Regioselective N-alkylation Research Articles

Vinyl-diazine triphenylamines and their N-methylated derivatives: Synthesis, photophysical properties and application for staining DNA

In this paper we describe the synthesis of vinyl-diazine triphenylamines. These compounds exhibit strong green–yellow fluorescence in dichloromethane solution, important emission solvatochromism and acidochromism. Regioselective N-alkylation of these dyes provides cationic compounds that exhibit affinity for double-stranded DNA. Binding to the biopolymer results in a strong bathochromic shift and increase of the emission intensity.

Direct N-alkylation of amino-azoles with alcohols catalyzed by an iridium complex/base system

The direct and regioselective N-alkylation of amino-azoles to the corresponding 2-N-(alkylamino)azoles using various alcohols as alkylating agents with good to excellent yields has been accomplished by an iridium complex/base system.

ZnO nanoparticles-mediated regioselective synthesis of methyl-N-alkylated 1,2,3-triazole-4-carboxylates

The 1,2,3-triazoles are versatile synthetic intermediates of many biologically active compounds, and their N-1 substituted analogues are potential pharmaceutically important derivatives. In this study, an efficient regioselective N-alkylation reaction of methyl-1H-1,2 3-triazole-4-carboxylate 3 with alkyl halides 4 catalyzed by ZnO nanoparticles in the presence of potassium hydroxide as base and DMSO as solvent is reported which leads to methyl N 1-alkylated 1,2,3-triazole-4-carboxylates 5 in good yields.

Regioselective N-alkylation of (2-chloroquinolin-3-yl) methanol with N-heterocyclic compounds using the Mitsunobu reagent

AbstractThe Mitsunobu reaction is a well-established fundamental reaction and has been widely applied in organic synthesis. In this paper, under Mitsunobu conditions dehydration proceeds between (2-chloroquinolin-3-yl)methanol and nitrogen heterocyclic compounds such as quinazolinone, pyrimidone, 2-oxoquinoline in dry THF in the presence of triethylamine, triphenylphosphane and diethyl azodicarboxylate to give the corresponding products. As part of our recent research, we attempted to couple two N-heterocyclic compounds under Mitsunobu reaction conditions to provide efficient building blocks for natural product synthesis.

General Solution to the Synthesis of N-2-Substituted 1,2,3-Triazoles

The regioselective N-alkylation of 1,2,3-triazoles 1-6 was studied. Good to excellent N-2 selectivity and high chemical yields for N-2-substituted 4,5-dibromotriazoles 7 were obtained with 4,5-dibromo- and 4-bromo-5-trimethylsilyl-1,2,3-triazoles. These building blocks can be readily converted to 2-mono-, 2,4-di-, and 2,4,5-polysubstituted triazoles 10-15, providing a general, protective, group-free method for the synthesis of N-2-substituted triazoles. Observed regioselectivities can be rationalized by a combination of Frontier Molecular Orbital, steric, and electrostatic directing effects on the heterocyclic scaffolds.

C-H bonds as ubiquitous functionality: a general approach to complex arylated imidazoles via regioselective sequential arylation of all three C-H bonds and regioselective N-alkylation enabled by SEM-group transposition.

Imidazoles are an important group of the azole family of heterocycles frequently found in pharmaceuticals, drug candidates, ligands for transition metal catalysts, and other molecular functional materials. Owing to their wide application in academia and industry, new methods and strategies for the generation of functionalized imidazole derivatives are in demand. We here describe a general and comprehensive approach for the synthesis of complex aryl imidazoles, where all three C-H bonds of the imidazole core can be arylated in a regioselective and sequential manner. We report new catalytic methods for selective C5- and C2-arylation of SEM-imidazoles and provide a mechanistic hypothesis for the observed positional selectivity based on electronic properties of C-H bonds and the heterocyclic ring. Importantly, aryl bromides and low-cost aryl chlorides can be used as arene donors under practical laboratory conditions. To circumvent the low reactivity of the C-4 position, we developed the SEM-switch that transfers the SEM-group from N-1 to N-3 nitrogen and thus enables preparation of 4-arylimidazoles and sequential C4-C5-arylation of the imidazole core. Furthermore, selective N3-alkylation followed by the SEM-group deprotection (trans-N-alkylation) allows for regioselective N-alkylation of complex imidazoles. The sequential C-arylation enabled by the SEM-switch allowed us to produce a variety of mono-, di-, and triarylimidazoles using diverse bromo- and chloroarenes. Using our approach, the synthesis of individual compounds or libraries of analogues can begin from either the parent imidazole or a substituted imidazole, providing rapid access to complex imidazole structures.

ChemInform Abstract: Regioselective N-Alkylation of 4-Formylimidazole.

Abstract We describe here a high yield and highly regioselective N-alkylation of 4-formylimidazole via reversible Michael Reaction.

Michael-type Addition as a Convenient Method for Regioselective N-Alkylation of Ambident Uracils

A review of the Michael-type addition as one of the convenient synthetic methods to N-functionalisation of the uracil ring - against the background of other typical alkylation methods - is presented. The topic of N1- versus N3-regioselectivity in alkylation reactions is emphasised since this differentiation is essential in the various, especially medicinal, applications of substituted uracils. Specifically, the addition of uracils to acrylic acceptors at the N1-position is frequently used in the first stage of the synthesis of pyrimidinic acyclic nucleosides. In turn, the N3-position of the uracil ring is useful in further transformations, like anchoring of biologically active fragments in conjugates for radiochemotherapy or carriage of covalently bonded drug molecules. Nevertheless, N3-substituted derivatives of pyrimidine nucleosides can, themselves, play various therapeutic roles. Fundamental theoretical premises are also detailed, with regard to the rationale behind the orientation of alkylation.

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

Abstract 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.

Regioselective N-alkylation of imidazo[4,5- b]pyridine-4-oxide derivatives: an experimental and DFT study

Regioselectivities were determined for N-alkylations of imidazo[4,5- b]pyridine-4-oxide and 2-methyl-imidazo[4,5- b]pyridine-4-oxide with benzyl bromide or benzyl iodide at RT using K 2CO 3 in DMF as a base. Experimental attempts have shown that N-1/ N-3 ratios slightly varied according to the substitution on C-2 position. This was confirmed by DFT calculations in solvent phase. This computational study has shown first that this N -benzylation reaction passed through a S N2 mechanism. Moreover, regioselectivity of N-benzylation has appeared essentially governed by ‘steric approach control’. It explained that opposite N-1/ N-3 ratios were obtained with imidazo[4,5- b]pyridine-4-oxide and its 2-methyl-substituted analog. Finally, regioselectivities slightly varied with the nature of benzyl halide.

Synthesis of 3-(4-Chloro-2-methoxy-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)propanoic acid – An N(9)-Functionalized 7-Deazapurine

Regioselective N-alkylation of 4-chloro-2-methoxy-7H-pyrrolo[2,3- d]pyrimidine (6) with ethyl 3-bromopropionate under liquid-liquid phase-transfer reactionconditions gave the ester 7a. Its saponification yielded the acid 7b. The logP values of a series of N(9)-functionalized purines and purine isosteres were calculated.

Highly regioselective N-alkylation of benzotriazole under solvent-free conditions

An efficient, simple and solvent-free method for highly regioselective N-alkylation of benzotriazole in the presence of SiO2, K2CO3 and tetrabutylammonium bromide (TBAB) under thermal and microwave conditions has been described. In this method, 1-alkyl benzotriazoles were obtained regioselectively in moderate to high yields and short reaction times.

Microwave-assisted regioselective N-alkylation of cyclic amidines

A simple and efficient methodology for regioselective alkylation of exocyclic nitrogen of cyclic amidines was developed by microwave-assisted heating in the presence of amines. Novel N-alkylated 3,4-dihydropyrazino[2,1- b]quinazolin-6-ones were prepared in good yields. The reaction occurred via a transamination (addition–elimination) process involving a first attack of the amine on the electrophilic carbon of the amidine function.

Synthesis of 3-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propanoic acid – A Functionalized Base Derivative of the Nucleoside Antibiotic Tubercidin

Regioselective N-alkylation of 4-chloro-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine (1) with ethyl 3-bromopropionate under liquid-liquid phase transfer reaction conditions and further saponification of the ester function under formation of compound 3b is described. Subsequent SNAr substitution of the 4-chloro substituent by an amino function and reductive removal of the 2-methylthio group of 3b gives, via 4a, the title compound 4b.

Novel and Efficient Synthesis of 2-Aminooxazoles from Pyrimidin-2(1H)-one

Stepwise conversion of pyrimidin-2(1H)-one to 2-amino-5-aryloxazoles via oxazolo[3,2-a]pyrimidinium salts is reported. The sequence involves, (i) regioselective N-alkylation of pyrimidone by phenacyl bromides, (ii) cyclization of obtained 1-(2-aryl-2-oxoethyl)pyrimidin-2(1H)-ones into oxazolo[3,2-a]pyrimidinium salts under the action of fuming sulfuric (or triflic) acid, and (iii) reaction of the obtained salts with hydrazine leading to 2-amino-5-aryloxazoles.

Regioselective Synthesis of Novel N2- and N4-Substituted 7-Methylpyrazolo[4,5-e][1,2,4]thiadiazines

The new compound 7-methylpyrazolo[4,5-e][1,2,4]thiadiazin-3(2H,4H)-one1,1-dioxide (5) was synthesized and its novel mono N2- or N4-substituted derivatives 6 and 7 were prepared by regioselective N-alkylation of 5 with different molar ratios of NaH and alkyl halides. Based on the regioselective alkylation conditions found a facile one-pot synthesis of N2,N4-disubstituted pyrazolo[4,5-e][1,2,4] thiadiazines 8 was developed. The structures of the newly synthesized compounds were confirmed by IR,(1)H-NMR, (13)C-NMR and MS spectral analysis.

Ring-Selective Functionalization of N,N‘-Diarylureas by Regioselective N-Alkylation and Directed Ortho Metalation

[reaction: see text]. Unsymmetrical N,N'-diarylureas may be alkylated regioselectively at the more sterically congested nitrogen atom. The resulting mono-N-alkylated ureas undergo directed metalation (ortholithiation) with sec-BuLi to yield, on electrophilic quench, products functionalized regioselectively at the ring bearing the alkylated nitrogen atom.

Highly regioselective N-alkylation of nonracemic Betti base: a novel one-pot synthesis of chiral N-methyl- N-alkyl Betti bases

A novel one-pot preparation of chiral N-methyl- N-alkyl Betti bases has been developed involving a highly regioselective N-alkylation of ( S)-(+)-Betti base. The strategy involved formation-cleavage of the oxazine ring and N-methylation with BtCH 2OH under neutral conditions.

N‐(Diethoxyphosphoryl)‐O‐benzylhydroxylamine — A Convenient Substrate for the Synthesis of N‐Substituted O‐Benzylhydroxylamines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

N-(Diethoxyphosphoryl)- O-benzylhydroxylamine—a convenient substrate for the synthesis of N-substituted O-benzylhydroxylamines

Easily available N-(diethoxyphosphoryl)- O-benzylhydroxylamine was shown to be convenient, orthogonally protected substrate for regioselective N-alkylation by means of diverse halides under basic conditions (sodium hydride/tetrabutylammonium bromide). An efficient procedure for dephosphorylation of N-substituted N-(diethoxyphosphoryl)- O-benzylhydroxylamine to provide N-substituted O-benzylhydroxylamines was also established.