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.     

Reductive desulfurization of 3-cyano-2-methylthiopyridines under the action of Raney nickel

The action of Raney nickel on substituted 3-cyano-2-methylthiopyridines was studied. Under conditions of catalytic hydrogenation, the reaction yields a mixture containing the aminosulfide resulting from reduction of the nitrile group with retention of the methylthio group, the nitrile resulting from elimination of the methylthio group, and the amine resulting from both reduction of the nitrile group and elimination of the methylthio group. Treatment of 3-cyano-2-methylthiopyridines with a large amount of Raney nickel under desulfurization conditions induces simultaneous elimination of the methylthio group and reduction of the nitrile group to the aminomethyl group. When reductive desulfurization is carried out in methanol or THF, primary amines are formed, while the reactions in isopropyl or ethyl alcohol give secondary or tertiary amines, which are formed upon alkylation of the amino group with alcohols. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2497–2500, November, 2005.     

Microwave-assisted solventless reaction of iridium-catalyzed alkylation of amines with alcohols in the absence of base

Microwave-assisted iridium catalyzed alkylation of amines with alcohols was undertaken under solvent-free and base-free conditions. Such alkylation reactions are green, atom-economic, and effective for mono-, di-, and triaklyation of amines. Good isolated yields were obtained for mono- and dialkylated amines using stoichiometric amounts of amines and alcohols, in the presence of 1 mol % [Cp*IrCl(2)](2). Reasonable yields of trialkylated products were obtained using 4 equiv of alcohols.     

In-water dehydrative alkylation of ammonia and amines with alcohols by a polymeric bimetallic catalyst

An in-water dehydrative alkylation with a novel heterobimetallic polymeric catalyst is described. Thus, a boron-iridium heterobimetallic polymeric catalyst was prepared by ionic convolution of a poly(catechol borate) and an iridium complex. The alkylation of ammonia and amines with alcohols, alkylating agents, was performed with 1 mol % Ir of the heterogeneous catalyst in water without the use of organic solvents under aerobic conditions to give the corresponding alkylated amines.     

Alkylation of Amines with Alcohols and Amines by a Single Catalyst under Mild Conditions

An efficient catalytic system for the alkylation of amines with either alcohols or amines under mild conditions has been developed, using cyclometallated iridium complexes as catalysts. The method has broad substrate scope, allowing for the synthesis of a diverse range of secondary and tertiary amines with good to excellent yields. By controlling the ratio of substrates, both mono‐ and bis‐alkylated amines can be obtained with high selectivity. In particular, methanol can be used as the alkylating reagent, affording N‐methylated products selectively. A strong solvent effect is observed for the reaction.     

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.     

Highly efficient synthesis of α-amino amidines from ynamides by the Cu-catalyzed three-component coupling reactions

Using ynamides as one of the reacting components, the Cu-catalyzed three-component reaction of sulfonyl or phosphoryl azides and amines affords α-amino amidines in high yields under mild conditions. Synthetic utility of the produced compounds was demonstrated in the diastereoselective alkylation of α-amino amidines bearing a chiral oxazolidinone moiety. It was also shown that α-amino imidates could be readily prepared by employing alcohols instead of amines.     

Nouveaux hétérocycles à partir d'esters cyaniques. Arylimino-2 et arylamino-2 4H-benzoxazin-1,3 ones-4, leur tautomérie et étude de leur alkylation régiosélective

New 2-substituted benzoxazinones have been prepared by reaction of primary aromatic amines with aryl cyanates having an ethoxycarbonyl group in the ortho position By ir and nmr studies, a 2-arylimino-4H-1,3-benzoxazin-4-one structure is assigned to their predominant tautomers. The regioselective synthesis of their alkylated derivatives on the cyclic and exocyclic nitrogens by alkylation in ethanol, dimethylformamide and under sloid-liquid phase transfer conditions has been achieved     

Phase-transfer-catalyzed alkylation of guanidines by alkyl halides under biphasic conditions: a convenient protocol for the synthesis of highly functionalized guanidines

An operationally straightforward and efficient method for the alkylation of carbamate-protected guanidines with various alkyl halides and mesylates is described. This protocol proceeds via deprotonation of the acidic N-carbamate hydrogen of the guanidine under biphasic conditions using a catalytic amount of a tetrabutylammonium salt as a phase-transfer catalyst. In this manner, highly functionalized guanidines can be obtained. The reaction is tolerant of a wide range of functional groups on both the alkyl halide and guanidine component. In addition, the reaction is sufficiently mild such that simple aqueous workup and filtration through a short silica gel column yields the substituted guanidines in high purity. In conjunction with the EDCI-mediated guanylation of disubstituted thioureas with amines, phase-transfer catalyzed alkylation of guanidines via a one-pot, three-component synthesis of substituted guanidines was achieved.     

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.     

Preparation of functionalized, conformationally constrained DTPA analogues from L- or D-serine and trans-4-hydroxy-L-proline. Hydroxymethyl substituents on the central acetic acid and on the backbone

The enantio- and diastereospecific syntheses of conformationally constrained diethylenetriaminepentaacetic acid (DTPA) analogues that are functionalized with a hydroxymethyl linker substituent on the central acetic acid or on the backbone are described. Key synthetic steps include (i) displacement of the 4-hydroxyl group of N-BOC-trans-4-hydroxy-L-proline benzyl ester, via activation as the triflate, with suitable amines derived from L- or D-serine, (ii) the low-temperature alkylation of diethylenetriamines with the triflate of benzyl glycolate, thereby minimizing competitive lactamization, to give DTPA pentabenzyl esters, and (iii) deprotection to afford the corresponding DTPA analogues under very mild hydrogenolysis conditions.     

Colloid and nanodimensional catalysts in organic synthesis: III. Alkylation of amines with primary alcohols catalyzed by colloidal nickel and cobalt

Alkylation of primary amines with primary alcohols has been performed under catalysis by colloidal nickel and cobalt particles. The synthesis of the catalyst and alkylation of amines have been carried out in a one-pot mode. The alkylation at 160–180°C in 6–12 h yields 55–90% of secondary amines.     

Synthesis and some conversions of N-substituted benzimidazole-2-sulfonic acids

A series of N-substituted benzimidazole-2-sulfonic acids was synthesized in good yield by the N-alkylation of benzimidazole-2-sulfonic acids by alkylation with simple and functionalized alkylating agents under mild conditions. The corresponding N-substituted benzimidazolones and also primary, secondary, and tertiary amines were obtained by the action on the obtained compounds of alkali, ammonia, ammonium acetate, and amines. __________ Translated from Khimiya Geterotsiklicheskikh, No. 4, pp. 528–534.     

Catalyst‐Free Deaminative Functionalizations of Primary Amines by Photoinduced Single‐Electron Transfer

The use of pyridinium‐activated primary amines as photoactive functional groups for deaminative generation of alkyl radicals under catalyst‐free conditions is described. By taking advantage of the visible light absorptivity of electron donor–acceptor complexes between Katritzky pyridinium salts and either Hantzsch ester or Et₃N, photoinduced single‐electron transfer could be initiated in the absence of a photocatalyst. This general reactivity platform has been applied to deaminative alkylation (Giese), allylation, vinylation, alkynylation, thioetherification, and hydrodeamination reactions. The mild conditions are amenable to a diverse range of primary and secondary alkyl pyridiniums and demonstrate broad functional group tolerance.     

Pd.Et3B-catalyzed alkylation of amines with allylic alcohols

A combination of catalytic amounts of Pd (0.05 mmol) and Et3B (0.3 mmol) promotes allylic alkylation of primary and secondary aromatic and aliphatic amines (1.0 mmol) by the direct use of allylic alcohols, providing tertiary amines in excellent yields under mild conditions (room temperature approximately 50 degrees C).     

Tailored Cobalt‐Catalysts for Reductive Alkylation of Anilines with Carboxylic Acids under Mild Conditions

The first cobalt‐catalyzed hydrogenative N‐methylation and alkylation of amines with readily available carboxylic acid feedstocks as alkylating agents and H₂ as ideal reductant is described. Combination of tailor‐made triphos ligands with cobalt(II) tetrafluoroborate significantly improved the efficiency, thus promoting the reaction under milder conditions. This novel protocol allows for a broad substrate scope with good functional group tolerance, even in the presence of reducible alkenes, esters, and amides.     

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.     

Cobalt‐Catalyzed Alkylation of Aromatic Amines by Alcohols

The implementation of inexpensive, Earth‐abundant metals in typical noble‐metal‐mediated chemistry is a major goal in homogeneous catalysis. A sustainable or green reaction that has received a lot of attention in recent years and is preferentially catalyzed by Ir or Ru complexes is the alkylation of amines by alcohols. It is based on the borrowing hydrogen or hydrogen autotransfer concept. Herein, we report on the Co‐catalyzed alkylation of aromatic amines by alcohols. The reaction proceeds under mild conditions, and selectively generates monoalkylated amines. The observed selectivity allows the synthesis of unsymmetrically substituted diamines. A novel Co complex stabilized by a PN₅P ligand catalyzes the reactions most efficiently.     

Chromium-Catalyzed Alkylation of Amines by Alcohols

The alkylation of amines by alcohols is a broadly applicable, sustainable, and selective method for the synthesis of alkyl amines, which are important bulk and fine chemicals, pharmaceuticals, and agrochemicals. We show that Cr complexes can catalyze this C−N bond formation reaction. We synthesized and isolated 35 examples of alkylated amines, including 13 previously undisclosed products, and the use of amino alcohols as alkylating agents was demonstrated. The catalyst tolerates numerous functional groups, including hydrogenation-sensitive examples. Compared to many other alcohol-based amine alkylation methods, where a stoichiometric amount of base is required, our Cr-based catalyst system gives yields higher than 90 % for various alkyl amines with a catalytic amount of base. Our study indicates that Cr complexes can catalyze borrowing hydrogen or hydrogen autotransfer reactions and could thus be an alternative to Fe, Co, and Mn, or noble metals in (de)hydrogenation catalysis.     

Silica-Functionalized CuI: An Efficient and Selective Catalyst for N-Benzylation,Allylation, and Alkylation of Primary and Secondary Amines in Water

Silica-functionalized CuI has been reported as an efficient and selective catalyst for the selective mono-N- and N,N-dibenzylation, allylation, and alkylation of primary amines with benzylic, allylic, and alkyl halides using NaOH as base in aqueous medium. By changing the reaction temperature, mono- or di-benzylation, allylation, or alkylation could be achieved in good yield and selectivity. Secondary amines have also been benzylated, allylated, and alkylated under similar conditions. SiO₂-CuI has been characterized by Fourier transform–infrared, atomic absorption spectrometry, thermalgravimetric analysis, X-ray diffraction, scanning electron microscopy, and transmission electron microscopy, and found to be highly selective and recyclable under the reaction conditions.

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