Catalytic reductive alkylation of secondary amine with aldehyde and silane by an iridium compound

[reaction: see text] An efficient methodology for the reductive alkylation of secondary amine with aldehyde and Et(3)SiH using an iridium complex as a catalyst has been developed. For example, treatment of dibutylamine with butyraldehyde and Et(3)SiH (a 1:1:1 molar amount of amine, aldehyde, and silane) in 1,4-dioxane at 75 degrees C under the influence of a catalytic amount of [IrCl(cod)](2) gave tributylamine in quantitative yield. In this reaction, no reduction of aldehyde took place. It was found that IrCl(3), which is a starting material for preparation of iridium complexes such as [IrCl(cod)](2), acts as an efficient catalyst for the present reductive alkylation of amine. In addition, a cheaper, easy-to-handle, and environmentally friendly reducing reagent such as polymethylhydrosiloxane (PMHS) in place of Et(3)SiH was also useful. Thus, a variety of secondary amines could be alkylated by allowing them to react with aldehydes and PMHS in the presence of an iridium catalyst to afford the corresponding tertiary amines in good to excellent yields. From the deuterium label experiments, it was revealed that silane and water, generated during the formation of enamine by the reaction of amine and aldehyde, seem to behave as a hydrogen source. The catalytic cycle was discussed.     

The “Borrowing Hydrogen Strategy” by Supported Ruthenium Hydroxide Catalysts: Synthetic Scope of Symmetrically and Unsymmetrically Substituted Amines

The N‐alkylation of ammonia (or its surrogates, such as urea, NH₄HCO₃, and (NH₄)₂CO₃) and amines with alcohols, including primary and secondary alcohols, was efficiently promoted under anaerobic conditions by the easily prepared and inexpensive supported ruthenium hydroxide catalyst Ru(OH)_x/TiO₂. Various types of symmetrically and unsymmetrically substituted “tertiary” amines could be synthesized by the N‐alkylation of ammonia (or its surrogates) and amines with “primary” alcohols. On the other hand, the N‐alkylation of ammonia surrogates (i.e., urea and NH₄HCO₃) with “secondary” alcohols selectively produced the corresponding symmetrically substituted “secondary” amines, even in the presence of excess amounts of alcohols, which is likely due to the steric hindrance of the secondary alcohols and/or secondary amines produced. Under aerobic conditions, nitriles could be synthesized directly from alcohols and ammonia surrogates. The observed catalysis for the present N‐alkylation reactions was intrinsically heterogeneous, and the retrieved catalyst could be reused without any significant loss of catalytic performance. The present catalytic transformation would proceed through consecutive N‐alkylation reactions, in which alcohols act as alkylating reagents. On the basis of deuterium‐labeling experiments, the formation of the ruthenium dihydride species is suggested during the N‐alkylation reactions.     

TiCl(OPr)3 and NaBH(OAc)3: an efficient reagent combination for the reductive amination of aldehydes by electron-deficient amines

Sodium triacetoxyborohydride, NaBH(OAc)₃ with tri-isopropoxytitanium chloride, TiCl(OⁱPr)₃ is a useful reagent combination for reductive amination. Electron-deficient amines and heteroaromatic amines such as 2-aminopyrimidine and 2-aminothiazole can be reductively alkylated at room temperature to afford the corresponding secondary amines in good yields.     

Selective N-alkylation of amines using nitriles under hydrogenation conditions: facile synthesis of secondary and tertiary amines

Nitriles were found to be highly effective alkylating reagents for the selective N-alkylation of amines under catalytic hydrogenation conditions. For the aromatic primary amines, the corresponding secondary amines were selectively obtained under Pd/C-catalyzed hydrogenation conditions. Although the use of electron poor aromatic amines or bulky nitriles showed a lower reactivity toward the reductive alkylation, the addition of NH(4)OAc enhanced the reactivity to give secondary aromatic amines in good to excellent yields. Under the same reaction conditions, aromatic nitro compounds instead of the aromatic primary amines could be directly transformed into secondary amines via a domino reaction involving the one-pot hydrogenation of the nitro group and the reductive alkylation of the amines. While aliphatic amines were effectively converted to the corresponding tertiary amines under Pd/C-catalyzed conditions, Rh/C was a highly effective catalyst for the N-monoalkylation of aliphatic primary amines without over-alkylation to the tertiary amines. Furthermore, the combination of the Rh/C-catalyzed N-monoalkylation of the aliphatic primary amines and additional Pd/C-catalyzed alkylation of the resulting secondary aliphatic amines could selectively prepare aliphatic tertiary amines possessing three different alkyl groups. According to the mechanistic studies, it seems reasonable to conclude that nitriles were reduced to aldimines before the nucleophilic attack of the amine during the first step of the reaction.     

Ns strategies: a highly versatile synthetic method for amines

A highly efficient and versatile synthetic method for amines was established using nitrobenzenesulfonamides (Ns-amides) as both a protecting and activating group. The alkylation of N-monosubstituted Ns-amides either proceeded conventionally or under Mitsunobu conditions to provide the N,N-disubstituted sulfonamides, and the Ns group was removed easily with soft nucleophiles via Meisenheimer complexes to give the corresponding secondary amines. The major advantage of this protocol is that both alkylation and deprotection proceed under mild conditions. Thus, with this methodology, the total synthesis of linear and/or macrocyclic natural polyamines can be accomplished efficiently.     

Enantioselective synthesis of cyclic secondary amines through Mo-catalyzed asymmetric ring-closing metathesis (ARCM)

Carbocyclic amines are synthesized efficiently in up to 93% ee by asymmetric ring-closing metathesis (ARCM) with 2-5 mol % chiral Mo complexes. An example is provided where the catalyst is prepared in situ (catalyst isolation not needed) to afford secondary amines that cannot be prepared by alternative methods. [reaction: see text]     

Fragmentation of Optically Active (1-Phenylethyl)- and (1-Naphthylethyl)ureas in Refluxing Alcohols: Easy Preparation of Optically Active Amines of High Optical Purity

(1-Phenylethyl)- and (1-naphthylethyl)ureas, obtained in the reaction of racemic amines with optically pure isocyanates, are separated and then decomposed in refluxing alcohols, to afford optically pure secondary amines and optically pure alkyl carbamates in quantitative yields. The scope of this fragmentation for the resolution of racemic mixtures of amines is illustrated by several examples of biologically important compounds. Carbamates obtained by this fragmentation can readily be recycled.     

A strategy for the synthesis of aryl alpha-ketoamides based upon the acylation of anions derived from cyanomethylamines followed by oxidative cleavage

[reaction: see text] Cyanomethylamines, prepared by alkylation of amines with chloroacetonitrile, were deprotonated using NaHDMS in THF, reacted with heteroaryl or substitutedphenyl esters, and then oxidized by adding Clorox(TM) to afford aryl alpha-ketoamides in a single operation in good overall yields.     

Boron‐Catalyzed N‐Alkylation of Amines using Carboxylic Acids

A boron‐based catalyst was found to catalyze the straightforward alkylation of amines with readily available carboxylic acids in the presence of silane as the reducing agent. Various types of primary and secondary amines can be smoothly alkylated with good selectivity and good functional‐group compatibility. This metal‐free amine alkylation was successfully applied to the synthesis of three commercial medicinal compounds, Butenafine, Cinacalcet. and Piribedil, in a one‐pot manner without using any metal catalysts.     

Reaction of vinyl triflates of α-keto esters and imides with secondary amines: synthesis of α,β-diamino carboxylic acid derivatives through aziridinium ions

Reaction between secondary amines and vinyl triflates of α-keto esters and imides under solvent-free condition provides a ready access to α,β-diamino carboxylates.     

Kondensationsprodukte durch N-Aminomethylierung von Carbonsäureimiden

The common identification reaction of amines with phthalimide and formaldehyde yielding N-aminomethylimides is extended to other imides. The reaction of pyromellitic diimide with various diamines in the presence of formaldehyde leads to oligomeric products. p-Substituted aromatic diamines afford higher yields than o-substituted diamines, m-substituted diamines do not react at all according to the N-aminomethylation reaction. It was shown that imides of the following structure $$R - - \begin{array}{*{20}c} { / CH_2 CO} \\ N \\ { \setminus CH_2 CO} \\ \end{array} \begin{array}{*{20}c} \setminus \\ {NH} \\ / \\ \end{array} $$ generally do not react with formaldehyde (and amine), owing to the influence of the amine nitrogen on the imidic nitrogenhydrogen bond.     

Synthesis of vicinal (alkylamino)alkynylcyclopropanes from geminal alkynyl(chloro)cyclopropanes

New N-Boc-alkyl(2-alkynylcyclopropyl)amines were synthesized from 1-alkynyl-1-chlorocyclopropanes and N-Boc- alkylamines under the action of Bu^tOK in DMSO, the intermediates having been the corresponding conjugated alkynylcyclopropenes. The Boc-derivatives can be converted into free secondary 2-alkynylcyclopropylamines, as well as β-lithiated with subsequent alkylation.     

Transition‐Metal‐Free Hydrogen Autotransfer: Diastereoselective N‐Alkylation of Amines with Racemic Alcohols

A practical method for the synthesis of α‐chiral amines by alkylation of amines with alcohols in the absence of any transition‐metal catalysts has been developed. Under the co‐catalysis of a ketone and NaOH, racemic secondary alcohols reacted with Ellman's chiral tert‐butanesulfinamide by a hydrogen autotransfer process to afford chiral amines with high diastereoselectivities (up to >99:1). Broad substrate scope and up to a 10 gram scale production of chiral amines were demonstrated. The method was applied to the synthesis of chiral deuterium‐labelled amines with high deuterium incorporation and optical purity, including examples of chiral deuterated drugs. The configuration of amine products is found to be determined solely by the configuration of the chiral tert‐butanesulfinamide regardless of that of alcohols, and this is corroborated by DFT calculations. Further mechanistic studies showed that the reaction is initiated by the ketone catalyst and involves a transition state similar to that proposed for the Meerwein–Ponndorf–Verley (MPV) reduction, and importantly, it is the interaction of the sodium cation of the base with both the nitrogen and oxygen atoms of the sulfinamide moiety that makes feasible, and determines the diastereoselectivity of, the reaction.     

Microwave acceleration in DABAL-Me3-mediated amide formation

Facile direct coupling of esters and secondary amines to afford tertiary amides proceeds under microwave irradiation using the air-stable trimethylaluminium source DABAL-Me₃ [(DABCO)(AlMe₃)₂]. Excellent yields (88-98%) are attained for cyclic secondary amines in reactions that are complete in 5-16 min. The process can be extended to the formation of Weinreb amides (upto 76% from commercial MeNHOMe·HCl) in a one-pot procedure using NaH to liberate the free methoxyamine.     

Development of a General Non‐Noble Metal Catalyst for the Benign Amination of Alcohols with Amines and Ammonia

The N‐alkylation of amines or ammonia with alcohols is a valuable route for the synthesis of N‐alkyl amines. However, as a potentially clean and economic choice for N‐alkyl amine synthesis, non‐noble metal catalysts with high activity and good selectivity are rarely reported. Normally, they are severely limited due to low activity and poor generality. Herein, a simple NiCuFeO_x catalyst was designed and prepared for the N‐alkylation of ammonia or amines with alcohol or primary amines. N‐alkyl amines with various structures were successfully synthesized in moderate to excellent yields in the absence of organic ligands and bases. Typically, primary amines could be efficiently transformed into secondary amines and N‐heterocyclic compounds, and secondary amines could be N‐alkylated to synthesize tertiary amines. Note that primary and secondary amines could be produced through a one‐pot reaction of ammonia and alcohols. In addition to excellent catalytic performance, the catalyst itself possesses outstanding superiority, that is, it is air and moisture stable. Moreover, the magnetic property of this catalyst makes it easily separable from the reaction mixture and it could be recovered and reused for several runs without obvious deactivation.     

Mannich Synthesis of Acetylenic Amino Alcohols in Aqueous Ionic Liquids

Terminal alkynols react with formaldehyde and secondary amines in aqueous ionic liquid [emim]HSO^–₄ in the presence of Cu(OAc) to afford the corresponding 1-(a-hydroxyalkyl)- or 1-(b-hydroxyalkyl)-2-(aminomethyl)acetylenes in better yields in comparison with the reaction in conventional organic solvents. The catalytic system can be easily recovered and recycled.     

Facile N‐Alkylation/N′‐Arylation Process: A Direct Approach to Aromatic Aminoalkyl Amines

An intriguing C?N transformation involving a catalyst‐free N‐alkylation/N′‐arylation process in a multicomponent reaction with secondary amines, cyclic tertiary amines and electron‐deficient aryl halides has been described. In this case, the N‐alkylation of secondary amines, utilizing cyclic tertiary amines as alkyl group sources, is enabled by a facile C?N cleavage. Such an operationally simple method could facilitate access to aromatic aminoalkyl amines, nitrogen‐containing bioactive molecules, in good to excellent yields.     

环状酰亚胺不对称还原烷基化的一些结果

苹果酰亚胺的不对称还原烷基化是合成γ-内酰胺的有效方法,为扩大该法的应用范围,本文研究了多种环状酰亚胺的还原烷基化反应。探讨了影响还原烷基化反应的因素并提出相关的解释。总结出3-取代和3,4-二取代琥珀酰亚胺可成功地进行还原烷基化的规律,并提出了相应的解释。     

KF/Al2O3‐Mediated N‐Alkylation of Amines and Nitrogen Heterocycles and S‐Alkylation of Thiols

KF/Al₂O₃ efficiently catalyzes N‐alkylation of heterocyclic, primary, and secondary amines and S‐alkylation of thiols with a variety of alkyl halides. The N‐alkylation and S‐alkylation adducts were produced in good to excellent yields and in short times.     

N-Boc ethyl oxamate: a new nitrogen nucleophile for use in Mitsunobu reactions

N-Boc ethyl oxamate can be directly coupled with primary and secondary alcohols under Mitsunobu conditions to afford various N-Boc amines after mild deprotection.