Sodiated Oppolzer Enolates: Solution Structures, Mechanism of Alkylation, and Origin of Stereoselectivity.

NMR spectroscopic studies reveal camphorsultam-derived sodium enolates known as Oppolzer enolates reside as monomers in neat THF and THF/HMPA solutions and as dimers in toluene when solvated by N,N,N',N'-tetramethylethylenediamine (TMEDA) and N,N,N',N'',N''-pentamethyldiethylenediamine (PMDTA). Density functional theory (DFT) computations attest to the solvation numbers. Rate studies show analogy with previously studied lithiated Oppolzer enolates in which alkylation occurs through non-chelated solvent-separated ion pairs. The origins of the selectivity trace to transition structures in which the alkylating agent is guided to the exo face of the camphor owing to stereoelectronic preferences imparted by the sultam sulfonyl moiety. Marked secondary-shell solvation effects are gleaned from the rate studies.

Carbon-Nitrogen Bond Formation Using Sodium Hexamethyldisilazide: Solvent-Dependent Reactivities and Mechanisms.

The solvent-dependent reactivity of sodium hexamethyldisilazide (NaHMDS) toward carbon-centered electrophiles reveals reactions that are poorly represented or unrepresented in the literature, including direct aminolysis of aromatic methyl esters to give carboxamides, nitriles, or amidines, depending on the choice of solvent. SNAr substitutions of aryl halides and opening of terminal epoxides are also examined. A combination of 1H and 29Si nuclear magnetic resonance (NMR) spectroscopic studies using [15N]NaHMDS, kinetic studies, and computational studies reveals the complex mechanistic basis of the preferences for simple aryl carboxamides in toluene and dimethylethylamine and arylnitriles or amidines in tetrahydrofuran (THF). A prevalence of dimer- and mixed dimer-based chemistry even starting from the observable NaHMDS monomer in THF solution is notable.

Lithiated Oppolzer Enolates: Solution Structures, Mechanism of Alkylation, and Origin of Stereoselectivity.

Camphorsultam-based lithium enolates referred to colloquially as Oppolzer enolates are examined spectroscopically, crystallographically, kinetically, and computationally to ascertain the mechanism of alkylation and the origin of the stereoselectivity. Solvent- and substrate-dependent structures include tetramers for alkyl-substituted enolates in toluene, unsymmetric dimers for aryl-substituted enolates in toluene, substrate-independent symmetric dimers in THF and THF/toluene mixtures, HMPA-bridged trisolvated dimers at low HMPA concentrations, and disolvated monomers for the aryl-substituted enolates at elevated HMPA concentrations. Extensive analyses of the stereochemistry of aggregation are included. Rate studies for reaction with allyl bromide implicate an HMPA-solvated ion pair with a +Li(HMPA)4 counterion. Dependencies on toluene and THF are attributed to exclusively secondary-shell (medium) effects. Aided by density functional theory (DFT) computations, a stereochemical model is presented in which neither chelates nor the lithium gegenion serves roles. The stereoselectivity stems from the chirality within the sultam ring and not the camphor skeletal core.

Sodium Isopropyl(trimethylsilyl)amide: A Stable and Highly Soluble Lithium Diisopropylamide Mimic.

The preparation, structure, physical properties, and reactivities of sodium isopropyl(trimethylsilyl)amide (NaPTA) are described. The solubilities at room temperature range from n-heptane (0.55 M), n-hexane (0.60 M), toluene (0.65 M), MTBE (1.7 M), Et3N (3.2 M), and THF (>6.0 M). The half-life to destruction in neat THF is >1 year at 25 °C and 7 days at 70 °C, which compares favorably to 2.5 months and 1.5 days, respectively, for LDA in neat THF. This study focuses on NaPTA in THF. 29Si NMR spectroscopy shows exclusively a mixture of cis and trans stereoisomeric dimers in 0.10-12 M THF in hexane. Density functional theory (DFT) computations suggest that the pKb is intermediate between dimeric sodium diisopropylamide (NaDA) and dimeric sodium hexamethyldisilazide (NaHMDS). Metalations of arenes, epoxides, ketones, hydrazones, alkenes, and alkyl halides show higher reactivities than LDA (kNaPTA/LDA = 1-30). While the rates of arene metalation are high, the lower pKb of NaPTA limits the substrates. Metalation of pseudoephedrate-based carboxamides to form disodiated Myers enolates solves several challenging technical problems.

Ketone Enolization with Sodium Hexamethyldisilazide: Solvent- and Substrate-Dependent E-Z Selectivity and Affiliated Mechanisms.

Ketone enolization by sodium hexamethyldisilazide (NaHMDS) shows a marked solvent and substrate dependence. Enolization of 2-methyl-3-pentanone reveals E-Z selectivities in Et3N/toluene (20:1), methyl-t-butyl ether (MTBE, 10:1), N,N,N',N″,N″-pentamethyldiethylenetriamine (PMDTA)/toluene (8:1), TMEDA/toluene (4:1), diglyme (1:1), DME (1:22), and tetrahydrofuran (THF) (1:90). Control experiments show slow or nonexistent stereochemical equilibration in all solvents except THF. Enolate trapping with Me3SiCl/Et3N requires warming to -40 °C whereas Me3SiOTf reacts within seconds. In situ enolate trapping at -78 °C using preformed NaHMDS/Me3SiCl mixtures is effective in Et3N/toluene yet fails in THF by forming (Me3Si)3N. Rate studies show enolization via mono- and disolvated dimers in Et3N/toluene, disolvated dimers in TMEDA, trisolvated monomers in THF/toluene, and free ions with PMDTA. Density functional theory computations explore the selectivities via the E- and Z-based transition structures. Failures of theory-experiment correlations of ionic fragments were considerable even when isodesmic comparisons could have canceled electron correlation errors. Swapping 2-methyl-3-pentanone with a close isostere, 2-methylcyclohexanone, causes a fundamental change in the mechanism to a trisolvated-monomer-based enolization in THF.

Reactions of Sodium Diisopropylamide: Liquid-Phase and Solid-Liquid Phase-Transfer Catalysis by N,N,N',N″,N″-Pentamethyldiethylenetriamine.

Sodium diisopropylamide (NaDA) in N,N-dimethylethylamine (DMEA) and DMEA-hydrocarbon mixtures with added N,N,N',N″,N″-pentamethyldiethylenetriamine (PMDTA) reacts with alkyl halides, epoxides, hydrazones, arenes, alkenes, and allyl ethers. Comparisons of PMDTA with N,N,N',N'-tetramethylethylenediamine (TMEDA) accompanied by detailed rate and computational studies reveal the importance of the trifunctionality and κ2-κ3 hemilability. Rate studies show exclusively monomer-based reactions of 2-bromooctane, cyclooctene oxide, and dimethylresorcinol. Catalysis with 10 mol % PMDTA shows up to >30-fold accelerations (kcat > 300) with no evidence of inhibition over 10 turnovers. Solid-liquid phase-transfer catalysis (SLPTC) is explored as a means to optimize the catalysis as well as explore the merits of heterogeneous reaction conditions.

Aggregation and Solvation of Sodium Hexamethyldisilazide: Across the Solvent Spectrum.

We report solution structures of sodium hexamethyldisilazide (NaHMDS) solvated by >30 standard solvents (ligands). These include: toluene, benzene, and styrene; triethylamine and related trialkylamines; pyrrolidine as a representative dialkylamine; dialkylethers including THF, tert-butylmethyl ether, and diethyl ether; dipolar ligands such as DMF, HMPA, DMSO, and DMPU; a bifunctional dipolar ligand nonamethylimidodiphosphoramide (NIPA); polyamines N,N,N',N'-tetramethylenediamine (TMEDA), N,N,N',N″,N″-pentamethyldiethylenetriamine (PMDTA), N,N,N',N'-tetramethylcyclohexanediamine (TMCDA), and 2,2'-bipyridine; polyethers 12-crown-4, 15-crown-5, 18-crown-6, and diglyme; 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane ([2.2.2] cryptand); and tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1). Combinations of 1H, 13C, 15N, and 29Si NMR spectroscopies, the method of continuous variations, X-ray crystallography, and density functional theory (DFT) computations reveal ligand-modulated aggregation to give mixtures of dimers, monomers, triple ions, and ion pairs. 15N-29Si coupling constants distinguish dimers and monomers. Solvation numbers are determined by a combination of solvent titrations, observed free and bound solvent in the slow exchange limit, and DFT computations. The relative abilities of solvents to compete in binary mixtures often match that predicted by conventional wisdom but with some exceptions and evidence of both competitive and cooperative (mixed) solvation. Crystal structures of a NaHMDS cryptate ion pair and a 15-crown-5-solvated monomer are included. Results are compared with those for lithium hexamethyldisilazide, lithium diisopropylamide, and sodium diisopropylamide.

Sodium Hexamethyldisilazide: Using 15N-29Si Scalar Coupling to Determine Aggregation and Solvation States.

29Si NMR spectroscopy, the method of continuous variations, and density functional theory computations show that sodium hexamethyldisilazide (NaHMDS) is a disolvated dimer in toluene, a mixture of disolvated dimer and tetrasolvated monomer in THF/toluene, and exclusively monomer in neat THF. The dioxane-solvated NaHMDS only partially deaggregates to monomer even in neat dioxane. 15N-29Si coupling constants and 29Si chemical shifts show a high and dependable correlation with the aggregation state. Monitoring either chemical shift or coupling constant versus THF concentration even in the high-temperature, rapid-exchange limit affords the solvation numbers consistent with DFT computations. The preparation of 15N-labeled NaHMDS has been improved.

Structure, Reactivity, and Synthetic Applications of Sodium Diisopropylamide.

The 60-year history of sodium diisopropylamide (NaDA) is described herein. We review various preparations, solvent-dependent stabilities, and solution structures. Synthetic applications of NaDA reported to date are framed by a mechanism-driven approach, emphasizing selectivities when appropriate. We conclude with examples beyond metalation in which NaDA plays a central role and a few thoughts on where future applications could be focused.

Disodium Salts of Pseudoephedrine-Derived Myers Enolates: Stereoselectivity and Mechanism of Alkylation.

Pseudoephedrine-derived dianionic Myers enolates were generated using sodium diisopropylamide (NaDA) in THF solution. The reactivities and selectivities of the disodium salts largely mirror those of the dilithium salts but without the requisite large excesses of inorganic salts (LiCl) or mandated dilute solutions. The disodium salts require careful control of temperature to preclude deleterious aggregate aging effects traced to changes in the aggregate structure and intervening O-alkylations. Structural studies and density functional theory (DFT) computations show a dominant highly symmetric polyhedron quite different from the lithium analogue. No enolate-NaDA mixed aggregates are observed with excess NaDA. Rate studies show an alkylation mechanism involving an intervening tetramer-monomer pre-equilibrium followed by rate-limiting alkylation of tetrasolvated monomers. DFT computations were conducted to explore the possible influences on stereochemistry. A crystal deriving from samples aged at ambient temperature contains six dianionic subunits and two monoanionic (alkoxide-only) subunits. A new preparation of concentrated solutions of NaDA in THF solution is described.

Enantioselective Alkylation of 2-Alkylpyridines Controlled by Organolithium Aggregation.

Direct enantioselective α-alkylation of 2-alkylpyridines provides access to chiral pyridines via an operationally simple protocol that obviates the need for prefunctionalization or preactivation of the substrate. The alkylation is accomplished using chiral lithium amides as noncovalent stereodirecting auxiliaries. Crystallographic and solution NMR studies provide insight into the structure of well-defined chiral aggregates in which a lithium amide reagent directs asymmetric alkylation.

Sodium Diisopropylamide-Mediated Dehydrohalogenations: Influence of Primary- and Secondary-Shell Solvation.

Eliminations of alkyl halides by sodium diisopropylamide (NaDA) in tetrahydrofuran (THF)/hexane or THF/N,N-dimethylethylamine (DMEA) solutions are facile and complementary to analogous reactions of lithium diisopropylamide in THF. Rate studies show a dominance of monomer-based metalations and prevalent secondary-shell solvation effects overlaid on primary-shell effects. 1-Halooctanes exclusively undergo elimination rather than substitution. Rate and isotopic labeling studies on 1-bromooctane reveal an E2-like elimination pathway via trisolvated NaDA monomer. By contrast, 1-chlorooctane is eliminated via disolvated monomer through a carbenoid mechanism. exo-2-Norbornyl chloride and bromide are also eliminated via disolvated monomer; a syn E2 mechanism is inferred for these substrates. The cis- and trans-4-tert-butylcyclohexyl bromides show a preference for the elimination of the cis isomer (kcis/ax/ktrans/eq = 10). Rate and isotopic labeling studies are consistent with a trans-diaxial E2 elimination via trisolvated monomer for the cis isomer and a carbenoid mechanism via disolvated monomer for the trans isomer. Vicinal haloethers show substrate-dependent reactivities, affording alkynes and enol ethers. trans-1-Bromo-2-methoxycyclohexane provides enol ether 1-methoxycyclohexene, while trans-1-bromo-2-methoxycyclooctane provides dimeric products consistent with fleeting cycloocta-1,2-diene (cyclic allene), which was fully characterized as two conformers.

Wittig Rearrangements of Boron-Based Oxazolidinone Enolates.

[2,3]-Sigmatropic rearrangements (Wittig rearrangements) of α-alkoxy oxazolidinone enolates are described. Whereas alkali metal enolates fail, owing to facile deacylation, boron enolates generated from di-n-butylboron triflate and triethylamine rearranged in good yields and high selectivities with exceptions noted. IR and NMR spectroscopies show the boron is chelated by the α-alkoxy group rather than the more distal oxazolidinone carbonyl in the complex and enolate. The rearrangement product contains a boron alkoxide that remains unchelated by either carbonyl. Optimization was guided by density functional theory computations, suggesting that valine-derived oxazolidinones would be superior to the phenylalanine-derived analogues.

Aryl Carbamates: Mechanisms of Orthosodiations and Snieckus-Fries Rearrangements.

Aryl carbamates are orthometalated by sodium diisopropylamide (NaDA) in tetrahydrofuran. The resulting arylsodiums undergo Snieckus-Fries rearrangement to give orthoacylated phenols in good yield. The intermediate arylsodiums and resulting orthoacylated phenolates are suggested to be monomeric. The rate-limiting step in the two-step sequence depends on the steric demands of the carbamoyl moiety and the substituents in the meta position of the arene. Rate studies reveal a dominant disolvated-monomer-based orthometalation followed by a di- or trisolvated arylsodium monomer-based rearrangement. Kinetic evidence of a NaDA-catalyzed Snieckus-Fries rearrangement suggests the intermediacy of mixed trimers. Competitive halide eliminations to form benzyne are also discussed.

Pseudophedrine-Derived Myers Enolates: Structures and Influence of Lithium Chloride on Reactivity and Mechanism.

The structures and reactivities of pseudoephedrine-derived dianionic Myers enolates are examined. A combination of NMR and IR spectroscopic, crystallographic, and computational data reveal that the homoaggregated dianions form octalithiated tetramers displaying S4-symmetric Li8O8 cores and overall C2 symmetry. Computational and isotopic labeling studies reveal strong N-Li contacts in the carboxamide enolate moiety. The method of continuous variations proves deceptive, as octalithiated tetrameric homoaggregates afford hexalithiated trimeric heteroaggregates. A lithium diisopropylamide-lithium enolate mixed aggregate is found to be a C2-symmetric hexalithiated species incorporating two enolate dianions and two lithium diisopropylamide (LDA) subunits. Structural and rate studies show that lithium chloride has little effect on the dynamics of the enolate homoaggregates but forms adducts of unknown structure. Rate studies of alkylations indicate that the aging of the aggregates can have effects spanning orders of magnitude. The LiCl-enolate adduct dramatically accelerates the reaction but requires superstoichiometric quantities owing to putative autoinhibition. Efforts and progress toward eliminating the requisite large excess of LiCl are discussed.

Structures and Reactivities of Sodiated Evans Enolates: Role of Solvation and Mixed Aggregation on the Stereochemistry and Mechanism of Alkylations.

Oxazolidinone-based sodiated enolates (Evans enolates) were generated using sodium diisopropylamide (NaDA) or sodium hexamethyldisilazide (NaHMDS) in the presence of N,N,N',N'-tetramethylethylenediamine (TMEDA), ( R,R)- trans- N,N,N',N'-tetramethylcyclohexanediamine [( R,R)-TMCDA], or ( S,S)-TMCDA. 13C NMR spectroscopic analysis in conjunction with the method of continuous variations (MCV), x-ray crystallography, and density functional theory (DFT) computations revealed the enolates to be octahedral bis-diamine-chelated monomers. Rate and computational studies of an alkylation with allyl bromide implicate a bis-diamine-chelated-monomer-based transition structure. The sodiated Evans enolates form mixed dimers with NaHMDS, NaDA, or sodium 2,6-di- tert-butylphenolate, the reactivities of which are examined. Stereoselective quaternizations, aldol additions, and azaaldol additions are described.

Case for Lithium Tetramethylpiperidide-Mediated Ortholithiations: Reactivity and Mechanisms.

Rate and mechanistic studies of ortholithiations by lithium 2,2,6,6-tetramethylpiperidide focus on four arenes: 1,4-bis(trifluoromethyl)benzene, 1,3-bis(trifluoromethyl)benzene, 1,3-dimethoxybenzene, and 4,4-dimethyl-2-phenyl-2-oxazoline. Metalations occur via substrate-dependent combinations of monosolvated monomer, disolvated monomer, and tetrasolvated dimer (triple ions). Density functional theory computational studies augment the experimental data. We discuss the challenges presented by shifting dimer-monomer proportions in determining the observable reaction orders and our mathematical treatment of such shifting in reactant structure.

Lithium Amino Alkoxide-Evans Enolate Mixed Aggregates: Aldol Addition with Matched and Mismatched Stereocontrol.

Building on structural and mechanistic studies of lithiated enolates derived from acylated oxazolidinones (Evans enolates) and chiral lithiated amino alkoxides, we found that amino alkoxides amplify the enantioselectivity of aldol additions. The pairing of enantiomeric series affords matched and mismatched stereoselectivities. The structures of mixed tetramers showing 2:2 and 3:1 (alkoxide-rich) stoichiometries are determined spectroscopically. Rate and computational studies provide a viable mechanistic and stereochemical model based on the direct reaction of the 3:1 mixed tetramers, but they raise unanswered questions for the 2:2 mixed aggregates.

Sodium Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and Mechanisms of Arene Metalations.

Sodium diisopropylamide (NaDA)-mediated metalations of arenes in tetrahydrofuran (THF)/hexane or THF/Me2NEt solutions are described. A survey of >40 benzenoid- and pyridine-based arenes with a range of substituents demonstrates the efficacy and regioselectivity of metalation. Metalations of activated disubstituted arenes and selected monosubstituted arenes are rapid at -78 °C. Rate studies of 1,3-dimethoxybenzene and related methoxylated arenes show exclusively monomer-based orthometalations with two or three coordinated THF ligands. Rate studies of the isotopic exchange of benzene and monosubstituted arenes with weakly activating groups reveal analogous di- and trisolvated monomer-based metalations. Cooperative inductive, mesomeric, steric, and chelate effects are discussed.

Lithium Hexamethyldisilazide-Mediated Enolization of Highly Substituted Aryl Ketones: Structural and Mechanistic Basis of the E/Z Selectivities.

Enolizations of highly substituted acyclic ketones used in the syntheses of tetrasubstituted olefin-based anticancer agents are described. Lithium hexamethyldisilazide (LiHMDS)-mediated enolizations are moderately Z-selective in neat tetrahydrofuran (THF) and E-selective in 2.0 M THF/hexane. The results of NMR spectroscopy show the resulting enolates to be statistically distributed ensembles of E,E-, E,Z-, and Z,Z-enolate dimers with subunits that reflect the selectivities. The results of rate studies trace the preference for E and Z isomers to tetrasolvated- and pentasolvated-monomer-based transition structures, respectively. Enolization using LiHMDS in N,N-dimethylethylamine or triethylamine in toluene affords a 65:1 mixture of LiHMDS-lithium enolate mixed dimers containing E and Z isomers, respectively. Spectroscopic studies show that condition-dependent complexation of ketone to LiHMDS occurs in trialkylamine/toluene. Rate data attribute the high selectivity exclusively to monosolvated-dimer-based transition structures.