Regioselectivity in deprotonation of ketone dimethylhydrazones with lithium amide bases

The regiochemistry of deprotonation of 3-pentanone dimethylhydrazone by lithium amide bases has been studied by ¹³C-NMR spectroscopy of ¹³C-enriched samples.     

Rearrangement of spirocyclic oxindoles with lithium amide bases

Spirocyclohexa-2,5-dienes were shown to rearrange at -40 degrees C, when treated with 1 equiv of LDA. Alkyl halides and aldehydes then reacted with the resulting phenanthridinone lithium enolate intermediates, with distinct regioselectivities and high diastereocontrol, to afford functionalized dearomatized phenanthridinones which were elaborated further. A mechanistic scheme involving a diisopropylamine-mediated proton transfer was proposed to rationalize the rearrangement.     

Scope and limitations of the catalytic asymmetric rearrangement of epoxides to allylic alcohols using chiral lithium amide bases/lithiated imidazoles

The catalytic asymmetric rearrangement of functionalised cyclohexene and cyclopentene oxides has been studied using sub-stoichiometric amounts of a chiral lithium amide in combination with a stoichiometric amount of three different lithiated imidazoles. 1-Methylimidazole that had been lithiated at the C-2 aryl position gave the highest enantioselectivity (82% ee). With 1,2-dimethylimidazole that had been lithiated at the C-2 methyl group, epoxide ring opening occurred as an unexpected and competing process. Ultimately, ring opening was suppressed using a more sterically hindered imidazole. In all catalytic examples, a racemic background reaction (presumably due to rearrangement by the lithiated imidazoles) was observed.     

Computational study of solvation and stereoselectivity in deprotonation of cyclohexene oxide by a chiral lithium amide

A detailed computational investigation of possible activated complexes in the epoxide opening of cyclohexene oxide by a chiral lithium amide is presented. Transition states for the two routes giving (S)- and (R)-alkoxides with and without solvent have been calculated. Geometry optimizations at PM3 and HF/3-21G levels of theory, and single point calculations at B3LYP/6-31+G(d) level have been used. The experimentally obtained stereoselectivity is semi-quantitatively reproduced at all levels except PM3//PM3. The factors found to control the stereoselectivity are solvation and some non-bonded interactions other than those previously proposed.     

The first example of enantioselective isocyanosilylation of meso epoxides with TMSCN catalyzed by novel chiral organogallium and indium complexes

The desymmetrization ring opening of meso epoxides using trimethylsilyl cyanide catalyzed by organogallium and indium complexes with binaphthol monoether derivatives as chiral ligands gave beta-isocyanohydrins with moderate to excellent enantioselectivities of up to 95% ee.     

On the deprotonation of 3,5-dichloropyridine using lithium bases: in situ infrared spectroscopic studies

Deprotonation of 3,5-dichloropyridine using LTMP and BuLi was monitored in real time by infrared spectroscopy. It appeared that the substrate was rapidly deprotonated. Transient structures between the substrate and the lithio derivative were detected. The absorbances recorded for the lithio derivative showed that the structures obtained using LTMP and BuLi were similar. When BuLi was used to deprotonate, a complete deuteration of the lithio derivative was noted upon quenching with D₂O. The latter did not allow the quantification of the lithio derivative when LTMP was used, since only partial deuteration was observed.     

Application of chiral lithium amide bases to the thia-Sommelet dearomatization reaction

Thia-Sommelet dearomatization reactions of benzylsulfonium ylides can create highly congested quaternary centers. Chiral bis-lithium amide bases were shown to effect enantiotopic deprotonation of benzylsulfonium ions, leading to thia-Sommelet rearrangement. The chiral trienes were generated in up to 50% ee.     

Composition of the activated complex in the stereoselective deprotonation of cyclohexene oxide by a chiral lithium amide

Chiral lithium amides are being developed for stereoselective synthesis of chiral allylic alcohols in high yields and with high enantiomeric excess. However, rational design of the amides for improved stereoselectivity by computational methods, for example, has not been possible due to lack of knowledge of the activated complexes involved in the reactions. Kinetic results are presented for the stereoselective deprotonation by lithium (S)-1-(2-pyrrolidinylmethyl)pyrrolidide (1-Li) of cyclohexene oxide 2, in diethyl ether (DEE), to form (S)-2-cyclohexen-1-ol (S)-3 in high enantiomeric excess. The results show that the rate limiting activated complex is composed of one lithium amide monomer and one molecule of 2 and presumably a solvent molecule. The diamine 1 is found to catalyze the deprotonation.     

Highly enantioselective synthesis of rigid, quaternary 1,4-benzodiazepine-2,5-diones derived from proline

[reaction: see text] Proline-derived 1,4-benzodiazepine-2,5-diones are extremely useful scaffolds in medicinal chemistry. In this paper, we describe a protocol for retentive C3 alkylation of these materials, thus accomplishing the direct synthesis of enantiopure quaternary 1,4-benzodiazepine-2,5-diones. The high enantioselectivities (up to 99.5%) are attributed to memory of chirality.     

One-step deprotonation route to zinc amide and ester enolates for use in aldol reactions and Negishi couplings

Simple amides and esters are conveniently deprotonated by Zn(tmp)₂ (tmp = 2,2,6,6-tetramethylpiperidinyl anion) to generate Zn enolates. Enolates formed by this method are suitable for use in aldol reactions that tolerate base-sensitive functional groups. Additionally, the Zn enolates are readily coupled with aryl bromides using typical Pd-catalyzed coupling methods.     

Characterization of dimeric chiral lithium amide structures derived from N-isopropyl-O- triisopropylsilyl valinol

The dimeric structure is characterized for a chiral amide base complex consisting of an (S)-N-isopropyl-O-triisopropylsilyl valinol ligand and lithium. The complex is characterized by a variety of NMR techniques, including multinuclear one- and two-dimensional NMR experiments and diffusion-ordered NMR spectroscopy (DOSY) as well as diffusion coefficient-formula weight (D-fw) correlation analyses. Spartan calculations are presented which support the structural assignment. This structural characterization leads to an explanation of the behavior and the reactivity of these complexes in solution.     

Bridgehead enolates: substitution and asymmetric desymmetrization of small bridged carbonyl compounds by lithium amide bases

[reaction: see text] Contrary to expectations, a number of bridged carbonyl compounds undergo facile bridgehead metalation with lithium amide bases. Diketone, lactone, lactam, and imide functions are all demonstrated to participate in this type of "bridgehead enolate" chemistry, leading to a range of substituted products. Meso compounds can also be desymmetrized in very high ee by asymmetric bridgehead metalation.     

An experimental and computational investigation of the enantioselective deprotonation of Boc-piperidine

The asymmetric deprotonation of N-Boc-piperidine (3) by the 1:1 complex of a sec-alkyllithium and (-)-sparteine has been investigated both experimentally and computationally. The lithiation of 3 with sec-BuL-(-)-sparteine at -78 degrees C, which is a much slower process than is the analogous deprotonation of N-Boc-pyrrolidine (1) and a minor reaction relative to the competing addition of sec-BuLi to the carbamate, proceeds with a moderate degree of selectivity (er = 87:13) for removal of the pro-S hydrogen of 3. The related deprotonation of N-Boc-4-tosyloxypiperidine (6) with two molar equiv of sec-BuL-(-)-sparteine also involves preferential transfer of the pro-S hydrogen. The computational study of the deprotonation of (3) by i-PrL-(-)-sparteine found that the proton that is preferentially transferred within three-component intermediate complex is the thermodynamically least acidic alpha-hydrogen of 3. The asymmetric deprotonation of 3 is calculated to proceed with poor enantioselectivity and to have an activation energy considerably higher than that calculated for deprotonation of N-Boc-pyrrolidine (1). The experimental and computational results are in good agreement.     

Composition and structure of activated complexes in stereoselective deprotonation of cyclohexene oxide by a mixed dimer of chiral lithium amide and lithiated imidazole

Stereoselective deprotonation of cyclohexene oxide, using a mixed dimer built of the chiral lithium amide, lithium (1R,2S)-N-methyl-1-phenyl-2-pyrrolidinyl-propanamide, and 2-lithio-1-methylimidazole, has been studied. The composition of the rate limiting activated complex was determined by kinetics to be built from one mixed dimer molecule and one epoxide molecule. Based on this knowledge computational chemistry has been applied to gain insight into possible structures of the activated complexes.     

Preparation and characterization of TADDOLs immobilized on hydrophobic controlled-pore-glass silica gel and their use in enantioselective heterogeneous catalysis

Highly porous silica gel (controlled-pore glass, CPG, ca. 300 m2 g(-1)) with covalently attached TADDOLs (loading 0.3-0.4 mmol g(-1)) and Me3Si-hydrophobized surface has been prepared: First, mercaptopropyl groups were attached to the silica gel by treatment with (mercaptopropyl)trimethoxysilane; then the SH groups were trityl-protected, and the remaining accessible SiOH groups hydrophobized by silylation (heating with Me3Si-imidazole); after deprotection, the SH groups were used as nucleophiles for benzylation with TADDOLs carrying a 4-bromomethyl-phenyl group in the 2-position of their dioxolane rings; alternatively, the SH groups have been benzylated with the 4-bromomethyl-benzaldehyde acetal of diethyltartrate, and the diarylmethanol moieties of the TADDOLs created on the solid support by addition of excess phenyl, or 1- or 2-naphthyl magnesium bromide. Each step of the immobilizing procedure was carefully monitored and analyzed (Ellman's test, methyl-red test), and resulting materials characterized by electron microscopy, DRIFT spectroscopy (IR), 13C- and 29Si NMR solid-state NMR spectroscopy, and elemental analysis. The immobilized TADDOLs were titanated to give (iPrO)2Ti-, Cl2Ti-, or (TosO)2Ti-TADDOLates which were used for catalyzing the additions of Et2Zn or Bu2Zn to PhCHO and of diphenyl nitrone to 3-crotonoyl-oxazolidinone. The following findings are remarkable: i) The enantioselectivities and conversions of the reactions mediated by the CPG-immobilized Ti-TADDOLates match those observed under standard homogeneous conditions. ii) If and when the rates and/or the enantioselectivities of reactions have dropped after several applications of the same catalyst batch, washing with aqueous HCl/acetone and reloading with titanate leads to full restoration of its performance. iii) There is no detectable loss of the hydrophobizing Me3Si groups after nine acidic washes! iv) There is a seasoning of the catalyst material in the Cl2Ti-TADDOLate-mediated [3+2] cycloaddition of diphenylnitrone: Initially it is necessary to use 0.5 equivalents of the immobilized catalyst to match the performance of the homogeneous catalyst; after three runs the reaction rate, enantio- and diastereoselectivity have dropped considerably; acidic washing after each subsequent run completely restores the performance; after a total of seven runs the amount of catalyst can be reduced to 0.4, 0.3, 0.2, and 0.1 equivalents in the following runs, with identical good results!     

Polyfluorovinyl lithium reagents and their use in synthesis

The use of polyfluorovinyl lithium reagents in synthesis since their original discovery almost simultaneously by Seyferth and Tarrant and their development by Normant is reviewed. More recent developments in the field using CFC replacements as starting materials has given a new impetus to the use of these important reagents as building blocks for the development of new materials. These new reactions are also reviewed.     

Spectrothermodynamic relationship of cationic vs anionic species derived from protonation vs deprotonation of pyrrolo-aza-aromatic bases in homologous series.

Theoretical research on the spectroscopy and protonation energies of ionic species related to the neutral pyrrolo-aza-aromatic bases has been carried out, using Density Functional Theory (DFT) and its time dependent form (TDDFT). In the ionic species the skeleton localized (+) and (-) charge in the protonated and deprotonated species is shown to have a strong perturbation of the pi-electronic states. The lowest electronic S(0) --> S(1) (pi,pi*) transitions are shown to have near-coincidence for each cation and anion for the whole homologous series, in agreement with the Valle-Kasha-Catalán rule previously stated. It is further demonstrated that simultaneous dramatic changes, upon electronic excitation, in acidity and basicity at the pyrrolo- and aza-positions of the molecular skeleton are the driving force for the biprotonic phototransfer processes in these bases. This constitutes confirmation of the proton-transfer rather than H-atom transfer as the reaction mechanism.