Published on Web 02/20/2004
Reaction of Ketones with Lithium Hexamethyldisilazide: Competitive Enolizations and 1,2-Additions Pinjing Zhao, Anthony Condo, Ivan Keresztes, and David B. Collum* Contribution from the Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell UniVersity, Ithaca, New York 14853-1301 Received October 10, 2003; E-mail:
[email protected] Abstract: Reaction of 2-methylcyclohexanone with lithium hexamethyldisilazide (LiHMDS, TMS2NLi) displays highly solvent-dependent chemoselectivity. LiHMDS in THF/toluene effect enolization. Rate studies using in situ IR spectroscopy are consistent with a THF concentration-dependent monomer-based pathway. LiHMDS in pyrrolidine/toluene affords exclusively 1,2-addition of the pyrrolidine fragment to form an R-amino alkoxide-LiHMDS mixed dimer shown to be a pair of conformers by using 6Li, 15N, and 13C NMR spectroscopies. Rate studies are consistent with a monomer-based transition structure [(TMS2NLi)(ketone)(pyrrolidine)3]q. The partitioning between enolization and 1,2-addition is kinetically controlled.
Introduction
Recent studies have shown that lithium hexamethyldisilazide (LiHMDS) solvated by hindered ethers or hindered di- and trialkylamines mediates the enolization of 2-methylcyclohexanone via a dimer-based mechanism.1 The amines elicit substantial accelerations relative to ethers attributable to both a steric destabilization of the reactants and an electronic stabilization of the dimer-based transition structures. We describe herein the reaction of 2-methylcyclohexanone (1) with LiHMDS solvated by two sterically unhindered ligands: THF and pyrrolidine. Despite the isostructural relationship of THF and pyrrolidine, LiHMDS/THF mixtures effect clean enolization, whereas LiHMDS/pyrrolidine mixtures afford exclusively 1,2-addition of pyrrolidine (eq 1). Rate studies suggest that both reactions occur via highly solvated monomerbased transition structures. The potential implications of the 1,2addition to organic synthesissboth positive and negativesare considered.
Results
LiHMDS/THF: Kinetics of Enolization. Addition of ketone 1 to LiHMDS in either THF or THF/hydrocarbon mixtures at -78 °C was monitored by in situ IR spectroscopy.2 The absorbance of 1 at 1722 cm-1 is observed to the exclusion of absorbances in the lower frequency region of the spectrum (1) (a) Zhao, P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 4008. (b) Zhao, P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 14411. (c) Zhao, P.; Lucht, B. L.; Kenkre, S.; Collum, D. B. J. Org. Chem. 2004, 69, 242-249. 10.1021/ja030582v CCC: $27.50 © 2004 American Chemical Society
(1710-1700 cm-1),1 showing that 1 does not measurably bind to LiHMDS.3,4 Pseudo-first-order conditions were established by maintaining low concentrations of ketone 1 (0.004-0.01 M) and high, yet adjustable, concentrations of recrystallized5 LiHMDS (0.05-0.40 M) and THF (0.15-12.0 M) using toluene as the cosolvent. The loss of the ketone or its less reactive deuterated analogue 1-d36 follows clean first-order decays to g5 half-lives. Reestablishing the IR baseline and monitoring a second injection reveals no significant change in the rate constant, showing that conversion-dependent autocatalysis or autoinhibition is unimportant under these conditions. Comparison of 1 versus 1-d3 provided a large isotope effect (kH/kD ) 11 ( 1), consistent with a rate-limiting proton transfer. A plot of kobsd versus [THF] (Figure 1) shows a nearly first-order dependence on the THF concentration with a slight downward curvature. Superficially, this curvature is consistent with a THF concentration-dependent deaggregation manifesting incomplete first-order saturation kinetics (as illustrated by the least-squares fit). However, neither the first-order dependence nor the substantially incomplete saturation behavior are fully consistent with formation of predominantly trisolVated monomers in 12 M THF (eq 2).7 We believe the relatively simple THF dependence belies a greater underlying complexity. (2) (a) Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2000, 122, 2452. (b) Review: Rein, A. J.; Donahue, S. M.; Pavlosky, M. A. Curr. Opin. Drug DiscoVery DeV. 2000, 3, 734. (3) For leading references and recent examples of detectable organolithiumsubstrate precomplexation, see: (a) Klumpp, G. W. Recl. TraV. Chim. PaysBas 1986, 105, 1. (b) Andersen, D. R.; Faibish, N. C.; Beak, P. J. Am. Chem. Soc. 1999, 121, 7553. (c) Pippel, D. J.; Weisenberger, G. A.; Faibish, N. C.; Beak, P. J. Am. Chem. Soc. 2001, 123, 4919. (d) Bertini-Gross, K. M.; Beak, P. J. Am. Chem. Soc. 2001, 123, 315. (4) For a general discussion of ketone-lithium complexation and related ketone-Lewis acid complexation, see: Shambayati, S.; Schreiber, S. L. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 1, p 283. (5) Romesberg, F. E.; Bernstein, M. P.; Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.; Collum, D. B. J. Am. Chem. Soc. 1993, 115, 3475. (6) Peet, N. P. J. Labelled Compd. 1973, 9, 721. (7) Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1995, 117, 9863. J. AM. CHEM. SOC. 2004, 126, 3113-3118
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Figure 1. Plot of kobsd vs [THF] in toluene for the enolization of 1 (0.004 M) by LiHMDS (0.10 M) at -78 °C. The curve depicts the results of an unweighted least-squares fit to kobsd ) (a + bx)/(1 + cx) (a ) 1 ( 4 × 10-5, b ) 2.9 ( 0.3 × 10-4, c ) 0.05 ( 0.01).
A plot of kobsd versus [LiHMDS] in 7.1 M THF in toluene (Figure 2) reveals a fractional order (0.61 ( 0.08).8 A fractional order of >0.5 is consistent with a monomer-based enolization starting with the mixture of monomer and dimer (eq 2). The rate of enolization is not influenced by added hexamethyldisilazane (HMDS). LiHMDS/Pyrrolidine: Structure of the 1,2-Adduct. Reactions of ketone 1 with LiHMDS/pyrrolidine at -78 °C under analogous pseudo-first-order conditions were monitored by in situ IR spectroscopy. The absence of ketone-LiHMDS complexation and a clean first-order loss of ketone over time are consistent with a simple mechanistic picture. A number of observations, however, suggested that ketone enolization was not occurring. The IR spectra show no absorbances in the 16101625 cm-1 region attributable to the anticipated CdC absorbance of the enolate. Attempts to trap the putative enolate with TMSCl failed completely. A small isotope effect (kH/kD ) 1.4 ( 0.1) was also troublesome (and was curiously similar to the isotope effect for the 1,2-addition of MeOH to 2,2,5,5tetradeuteriocyclopentanone).9 Although an equilibrium isotope effect arising from a reversible deprotonation-reprotonation facilitated by the pyrrolidine would likely be small, reaction of ketone 1-d3 with LiHMDS/pyrrolidine followed by quenching with H2O afforded 1-d3 with no (
