, suggesting that ortho-aluminated aromatics are incapable of exhibiting stepwise deprotonative reactivity of the type recently shown to pertain to the related field of ortho zincation chemistry. Density functional theory calculations corroborate this view and reveal the existence of substantial kinetic barriers both to one-step alkyl exchange and to amido-alkyl exchange after an initial amido deprotonation reaction by aluminate bases. Rationalization of this dichotomy comes from an evaluation of the inherent Lewis acidities of the Al and Zn centers. As a representative synthetic application of this high kinetic reactivity of the TMP-aluminate, the highly regioselective deprotonative functionalization of unsymmetrical ketones both under mild conditions and at elevated temperatures is also presented.
Naka
Hiroshi
H
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan. naka@mail.pharm.tohoku.ac.jp
Morey
James V
JV
Haywood
Joanna
J
Eisler
Dana J
DJ
McPartlin
Mary
M
García
Felipe
F
Kudo
Hironaga
H
Kondo
Yoshinori
Y
Uchiyama
Masanobu
M
Wheatley
Andrew E H
AE
D000478:Alkylation; D000535:Aluminum / Q000737:chemistry*; D000577:Amides / Q000737:chemistry*; D018360:Crystallography, X-Ray; D007536:Isomerism; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure
D000577:Amides; D000535:Aluminum