Asymmetric deprotonation-substitution of N-Pop-benzylamines using [RLi/(-)-sparteine]. Enantioselective sequential reactions and synthesis of N-heterocycles

Pop-directed asymmetric deprotonation of benzylic amines using [n-BuLi/(-)-sparteine] provides an efficient method for the synthesis of chiral NC alpha and NC alpha,alpha' derivatives with total selectivity with respect to competing allylic and ortho lithiation. The method described herein offers a straightforward route of accessing chiral N-Pop-protected nitrogen heterocycles.     

Palladium catalysts on alkaline-earth supports for racemization and dynamic kinetic resolution of benzylic amines

Palladium catalysts on alkaline-earth supports were studied as new heterogeneous catalysts for racemization of chiral benzylic amines such as 1-phenylethylamine. Particularly 5 % Pd/BaSO(4) and 5 % Pd/CaCO(3) were able to selectively racemize amines, with minimal formation of secondary amines or hydrogenolysis to ethylbenzene. In contrast, these side reactions were pronounced on Pd/C. A reaction mechanism is proposed that is consistent with the reaction kinetics. The catalyst activity was found to depend on the number of available surface Pd atoms, determined by titration with CO. The selectivity crucially depends on the rate of condensation of the amine and the primary imine, which is highest on Pd/C. The racemization catalysts were combined in one pot with an immobilized lipase to perform dynamic kinetic resolution of chiral amines. High yields (up to 88 %) of essentially enantiopure amides were obtained in a single step. The chemo-enzymatic catalyst system proved to be stable and could be reused without losing the initial activity.     

Pd(OAc)2-catalyzed carbonylation of amines

A phosphine-free catalytic system [Pd(OAc)2-Cu(OAc)2-air] induced a substrate-specific carbonylation of amines in boiling toluene under CO gas (1 atm). Symmetrical N,N'-dialkylureas were obtained by the carbonylation of primary amines. N,N,N'-Trialkylureas were selectively formed by addition of a secondary amine to the above reaction vessel. Secondary amines did not give tetraalkylureas. However, dialkylamines with a phenyl group on their alkyl chains, such as N-monoalkylated benzylic amine or phenethylamine derivatives, underwent a direct aromatic carbonylation to afford five- or six-membered benzolactams. In the carbonylation, the chelation effect or steric repulsion between Pd(II) and the meta-substituent in the ortho-palladation and the ring sizes of cyclopalladation products that were formed prior to carbonylation were found to generate good site selectivity and increase the reaction rate. In contrast, carbonylation of omega-arylalkylamines with a hydroxyl group gave neither ureas nor benzolactams but instead produced 1,3-oxazolidinones smoothly. Hydrochlorides of amines also underwent carbonylation to afford the corresponding amides under the conditions used. This procedure made it possible to prepare ureas of amino acid esters and N-alkylcarbamates in practical yields.     

Kinetics of amine-cyclic anhydride reactions in moderately polar solutions

The validity of extrapolating the reactivity of low molar mass compounds in solution to the polymer-analogous chemistry between polymer-bound functionality is investigated for the reaction of primary amines with cyclic anhydrides in the moderately polar solvents, anisole and tetraethyleneglycol dimethylether. The kinetics of amic-acid formation and imidization of polymeric and small molecule mixtures measured by Fourier-Transform Infrared Spectroscopy at near-ambient and elevated temperatures are compared. A Significant decrease in both reaction rates is observed upon changing the primary amine from aliphatic to benzylic, benzylic to 1,2-diphenylethylamine, and 1,2-diphenylethylamine to polystyrene-bound 1,2-diphenylethylamine. Reasons for the influence of polymer-bound chemical functionality on the reaction rates for these amines are discussed. The imidization step is found to be rate limiting in the reaction of phthalic anhydride with benzylamine at the functional group concentrations reported (0.14M or less). © 1995 John Wiley & Sons, Inc.     

Visible-light-induced selective photocatalytic aerobic oxidation of amines into imines on TiO2

Imines are important intermediates for the synthesis of fine chemicals, pharmaceuticals, and agricultural chemicals. Selective oxidation of amines into their corresponding imines with dioxygen is one of the most-fundamental chemical transformations. Herein, we report the oxidation of a series of benzylic amines into their corresponding imines with atmospheric dioxygen as the oxidant on a surface of anatase TiO(2) under visible-light irradiation (λ>420 nm). The visible-light response of this system was caused by the formation of a surface complex through the adsorption of a benzylic amine onto the surface of TiO(2). From the analysis of products of specially designed benzylic amines, we demonstrated that a highly selective oxygenation reaction proceeds via an oxygen-transfer mechanism to afford the corresponding carbonyl compound, whose further condensation with an amine would generate the final imine product. We found that when primary benzylic amines (13 examples), were chosen as the substrates, moderate to excellent selectivities for the imine products were achieved (ca. 38-94%) in moderate to excellent conversion rates (ca. 44-95%). When secondary benzylic amines (15 examples) were chosen as the substrates, both the corresponding imines and aldehydes were detected as the main products with moderate to high conversion rates (ca. 18-100%) and lower selectivities for the imine products (ca. 14-69%). When tribenzylamine was chosen as the substrate, imine (27%), dibenzylamine (24%), and benzaldehyde products (39%) were obtained in a conversion of 50%. This report can be viewed as a prototypical system for the activation of C-H bonds adjacent to heteroatoms such as N, O, and S atoms, and oxofuctionalization with air or dioxygen as the terminal oxidant under visible-light irradiation using TiO(2) as the photocatalyst.     

Development of one-pot benzylic amination reactions of azine N-oxides

An efficient one-pot synthetic methodology has been developed for the benzylic amination reactions of methyl-substituted azine N-oxides that operate under mild conditions. The reaction was found to tolerate quinoline and isoquinoline N-oxides with electron donating and withdrawing substituents as the electrophilic reaction partners as well as a broad range of nucleophilic primary, secondary and aromatic amines, affording the benzylic amination products in up to 82% yield.     

Visible‐Light‐Induced Selective Photocatalytic Aerobic Oxidation of Amines into Imines on TiO2

Imines are important intermediates for the synthesis of fine chemicals, pharmaceuticals, and agricultural chemicals. Selective oxidation of amines into their corresponding imines with dioxygen is one of the most‐fundamental chemical transformations. Herein, we report the oxidation of a series of benzylic amines into their corresponding imines with atmospheric dioxygen as the oxidant on a surface of anatase TiO₂ under visible‐light irradiation (λ>420 nm). The visible‐light response of this system was caused by the formation of a surface complex through the adsorption of a benzylic amine onto the surface of TiO₂. From the analysis of products of specially designed benzylic amines, we demonstrated that a highly selective oxygenation reaction proceeds via an oxygen‐transfer mechanism to afford the corresponding carbonyl compound, whose further condensation with an amine would generate the final imine product. We found that when primary benzylic amines (13 examples), were chosen as the substrates, moderate to excellent selectivities for the imine products were achieved (ca. 38–94 %) in moderate to excellent conversion rates (ca. 44–95 %). When secondary benzylic amines (15 examples) were chosen as the substrates, both the corresponding imines and aldehydes were detected as the main products with moderate to high conversion rates (ca. 18–100 %) and lower selectivities for the imine products (ca. 14–69 %). When tribenzylamine was chosen as the substrate, imine (27 %), dibenzylamine (24 %), and benzaldehyde products (39 %) were obtained in a conversion of 50 %. This report can be viewed as a prototypical system for the activation of C? H bonds adjacent to heteroatoms such as N, O, and S atoms, and oxofuctionalization with air or dioxygen as the terminal oxidant under visible‐light irradiation using TiO₂ as the photocatalyst.     

水促进的三组分PBM反应合成三级胺

首次报道了甲醛衍生的胺缩醛和芳基硼酸在水的促进下,可以在没有催化剂的条件下高效的合成三级胺.在此基础上建立了一种利用多聚甲醛,二级胺和芳基或杂环硼酸合成三级胺的高效合成方法.此反应条件温和,操作简单,具有很好的底物适应性,目标产物的收率最高可达93%.     

Benzylic C–H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas

C(sp³)–H functionalization methods provide an ideal synthetic platform for medicinal chemistry; however, such methods are often constrained by practical limitations. The present study outlines a C(sp³)–H isocyanation protocol that enables the synthesis of diverse, pharmaceutically relevant benzylic ureas in high-throughput format. The operationally simple C–H isocyanation method shows high site selectivity and good functional group tolerance, and uses commercially available catalyst components and reagents [CuOAc, 2,2′-bis(oxazoline) ligand, (trimethylsilyl)isocyanate, and N-fluorobenzenesulfonimide]. The isocyanate products may be used without isolation or purification in a subsequent coupling step with primary and secondary amines to afford hundreds of diverse ureas. These results provide a template for implementation of C–H functionalization/cross-coupling in drug discovery.

A copper-based catalyst system composed of commercially available reagents enables C–H isocyanation with exquisite (hetero)benzylic site selectivity, enabling high-throughput access to pharmaceutically relevant ureas via coupling with amines.     

High-load, soluble oligomeric carbodiimide: synthesis and application in coupling reactions

A facile preparation of a high-load, soluble oligomeric alkyl cyclohexylcarbodiimide (OACC) reagent via ROM polymerization from commercially available starting materials is described. This reagent is exploited as a coupling reagent for esterification, amidation, and dehydration of carboxylic acids (aliphatic and aromatic) with an assortment of alcohols (aliphatic primary, secondary, and benzylic), thiols, phenols, and amines (aliphatic primary, secondary, benzylic, and aromatic/anilines), respectively. Following the coupling event, precipitation with an appropriate solvent (Et(2)O, MeOH, or EtOAc), followed by filtration through a SPE provides the products in good to excellent yield and purity.     

Deallyloxy- and debenzyloxycarbonylation of protected alcohols, amines and thiols via a naphthalene-catalysed lithiation reaction

The naphthalene-catalysed lithiation of Alloc- and Cbz-protected alcohols, amines and thiols in THF at 0 °C led, after quenching with methanol, to the recovery of the free alcohols, amines and thiols in short reaction times and with very good yields. The selectivity for the removal of the Alloc- or the Cbz- group in a polyfunctionalised substrate has been studied. The selective reductive cleavage of a benzylic carbon-oxygen bond was achieved in the presence of an allylic carbon-oxygen or carbon-nitrogen bond. This method represents a great improvement in comparison with the previously reported deprotection procedures by dissolving metals, since it avoids the use of the toxic liquid ammonia and, therefore, the need to perform the reaction at low temperatures.     

A concise three-component synthesis of α-amino esters derived from phenylglycine and phenylalanine

α-Amino esters have been synthesized using a straightforward three-component reaction among preformed or in situ-generated aromatic or benzylic organozinc reagents, primary or secondary amines and ethyl glyoxylate. The procedure, which is characterized by its simplicity, allows the concise synthesis of phenylglycine and phenylalanine derivatives.     

Efficient and Selective Halogenation of Allylic and Benzylic Alcohols under Mild Conditions

Summary. A simple, mild, and high yielding procedure for the halogenation of allylic and benzylic alcohols using a combination of SOCl₂, benzotriazole, and potassium halides in DMF is described. The effectiveness of the protocol is manifested in its selectivity towards allylic and benzylic alcohols whereas other simple alcohols such as primary, secondary, and tertiary are found to be unreactive.     

Synthesis of optically-active benzylic amines; asymmetric reduction of ketoxime ethers with chiral oxazaborolidines

The preparation of novel optically active benzylic amines by the enantioselective reduction of phenone oximes using chiral oxazaborolidine is described. The choice of the chiral 1,2-amino alcohol (S)-diphenylvalinol as chiral inducer and that of the benzyl group for the O-oxime substituent is explained. 23 primary amines are obtained, with high enantioselectivity (e.e.=98%), good yield (74%) on preparative scale. A mechanistic explanation is proposed.     

Indium-mediated mild and efficient one-pot synthesis of alkyl phenyl selenides

A mild and convenient one-pot process for synthesizing alkyl phenyl selenides is developed using indium metal. The reaction shows the selectivity for tert-alkyl, benzylic, and allylic halides over primary and secondary alkyl halides.     

Catalytic Enantioselective Intermolecular Benzylic C(sp3)−H Amination

A practical general method for asymmetric intermolecular benzylic C(sp³)?H amination has been developed by combining the pentafluorobenzyl sulfamate PfbsNH₂ with the chiral rhodium(II) catalyst Rh₂(S‐tfptad)₄. Various substrates can be used as limiting components and converted to benzylic amines with excellent yields and high levels of enantioselectivity. Additional key features for the reaction are the low catalyst loading and the ability to remove the Pfbs group under mild conditions to give NH‐free benzylic amines.     

Primary amines via electrophilic amination of organometallic compounds with o-(diphenylphosphinyl)hydroxylamine

It is shown that O-(diphenylphosphinyl)hydroxylamine $\text{4a}$ transforms all kinds of “carbanions” into primary amines; best yields are received with “stabilized anions”, e.g. of the benzylic type.     

Tropene derivatives by sequential intermolecular and transannular, intramolecular palladium-catalyzed hydroamination of cycloheptatriene

A consecutive inter- and intramolecular hydroamination of cycloheptatriene with primary aromatic amines, benzylic amines, and beta-phenethylamines occurs to produce pharmaceutically relevant tropene (8-azabicyclo[3.2.1]octene) frameworks in good to excellent yields. This reaction occurs in the presence of a catalyst generated from palladium trifluoroacetate, 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and a mild acid. Mechanistic studies reveal that the overall process has some reversible steps, but that the rate of these reverse reactions are far slower than the rates of the forward catalytic process.     

Intermolecular Enantioselective Benzylic C(sp3)−H Amination by Cationic Copper Catalysis**

Chiral benzylic amines are privileged motifs in pharmacologically active molecules. Intramolecular enantioselective radical C(sp³)−H functionalization by hydrogen-atom transfer has emerged as a straightforward, powerful tool for the synthesis of chiral amines, but methods for intermolecular enantioselective C(sp³)−H amination remain elusive. Herein, we report a cationic copper catalytic system for intermolecular enantioselective benzylic C(sp³)−H amination with peroxide as an oxidant. This mild, straightforward method can be used to transform an array of feedstock alkylarenes and amides into chiral amines with high enantioselectivities, and it has good functional group tolerance and broad substrate scope. More importantly, it can be used to synthesize bioactive molecules, including chiral drugs. Preliminary mechanistic studies indicate that the amination reaction involves benzylic radicals generated by hydrogen-atom transfer.     

Attack of S- vs N-Nucleophiles on 2-halomethylquinazoline 3-Oxides

A comparison is made of thiols with amines in their mode of reaction with different substituted 2-halomethylquinazoline 3-oxides. Whereas the reaction of some amines (particularly small primary ones), as has long been known, leads to ring-enlarging rearrangement under certain conditions, all thiol nucleophiles we have observed, ranging from small to large, lead without rearrangement to direct benzylic substitution only. Preformed aminomethylquinazoline 3-oxides are shown not to rearrange to the corresponding 1,4-benzodiazepine 4-oxides. The mechanistic implications of these and other observations are discussed. Data on over forty new compounds are presented.