A R T I C L E S
Zhao et al.
equimolar mixture of two adducts; MMX calculations reveal
that the lowest energy conformer of the cis adduct (28) is only
0.7 kcal/mol more stable than the analogous trans adduct (27).
In this instance, a kinetic addition of a hindered nucleophile
derived from LiHMDS/pyrrolidine to 2-methylcyclohexanone
via 21 should be highly trans selective.26
in the presence of i-Pr2NH and related protic amines to be a
little disturbing.35,36 As a last cautionary note, our limited
experience with protic amines and protic amides suggests that
structural and mechanistic complexities are pervasive.12,32
Experimental Section
Reagents and Solvents. Amines and hydrocarbons were routinely
distilled by vacuum transfer from blue or purple solutions containing
sodium benzophenone ketyl. The hydrocarbon stills contained 1%
tetraglyme to dissolve the ketyl. 6Li metal (95.5% enriched) was
obtained from Oak Ridge National Laboratory. The LiHMDS,17 ketone
1-d3,6 and 2,2,6,6-tetradeuteriocyclohexanone6 were prepared as de-
scribed. Air- and moisture-sensitive materials were manipulated under
argon or nitrogen using standard glovebox, vacuum line, and syringe
techniques.
NMR Spectroscopic Analyses. Samples were prepared, and the
6Li, 15N, and 13C NMR spectra were recorded as described elsewhere.17
The samples of LiHMDS containing ketone 1 were prepared using a
specific protocol designed to minimize rapid reaction.1b
IR Spectroscopic Analyses. In situ IR spectra were recorded with
a 30-bounce silicon-tipped probe.2
Acknowledgment. We thank the National Institutes of Health
for direct support of this work. We also thank DuPont
Pharmaceuticals, Merck Research Laboratories, Pfizer, Aventis,
R. W. Johnson, and Schering Plough for indirect support. P. Z.
thanks Boehringer-Ingelheim for a fellowship. We also ac-
knowledge the National Science Foundation Instrumentation
Program (CHE 7904825 and PCM 8018643), the National
Institutes of Health (RR02002), and IBM for support of the
Cornell Nuclear Magnetic Resonance Facility.
The unanticipated and facile net 1,2-addition of lithium
pyrrolidide intersects with many synthetic and mechanistic
issues. Tetrahedral adducts analogous to 3 are key intermediates
in a number of synthetically important reactions.27 If the 1,2-
addition proceeds via a lithium amide attack on the ketone
(rather than a reversible addition of the amine), analogous 1,2-
additions to esterssdirect ester amidolysessor other additions
to CdX bonds might perhaps prove to be synthetically use-
ful.28,29 There is also a growing number of synthetically
important reactions, however, in which 1,2-additions by protic
amines30 and protic lithium amides31,32 to carbonyl-based
electrophiles could pose problems. Enolizations of aldehydes
by lithium amides, for example, fail largely due to rapid 1,2-
addition.23,33,34 Could the 1,2-additions to ketones occasionally
intervene when protic amines or protic amides are present? It
is in this context that we find the failures of some enolizations
Supporting Information Available: Rate data (PDF). This
material is available free of charge via the Internet at
JA030582V
(31) (a) Armstrong, D. R.; Carstairs, A.; Henderson, K. W. Organometallics
1999, 18, 3589. (b) Boche, G.; Ledig, B.; Marsch, M.; Harms, K. Acta
Crystallogr., Sect. E 2001, 57, m570. (c) Liddle, S. T.; Clegg, W. J. Chem.
Soc., Dalton Trans. 2001, 3549.
(32) Leading references: (a) Rutherford, J. L.; Collum, D. B. J. Am. Chem.
Soc. 2001, 123, 199. (b) Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc.
1996, 118, 3529.
(33) (a) Nudelman, N. S.; Garc´ıa-Linares, G. E. J. Org. Chem. 2000, 65, 1629.
(b) Matsumoto, T.; Hamura, T.; Kuriyama, Y.; Suzuki, K. Tetrahedron
Lett. 1997, 38, 8985. (c) Armstrong, D. R.; Davies, R. P.; Raithby, P. R.;
Snaith, R.; Wheatley, A. E. H. New J. Chem. 1999, 23, 499. (d) Corruble,
A.; Valnot, J.-Y.; Maddaluno, J.; Duhamel, P. J. Org. Chem. 1998, 63,
8266. (e) Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Duhamel, P.
Tetrahedron: Asymmetry 1997, 8, 1519. (f) Reynolds, K. A.; Finn, M. G.
J. Org. Chem. 1997, 62, 2574. (g) Nudelman, N. S.; Garc´ıa-Linares, G. E.
J. Org. Chem. 2000, 65, 1629. (h) Fressigne´, C.; Maddaluno, J.; Marquez,
A.; Giessner-Prettre, C. J. Org. Chem. 2000, 65, 8899. (i) Davies, J. E.;
Raithby, P. R.; Snaith, R.; Wheatley, A. E. H. J. Chem. Soc., Chem.
Commun. 1997, 1721. (j) Armstrong, D. R.; Davies, J. E.; Davies, R. P.;
Raithby, P. R.; Snaith, R.; Wheatley, A. E. H. New J. Chem. 1999, 23, 35.
(k) See also ref 24.
(27) (a) Larsen, R. D.; Corley, E. G.; King, A. O.; Carroll, J. D.; Davis, P.;
Verhoeven, T. R.; Reider, P. J.; Labelle, M.; Gauthier, J. Y.; Xiang, Y. B.;
Zamboni, R. J. J. Org. Chem. 1996, 61, 3398. (b) Comins, D. L.; Killpack,
M. O. J. Org. Chem. 1990, 55, 69. (c) Kaiser, F.; Schwink, L.; Velder, J.;
Schmalz, H.-G. J. Org. Chem. 2002, 67, 9248. (d) Roschangar, F.; Brown,
J. C.; Cooley, B. E.; Sharp, M. J.; Matsuoka, R. T. Tetrahedron 2002, 58,
1657. (e) Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay,
T.; Simson, M.; Seebach D. Synthesis 1993, 1271. (f) Comins, D. L.; Brown,
J. D.; Mantlo, N. B. Tetrahedron Lett. 1982, 23, 3979. (g) Hart, D. J.;
Kanai, K.; Thomas, D. G.; Yang, T.-K. J. Org. Chem. 1983, 48, 289.
(28) For the direct amidolysis of methyl esters by lithium amides, see: (a)
Lebegue, N.; Flouquet, N.; Berthelot, P.; Pfeiffer, B.; Renard, P. Synth.
Commun. 2002, 32, 2877. (b) Koide, H.; Uemura, M. Chirality 2000, 12,
352.
(29) A seemingly related amidolysis of esters using NaHMDS/R2NH mixtures
has been reported: Riviere-Baudet, M.; Morere, A.; Dias, M. Tetrahedron
Lett. 1992, 33, 6453.
(30) Eames, J.; Weerasooriya, N.; Coumbarides, G. S. Eur. J. Org. Chem. 2002,
181. For additional leading references to synthetic applications of orga-
nolithiums solvated by protic amines, see ref 32.
(34) Treatment of simple aldehydes with [6Li,15N]LDA affords the 1,2-adduct
1
displaying JC-N coupling: Sun, X.; Collum, D. B. Unpublished work.
(35) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624. (b) Aebi, J.
D.; Seebach, D. HelV. Chim. Acta 1985, 68, 1507. (c) Laube, T.; Dunitz,
J. D.; Seebach, D. HelV. Chim. Acta 1985, 68, 1373. (d) Seebach, D.; Boes,
M.; Naef, R.; Schweizer, W. B. J. Am. Chem. Soc. 1983, 105, 5390.
(36) For example, see: Mohrig, J. R.; Lee, P. K.; Stein, K. A.; Mitton, M. J.;
Rosenberg, R. E. J. Org. Chem. 1995, 60, 3529. For an excellent discussion
and leading references, see: Vedejs, E.; Lee, N. J. Am. Chem. Soc. 1995,
117, 891.
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