Reaction of Acetals with Various Carbon Nucleophiles under Non‐Acidic Conditions: C?C Bond Formation via a Pyridinium‐Type Salt

Mild substitution reactions of acetals with carbon nucleophiles via the pyridinium‐type salts generated by the treatment of acetals with TESOTf‐2,4,6‐collidine or 2,2′‐bipyridyl have been developed. Various carbon nucleophiles, such as organocuprates, silyl enol ethers, enamines, etc., reacted with the pyridinium‐type salts to give the corresponding substituted products in good yields. The reactions proceeded under very mild conditions (non‐acidic conditions) and thus acid‐sensitive functional groups can be tolerated during the reaction. In addition, only an acetal can form the pyridinium‐type salt and react with nucleophiles in the presence of a ketal. This unusual selectivity is in contrast to general methods conducted under acidic conditions.     

4‐(Azulen‐1‐yl) six‐membered heteroaromatics substituted with thiophen‐2‐yl or furan‐2‐yl moieties in 2 and 6 positions

Pyranylium perchlorates with azulen‐1‐yl moiety in 4‐position and thiophen‐2‐yl or furan‐2‐yl in 2 and 6‐positions were obtained by the substitution of 4‐chloro corresponding salts with azulenes. The pyranylium salts are used as starting materials for the synthesis of pyridine and pyridinium salts. The products were characterized and for pyridines pKa was spectroscopically determined. Several attempts were made for pyridine complexation with metal cations as Hg²⁺ or Ag⁺. J. Heterocyclic Chem., (2011).     

Palladium‐Catalyzed Dearomative syn‐1,4‐Oxyamination

A palladium‐catalyzed dearomative syn‐1,4‐oxyamination protocol using non‐activated arenes has been developed. This one‐pot procedure utilizes arenophile chemistry, and the corresponding para‐cycloadducts are treated with oxygen nucleophiles via formal allylic substitution, providing direct access to syn‐1,4‐oxyaminated products. The reaction conditions permit a range of arenes, as well as different O‐nucleophiles, such as oximes and benzyl alcohols. Moreover, this process was established in an asymmetric fashion, delivering products with high enantioselectivity. The dearomatized products are amenable to a multitude of further derivatizations ranging from olefin chemistry to C?H activation, giving rise to a diverse set of new functionalities. Overall, this dearomative functionalization offers rapid and controlled formation of molecular complexity, enabling straightforward access to functionalized small molecules from simple and readily available arenes.     

2‐(Azulen‐1‐yl)‐4,6‐diphenyl substituted six‐membered heteroaromatics

2‐(Azulen‐1‐yl)‐4,6‐diphenyl substituted pyranylium salts, pyridinium salts and pyridines were efficiently synthesized and the new obtained compounds were completely characterized. Comparative structural analysis between these compounds and their corresponding isomers that contain the azulen‐1‐yl moiety in the 4‐position of the heterocycle, were carried out. These studies are based on calculated dihedral angles formed between central heterocycle and the aromatic substituents and on the obtained electronic and NMR spectra. Due to the restriction in the rotation around azulenyl‐pyridinium bond produced by the quaternary nitrogen substituent, in the herein reported pyridinium salts, the substitution groups of the quaternary nitrogen atom are prochiral. This property leads to the non‐equivalence of gem‐protons or gem‐methyl groups of N‐substituents in the ¹H nmr spectra of the synthesized pyridinium salts.     

Heterocyclic compounds from 4h‐3,1‐benzoxazin‐4‐one derivatives as anticancer agent

Behaviour of 2‐(4‐oxo‐4H‐benzo[d][l,3]oxazin‐2‐yl)‐benzoic acid (1) towards nitrogen nucleophiles namely, hydrazine hydrate, in different solvents, ammonium acetate, and o‐phenylenediamine has been investigated to give aminoquinazolin‐4‐one, benzotriazepinone, spiro‐type compound, and nitrogen bridgehead compounds 3‐5 , respectively. Also, reactivity of the aminoquinazolin‐4‐one 2 towards carbon elec‐trophiles such as ethyl acetoacetate, ethyl phenylacetate, ethyl chloroacetate, and aromatic aldehydes has been discussed. Reaction of Schiff s base 8 with sulfur nucleophiles namely o‐aminothiophenol and/or thio‐glycolic acid afforded Michael type adducts. Structural assignments, of products 1‐24 have been confirmed by elemental analysis and spectral data (¹H‐ and ¹³C ‐NMR and MS fragmentation). The bioassay indicates that some of the target compounds obtained have good selective anticancer activity.     

Cationic photopolymerization with the aid of pyridinium‐type salts

Pyridinium‐type salts containing an N‐ethoxy group belong to the family of onium salts and are photoinitiators appropriate for the polymerization of monomers such as oxiranes and vinyl ethers which are not polymerizable by a free radical mechanism. The initiation is accomplished by direct or indirect (sensitized) photolysis of the onium ion, with the former being restricted to the wavelength range of self absorption, the latter being applicable at wavelengths of visible light. An additionally useful tool, namely free radical‐mediated generation of initiating species enlarges the versatility of pyridinium salts as photoinitiators. In this connection, the oxidation of free radicals by pyridinium‐type ions and the free radical‐induced fragmentation of alkoxy pyridinium ions are addressed in this article. Moreover, an interesting application is noted concerning the synthesis of novel block copolymers with the aid of the onium salt‐based photopolymerization technique.     

Ring‐Opening Reactions of 3‐Aryl‐1‐benzylaziridine‐2‐carboxylates and Application to the Asymmetric Synthesis of an Amphetamine‐Type Compound

Nucleophilic ring‐opening reactions of 3‐aryl‐1‐benzylaziridine‐2‐carboxylates were examined by using O‐nucleophiles and aromatic C‐nucleophiles. The stereospecificity was found to depend on substrates and conditions used. Configuration inversion at C(3) was observed with O‐nucleophiles as a major reaction path in the ring‐opening reactions of aziridines carrying an electron‐poor aromatic moiety, whereas mixtures containing preferentially the syn‐diastereoisomer were generally obtained when electron‐rich aziridines were used (Tables 1–3). In the reactions of electron‐rich aziridines with C‐nucleophiles, S_N2 reactions yielding anti‐type products were observed (Table 4). Reductive ring‐opening reaction by catalytic hydrogenation of (+)‐trans‐(2S,3R)‐3‐(1,3‐benzodioxol‐5‐yl)aziridine‐2‐carboxylate (+)‐trans‐ 3c afforded the corresponding α‐amino acid derivative, which was smoothly transformed into (+)‐tert‐butyl [(1R)‐2‐(1,3‐benzodioxol‐5‐yl)‐1‐methylethyl]carbamate((+)‐ 14 ) with high retention of optical purity (Scheme 6).     

Molecular structures of 3‐[(2,2,3,3‐tetrafluoropropoxy)methyl]‐ and 3‐[(2,2,3,3,3‐pentafluoropropoxy)methyl]pyridinium saccharinates

The salts 3‐[(2,2,3,3‐tetrafluoropropoxy)methyl]pyridinium saccharinate, C₉H₁₀F₄NO⁺·C₇H₄NO₃S⁻, (1), and 3‐[(2,2,3,3,3‐pentafluoropropoxy)methyl]pyridinium saccharinate, C₉H₉F₅NO⁺·C₇H₄NO₃S⁻, (2), i.e. saccharinate (or 1,1‐dioxo‐1λ⁶,2‐benzothiazol‐3‐olate) salts of pyridinium with –CH₂OCH₂CF₂CF₂H and –CH₂OCH₂CF₂CF₃meta substituents, respectively, were investigated crystallographically in order to compare their fluorine‐related weak interactions in the solid state. Both salts demonstrate a stable synthon formed by the pyridinium cation and the saccharinate anion, in which a seven‐membered ring reveals a double hydrogen‐bonding pattern. The twist between the pyridinium plane and the saccharinate plane in (2) is 21.26 (8)° and that in (1) is 8.03 (6)°. Both salts also show stacks of alternating cation–anion π‐interactions. The layer distances, calculated from the centroid of the saccharinate plane to the neighbouring pyridinium planes, above and below, are 3.406 (2) and 3.517 (2) Å in (1), and 3.409 (3) and 3.458 (3) Å in (2).     

Organocatalyzed Aldol Reaction between Pyridine‐2‐carbaldehydes and α‐Ketoacids: A Straightforward Route towards Indolizidines and Isotetronic Acids

Enantioselective aldol reactions between substituted pyridine carbaldehydes and α‐ketoacids were shown to provide isotetronic acids or their corresponding pyridinium salts, depending on the nature of the substituents on the pyridine ring. The pyridinium salts were generated through nucleophilic attack of the pyridine nitrogen atom onto the reactive keto functional group. Moderate‐to‐good yields of both compounds were typically obtained and high levels of enantioselectivity were observed by using benzimidazole pyrrolidine I as a catalyst. Hydrogenation of the resulting pyridinium salts led to new indolizidines with high ee values and diastereocontrol. X‐ray diffraction studies allowed the determination of the relative configuration of the products. Finally, DFT calculations were performed to rationalize the divergent pathway as a function of the pyridine substituents.     

S‐((Phenylsulfonyl)difluoromethyl)thiophenium Salts: Carbon‐Selective Electrophilic Difluoromethylation of β‐Ketoesters, β‐Diketones,and Dicyanoalkylidenes

S‐((Phenylsulfonyl)difluoromethyl)thiophenium salts were designed and prepared by a triflic acid catalyzed intramolecular cyclization of ortho‐ethynyl aryldifluoromethyl sulfanes. The thiophenium salts were found to be efficient as electrophilic difluoromehtylating reagents for introduction of a CF₂H group to sp³‐hybridized carbon nucleophiles such as of β‐ketoesters and dicyanoalkylidenes. The (phenylsulfonyl)difluoromethyl group can be readily transformed into CF₂H under mild reaction conditions. Enantioselective electrophilic difluoromethylation was also achieved in the presence of bis(cinchona) alkaloids.     

S‐((Phenylsulfonyl)difluoromethyl)thiophenium Salts: Carbon‐Selective Electrophilic Difluoromethylation of β‐Ketoesters, β‐Diketones,and Dicyanoalkylidenes

S‐((Phenylsulfonyl)difluoromethyl)thiophenium salts were designed and prepared by a triflic acid catalyzed intramolecular cyclization of ortho‐ethynyl aryldifluoromethyl sulfanes. The thiophenium salts were found to be efficient as electrophilic difluoromehtylating reagents for introduction of a CF₂H group to sp³‐hybridized carbon nucleophiles such as of β‐ketoesters and dicyanoalkylidenes. The (phenylsulfonyl)difluoromethyl group can be readily transformed into CF₂H under mild reaction conditions. Enantioselective electrophilic difluoromethylation was also achieved in the presence of bis(cinchona) alkaloids.     

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.     

Ultrasonic Aptitude of Regioselective Reaction of 6‐bromo‐spiro‐3,1‐benzoxazinone2,1′‐isobenzofuran‐3′,4‐dione Towards Some Electrophilic and Nucleophilic Reagents

In the present work, the 2‐benzoxazinonyl benzoic acid (BBA) could be isomerized to the stereogenic spiro products (SBI) via ultrasonic and basic reaction conditions. The spiro compounds (SBI) have both electrophilic and nucleophilic centers. A series of nitrogen nucleophiles such as hydrazine hydrate, glycine, 2‐aminopyridine, 2‐picolinylamine, 4‐anisidine, 4‐aminoacetophenone and carbon electrophiles such as oxiranylmethylchloride, ethylchloroacetate, chloroacetylchloride, Mannich reagents, for example, formaldehyde with piperidine or morpholine can be treated with 2‐benzoxazine‐2‐yl benzoic acid (BBA) via multicomponent reaction. The basicity of previous nucleophiles can be controlled on the course of reaction of 2‐benzoxazinonyl benzoic acid. The chemical structure of the synthesized compounds can be confirmed by microanalytical, spectral data and optimized by quantum chemical parameters.     

Oligoethylene Glycols as Highly Efficient Mutifunctional Promoters for Nucleophilic‐Substitution Reactions

Herein, we report the promising use of n‐oligoethylene glycols (oligoEGs) as mutifunctional promoters for nucleophilic‐substitution reactions employing alkali metal salts. Among the various oligoEGs tested, pentaethylene glycol (pentaEG) had the most efficient catalytic activity. In particular, when compared with other nucleophiles examined, a fluorine nucleophile generated from CsF was significantly activated by the pentaEG promoter. We also performed various facile nucleophilic‐displacement reactions, such as the halogenation, acetoxylation, thioacetoxylation, nitrilation, and azidation of various substrates with potassium halides, acetate, thioacetate, cyanide, and sodium azide, respectively, in the presence of the pentaEG promoter. All of these reactions provided their desired products in excellent yields. Furthermore, the combination of pentaEG and a tert‐alcohol medium showed tremendous efficiency in the nucleophilic‐displacement reactions (fluorination and methoxylation) of base‐sensitive substrates with basic nucleophiles (cesium fluoride and potassium methoxide, respectively). The catalytic role of oligoEGs was examined by quantum‐chemical methods. The oxygen atoms in oligoEGs were found to act as Lewis bases on the metal cations to produce the “flexible” nucleophile, whereas the two terminal hydroxy (OH) groups acted as “anchors” to orientate the nucleophile and the substrate into an ideal configuration for the reaction.     

1,3‐Dichloro‐tetra‐n‐butyl‐distannoxane: a new application for catalyzing the direct substitution of 9H‐xanthen‐9‐ol at room temperature

1,3‐Dichloro‐tetra‐n‐butyl‐distannoxane was firstly used to catalyze the direct substitution of 9H‐xanthen‐9‐ol with indoles at room temperature to afford a class of 3‐(9H‐xanthen‐9‐yl)‐1H‐indole derivatives in good to excellent isolating yield. Moreover, other nucleophiles (such as diketone and pyrrole) could also proceed smoothly in this methodology. Copyright © 2012 John Wiley & Sons, Ltd.     

Solid‐State [2+2] Photodimerization of 1‐Aryl‐4‐pyridylbutadienes in Cation‐π‐Controlled Crystals

Irradiation of HX (X=CF₃SO₃ or CF₃CO₂) salts of 1‐aryl‐4‐pyridylbutadienes 1 a – 1 c in the solid‐state afforded syn head‐to‐tail dimers in good yields among a number of possible dimers, whereas irradiation of the neutral substrates gave a complex mixture or no products. A comparison of the X‐ray crystal structures of the neutral compounds and the HX salts clarified that their orientation modes are head‐to‐head and head‐to‐tail, respectively. Moreover, while the distances between the two neighboring double bonds of the neutral compounds are relatively far apart from each other, those of HX salts are close together, satisfying Schmidt's requirement. These findings suggested that cation‐π interactions between the pyridinium and aromatic rings are effective for the preorientation of the HX salts of substrates, leading to photodimers in high regio‐ and stereoselectivities.     

Synthesis and reactions of pyrido[3,2,1‐jk]carbazole‐4,6‐diones

Pyrido[3,2,1‐jk]carbazoles 1 , synthesized from carbazoles and alkyl‐ or arylmalonates, gave regioselective electrophilic substitution reactions at position 5 such as chlorination to 5‐chloro derivatives 2 , nitration to 5‐nitro compounds 3 , or hydroxylation to 5‐hydroxy derivatives 4 . 5‐Hydroxy compounds 4 gave on treatment with strong bases ring contraction to 5 , 6 or the ring opening product 7 . Exchange of the chloro group in 2 with azide or amines gave the corresponding azides 8 and the 5‐amino derivatives 9 and 10 . Alkylation of 1 with benzyl chloride or allyl bromide resulted in the formation of 5‐C‐alkylated products 11 together with 4‐alkyloxy derivatives 12 . J. Heterocyclic Chem., 48, 1039 (2011).     

Photoredox‐Catalyzed Alkenylation of Benzylsulfonium Salts

Visible light‐mediated radical alkenylation of benzylsulfonium salts was achieved by means of fac‐Ir(ppy)₃ as a photocatalyst, giving allylbenzenes as products. A variety of functional groups, such as halogen, ester, and cyano, were well tolerated in this transformation. Starting benzylsulfonium salts could be readily prepared from benzyl alcohols by an acid‐mediated substitution, increasing the synthetic utility of this transformation.     

An Efficient New Route for the Synthesis of Some 3‐Hterocyclylquinolinones via Novel 3‐(1,2‐Dihydro‐4‐hydroxy‐1‐methyl‐2‐oxoquinolin‐3‐yl)‐3‐oxopropanal and Their Antioxidant Screening

3‐(4‐hydroxy‐1‐methylquinoline‐3‐yl)‐3‐oxoproponal ( 5 ) was synthesized from 3‐[(E)‐3‐(dimethylamino)‐2‐propenoyl]‐4‐hydroxy‐1‐methyl‐2(1H )‐quinolinone ( 3 ) and was utilized as a starting precursor material. A convenient new route to functionalized 3‐heterocyclyl 4‐hydroxy‐2(1H )‐quinolinones such as pyrazolyl, isoxazolyl, pyrimidinyl, azepineyl , pyridonyl, and pyranyl heterocycles was described via cyclization of compound 5 with some N and C ‐nucleophiles. The newly synthesized aldehyde 5 showed only one ring closure possibility with maximum yield instead of using compound 3 that exhibited different regioselective ring closure routes with minimum yields. All newly synthesized products were structurally elucidated on the basis of their relevant spectroscopic data and elemental microanalyses. The antioxidant activity of the products was screened in a series of in vitro tests.     

Identification of 2‐chloropyrazine oxidation products and several derivatives by multinuclear magnetic resonance

¹H, ¹³C, ¹⁴N and ¹⁵N NMR chemical shifts were used to prove the structures of the products of 2‐chloropyrazine oxidation. It was shown that oxidation by hydrogen peroxide in acetic acid or m‐chloroperbenzoic acid leads to the N4‐oxide, whereas potassium persulfate in sulfuric acid gives the N1‐oxide as the main product. Additionally, the results of NMR measurements of products from the nucleophilic substitution of the chlorine atom by azide anion, yielding the respective azides, and ethylation reactions of both 2‐chloropyrazine N‐oxides leading to the N‐ethyl salts confirm the structures of both isomeric N‐oxides. Protonation studies of the compounds obtained are also reported. The favoured protonation site is found to be the N atom that is not hindered by any substituents, and in some cases probably the oxygen atom of the N‐oxide function. Copyright © 2003 John Wiley & Sons, Ltd.