Kinetically Controlled,Highly Chemoselective Acylation of Functionalized Grignard Reagents with Amides by N−C Cleavage

The direct transition-metal-free acylation of amides with functionalized Grignard reagents by highly chemoselective N−C cleavage under kinetic control has been accomplished. The method offers rapid and convergent access to functionalized biaryl ketones through transient tetrahedral intermediates. The direct access to functionalized Grignard reagents by in situ halogen–magnesium exchange promoted by the versatile turbo-Grignard reagent (iPrMgCl ⋅ LiCl) permits excellent substrate scope with respect to both the amide and Grignard coupling partners. These reactions enable facile, operationally simple and chemoselective access to tetrahedral intermediates from amides under significantly milder conditions than chelation-controlled intermediates. This novel direct two-component coupling sets the stage for using amides as acylating reagents in an alternative paradigm to the metal-chelated approach, acyl metals and Weinreb amides.     

Preparation and Application of Solid,Salt‐Stabilized Zinc Amide Enolates with Enhanced Air and Moisture Stability

The treatment of various N‐morpholino amides with TMPZnCl⋅LiCl (TMP=2,2,6,6‐tetramethylpiperidyl) and Mg(OPiv)₂ in THF at 25 °C provides solid zinc enolates with enhanced air and moisture stability (t _1/2 in air: 1–3 h) after solvent evaporation. These enolates undergo Pd‐ and Cu‐catalyzed cross‐couplings with (hetero)aryl bromides as well as allylic and benzylic halides. The arylated N‐morpholino amides were converted into various ketones by LaCl₃⋅2 LiCl mediated acylation with Grignard reagents. The new, solid enolates were used to prepare a potent anti‐breast‐cancer drug candidate in six steps and 23 % overall yield.     

Practical Synthesis of Phosphinic Amides/Phosphoramidates through Catalytic Oxidative Coupling of Amines and P(O)−H Compounds

Herein, we report a highly efficient ZnI₂-triggered oxidative cross-coupling reaction of P(O)−H compounds and amines. This operationally simple protocol provides unprecedented generic access to phosphinic amides/phosphoramidate derivatives in good yields and short reaction time. Besides, the reaction proceeds under mild conditions, which avoids the use of hazardous reagents, and is applicable to scale-up syntheses as well as late-stage functionalization of drug molecules. The stereospecific coupling is also achieved from readily available optically enriched P(O)−H compounds.     

Regio- and chemoselective metalation of arenes and heteroarenes using hindered metal amide bases

The preparation of highly functionalized organometallic compounds can be achieved by direct C H activation of a broad range of unsaturated substrates using lithium chloride solubilized 2,2,6,6‐tetramethylpiperidide bases (TMP_nMX_m⋅p LiCl). These are excellent reagents for converting a wide range of aromatic and heterocyclic substrates into valuable organometallic reagents with broad applications in organic synthesis.     

Thermodynamic characteristics of double salts crystallizing in LiCl-RbCl-H<Subscript>2</Subscript>O system at 298.15 K

The Pitzer ion-interaction model has been used for calculations of thermodynamic characteristics of double salts 3RbCl · LiCl · 2H₂O and RbCl · 2LiCl · 4H₂O in the ternary system LiCl-RbCl-H₂O at 298.15 K. The standard molar Gibbs energy of formation of the two double salts from the corresponding simple salts LiCl · H₂O and RbCl, as well as the standard molar Gibbs energy of formation have been determined.     

Synthesis of pinacol esters of 2,3-alkadienylboronic acid via the copper(I) mediated coupling reaction of Knochel's (dialkoxyboryl)methylzinc reagents with propargylic tosylates

The reaction of propargyl tosylates (1) with (dialkoxyboryl)methyl-copper(I) reagents, prepared in situ from Knochel's (dialkoxyboryl)-methylzinc iodide (2) and CuCN · 2LiCl, produced 2,3-alkadienyl-boronates (3) in moderate yields. The reaction proceeded regioselectively to provide an S_N2' substitution product without contamination by other products such as 3-alkynylboronate.     

Synthesis,structures and properties ofN-(trihalogermylmethyl)-substituted amides,lactams and imides,the derivatives of the five-coordinate germanium

The formation of trichlorogermyl-substituted amides, lactams, and imides occurs when 2Et₂O·HGeCl₃ is condensed with compounds possessing the -NCH₂Cl fragment and equally well when HGeCl₃ interacts with compounds containing -NCH₂OH and-NCH₂OSiMe₃ groups. In some cases, the use of the latter is more advantageous from the preparative point of view. In compounds thus obtained, the germanium is five-coordinate due to the coordination . Deceased August 13, 1993. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1793–1799, October, 1993.     

Microwave-assisted synthesis of α-aminophosphine oxides by the Kabachnik–Fields reaction applying amides as the starting materials

A series of acylated α-aminophosphine oxides were synthesized by the microwave-assisted Kabachnik–Fields reaction of a series of carboxylic acid amides, formaldehyde and secondary phosphine oxides. To compensate the lower reactivity of the –NH₂ reagents, they had to be used in an excess. The solvolytic condensations furnished the α-aminophosphine oxides in yields of 58–93% after purification by chromatography.     

Carbamoylimidazolium salts as diversification reagents: an application to the synthesis of tertiary amides from carboxylic acids

An efficient method for the preparation of tertiary amides from carbamoylimidazolium salts and carboxylic acids is described. The transformation occurs at room temperature and under relatively mild conditions. The carbamoylimidazolium salts are obtained from the reaction of secondary amines with N,N′-carbonyldiimidazole, followed by methylation with methyl iodide. The utility of this reaction was demonstrated in the formation of Weinreb amides and in a short synthesis of fused bicyclic amides. The introduction of this reaction now permits carbamoylimidazolium salts to be utilized in the formation of tertiary amides, ureas, carbamates and thiocarbamates under a single set of conditions.     

Synthese und Charakterisierung von Fluorenylgallaten und Fluorenylindaten

Synthesis and Characterization of Fluorenyl Gallates and Fluorenyl Indates GaCl₃ reacts with Fluorenyllithium (LiFl) in the ratio 1:4 in Et₂O to [Li(THF)₄][GaFl₄] ( 1 ). The addition of DME (1,2-dimethoxyethane) to solutions of 1 in THF leads to [Li(DME)₃][GaFl₄] ( 2 ) under replacement of THF molecules by DME molecules in the coordination sphere of the Li⁺ ions. Treatment of InCl with LiFl in Et₂O and recrystallization from THF gives [Li(THF)₄][ClInFl₃] ( 3 ), which is formed by an disproportionation reaction. 3 can also be obtained by the reaction of InCl with FlZnCl/LiCl in Et₂O and recrystallization from THF. 1 and 2 crystallize from THF and THF/DME as [Li(THF)₄][GaFl₄] · THF ( 1 · THF) and [Li(DME)₃][GaFl₄] · THF ( 2 · THF), respectively. Crystalline 3 is isolated from the reaction of InCl and FlZnCl/LiCl, while the reaction mixture of InCl and LiFl gives after recrystallization in THF 3 · 1,5 THF. The gallate ions in 1 and 2 differ mainly in the position of the fluorenyl ligands. The unit cells of 3 and 3 · 1,5 THF contain two crystallographic unique ion pairs of [Li(THF)₄][ClInFl₃].     

Synthesis, characterization and ion transportation studies of some novel cyclophane amides

Various novel cyclophane amides with a large cavity have been synthesized. The structures of cyclophane amides 14 and 15 were resolved using XRD studies. Cyclophane amide 28 shows a shift in λ_max in the UV/Vis. spectra when treated with Cu (II) ion as well as with Pb (II) ion. Ion transportation studies were carried out with cyclophane amide 14 which proved that the Na⁺ ion passes through the cavity while K⁺ ions are retained.     

Regioselective Magnesiation and Zincation Reactions of Aromatics and Heterocycles Triggered by Lewis Acids

Mixed TMP-bases (TMP=2,2,6,6-tetramethylpiperidyl), such as TMPMgCl ⋅ LiCl, TMP₂Mg ⋅ 2LiCl, TMPZnCl ⋅ LiCl and TMP₂Zn ⋅ 2LiCl, are outstanding reagents for the metalation of functionalized aromatics and heterocycles. In the presence of Lewis acids, such as BF₃ ⋅ OEt₂ or MgCl₂, the metalation scope of such bases was dramatically increased, and regioselectivity switches were achieved in the presence or absence of these Lewis acids. Furthermore, highly reactive lithium bases, such as TMPLi or Cy₂NLi, are also compatible with various Lewis acids, such as MgCl₂ ⋅ 2LiCl, ZnCl₂ ⋅ 2LiCl or CuCN ⋅ 2LiCl. Performing such metalations in continuous flow using commercial setups permitted practical and convenient reaction conditions.     

Benzazoles. 4. Synthesis and chemical reactions of 6-chlorosulfonylbenzoxazolin-2-ones

The corresponding 6-chlorosulfonyl derivatives were synthesized from benzoxazolin-2-one and its 3-methyl derivative by treatment with chlorosulfonic acid. By treatment of the compounds obtained with water and other nucleophilic reagents (aliphatic and heterocyclic amines) 2-oxobenzoxazoline-6-sulfonic acids and a series of their amides were obtained, while reduction with SnCl₂·2H₂O gave 6-mercaptobenzoxazolin-2-ones.     

Stereospecific polymerization of isobutyl vinyl ether by AlR3–VCln catalysts. I. Influence of preparative conditions of the catalysts

The polymerization of isobutyl vinyl ether by the VCl_n–AIR₃ system was carefully studied. The vanadium components were prepared by the reaction between VCl₄ and AlEt₃ or n-BuLi as a reducing agent. VCl₃·LiCl and VCl₂·2LiCl are the effective catalysts for the stereospecific polymerization of isobutyl vinyl ether. When VCl₃·LiCl is combined with AlR₃, a new catalytic system is formed. The effect of the preparative conditions of the various vanadium component in the AlR₃–VCl_n system shows that the effective vanadium component is trivalent. In the polymerization by VCl₃·LiCl–Al (i-Bu)₃ system, a change of the polymerization mechanism may occur at Al(i-Bu)₃/VCl₃·LiCl ratio at around 5. When the ratio is lower than 5, a cationic polymerization by VCl₃·LiCl takes place predominantly, while at ratios higher than 5, it is suggested that the polymerization proceeds by means of a VCl₃·LiClA–Al(i-Bu)₃ complex by a coordinated anionic mechanism. The polymers obtained by these catalysts are highly crystalline. Styrene was also polymerized by using the same catalysts. VCl₃·LiCl and VCl₃·LiCl–THF complex yielded amorphous polymer by cationic polymerization. When VCl₃·LiCl was combined with 6 mole-eq of Al(i-Bu)₃, the resulting polystyrene was highly crystalline and had an isotactic structure, while the VCl₂·2LiCl–Al(i-Bu)₃ (1:6) system yielded traces of polymer of extremely low stereoregularity. The results indicate that the effective vanadium component at Al/V ≧ 6 is trivalent and that the mechanism is a coordinated anionic one.     

Stereoselective Retentive Domino Transmetalations of Secondary Alkyllithium Compounds to Functionalized Secondary Alkylcopper Reagents

Functionalized secondary alkyllithium reagents obtained by I/Li exchange from the corresponding secondary alkyl iodides undergo two successive transmetalations with Me₃SiCH₂ZnBr?LiBr and CuBr?2 LiCl?Me₂S to provide functionalized secondary alkylcopper compounds with high retention of configuration. These alkylcopper derivatives react further with electrophiles such as alkynyl esters, acid chlorides, allylic chlorides, ketals, ethylene oxide, and 3‐iodocyclopentanone with high retention of configuration. A related sequence of transmetalations with MeMgI and LaCl₃?2 LiCl allows a retentive addition of secondary alkyllithium reagents to acetone. The influence of the solvent on the configurational stability of secondary alkylzinc reagents is described.     

Ru-catalyzed highly enantioselective hydrogenation of α-keto Weinreb amides

Asymmetric hydrogenation of α-keto Weinreb amides has been realized with [Ru((S)-Sunphos)(benzene)Cl]Cl as the catalyst and CeCl 3·7H2O as the additive.A series of enantiopure α-hydroxy Weinreb amides(up to 97% ee) have been obtained.Catalytic amount of CeCl3·7H2O is essential for the high reactivity and enantioselectivity and the ratio of CeCl3·7H2O to [Ru((S)-Sunphos)(benzene)Cl]Cl plays an important role in the hydrogenation reaction.     

A Practical and General Amidation Method from Isocyanates Enabled by Flow Technology

The addition of carbon nucleophiles to isocyanates represents a conceptually flexible and efficient approach to the preparation of amides. This general synthetic strategy has, however, been relatively underutilized owing to narrow substrate tolerance and the requirement for less favourable reaction conditions. Herein, we disclose a high‐yielding, mass‐efficient, and scalable method with appreciable functional group tolerance for the formation of amides by reaction of Grignard reagents with isocyanates. Through the application of flow chemistry and the use of substoichiometric amounts of CuBr₂, this process has been developed to encompass a broad range of substrates, including reactants found to be incompatible with previously published procedures.     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

Correlation between the reactivity and spectroscopic properties of N‐substituted secondary thioamides. New intramolecular N···H+···N binding approach and proton complexes based on thioamide ligation

On the basis of a comparison of chemical shifts and wavenumbers of several secondary thioamides and amides having monocationic substituents attached to thiocarbamoyl or carbamoyl groups by a polymethylene chain, new intramolecular unconventional N···H⁺···N hydrogen bonding effects were discovered. It is argued that the CH₂—N rotation is hindered and two ⁺H···NHCH₃ non‐equivalent protons occur in a proton spectrum of hydrochloride 1a (at 10.68 and 2.77 ppm, respectively) instead of two ⁺NH₂CH₃ protons. Presumably, the above steric factors inhibit the acidic hydrolysis of 1a (stabilized by strong intramolecular N···H⁺···N hydrogen bonds) to an amide and prevent intramolecular cyclization of 2a (stabilized by strong intramolecular neutral–neutral N···HN hydrogen bonds) to a cyclic amidine. Postulation of additional dihydrogen bond formation is helpful in understanding the spectroscopic differences of 4 and 5 . The above new bonding is also compared with intramolecular N···H—N⁺ hydrogen bonds in primary amine salts 7 and 8 . In contrast to 3 , a cooperative hydrogen bonded system is observed in 9 and 10 . The weak hydrogen bonds in 7 – 10 facilitate the hydrolysis and cyclization reactions of secondary thioamides. The spectroscopic data for secondary (thio)amides are especially useful for characterizing the electronic situation at the (thio)carbamoyl nitrogen atoms and they are perfectly correlated with the reactivity. Examples of chelation of protons by thioamides ( 11 and 12 ), which contain strongly electron‐donating pyrimidine groups, are presented to show the contribution of dihydrogen bonding in the protonation reaction similar to 1 and 4 . Copyright © 2003 John Wiley & Sons, Ltd.     

Aminolysis of 3-Phenyl Propylthiol Esters Leading to Diverse Sets of Amides

3-Phenyl propylthiol esters were investigated as “activatable” solution phase linkers. These linkers can be activated with silver salts and upon treatment with amines can be converted to the corresponding amides. Under unactivated conditions, the linker is stable to a variety of reagents and reaction conditions including treatment with amines.