Published on Web 11/07/2007
Lithium Diisopropylamide-Mediated Reactions of Imines,
Unsaturated Esters, Epoxides, and Aryl Carbamates:
Influence of Hexamethylphosphoramide and Ethereal
Cosolvents on Reaction Mechanisms
Yun Ma and David B. Collum*
Contribution from the Department of Chemistry and Chemical Biology, Baker Laboratory,
Cornell UniVersity, Ithaca, New York 14853-1301
Received June 21, 2007; E-mail: dbc6@cornell.edu
Abstract: Several reactions mediated by lithium diisopropylamide (LDA) with added hexamethylphos-
phoramide (HMPA) are described. The N-isopropylimine of cyclohexanone lithiates via an ensemble of
monomer-based pathways. Conjugate addition of LDA/HMPA to an unsaturated ester proceeds via di-
and tetra-HMPA-solvated dimers. Deprotonation of norbornene epoxide by LDA/HMPA proceeds via an
intermediate metalated epoxide as a mixed dimer with LDA. Ortholithiation of an aryl carbamate proceeds
via a mono-HMPA-solvated monomer-based pathway. Dependencies on THF and other ethereal cosolvents
suggest that secondary-shell solvation effects are important in some instances. The origins of the inordinate
mechanistic complexity are discussed.
Introduction
transition structures? Why does HMPA sometimes fail to elicit
high reactivities?2
Hexamethylphosphoramide (HMPA) is one of the most
prominent additives used to influence the yields, rates, and
selectivities of organolithium reactions.1 A preponderance of
what is known about solvation of lithium ions by HMPA derives
from the studies of Reich and co-workers.2 Their spectroscopic
analyses of lithium salts in the limit of slow exchange of free
and lithium-ion-coordinated HMPA offer intimate details of
HMPA-mediated deaggregation and ionization. Despite the
sound understanding of how HMPA influences the structures
of lithium salts, the oft-cited influence of HMPA on reactivity
is not well understood and leaves many questions unanswered.3
Does the marked tendency of HMPA to serially solvate
organolithiums foreshadow a similar structural diversity in the
rate-limiting transition structures? Do dramatic accelerations
result from the capacity of HMPA to promote high solvation
numbers and low aggregation numbers in the rate-limiting
We have begun addressing some of these questions in the
context of lithium diisopropylamide (LDA),4-9 a prevalent base
in organic synthesis.10 We describe herein investigations of four
reactions mediated by LDA/HMPA-lithiation of imine 1 (eq
1),7f,8b,11,12 1,4-addition to unsaturated ester 3 (eq 2),13,14 opening
(4) (a) Sun, X.; Kenkre, S. L.; Remenar, J. F.; Gilchrist, J. H.; Collum, D. B.
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(10) For an incisive review of lithium amides in organic synthesis, see: Eames,
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(12) For leading references to the organolithium chemistry of imines, see:
Meyers, A. I. J. Org. Chem. 2005, 70, 6137.
(1) (a) Dykstra, R. R. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 4, p 2668. (b) For a
particularly interesting survey of stereo- and regioselectivity affiliated with
organolithium chemistry, see: Clayden, J. Organolithiums: SelectiVity for
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J. AM. CHEM. SOC. 2007, 129, 14818-14825
10.1021/ja074554e CCC: $37.00 © 2007 American Chemical Society