A Metal‐Free Three‐Component Reaction for the Regioselective Synthesis of 1,4,5‐Trisubstituted 1,2,3‐Triazoles

A metal‐free three‐component reaction to synthesize 1,4,5‐trisubstituted 1,2,3‐triazoles from readily available building blocks, such as aldehydes, nitroalkanes, and organic azides, is described. The process is enabled by an organocatalyzed Knoevenagel condensation of the formyl group with the nitro compound, which is followed by the 1,3‐dipolar cycloaddition of the azide to the activated alkene. The reaction features an excellent substrate scope, and the products are obtained with high yield and regioselectivity. This method can be utilized for the synthesis of fused triazole heterocycles and materials with several triazole moieties.     

Synthesis of polysubstituted N-H pyrroles from vinyl azides and 1,3-dicarbonyl compounds

Two synthetic methods for tetra- and trisubstituted N-H pyrroles are presented: (i) the thermal pyrrole formation by the reaction of vinyl azides with 1,3-dicarbonyl compounds via the 1,2-addition of 1,3-dicarbonyl compounds to 2H-azirine intermediates generated in situ from vinyl azides; (ii) the Cu(II)-catalyzed synthesis of pyrroles from alpha-ethoxycarbonyl vinyl azides and ethyl acetoacetate through the 1,4-addition reaction of the acetoacetate to the vinyl azides. By applying these two methods, regioisomeric pyrroles can be prepared selectively starting from the same vinyl azides.     

Enantioselective Hydroazidation of Trisubstituted Non‐Activated Alkenes

A one‐pot procedure for the enantioselective hydroazidation of non‐activated trisubstituted alkenes is described. Hydroboration with monoisopinocampheylborane (IpcBH₂) provides dialkylboranes that are in situ selectively converted into monoalkyl‐substituted catecholboranes; these undergo radical azidation upon treatment with benzenesulfonyl azide and a radical initiator. Enantiomerically enriched azides were thus obtained in yields of 59–81 % and enantioselectivities of up to 94:6 e.r. (98:2 e.r. if the intermediate dialkylborane is purified by crystallization). A rapid access to enantiomerically pure (+)‐rodocaine is also described. The use of other arenesulfonyl radical traps enables enantioselective hydroallylation, hydrosulfanylation, and hydrobromination reactions with yields of 71–86 %.     

Rh2(II)-catalyzed nitro-group migration reactions: selective synthesis of 3-nitroindoles from β-nitro styryl azides

Rhodium carboxylate complexes (1 mol %) catalyze the migration of electron-withdrawing groups to selectively produce 3-substituted indoles from β-substituted styryl azides. The relative order of migratorial aptitude for this transformation is ester ? amide < H < sulfonyl < benzoyl ? nitro.     

One-step synthesis of oxazoline and dihydrooxazine libraries

The reactions of 1,2- and 1,3-hydroxyalkyl azides and aldehydes in the presence of Lewis acid result in the one-step construction of oxazolines and dihydrooxazines, respectively. The reaction was adapted to parallel synthesis using a polymer-bound phosphine to scavenge excess hydroxyalkyl azide. Thus, a 60-member library of various disubstituted oxazolines and di- and trisubstituted dihydrooxazines was generated.     

Efficient Polymerization of Azide and Active Internal Alkynes

The 1,3‐dipolar cycloaddition of azides and active internal alkynes has been well studied, but is rarely utilized as a tool for polymer preparation. In this work, an efficient polymerization route is developed. Polycycloaddition of diazide ( 4 ) and bis(benzoylethynyl)‐benzenes and ‐butane ( 3 ) at elevated temperature has produced the first examples of soluble 1,4,5‐trisubstituted polytriazoles P I with satisfactory molecular weights (M _w up to 16 400) in excellent yields (up to 98.6%). All the obtained polymers are thermally stable, losing merely 5% of their weights at temperatures higher than 367 °C. They exhibit higher refractive indices than some commercial plastics and can be crosslinked upon UV irradiation to generate a 3D photopattern with high resolution. The metal‐free feature of such a methodology offers a facile tool to prepare functional materials free from the contamination of metal species.     

Novel Method for Soluble‐Polymer‐Supported Synthesis of 3,4,5‐Trisubstituted Isoxazoles

A practical and efficient liquid‐phase synthesis of 3,4,5‐trisubstituted isoxazoles using poly(ethylene glycol) as supported is described. Soluble‐polymer‐supported nitrile oxide generated in situ reacted with chalcones to afford polymer‐supported isoxazolines, which were cleaved by sodium methoxide to generate 3,4,5‐trisubstituted isoxazoles instead of 3,4,5‐trisubstituted isoxazolines. This sequential process provided a novel method to synthesize 3,4,5‐trisubstituted isoxazoles.     

Hydrazines and azides via the metal-catalyzed hydrohydrazination and hydroazidation of olefins

The discovery, study, and implementation of the Co- and Mn-catalyzed hydrohydrazination and hydroazidation reactions of olefins are reported. These reactions are equivalent to direct hydroaminations of C-C double bonds with protected hydrazines or hydrazoic acid but are based on a different concept in which the H and the N atoms come from two different reagents, a silane and an oxidizing nitrogen source (azodicarboxylate or sulfonyl azide). The hydrohydrazination reaction using di-tert-butyl azodicarboxylate is characterized by its ease of use, large functional group tolerance, and broad scope, including mono-, di-, tri-, and tetrasubstituted olefins. Key to the development of the hydroazidation reaction was the use of sulfonyl azides as nitrogen sources and the activating effect of tert-butyl hydroperoxide. The reaction was found to be efficient for the functionalization of mono-, di-, and trisubstituted olefins, and only a few functional groups are not tolerated. The alkyl azides obtained are versatile intermediates and can be transformed to the free amines or triazoles without isolation of the azides. Preliminary mechanistic investigations suggest a rate-limiting hydrocobaltation of the alkene, followed by an amination reaction. Radical intermediates cannot be ruled out and may be involved.     

Interaction of Crown Ether‐Annelated Styryl Dyes with Double‐Stranded DNA

DNA‐binding properties of 15‐crown‐5‐derived mono‐ and bis‐styryl dyes were investigated in the presence of calf thymus DNA. To access the factors that influence the DNA association in the series of these ligands, the structure of the molecules was varied by either changing size of the heterocyclic moiety or altering the position of the styryl substituents. The major binding mode for the monostyryl dyes is intercalation. Notably, binding of the dyes to the nucleic acids leads to a fluorescence enhancement by a factor of up to 54. Therefore, these cationic styryl derivatives may be applied as fluorescent “light‐up” probes for DNA detection.     

Synthesis of 3‐(2‐benzyloxy‐6‐hydroxyphenyl)‐1‐methylpyrazoles by the reaction of chromones with methylhydrazine

The 3‐(2‐benzyloxy‐6‐hydroxyphenyl)‐5‐(methyl, phenyl or styryl)pyrazoles were prepared from the reaction of 2‐(methyl, phenyl or styryl)chromones with methylhydrazine. The structure of these compounds has been determined by several nmr techniques, and the reaction mechanism is discussed.     

One‐Pot Synthesis of 3‐Substituted 3,4‐Dihydro‐1,2,3‐benzotriazine Derivatives Based on the Reaction of o‐Bromobenzyl Azides with Butyllithium

An efficient one‐pot procedure for the preparation of 3‐substituted 3,4‐dihydro‐1,2,3‐benzotriazines 2, 3 , and 4 from o‐bromobenzyl azides 1 is described. The reaction of these azides with BuLi in THF at ?78° generates o‐lithiobenzyl azides via the Br/Li exchange. These lithium compounds immediately undergo intramolecular cyclization to give the corresponding (dihydro‐1,2,3‐benzotriazinyl)lithium intermediates, which are trapped with a variety of acylating agents or BnBr at N(3) exclusively to provide the desired products in moderate to good yields.     

Synthesis and ring closure reactions of pyrido[3,2,1‐jk]carbazol‐6‐ones

4‐Hydroxy‐5‐phenylpyrido[3,2,1‐jk]carbazol‐6‐ones ( 4, 5 ), which were obtained from carbazoles 1 and malonates 2 or 3 , were converted to reactive intermediates such as 4‐chlorides 9 or 4‐tosylates 10 , which gave in turn 4‐azido‐5‐phenyl derivatives 11 . 5‐Alkyl‐4‐azides 11 were not obtained in this manner; however a new one‐pot azidation reaction was developed starting from 4‐hydroxy derivatives 4 which gave azides 11 in good yields. 4‐Azido‐5‐phenyl derivative 11f cyclized on thermolysis to the indole 12 . The thermal behaviour of the azides 11 was studied by thermoanalytical methods (DSC).     

Novel approach to the design of potential bioactive alkaloid anabasine conjugates using click chemistry methodology

Anabasine‐containing azides and acetylenes were used as building blocks in copper(I)‐catalyzed 1,3‐dipolar cycloaddition reactions with a series of acetylenes and azides via click methodology to provide a range of anabasine conjugates being potential ligands for neuronal nicotinic acetylcholine receptors.     

Manganese‐Catalyzed Oxidative Azidation of Cyclobutanols: Regiospecific Synthesis of Alkyl Azides by CC Bond Cleavage

A novel, manganese‐catalyzed oxidative azidation of cyclobutanols is described. A wide range of primary, secondary, and tertiary alkyl azides were generated in synthetically useful yields and exclusive regioselectivity. Aside from linear alkyl azides, otherwise elusive medium‐sized cyclic azides were also readily prepared. Preliminary mechanistic studies reveal that the reaction likely proceeds by a radical‐mediated C? C bond cleavage/C? N₃ bond formation pathway.     

Manganese‐Catalyzed Oxidative Azidation of Cyclobutanols: Regiospecific Synthesis of Alkyl Azides by C?C Bond Cleavage

A novel, manganese‐catalyzed oxidative azidation of cyclobutanols is described. A wide range of primary, secondary, and tertiary alkyl azides were generated in synthetically useful yields and exclusive regioselectivity. Aside from linear alkyl azides, otherwise elusive medium‐sized cyclic azides were also readily prepared. Preliminary mechanistic studies reveal that the reaction likely proceeds by a radical‐mediated C C bond cleavage/C N₃ bond formation pathway.     

One‐Pot Synthesis of Regioselective Polysubstituted Indolizines via Three‐Component Reactions of Dialkyl Acetylendicarboxylates,Dialkylchloro Malonates,and Pyridines

An efficient and novel approach to the synthesis of 1,2,3‐trisubstituted indolizines has been achieved via the reaction of pyridines, dialkyl acetylendicarboxylates, and dialkyl chloromalonates. The corresponding 1,2,3‐trisubstituted indolizines may be useful building blocks for the construction of complex indolizine derivatives.     

Utility of Ketonic Mannich Bases in Synthesis of Some New Functionalized 2‐Pyrazolines

The styryl ketonic Mannich base 2 has been used as a precursor in the synthesis of 2‐pyrazolines having a basic side chain at C‐3 and a phenolic Mannich base at C‐5. Treatment of the bis(styryl ketonic bases) 6a and 8a with phenylhydrazine affords the bis(3‐functionalized 2‐pyrazolines) 7 and 9 . The transamination between the styryl keto base 10 and 4‐aminoantipyrine leads to 12 , which reacts with piperazine to give 13 . N‐Nitrosation of the sec‐Mannich bases 15a – d followed by reductive cyclization affords 2‐pyrazolines 17a – d . The keto base 14b has been used for the synthesis of 2‐pyrazolines having a phenolic Mannich base at C‐3 and its reaction with 3,5‐dimethyl‐1H‐pyrazole affords 23 . The alkylation of 3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one with the bis(Mannich base) 25 was investigated.     

Synthesis of Novel (p‐Substituted Styryl) Spirobenzopyrans

A series of (p‐substituted styryl) spirobenzopyrans were synthesized by the Wittig reaction of Fisher's bases with 5‐(p‐substituted styryl) salicylaldehyde derivatives. The final spirobenzopyrans were characterized by the ¹H NMR, IR, UV, and GC‐MS analyses.     

Synthesis of 1‐substituted 5‐aryl‐3‐styryl‐2‐pyrazolines and 3‐aryl‐5‐styryl‐2‐pyrazolines by the reaction of dibenzylideneacetones and E,E‐cinnamylideneacetophenones with hydrazines

The reaction of dibenzylideneacetones or E,E‐cinnamylidene‐ acetophenones and hydrazine hydrate provided 1‐propionyl derivatives of 5‐aryl‐3‐styryl‐2‐pyrazolines and 3‐aryl‐5‐styryl‐2‐pyrazolines. These unsaturated ketones afforded 1‐(2‐carboxyphenyl) or 1‐(4‐carboxyphenyl) 5‐aryl‐3‐styryl‐2‐pyrazolines and 1‐(4‐carboxyphenyl) derivatives of 3‐aryl‐5‐styryl‐2‐pyrazolines on treatment with (2‐carboxyphenyl)‐hydrazine or (4‐carboxyphenyl)hydrazine in hot acetic acid. Structures of all new 2‐pyrazolines have been elucidated by microanalyses and a combined utilization of various spectroscopic methods.     

A Novel ‘Domino‐Click Approach’ to Unsymmetrical Bis‐1H‐1,2,3‐triazoles

Aryl azides 1 were treated with allenylmagnesium bromide ( 2 ) to generate 1,5‐disubstituted butynyl‐1H‐1,2,3‐triazoles 3 in a domino fashion, which upon Cu^I‐catalyzed 1,3‐dipolar cycloaddition with aryl azides 4 afforded novel bis‐1H‐1,2,3‐triazoles 5 in quantitative yields (Scheme 1 and Table).