One-pot synthesis of N-alkyl purine and pyrimidine derivatives from alcohols using TsIm: a rapid entry into carboacyclic nucleoside synthesis

A convenient and efficient one-pot N-alkylation of nucleobases from alcohols using N-(p-toluenesulfonyl)imidazole (TsIm) is described. In this method, treatment of alcohols with a mixture of purine or pyrimidine nucleobase, TsIm, K₂CO₃, and triethylamine in refluxing DMF regioselectively furnishes the corresponding N-alkyl nucleobases in good yields. This methodology is highly efficient for various structurally diverse primary alcohols.     

CpIr-catalyzed N-alkylation of amines with alcohols. A versatile and atom economical method for the synthesis of amines

A versatile and highly atom economical catalytic system consisting of [Cp^∗IrCl₂]₂/NaHCO₃ (Cp^∗=pentamethylcyclopentadienyl) for the N-alkylation of amines with primary and secondary alcohols as alkylating reagents has been developed. For example, the reaction of equimolar amounts of aniline and benzyl alcohol in the presence of [Cp^∗IrCl₂]₂ (1.0 mol % Ir) and NaHCO₃ (1.0 mol %) in toluene at 110 °C gives N-benzylaniline in 94% yield. The present catalytic system is applicable to the N-alkylation of both primary and secondary amines, and only harmless water is produced as co-product. A wide variety of secondary and tertiary amines can be synthesized with high atom economy under mild and less-toxic conditions. One-pot sequential N-alkylation leading to tertiary amines bearing three different substituents is also described.     

Copper-catalyzed one-pot N-alkenylation and N-alkylation of amides: an efficient synthesis of substituted 2,3-dihydropyrroles

A novel copper-catalyzed synthesis of substituted 2,3-dihydropyrroles via one-pot N-alkenylation and N-alkylation of amides with 1,4-diiodobut-1-ene derivatives has been developed. The reactions proceed in good to high yields using CuI as the catalyst, K₂CO₃ as the base, and rac-trans-N,N′-dimethylcyclohexane-1,2-diamine as the ligand.     

One-pot N-alkylation/Heck approach to substituted indoles

Here, we report the palladium-catalyzed one-pot N-alkylation/Heck cyclization of anilines to substituted indoles employing Pd(OAc)₂/XPhos. The scope and limitations of this methodology will be described.     

Selective Iron Catalyzed Synthesis of N-Alkylated Indolines and Indoles

Whereas iron catalysts usually promote catalyzed C3-alkylation of indole derivatives via a borrowing-hydrogen methodology using alcohols as the electrophilic partners, this contribution shows how to switch the selectivity towards N-alkylation. Thus, starting from indoline derivatives, N-alkylation was efficiently performed using a tricarbonyl(cyclopentadienone) iron complex as the catalyst in trifluoroethanol in the presence of alcohols leading to the corresponding N-alkylated indoline derivatives in 31–99 % yields (28 examples). The one-pot, two-step strategy for the selective N-alkylation of indolines is completed by an oxidation to give the corresponding N-alkylated indoles in 31–90 % yields (15 examples). This unprecedented oxidation methodology involves an iron salt catalyst associated with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) and a stoichiometric amount of t-BuOOH at room temperature.     

Gold-catalyzed substitution reaction with ortho-alkynylbenzoic acid alkyl ester as an efficient alkylating agent

ortho-Alkynylbenzoic acid alkyl esters behave as alkylating agents in combination with gold catalysts. The reaction with alcohols occurs smoothly in the presence of catalytic amounts of Ph₃PAuCl and AgOTf under mild conditions to produce the corresponding ether products in high yields. The protocol is also useful for Friedel-Crafts alkylation and N-alkylation of sulfonamides. The reaction likely proceeds through the gold-induced in situ construction of leaving groups and subsequent nucleophilic attack of nucleophiles, such as alcohols, aromatic compounds, and sulfonamides.     

A novel ruthenium-catalyzed amination of primary and secondary alcohols

An improved method for the N-alkylation of primary amines with primary and secondary alcohols has been developed. Novel, effective catalyst systems, for example, Ru₃(CO)₁₂ combined with tri-o-tolylphosphine or n-butyl-di-1-adamantylphosphine, allow for aminations in a good yield under comparatively mild conditions.     

Specific reactivity of 2,4,6-tri-tert-butylanilide anions and its application to benzylation reagent

The reaction of methyl iodide with an anilide anion prepared from 2,4,6-tri-tert-butylanilide and NaH in CH₃CN gave N-methyl anilide (N-alkylation product) as a major product, while in the reaction of benzyl bromide with the anilide anion in DMF, O-benzyl imidate (O-alkylation product) was obtained with almost complete selectivity. The treatment of O-benzyl imidate with alcohols and carboxylic acids in the presence of trifluoromethane sulfonic acid gave benzyl ethers and benzyl esters, respectively.     

A convenient microwave-assisted desulfitative dimethylamination of the 2(1H)-pyrazinone scaffold using N,N-dimethylformamide

A convenient microwave-assisted methodology is developed for the generation of 5-chloro-3-(dimethylamino)pyrazin-2(1H)-ones. The method entails a chemoselective desulfitative removal of a phenylthioether bond upon DMF/H₂O treatment in the presence of sodium carbonate, yielding the desired compounds in 73-96%.     

Heterogeneous bimetallic Pt-Sn/γ-Al2O3 catalyzed direct synthesis of diamines from N-alkylation of amines with diols through a borrowing hydrogen strategy

Direct synthesis of diamines has been efficiently realized from the N-alkylation of amines with diols by means of heterogeneous bimetallic Pt-Sn/γ-Al₂O₃ catalyst (0.5 wt % Pt, molar ratio Pt:Sn = 1:3) through a ‘Borrowing Hydrogen’ strategy under ligand-free conditions. The present methodology provides an environmentally benign route to diamines.     

Synthesis of 3-substituted benzo[g]isoquinoline-5,10-diones: a convenient one-pot Sonogashira coupling/iminoannulation procedure

A series of 3-substituted 5,10-dimethoxybenzo[g]isoquinolines were prepared by coupling of terminal alkynes with the tert-butylimine of 3-bromo-1,4-dimethoxy-2-naphthaldehyde in the presence of a Pd-catalyst and subsequent Cu-catalyzed cyclization of the intermediate 3-alkynyl-2-naphthylcarbaldehyde. A CAN-mediated oxidative demethylation yielded the corresponding 2-azaanthraquinones in excellent yields. Since this methodology proved to be limited to alkynes bearing aromatic groups, an alternative and more general Pd-catalyzed coupling procedure was developed, starting from 3-bromo-1,4-dimethoxy-2-naphthaldehyde. For more acidic terminal alkynes, like phenylacetylene, a combination of Pd(OAc)₂/P(t-Bu)₃/CuI (2/6/1) with potassium carbonate in DMF gave a complete conversion within 24 h. For less acidic acetylenes, 2 equiv of alkyne and caesium carbonate as a base were required in order to obtain complete conversion of the starting material within 24 h. These altered Sonogashira conditions also allowed the isolation of a benzo[f]indenone as an interesting side product in case Bu₄NCl was added to the reaction mixture. The 3-alkynyl-1,4-dimethoxy-2-naphthaldehyde acquired after completion of the Pd-catalyzed coupling could be cyclized by adding a solution of ethanolic ammonia and an extra equivalent of potassium carbonate to the reaction mixture. As such, this consecutive one-pot coupling/iminoannulation procedure was a convenient alternative to the Larock isoquinoline procedure, enabling the isolation of a series of 3-substituted 5,10-dimethoxybenzo[g]isoquinolines.     

Diastereoselective reductive N-alkylation of (R,R)-trans-1,2-diaminocyclohexane with prochiral ketones using the Ti(OiPr)4/NaBH4 system

A simple and convenient one-pot method for the reductive N-alkylation of (R,R)-trans-1,2-diaminocyclohexane by prochiral ketones using a Ti(OⁱPr)₄/NaBH₄ system to obtain the corresponding alkyl amine derivatives in 76–95% yields with good diastereoselectivity (dr = up to 23:1:1) is reported.     

N-Alkylation of carbamates and amides with alcohols catalyzed by a CpIr complex

New atom-economical catalytic systems consisting of [Cp^∗IrCl₂]₂/NaOAc (Cp^∗=pentamethylcyclopentadienyl) for the N-alkylation of carbamates and amides using alcohols as alkylating agents under solvent-free conditions have been developed. For example, the reaction of n-butyl carbamate with benzyl alcohol in the presence of [Cp^∗IrCl₂]₂ (5.0 mol % Ir) and NaOAc (5.0 mol %) at 130 °C under the absence of solvent gives n-butyl N-benzylcarbamate in the yield of 94%. The present catalytic system is applicable to not only carbamates but also amides, and only harmless water is produced as co-product.     

1,3-dimethylimidazolium-2-carboxylate: the unexpected synthesis of an ionic liquid precursor and carbene-CO2 adduct

1,3-Dimethylimidazolium-2-carboxylate is formed in good yield, rather than the anticipated organic salt, 1,3-dimethylimidazolium methyl carbonate, as the reaction product resulting from both N-alkylation and C-carboxylation of 1-methylimidazole with dimethyl carbonate; the crystal structure of the zwitterion exhibits pi-stacked rings and two-dimensional sheets constructed by hydrogen-bonds from imidazolium-ring hydrogens to the carboxylate group.     

Dual Tunability for Uncatalyzed N-Alkylation of Primary Amines Enabled by Plasma-Microdroplet Fusion

The fusion of non-thermal plasma with charged microdroplets facilitates catalyst-free N-alkylation for a variety of primary amines, without halide salt biproduct generation. Significant reaction enhancement (up to >200×) is observed over microdroplet reactions generated from electrospray. This enhancement for the plasma-microdroplet system is attributed to the combined effects of energetic collisions and the presence of reactive oxygen species (ROS). The ROS (e.g., O₂⋅⁻) act as a proton sink to increase abundance of free neutral amines in the charged microdroplet environment. The effect of ROS on N-alkylation is confirmed through three unique experiments: (i) utilization of radical scavenging reagent, (ii) characterization of internal energy distribution, and (iii) controls performed without plasma, which lacked reaction acceleration. Establishing plasma discharge in the wake of charged microdroplets as a green synthetic methodology overcomes two major challenges within conventional gas-phase plasma chemistry, including the lack of selectivity and product scale-up. Both limitations are overcome here, where dual tunability is achieved by controlling reagent concentration and residence time in the microdroplet environment, affording single or double N-alkylated products. Products are readily collected yielding milligram quantities in eight hours. These results showcase a novel synthetic strategy that represents a straightforward and sustainable C−N bond-forming process.     

A new approach to N-3 functionalized 3,4-dihydropyrimidine-2(1H)-ones with 1,2,4-oxadiazole group as amide isostere via ionic liquid-phase technology

New N-3 functionalized 3,4-dihydropyrimidine-2(1H)-ones with 1,2,4-oxadiazole group as amide isostere were synthesized in six steps by ionic liquid-phase organic synthesis (IoLiPOS) methodology from ILP bound acetoacetate. The 3,4-dihydropyrimidine-2(1H)-one (3,4-DHPM) core was prepared in the first step by one-pot three-component Biginelli condensation followed by N-alkylation with chloroacetonitrile. Then the nitrile group appended on the 3,4-DHPM heterocycle was quantitatively transformed into amidoxime. Addition of aliphatic carboxylic anhydride or aromatic carboxylic acid to the amidoxime produced the expected 1,2,4-oxadiazole via the O-acylamidoxime intermediate grafted on the ILP bound 3,4-DHPM using two convergent methods. After cleavage by transesterification under mild conditions, the target compounds were obtained in good overall yields. The structures and the purities of the reaction intermediates in each step were verified easily by routine spectroscopic analysis.     

Fe nano particles mediated C-N bond-forming reaction: Regioselective synthesis of 3-[(2-chloroquinolin-3-yl)methyl]pyrimidin-4(3H)ones

An efficient and regioselective N-alkylation of 4(3H)-pyrimidone with various electrophiles in the presence of Fe nano particle is reported. The catalyst initiates N-alkylation of amides by alkyl chlorides. The reaction of equimolar 4(3H)-pyrimidone and 2-chloro-3-(chloromethyl)quinolines in the presence of KOH and Fe nano particle (5 mol %) in DMSO solution under reflux condition formed 3-[(2-chloroquinolin-3-yl]methyl)pyrimidin-4(3H)ones.     

Mechanism of ring-opening and elimination cooligomerization of cyclic carbonates and ε-caprolactone: Formation of cyclic cooligomers

The cooligomerization reactions of the comonomers ethylene carbonate-propylene carbonate, ethylene carbonate-ε-caprolactone and propylene carbonate-ε-caprolactone initiated by the p-tert-butylphenol/KHCO₃ system were investigated by means of electrospray ionization mass spectrometry combined with liquid chromatography. Three major cooligomer series were found in each case which were identified such as cooligomers with tert-butylphenol and hydroxyl headgroups. The presence of cyclic cooligomers was also unambigously observed. In addition, cooligomers carrying carbonate linkages were also identified, however, their fraction was very small compared to the cooligomer series without carbonate linkages. Besides the cooligomerization reaction, homooligomerization of ethylene and propylene carbonate was observed, as well as no linear homooligomers of ε-caprolactone were detected. Based on the LC-ESI MS results a mechanism is proposed for the formation of cyclic co-oligomers and the chain degradation of cooligomers containing carbonate linkages.     

Synthesis and applications of Fe3O4-diisopropylaminoacetamide as a versatile and reusable magnetic nanoparticle supported N,N-diisopropylethylamine equivalent

A magnetic nanoparticle supported N,N-diisopropylaminoacetamide (Fe₃O₄-DIPA) was developed for application as a magnetic recoverable, and reusable N,N-diisopropylethylamine equivalent. The Fe₃O₄ nanoparticles were coated with a silica layer using the sol-gel method, followed by surface modification with 3-aminopropyltriethoxysilane. Subsequent acylation with chloroacetyl chloride and chlorine displacement with diisopropylamine afforded Fe₃O₄-DIPA in 90% yield with a loading of 0.96 mmol/g. The applicability of Fe₃O₄-DIPA was demonstrated in the synthesis of amine derivatives cv sulfonation, acylation, and N-alkylation reactions. The desired products were obtained in excellent yields and purities after scavenging the residual starting amines by treatment with silica-supported dichlorotriazine. Fe₃O₄-DIPA was readily recovered by separation using a magnet and could be reused several times without significant loss of reactivity.     

Resolution of a chiral alcohol through lipase-catalyzed transesterification of its mixed carbonate by poly(ethylene glycol) in organic media

A simple approach to the resolution of chiral alcohols through a lipase-catalyzed transesterification of one enantiomer of the corresponding trifluoroethyl carbonate by a low molecular weight poly(ethylene glycol), PEG, is described. The method was demonstrated through resolution of (RS)-sec-phenethyl alcohol. The alcohol was converted to its 2,2,2-trifluoroethyl carbonate, 2, and the (R)-enantiomer was selectively transesterified with PEG in warm diisopropyl ether using porcine pancreas lipase, PPL, as the catalyst. The two carbonate enantiomers were easily separated by cooling and filtering off the solid PEG having the (R)-alcohol covalently attached. Hydrolysis of the unchanged (S)-carbonate was achieved in dilute aqueous base, and the enantiomeric excess of the (S)-alcohol was found to be 80% by NMR in the presence of the chiral shift reagent Eu(hfc)₃. Methanolysis of the modified (R)-PEG carbonate yielded (R)-sec-phenethyl alcohol having enantiomeric excess=96% by NMR with Eu(hfc)₃.