One-pot reductive monoalkylation of nitro aryls with hydrogen over Pd/C

A range of different nitro aryls were converted in one-pot to the corresponding secondary alkyl amino aryls in good to excellent yields by using aldehydes as alkyl source and hydrogen over Pd/C (10%) as reducing agent. In all examples, but one, the secondary amine was the sole alkylation product isolated. When formaldehyde was used as the alkyl source, substantial amount of the corresponding tertiary amine was isolated, however, by altering the reaction conditions slightly the corresponding secondary amine could be isolated in superb yield.     

An efficient synthesis of tertiary amines from nitriles in aprotic solvents

Tertiary amines are utilized extensively as non-nucleophilic proton scavengers for a number of organic transformations. Herein we report the efficient syntheses of tertiary alkyl amines from their corresponding alkyl nitriles in the presence of a heterogeneous palladium catalyst and a source of dihydrogen in aprotic solvents. The reaction is atom economic, the conditions are mild, and the isolated yields are virtually quantitative. The degree of amine alkylation shows some solvent dependency; in polar protic solvents such as ethanol or methanol, the reaction affords a mixture of products with the secondary alkyl amine as the major product.     

Selective N-Monomethylation of Primary Amines via N-Trialkylsilyl-Lithioamines

Transformation of a primary amine to a secondary amine can be achieved by reaction with an alkyl halide in the presence of an excess of the primary amine to suppress multiple alkylation, but, in general, direct alkylation is not the preferred method when the product alkylated amine is more nucleophilic than the startirg amine. More efficient procedures involve a relative vitiation of the nucleophilicity of the monoalkylated product with respect to that of the unalkylated substrate. Such an effect may be realised by the incorporation of monovalent activating groups (Z), which increase the acidity of the amido-proton and allow alkylation of a stabilised amidoanion, often generated in situ, this species being more reactive than a simple amine. Since in the conversion of a primary to a secondary amine only one amido-proton remains after incorporation of the activating group, further N-alkylation is obviated (Scheme 1.)     

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.     

Practical stereoselective synthesis of beta-branched alpha-amino acids through efficient kinetic resolution in the phase-transfer-catalyzed asymmetric alkylations

Phase-transfer-catalyzed alkylation of glycinate Schiff base with racemic secondary alkyl halides proceeded with excellent levels of syn- and enantioselectivities under the influence of chiral quaternary ammonium bromide 1d and 18-crown-6. The alkylation product can be selectively converted to the corresponding anti isomer, allowing the preparation of all the stereoisomers of beta-alkyl-alpha-amino acid derivatives, an extremely valuable chiral building block.     

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.     

A Precautionary Note Regarding Derivatization of Secondary Amines with Dialkylacetals of Formamide Other Than the Diethyl Derivative

Abstract

We have extended our earlier work on alkylation of secondary amino compounds with dimethylformamide diethyl acetal to other alkyl acetals, such as dimethyl and dipropyl acetal. All the alkylating DMT-dialkyl acetal reagents tested gave only N-ethyl derivatives of the secondary amines. The reagent purity was tested by preparing the esters of carboxylic acids, where the appropriate alkyl (methyl or propyl) ester is obtained. It is concluded that all dimethylformamide dialkyl acetals yield a single N-ethyl derivative of secondary amine. The reaction mechanism is not understood.     

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.     

A direct functionalization of tertiary alkyl bromides with O-, N-, and C-nucleophiles

Silver oxide used in stoichiometric amounts promoted the direct functionalization of tert-alkyl bromides and provided the desired adducts in 39-96% isolated yield. Reaction of tert-bromides with carboxylic acids yielded esters, with alcohols and phenols yielded alkyl and aryl ethers, with amines and anilines yielded selectively mono-alkylated amines and anilines, and with a C-nucleophile yielded an all-carbon quaternary hydrocarbon. The method was applied to a sequential alkylation of a primary amine with two different alkyl bromides yielding selectively a tertiary amine with three different substituents in one-pot.     

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.     

Ni-catalyzed alkylative dimerization of vinyl grignard reagents using alkyl fluorides

Alkyl halides underwent unique cross-coupling reaction with vinylmagnesium chloride in the presence of Ni catalyst to give 2-alkyl-3-butenyl Grignard reagent (1) in high yields. This reaction proceeded efficiently at 25 degrees C in THF using primary and secondary alkyl fluorides. On the other hand, PhCH=CHMgBr gave double alkylative vinyl coupling product 4 in good yield as the sole coupling product. Alkyl fluorides react as the most suitable alkylating reagent in comparison to the corresponding chlorides, bromides, and iodides.     

Enthalpies of formation of primary, secondary, and tertiary amineborane adducts in tetrahydrofuran solution

The enthalpies of solution of primary, secondary, and tertiary amines in THF were determined from calorimetric experiments for five primary, five secondary, and three tertiary amines. The enthalpies of formation of amineborane adducts from borane and the corresponding amines in THF solution were also determined. The differences in adduct formation enthalpies from borane and the corresponding amines can be explained by taking into account steric effects and the chain length of the substituents on the amine. In general, as the alkyl chain length, branching, or the number of chains increases, the formation enthalpy of amineborane adducts is less exothermic. That is to say, the steric effect is more important in tertiary and secondary amines than in primary ones. The enthalpy of solution of linear primary amines in THF was more endothermic as the alkyl chain increased and a similar behavior was observed with linear secondary and tertiary ones. An analysis is made of the amine structural factors which affect the amineborane adduct formation.     

The facile preparation of primary and secondary amines via an improved Fukuyama-Mitsunobu procedure. Application to the synthesis of a lung-targeted gene delivery agent

An efficient modification of the Fukuyama-Mitsunobu procedure has been developed whereby primary or secondary amines can be synthesized from alkyl alcohols and the corresponding nosyl-protected/activated amine. Most importantly, the use of the DTBAD and diphenylpyridinylphosphine, as Mitsunobu reagents, generates reaction by-products that can be easily removed, providing a remarkably clean product mixture. This improved technique was implemented in the synthesis of a complex lipopeptide designed to target alpha9beta1-integrin proteins predominant on upper airway epithelial cells.     

Practical Synthesis of N‐Alkyl‐N‐alkyloxycarbonylaminomethyl Prodrug Derivatives of Acetaminophen,Theophylline, and 6‐Mercaptopurine

We report a novel synthesis of N‐alkyl‐N‐alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of acetaminophen, theophylline, and 6‐mercaptopurine by alkylation of the corresponding drug molecule with N‐alkyl‐N‐alkyloxycarbonylaminomethyl chlorides in good yield. Most of the alkylating agents were efficiently synthesized by chloromethylation of N‐alkyl carbamic acid alkyl esters, which in turn were made from alkyl amines and alkyl chloroformates. In cases where the alkyl chloroformates were not available, synthesis of N‐alkyl carbamic acid alkyl esters was accomplished by converting an alcohol to a chloroformate or to an activated acylating agent such as acyl imidazoles or p‐nitrophenylcarbonate esters, followed by their reaction with alkyl amines.     

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.     

Radical addition to "cation pool". Reverse process of radical cation fragmentation

The reaction of an N-acyliminium ion with an alkyl iodide and hexabutyldistannane took place to give the alkylation product. A mechanism involving the addition of an alkyl radical to an N-acyliminium ion to produce the corresponding radical cation has been suggested.     

Deaminative Strategy for the Visible‐Light‐Mediated Generation of Alkyl Radicals

A deaminative strategy for the visible‐light‐mediated generation of alkyl radicals from redox‐activated primary amine precursors is described. Abundant and inexpensive primary amine feedstocks, including amino acids, were converted in a single step into redox‐active pyridinium salts and subsequently into alkyl radicals by reaction with an excited‐state photocatalyst. The broad synthetic potential of this protocol was demonstrated by the alkylation of a number of heteroarenes under mild conditions.     

N-Acyl-4,5-dihydro-4,4-dimethyl-N-methyl-2-thiazolamine as a chemoselective acylating agent

2-Methylamino-2-thiazoline reacted with alkyl acyl halides to produce N-acyl-2-methylamino-2-thiazolines, exo-acylated product regioselectively, which were found to be highly chemoselective acylating agents for primary amine in the presence of secondary amine and for the less sterically hindered of two different primary amines.     

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.     

Cooperative catalytic reactions using organocatalysts and transition metal catalysts: enantioselective propargylic alkylation of propargylic esters with aldehydes

The enantioselective propargylic alkylation of propargylic esters with aldehydes in the presence of a copper complex and an optically active secondary amine as cocatalysts has been found to give the corresponding propargylic alkylated products in good yields as a mixture of two diastereoisomers with a high enantioselectivity.