Self-Assembly of 4,4'-Linked Dipyrromethanes from Unconventional Reactants─Propargylamines, 2-(Vinyloxy)ethyl Isothiocyanate, and Alkylating Agents under Basic Conditions.

Self-assembly of 4,4'-linked dipyrromethanes from 2-(vinyloxy)ethyl isothiocyanate, tertiary propargylamines, and alkylating agents has been discovered. The plausible reaction mechanism, the major stages of which have been confirmed experimentally, includes (1) the lithiation of propargylamine (with n-BuLi); (2) the formation of lithium N-[2-(vinyloxy)ethyl]but-2-ynimidothioate (product of the addition of monolithiated propargylamine to isothiocyanate); (3) isomerization of the latter in the corresponding allenylimidothioate (under the action of the t-BuOK/t-BuOH system); (4) low-temperature (<15 °C) intramolecular cyclization of the latter into potassium N-(5-amino-2-thienyl)-N-[2-(vinyloxy)ethyl]amide; (5) the base-induced cleavage of the C-O bond of the N-[2-(vinyloxy)ethyl] group and removal of vinyloxide-anion leading to acetaldehyde; (6) interaction of acetaldehyde with two molecules of N-(5-amino-2-thienyl)-N-[2-(vinyloxy)ethyl]amide-anion resulting in dithienomethane N-anionic intermediate; (7) recyclization of the latter into dipyrromethane S-anionic intermediate. Final S-alkylation affords synthetically challenging 4,4'-dipyrromethanes in a yield of 22-51%. The whole process is carried out in a single synthetic operation in a very short time (∼10-15 min, excluding alkylation time).

Catalyst- and solvent-free regiospecific SNHAr phosphinylation of pyridines with H-phosphinates mediated by benzoylphenylacetylene.

Pyridines undergo a facile SNHAr phosphinylation with H-phosphinates under catalyst- and solvent-free conditions (50-55 °C) in the presence of benzoylphenylacetylene to afford 4-phosphinylpyridines in up to 68% yield. In this reaction, benzoylphenylacetylene activates the pyridine ring by the formation of a 1,3(4)-dipolar complex, deprotonates H-phosphinates to generate P-centered anions and finally acts as an oxidizer, being eliminated from an intermediate ion pair. Terminal electron-deficient acetylenes (methyl propiolate and benzoylacetylene) are inefficient as mediators in the above SNHAr process.

Dihydropyrrole-3-thiones: one-pot synthesis from propargylamines, acyl chlorides and sodium sulfide.

An efficient one-pot synthesis of 1,2,5-trisubstituted-1,2-dihydro-3H-pyrrole-3-thiones (up to 91% yield), representatives of essentially new heterocyclic systems, by the successive treatment of available propargylamines with acyl chlorides (PdCl2/CuI/Ph3P/Et3N, toluene, 40-45 °C, 3 h) and sodium sulfide (Na2S·9H2O, EtOH, 20-25 °C, 7 h) has been developed. The synthesis comprises the addition of sulfide anions to the formed aminoacetylenic ketones followed by dehydrative cyclization of the prototropically rearranged adducts.

Acrylamide derivatives: A dynamic nuclear magnetic resonance study.

Substituted acrylamides have found an extensive application in organic and medical chemistry; therefore, it is very important to get insight into their features such as electronic structure, spectral properties, and stereochemical transformations. A correct interpretation of the chemical behavior and biological activity of these heteroatomic systems is impossible without knowledge of the structure of stereodynamic forms and factors determining their relative stability. The structure and peculiarities of stereodynamic behavior of substituted acrylamides and their model compounds were studied by dynamic and multinuclear 1 H, 13 C, and 15 N nuclear magnetic resonance (NMR) spectroscopy in CDCl3 and DMSO-d6 solution. It has been established that acrylamides in solution are realized as Z- and E-isomers, with the E-rotamer being somewhat predominant. The obtained experimental values of the free activation energy of rotamers vary within 15-17 kcal/mol, depending on the stereochemical structure of the molecule. 15 N NMR spectroscopy is the most reliable and fastest method for determining the structural and stereochemical features of nitrogen-containing compounds.

Catalyst-Free Double CH-Functionalization of Quinolines with Phosphine Oxides via Two SNHAr Reaction Sequences.

Quinolines undergo catalyst-free double CH-functionalization upon treatment with secondary phosphine oxides (70-75 °C, 20-48 h) followed by oxidation of the intermediate 2,4-bisphosphoryltetrahydroquinolines with chloranil. The yields of the target 2,4-bisphosphorylated quinolines are up to 77%. Thus, a double-SNHAr reaction sequence in the same molecule of quinoline has been realized. In the case of 2,4-bisphenylphosphoryltetrahydroquinolines, the aromatization occurs with elimination of one molecule of diphenylphosphine oxide to afford the products of monofunctionalization, 4-diphenylphosphorylquinolines, in 40-45% yields.

Remarkable Alkene-to-Alkene and Alkene-to-Alkyne Transfer Reactions of Selenium Dibromide and PhSeBr. Stereoselective Addition of Selenium Dihalides to Cycloalkenes.

The original goal of this research was to study stereochemistry of selenium dihalides addition to cycloalkenes and properties of obtained products. Remarkable alkene-to-alkene and alkene-to-alkyne transfer reactions of selenium dibromide and PhSeBr were discovered during this research. The adducts of selenium dibromide with alkenes or cycloalkenes easily exchange SeBr2 with other unsaturated compounds, including acetylenes, at room temperature, in acetonitrile. Similar alkene-to-alkene and alkene-to-alkyne transfer reactions of the PhSeBr adducts with alkenes or cycloalkenes take place. The supposed reaction pathway includes the selenium group transfer from seleniranium species to alkenes or alkynes. It was found that the efficient SeBr2 and PhSeBr transfer reagents are Se(CH2CH2Br)2 and PhSeCH2CH2Br, which liberate ethylene, leading to a shift in equilibrium. The regioselective and stereoselective synthesis of bis(E-2-bromovinyl) selenides and unsymmetrical E-2-bromovinyl selenides was developed based on the SeBr2 and PhSeBr transfer reactions which proceeded with higher selectivity compared to analogous addition reactions of SeBr2 and PhSeBr to alkynes under the same conditions.

Regio- and stereoselective synthesis of new ensembles of diversely functionalized 1,3-thiaselenol-2-ylmethyl selenides by a double rearrangement reaction.

The reaction of 2-(bromomethyl)-1,3-thiaselenole with potassium selenocyanate proceeded via a rearrangement with ring expansion, leading to a six-membered 2,3-dihydro-1,4-thiaselenin-2-yl selenocyanate (kinetic product) which in turn underwent rearrangement with ring contraction to a 1,3-thiaselenol-2-ylmethyl selenocyanate (thermodynamic product). These rearrangements occurred by a nucleophilic attack of the selenocyanate anion at two different carbon atoms of the seleniranium intermediate. The efficient regioselective synthesis of alkyl, allyl, 2-propynyl, benzyl, 4-fluorobenzyl, and 2-pyridinylmethyl 1,3-thiaselenol-2-ylmethyl selenides was developed based on the generation of sodium 1,3-thiaselenol-2-ylmethylselenolate from 1,3-thiaselenol-2-ylmethyl selenocyanate or bis(1,3-thiaselenol-2-ylmethyl) diselenide followed by nucleophilic substitution reactions. Sodium 1,3-thiaselenol-2-ylmethylselenolate underwent nucleophilic addition to alkyl propiolates in a regio- and stereoselective manner affording 1,3-thiaselenol-2-ylmethyl vinyl selenides in high yields predominantly with Z-configuration. Not a single representative of the 1,3-thiaselenol-2-ylmethyl selenide scaffold has been previously described in the literature.

Acetylene-Triggered Reductive Incorporation of Phosphine Chalcogenides into a Quinoline Scaffold: Toward SNHAr Reaction.

Quinolines react with acylacetylenes and secondary phosphine chalcogenides at 20-75 °C to afford N-acylvinyl-2(1)-chalcogenophosphoryldihydroquinolines in good and excellent yields. Unlike the pyridine-derived similar intermediates, which eliminate E-alkenes to give aromatic chalcogenophosphorylpyridines, thereby completing SNHAr reaction, with quinolines, the reaction stops at the formation of the above phosphorylated N-acylvinyl-dihydroquinolines, thus representing a pendant SNHAr process. This reaction opens a one-pot atom-economic single-step access to pharmaceutically targeted phosphorylated functionalized dihydroquinolines and isoquinolines.

A One-Pot Assembly of Fully Substituted Alkyl 5-Aminothiophene-2-carboxylates from Allenes, Isothiocyanates, and Alkyl 2-Bromoacetates.

A novel simple approach to highly functionalized multisubstituted thiophenes such as alkyl 4-alkoxy-5-amino-3-methylthiophene-2-carboxylates through the one-pot sequential reaction of α-lithiated alkoxyallenes with isothiocyanates and alkyl 2-bromoacetates has been discovered. The process proceeds quickly (30-45 min) via in situ formation and intramolecular cyclization of alkyl 2-[(2-alkoxybuta-2,3-dienimidoyl)sulfanyl]acetates (1-aza-1,3,4-trienes).

Study of spontaneous E/Z isomerization of bis[(Z)-cyanomethylidene]-diazapentacyclodienedicarboxylates by 1 H, 13 C, and 15 N NMR spectroscopy, X-ray, and quantum chemical calculation data.

X-ray data show that the diethyl 6,13-bis[(Z)-cyanomethylidene]-5,5,14,14-tetramethyl-4,15-dioxa-7,12-diazapentacyclo[9.5.2.02,10 .03,7 .012,16 ]octadeca-8,17-diene-10,17-dicarboxylate is formed as the ZZ isomer and diastereomer with the (1R*,2R*,3R*,10S*,11R*,12R*,16R*) configuration. The 1 H, 13 C, and 15 N NMR data exhibit that on standing in chloroform-d solution, there is a spontaneous isomerization of this compound resulting in a thermodynamically stable mixture of the ZZ, ZE, EE, and EZ isomers with the same backbone. Using the 2D [1 H-1 H] COSY, [1 H-13 C] HSQC, and [1 H-13 C, 1 H-15 N] HMBC NMR techniques and quantum chemical calculations makes it possible a complete assignment of signals in the 1 H, 13 C, and 15 N NMR spectra of each of the isomers. Such isomerization does not occur for similar compounds with the more bulky substituents at the 1,3-oxazolidine rings. Copyright © 2016 John Wiley & Sons, Ltd.

Aerobic addition of secondary phosphine oxides to vinyl sulfides: a shortcut to 1-hydroxy-2-(organosulfanyl)ethyl(diorganyl)phosphine oxides.

Secondary phosphine oxides react with vinyl sulfides (both alkyl- and aryl-substituted sulfides) under aerobic and solvent-free conditions (80 °C, air, 7-30 h) to afford 1-hydroxy-2-(organosulfanyl)ethyl(diorganyl)phosphine oxides in 70-93% yields.

Experimental and theoretical study of the intramolecular C-H···N and C-H···S hydrogen bonding effects in the 1H and 13C NMR spectra of the 2-(alkylsulfanyl)-5-amino-1-vinylpyrroles: a particular state of amine nitrogen.

In the (1)H NMR spectra of the 1-vinylpyrroles with amino- and alkylsulfanyl groups in 5 and 2 positions, an extraordinarily large difference between resonance positions of the HA and HB terminal methylene protons of the vinyl group is discovered. Also, the one-bond (1)J(C(ß),H(B)) coupling constant is surprisingly greater than the (1)J(C(ß),H(A)) coupling constant in pyrroles under investigation, while in all known cases, there was a reverse relationship between these coupling constants. These spectral anomalies are substantiated by quantum chemical calculations. The calculations show that the amine nitrogen lone pair is removed from the conjugation with the π-system of the pyrrole ring so that it is directed toward the HB hydrogen. These factors are favorable to the emergence of the intramolecular C-HB •••N hydrogen bonding in the s-cis(N) conformation. On the other hand, the spatial proximity of the sulfur to the HB hydrogen provides an opportunity of the intramolecular C-HB •••S hydrogen bonding in the s-cis(S) conformation. Presence of the hydrogen bond critical points as well as ring critical point for corresponding chelate ring revealed by a quantum theory of atoms in molecules (QTAIM) approach confirms the existence of the weak intramolecular C-H•••N and C-H•••S hydrogen bonding. Therefore, an unusual high-frequency shift of the HB signal and the increase in the (1)J(C(ß),H(B)) coupling constant can be explained by the effects of hydrogen bonding.

Synthesis, molecular structure, conformational analysis, and chemical properties of silicon-containing derivatives of quinolizidine.

A silicon analog of quinolizidine 3,3,7,7-tetramethylhexahydro-1H-[1,4,2]oxazasilino[4,5-d][1,4,2]oxazasilin-9a-yl)methanol 3 was synthesized. X-ray diffraction analysis confirmed the trans configuration and low temperature NMR spectroscopy both the flexibility (barrier of interconversion 5.8 kcal mol(-1)) and the conformational equilibrium (chair-chair and chair-twist conformers) of the compound. The relative stability of the different isomers/conformers of 3 was calculated also at the MP2/6-311G(d,p) level of theory. Intra- and intermolecular hydrogen bonding in 3 and the appropriate equilibrium between free and self-associated molecules was studied in solvents of different polarity. Both the N-methyl quaternary ammonium salt and the O-trimethylsilyl derivative of 3 could be obtained and their structure determined.

Study of stereospecificity of 1H, 13C, 15N and 77Se shielding constants in the configurational isomers of the selenophene-2-carbaldehyde azine by NMR spectroscopy and MP2-GIAO calculations.

In the (1)H and (13)C NMR spectra of selenophene-2-carbaldehyde azine, the (1)H-5, (13)C-3 and (13)C-5 signals of the selenophene ring are shifted to higher frequencies, whereas those of the (1)H-1, (13)C-1, (13)C-2 and (13)C-4 are shifted to lower frequencies on going from the EE to ZZ isomer or from the E moiety to the Z moiety of EZ isomer. The (15)N chemical shift is significantly larger in the EE isomer relative to the ZZ isomer and in the E moiety relative to the Z moiety of EZ isomer. A very pronounced difference (60-65 mg/g) between the (77)Se resonance positions is revealed in the studied azine isomers, the (77)Se peak being shifted to higher frequencies in the ZZ isomer and in the Z moiety of EZ isomer. The trends in the changes of the measured chemical shifts are reasonably reproduced by the GIAO calculations at the MP2 level of the (1)H, (13)C, (15)N and (77)Se shielding constants in the energy-favorable conformation with the syn orientation of both selenophene rings relative to the C = N groups. The NBO analysis suggests that such an arrangement of the selenophene rings may take place because of a higher energy of some intramolecular interactions.

Catalyst-Free Phosphorylation of Acridine with Secondary Phosphine Chalcogenides: Nucleophilic Addition vs SNHAr Reaction.

Acridine adds secondary phosphine chalcogenides HP(X)R2 (X = O, S, Se; R = Ar, ArAlk) under catalyst-free conditions at 70-75 °C (both in the presence and absence of the electron-deficient acetylenes) to give 9-chalcogenophosphoryl-9,10-dihydroacridines in 61-94% yields. This contrasts with pyridines, which under similar conditions undergo an SNHAr reaction, wherein electron-deficient acetylenes play the role of oxidants. For acridine, the SNHAr step has been accomplished by the oxidation of the intermediate 9-phosphoryl-9,10-dihydroacridines (X = O) with chloranil.

Metal-free site selective cross-coupling of pyridines with secondary phosphine chalcogenides using acylacetylenes as oxidants.

Pyridines undergo site selective cross-coupling with secondary phosphine chalcogenides (oxides, sulfides, and selenides) in the presence of acylphenylacetylenes under metal-free mild conditions (70-75 °C, MeCN) to afford 4-chalcogenophosphoryl pyridines in up to 71% yield. In this new type of SNHAr reaction acylacetylenes act as oxidants, being stereoselectively reduced to the corresponding olefins of the E-configuration.