Disparate behavior of ketones and thioketones on reaction with organolithiums

The reactions of alkyllithiums with ketones and thioketones proceed in fundamentally different ways. Whereas alkyllithiums add to the carbonyl carbon of ketones to give tertiary alcohols, the reaction with thioketones proceeds to give secondary thiols by reduction of the CS group. Transition states for the addition and reduction reactions of acetone and thioacetone in ethereal solution have been located and the computed activation free energies are in agreement with the observed behavior of ketones and thioketones in reactions with alkyllithiums.     

High yield acyl anion trapping reactions: direct nucleophilic acylation of isocyanates and isothiocyanates.

The reactions of t-BuLi, sec-BuLi and n-BuLi with CO in the presence of isothiocyanates and isocyanates gives, after hydrolytic work-up, α-oxothioamides, RC(O)C(S)NHR′, and α-oxoamides, RC(O)C(O)NHR′, respectively, in good yield. Competition from the direct reaction of RLi with the substrate is encountered only in the case of reactions of the n-BuLi/CO system with isocyanates.     

[1,4]‐S‐ to O‐Silyl Migration: Multicomponent Synthesis of α‐Thioketones through Chemoselective Transformation of Esters to Ketones with Organolithium Reagents

A [1,4]‐S‐ to O‐silyl migration has been exploited to chemoselectively transform esters into ketones by using organolithium reagents, allowing multicomponent synthesis of α‐thioketones. Mechanistic studies reveal that this migration proceeds in an intramolecular manner and is more favorable than the corresponding [1,5]‐S‐ to O‐ and [1,3]‐C‐ to O‐silyl migrations. The resulting α‐thioketones are valuable building blocks for the synthesis of cyclic or multifunctionalized organosulfur compounds.     

Computational study of the properties and reactions of small molecules containing O, S, and Se

The reactions and properties of a series of chalcogen-containing compounds (CH(3))(2)X and (CH(3))(2)C═X, where X = O, S, and Se, were studied computationally at the CBS-QB3 level to examine the differences among these molecules. The reactions and properties investigated include the double bond dissociation energy, the ionization potential, the interaction energies with a series of acids including a proton, CH(3)(+), Li(+), MeLi, and MeOH, and the enolization energies of the (CH(3))(2)C═X species. The effect of substituting the O of acetamide with S or Se also was studied. The changes that result from these reactions were examined via changes in structure and changes in charge distribution using the Hirshfeld charges.     

Effect of solvent on the lithium-bromine exchange of aryl bromides: reactions of n-butyllithium and tert-butyllithium with 1-bromo-4-tert-butylbenzene at 0 degrees C

The outcome of reactions of 1-bromo-4-tert-butylbenzene (1), a representative aryl bromide, with n-BuLi or t-BuLi at 0 degrees C in a variety of solvent systems has been investigated. The products of reactions of 1 with n-BuLi vary significantly with changes in solvent composition: 1 does not react with n-BuLi in pure heptane; the exchange reaction to give (4-tert-butylphenyl)lithium, which is slow in pure diethyl ether, is virtually quantitative in heptane containing a small quantity of THF; and the reaction of 1 with n-BuLi in THF leads to considerable coupling. Lithium-bromine exchange is the virtually exclusive outcome of reactions of 1 with t-BuLi in every solvent studied except pure heptane: the presence of a small quantity of any of a variety of structurally diverse ethers (Et(2)O, THF, THP, MTBE) in the predominantly hydrocarbon medium affords (4-tert-butylphenyl)lithium, assayed as tert-butylbenzene, in yields exceeding 97%. The only side products observed from reactions of 1 with t-BuLi are small amounts of benzyne-derived hydrocarbons.     

Spectroscopie RMN du Carbone-13 de Thiocétones Aliphatiques: Propanethione et Dérivés,Thiocétones Bicycliques et α Cyclopropaniques

Carbon-13 NMR spectra of various aliphatic ketones and thioketones were determined and interpreted. As shown by the relation between ¹³C chemical shifts in C=A groups, the C=S is more sensitive to the substituents than the C=O group. Conjugative effects are more pronounced in α-cyclopropyl thioketones than in α-cyclopropyl ketones.     

Chemistry of N-Boc-N-tert-butylthiomethyl-protected alpha-aminoorganostannanes: diastereoselective synthesis of primary beta-amino alcohols from alpha-aminoorganostannanes

Reaction of N-Boc-N-tert-butylthiomethyl-protected alpha-aminoorganostannanes with n-BuLi generates the corresponding alpha-aminoorganolithiums. Reactions of these organolithiums with aromatic aldehydes provides N-protected beta-amino alcohols with diastereoselectivities up to >99:1 anti/syn; with aliphatic aldehydes, diastereoselectivities were typically 1:1. Diastereoselectivities varied depending on the amount of aldehyde used. The N-protected beta-amino alcohols could be deprotected to primary amines by treatment with NaH to generate oxazolidinones followed by basic hydrolysis. Alternatively, treatment of the protected amino alcohols with acid furnished cyclic acetals that could be deprotected to primary amines with BF(3).OEt(2) and HS(CH(2))(3)SH. Transmetalation of enantiomerically enriched organostannanes with n-BuLi at -95 degrees C provided organolithiums that, although less configurationally stable than N-Boc-N-methyl-protected alpha-aminoorganolithiums, could be trapped with aldehydes with near-complete retention of configuration.     

Photochemical reactions of β-aminovinyl aryl thioketones

Irradiation of β-aminovinyl aryl thioketones ( 1a-b ) afforded β-aminovinyl aryl ketones ( 2a-b ). 2H-Thiopyran derivatives ( 4a-b ) were obtained when β-aminovinyl phenyl thioketone ( 1a ) was irradiated with methyl acrylate and acrylonitrile. 4H-Thiopyran derivatives ( 6,8 ) were also obtained thermally in the reaction of β-aminovinyl phenyl thioketone ( 1a ) and methyl propiolate and maleic anhydride.     

Thioformaldehyde S-methylide and thioacetone S-methylide: an ab initio MO study of structure and cycloaddition reactivity

The mechanisms of cycloaddition of thioformaldehyde S-methylide and thioacetone S-methylide, as models for an alkyl-substituted ylide, to thioformaldehyde and thioacetone, as well as to ethene as a model for a C=C double bond have been studied by ab initio calculations. Restricted and unrestricted B3LYP/6-31G* calculations were performed for the geometries of ground states, transition structures, and intermediates. Although basis sets with more polarization functions were tested, the 6-31G* basis set was applied throughout. Single-point CASPT2 calculations are reported for analysis of the unsubstituted system. The stabilities of structures with high biradical character seem to be overestimated by DFT methods in comparison to CASPT2. The general trends of the results are independent of the level of theory. Thioformaldehyde adds to thioformaldehyde S-methylide without activation energy, and the activation energies for two-step biradical pathways to 1,3-dithiolane are low. C,S biradicals are more stable than C,C biradicals. The two-step cycloaddition is not competitive with the concerted cycloaddition. Methyl substitution in the 1,3-dipole and the dipolarophile does not change the mechanistic relationships. TSs for the concerted formation of the regioisomeric cycloadducts of thioacetone Smethylide and thioacetone were located. Concerted addition remains the preferred reaction. The reactivity of the C=S double bond is high relative to that of the C=C double bond.     

Crystal structures of n-BuLi adducts with (R,R)-TMCDA and the consequences for the deprotonation of benzene

Combinations of organolithium compounds and diamine bases have become a powerful tool in synthetic chemistry. Because of the structure-reactivity relationship, the elucidation of reaction mechanisms of these reagents is strongly connected with the structural determination of intermediate species. In mixtures of the diamine TMCDA (N,N,N',N'-tetramethylcyclohexane-1,2-diamine) and n-butyllithium, two different structures, the dimeric [n-BuLi x (R,R)-TMCDA]2 and the aggregate [(n-BuLi)2 x (R,R)-TMCDA]2, can be isolated, depending on the n-BuLi/TMCDA ratio. Thereby, [(n-BuLi)2 x (R,R)-TMCDA]2 is a rare example of an organolithium compound with a ladder arrangement of the central four-membered Li-C-Li-C rings. Two isomers of the ladder structure are formed in the crystal by changing from the enantiomerically pure to racemic TMCDA. As n-BuLi/TMCDA mixtures are also able to deprotonate benzene, these structures give hint to possible mechanisms. Supported by theoretical studies, transition states based on the dimer, the ladder structure, and a hypothetical monomer are discussed.     

General and Efficient Insertions of Carbons Carrying Aryl and Heteroaryl Groups: Synthesis of alpha-Aryl- and alpha-Heteroaryl-Substituted Ketones

Anions formed from the lithiation of a variety of 1-(arylmethyl)- and 1-(heteroarylmethyl)benzotriazoles 1 with n-BuLi underwent addition to aliphatic and aromatic aldehydes and cyclic and acyclic ketones. Subsequent in situ thermal rearrangements of the intermediates in the presence of zinc bromide provided one-carbon chain-extended or ring-expanded alpha-aryl- and alpha-heteroaryl-substituted ketones 2 in moderate to excellent yields in simple one-pot operations with excellent regioselectivity in most cases. Substituent effects on the relative migration rates were investigated in the insertion reactions of 1-(4-methoxybenzyl)benzotriazole (1e) with XC(6)H(4)COPh. The small and negative Hammett rho(+) value (-0.92) suggested that the rearrangements proceed via early, reagent-like, electron deficient transition states.     

Regio- and Stereoselective Formation of 1,3-Oxathiolanes by Reactions of Thiocarbonyl Compounds with Oxiranes

Abstract

Lewis acid-catalyzed reactions of oxiranes with a variety of C═S compounds yield 1,3-oxathiolanes. The ring enlargement of monosubstituted oxiranes occurs regioselectively via cleavage of the O,C(3) bond of alkyl substituted oxiranes and the O,C(2) bond of phenyl oxirane. Furthermore, the reaction proceeds with inversion of the configuration at the center of the nucleophilic attack by the S-atom. The formation of thiocarbonylium ions as intermediates is supported by Wagner–Meerwein-type rearrangements. Enolized thioketones react with oxiranes to give enesulfanyl alcohols, which undergo an acid-catalyzed cyclization to yield 1,3-oxathiolanes.     

A DFT Study on the Molecular Mechanism of Additions of Electrophilic and Nucleophilic Carbenes to Non-Enolizable Cycloaliphatic Thioketones

The molecular mechanisms of addition of dihalocarbenes and dimethoxycarbene to thioketones derived from 2,2,4,4-tetrmethylcyclobutane-1,3-dione were examined on the basis of the DFT wb97xd/6-311g(d,p)(PCM) calculations. Obtained results demonstrated that the examined processes exhibit polar nature and in the case of electrophilic dichloro-, and dibromocarbenes are initiated by the attack of carbene species onto the sulfur atom of the C=S group. Remarkably, reactions involving more electrophilic carbenes (dichloro-, and dibromocarbene) proceeds via stepwise mechanism involving thiocarbonyl ylide as a transient intermediate. In contrast, analogous reactions with nucleophilic dimethoxycarbene occur via a single step reaction, which can be considered as the [2 + 1] cycloaddition reaction initiated by the attack onto the C=S bond. A computational study showed that difluorocarbene tends to react as a nucleophilic species and resembles rather dimethoxycarbene and not typical dihalocarbene species. Significantly higher reactivity of the thioketone unit in comparison to the ketone group, both present in 3-thioxo-2,2,4,4-tetramthylcyclobutanone molecule, was rationalized in the light of DFT computational study.     

NMR and calculational studies on the regioselective lithiation of 1-methoxynaphthalene

1-Methoxynaphthalene (1) undergoes regioselective lithiation in position 2 (n-BuLi/TMEDA) or in position 8 (t-BuLi), respectively. The detected formation of a n-BuLi/1 complex (1:1 n-BuLi/1 mixture) appears to have only minor influence on the regioselectivity (both products are obtained). The exchange of hydrogen atom H2 by deuterium results in a remarkably reduced reaction rate for the lithiation with n-BuLi in THF-d(8). This isotope effect and the formation of the thermodynamically less favorable 2-lithio compound suggest a kinetically controlled mechanism. The lack of an isotope effect for the reaction of 8-deuterio-1-methoxynaphthalene with t-BuLi and the formation of the thermodynamically preferred 8-lithiated product indicate a thermodynamically controlled mechanism. Slow conversion of the 2- into the 8-lithiated species (at higher temperatures) gives further evidence that n-BuLi and t-BuLi afford the kinetically and thermodynamically preferred products, respectively.     

Isoprene Polymerization by Butyllithium in Cyclohexane. I. Initiation Reaction

Kinetic studies, using a gas chromatographic method, of the consumption of n-, sec-, and t-butyllithium during the polymerization of isoprene in cyclohexane show in the three cases a sigmoidal curve. When the concentration of polyisoprenyllithium increases, the initiation rate goes through a maximum with n-butyllithium but continuously increases in the two other cases. The three corresponding lithium-butoxides have a drastic effect on the initiation rate. Thus, the addition of n-butoxide strongly increases the initial rate, but the rate further decreases except in the case of sec-butyl-lithium. The behavior of the sec-butoxide is roughly the same, but more limited, while the t-butoxide causes a slight initial promotion in the case of n-BuLi and sec-BuLi but decreases the initiation rate in the case of t-BuLi. These results are discussed in terms of association of organolithium molecules and ion pairs reactivity.     

Nickel-on-charcoal-catalyzed aromatic aminations and Kumada couplings: mechanistic and synthetic aspects

Protocols for aromatic aminations and Kumada couplings catalyzed by 'heterogeneous' nickel-on-charcoal (Ni/C) have been revised, making them simpler and more time efficient. For both types of reactions, reduction of the catalyst precursor Ni(II)/C using n-BuLi prior to addition of a substrate can be avoided. Instead, in amination reactions, the amine in combination with lithium tert-butoxide was found to convert Ni(II)/C to active Ni(0). For Kumada couplings, direct reduction of Ni(II)/C by the Grignard reagent is easily achieved. Reactions run in the presence of triarylphosphine ligands of varying substitution patterns and with differing electronic properties provided insight into the mechanism of these nickel-catalyzed transformations. Ligandless Kumada couplings were facile with aryl Grignards, which may be a consequence of pi-complexation of nickel by the aryl group in the reagent. Larger scale reactions of both types of couplings have been successfully performed, suggesting that Ni/C-based processes can be scaled-up as needed.     

Novel Cleavage of Propargylamines by Reaction with Organolithium Compounds

Treatment of secondary aliphatic 2-bromoallylamines with an excess of an organolithium compound led to saturated amines in which the organic group of the organolithium compound is incorporated at the alpha carbon. On the other hand, the successive reaction of the former amines with BuLi and t-BuLi between -80 degrees C and rt gave 1,3-diamines or hexahydropyrimidines depending on the reaction time. The formation of these unexpected products involves initial generation of lithium propargylamides, which subsequently undergo cleavage of the C propargylic-C acetylenic bond induced by the organolithium present in each case in the reaction medium. A mechanism which takes into account all the different reaction products has been proposed and additionally supported by successful trapping of dilithium acetylide.     

An unexpected base-induced [1,4]-phospho-Fries rearrangement

An unexpected [1,4]-phospho-Fries rearrangement that gives rise to the formation of a O,O,O,O-tetraethyl methylenebis(thiophosphonate) derivative is reported. The regioselectivity of the metallation with n-BuLi or t-BuLi is the key factor that explains either the [1,4] or [1,3] rearrangement observed.     

The use of sulfines in nucleophilic acylation reactions

The thiophilic addition of MeLi and BuLi to aromatic alkylthio- and arylthio sulfines has been studied. The resulting dithioacetal monoxides are isolated in high yields. Reactions of MeLi with aromatic arylsulphinyland arylsulfonyl sulfines give the corresponding dithioacetal di- and trioxidcs. Acid treatment of dithioacetal monoxides results in aromatic aldehydes. The nucleophilic acylation of the acylanion equivalents obtained from sulfines is investigated. Alkylation of the dithioacetal monoxide anions, prepared in situ from MeLi and sulflnes of the type Ar(RS)CSO. with primary alkyl halides leads to dithioketal monoxide which upon acidolysis under anhydrous conditions are converted into vinylsulfides. The mechanism of the formation of the vinyl sulfides is discussed. The acylanion equivalents are acylated with benzoylchloride, CO₂ and benzaldehyde. The use of Cu¹ and 18-crown-6 as a catalyst appears to be crucial in some reactions. Michael additions of the dithioacetal monoxides to acrylonitrile are described.     

(MeLi)4(dem)1.5]infinity] and [(thf)3Li3M3[(NtBu)3S--how to reduce aggregation of parent methyllithium

Organolithium compounds play the leading role among the organometallic reagents in synthesis and in industrial processes. Up to date industrial application of methyllithium is limited because it is only soluble in diethyl ether, which amplifies various hazards in large-scale processes. However, most reactions require polar solvents like diethyl ether or THF to disassemble parent organolithium oligomers. If classical bidentate donor solvents like TMEDA (TMEDA= N,N,N',N'tetramethyl-1,2-ethanediamine) or DME (DME=1,2-dimethoxyethane) are added to methyllithium, tetrameric units are linked to form polymeric arrays that suffer from reduced reactivity and/or solubility. In this paper we present two different approaches to tune methyllithium aggregation. In [[(MeLi)4(dem)1,5)infinity] (1; DEM = EtOCH2OEt, diethoxymethane) a polymeric architecture is maintained that forms microporous soluble aggregates as a result of the rigid bite of the methylene-bridged bidentate donor base DEM. Wide channels of 720 pm in diameter in the structure maintain full solubility as they are coated with lipophilic ethyl groups and filled with solvent. In compound 1 the long-range Li3CH3...Li interactions found in solid [[(MeLi)4]infinity] are maintained. A different approach was successful in the disassembly of the tetrameric architecture of [((MeLi)4]infinity]. In the reaction of dilithium triazasulfite both the parent [(MeLi)4] tetramer and the [[Li2[(NtBu)3S]]2] dimer disintegrate and recombine to give an MeLi monomer stabilized in the adduct complex [(thf)3Li3Me-[(NtBu)3S]] (2). One side of the Li3 triangle, often found in organolithium chemistry, is shielded by the tripodal triazasulfite, while the other face is mu3-capped by the methanide anion. This Li3 structural motif is also present in organolithium tetramers and hexamers. All single-crystal structures have been confirmed through solid-state NMR experiments to be the same as in the bulk powder material.