A R T I C L E S
Wiedemann et al.
Results
conditions were established with LiTMP at normal concentra-
tions (0.04-0.40 M) by restricting the epoxide concentration
to e0.004 M. “[LiTMP]” and “LiTMP concentration” refer to
the formal molarity of the monomer unit (normality). The
solvent concentration refers to the concentration of free (unco-
ordinated) donor solvent in pentane cosolvent. In all cases, the
loss of the epoxide substrate follows a clean first-order decay
to five half-lives. The reaction rates were monitored by
following loss of the epoxides and formation of products of
quenched samples by well-documented gas chromatographic
The results are presented successively as follows: (1) LiTMP
solution structures establish the aggregation and solvation states
of the lithium dialkylamide reactant; (2) rate studies display
solvent-dependent monomer- and dimer-based lithiation; and
(3) computations using density functional theory (DFT) il-
luminate details of the transition structures for R- and â-lithia-
tion.
Structures of LiTMP. Rate studies must be founded on a
firm understanding of solution structures because the rate law
provides the stoichiometry of the transition structure relatiVe
2
3
analyses. The resulting pseudo-first-order rate constants are
independent of the initial substrate concentration (0.004-0.04
M). Isotope effects were determined by comparing the lithiations
2
0
to the reactants. LiTMP in THF/pentane exists as C2h dimer
5
, whereas low concentrations of monomer 6 (≈20%) appear
9a,21
2
4
25
of epoxides 1 and 3 to deuterated analogues 1-d2, and 3-d12,
in neat THF.
In contrast, LiTMP forms exclusively (>95%)
respectively, and are all consistent with rate-limiting steps
involving C-H(D) cleavages. Notably, we observed relatively
unsolVated tetramer (7) in Me2NEt/hexane mixtures at all Me2-
NEt concentrations.9d,f All four conformers of the tetramer 7
have been characterized.9d
small isotope effects for the R-lithiation of 1 and large isotope
2
6
effects for the â-lithiation of 3. The results of the rate studies
are summarized in Table 1. Representative rate data are depicted
in Figures 1-8; additional data are included in the Supporting
Information.
LiTMP/THF/3. Rate studies of the LiTMP/THF-mediated
â-lithiation of 3 (eq 2) in pentane displayed the modest
complexity anticipated for a base that undergoes limited ligand-
concentration-dependent deaggregation. A plot of kobsd versus
THF concentration at 0.1 M LiTMP provides a zeroth-order
dependence on the THF concentration with a slight inverse
dependence at high THF concentration (Figure 1; Table 1). A
Rate Studies: General. The LiTMP used to study LiTMP/
2
2a
THF-mediated reactions was recrystallized
and used as
(
17) McDonald, R. N.; Steppel, R. N.; Cousins, R. C. J. Org. Chem. 1975, 40,
1694. Crandall, J. K.; Chang, L.-H. J. Org. Chem. 1967, 32, 532. Cope, A.
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freshly prepared stock solutions.9b Due to the limited solubility
of recrystallized LiTMP in Me2NEt, stable stock solutions of
LiTMP/Me2NEt were prepared in situ from 2,2,6,6-tetrameth-
ylpiperidine and recrystallized n-BuLi.22b,c Pseudo-first-order
(
12) Recent synthetic applications of the lithium dialkylamide-based rearrange-
ment of epoxides: Gayet, A.; Bertilsson, S. K.; Andersson, P. G. Org.
Lett. 2002, 4, 3777. Bertilsson, S. K.; S o¨ dergren, M. J.; Andersson, P. G.
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guishable from LiTMP.
(22) (a) Lappert, M.; Slade, M. J.; Singh, A.; Atwood, J. L.; Rogers, R. D.;
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4
655. Brookes, P. C.; Milne, D. J.; Murphy, P. J.; Spolaore, B. Tetrahedron
2
002, 58, 4675. S o¨ dergren, M. J.; Bertilsson, S. K.; Andersson, P. G. J.
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(
(
(
(
13) Reviews: Magnus, A.; Bertilsson, S. K.; Andersson, P. G. Chem. Soc. ReV.
2
002, 31, 223. Hodgson, D. M.; Gras, E. Synthesis 2002, 1625. Satoh, T.
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2
9, 345.
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Thummel, R. P.; Rickborn, B. J. Am. Chem. Soc. 1970, 92, 2064. (c) Cope,
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16) Other R-lithiations promoted by LiTMP leading to carbenoids: Creary, X.
J. Am. Chem. Soc. 1977, 99, 7632. Olofson, R. A.; Dougherty, C. M. J.
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(26) The secondary isotope effect expected for 3-d12 does not fully account for
the observed differences between R- and â-lithiation. March, J. In AdVanced
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15894 J. AM. CHEM. SOC.
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VOL. 125, NO. 51, 2003