Rapid, room-temperature self-organization of polyarylated 1-pyrroles from acetylenes and nitriles in the KOBu/DMSO system.

We have discovered that three molecules of arylacetylene are rapidly (15 min) assembled with one molecule of nitrile at room temperature in the KOBu/DMSO system to afford 2-aryl-3-arylethynyl-4-aryl-5-benzyl-1-pyrroles in up to 76% yield. We assume that this unprecedented self-organization process involves the cascade addition of acetylenic carbanions, first to the CN, then to the CC and CC bonds of the intermediates, followed by pyrrole ring closure the intramolecular nucleophilic addition of the NH functional group to the CC bond of the final intermediates.

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-3-pyrrole-3-thiones (up to 91% yield), representatives of essentially new heterocyclic systems, by the successive treatment of available propargylamines with acyl chlorides (PdCl/CuI/PhP/EtN, toluene, 40-45 °C, 3 h) and sodium sulfide (NaS·9HO, 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.

Concise assembly of 7-ethynyl-6,8-dioxabicyclo[3.2.1]octanes from acetylenes and ketones.

2-Acetyl-3,4-dihydropyrans, assembled from acetylene gas and ketones in a one-pot procedure, are ethynylated with acetylenes (KOBu/DMSO, 15 °C, 2 h) to give acetylenic alcohols, which readily cyclize (TFA, rt, 5 min) to 7-ethynyl-6,8-dioxabicyclo[3.2.1]octanes in up to 92% yield.

Diastereoselective synthesis of tetrahydropyrrolo[1,2-]oxadiazoles from functionalized Δ-pyrrolines and generated nitrile oxides.

Tetrahydropyrrolo[1,2-]oxadiazoles have been synthesized in good-to-excellent yields the cycloaddition of nitrile oxides ( generated from aldoximes) to readily accessible functionalized Δ-pyrrolines. The reaction proceeds smoothly at room temperature in a two-phase system in the presence of sodium hypochloride as an oxidant to diastereoselectively afford pharmaceutically prospective 1,2,4-oxadiazolines fused with a five-membered ring. The reaction tolerates a broad range of substrates, including those with oxidant-sensitive functional groups and competitive reaction sites.

Semistabilized Diazatrienyl Anions from Pyridine Imines and Acetylenes: An Access to ()-Stilbene/Imidazopyridine Ensembles, Benzyl Imidazopyridines, and Beyond.

Semistabilized diazatrienyl anions are generated by the reaction of 2-pyridylarylimines with arylacetylenes in superbase systems MOBu (M = Li, Na, K)/DMSO at ambient temperature for 15 min. The initial intermediate -centered propargyl-1,3-diaza-1,3,5-trienyl anions undergo intermolecular cyclization to benzyl imidazopyridine anions (formally [3 + 2] cycloaddition), further intercepting a second molecule of the starting pyridylimines or a proton of medium to afford ()-stilbene/imidazopyridine ensembles and benzyl imidazopyridines. The charge distribution in all intermediate anions and their synthetic evolution are consistent with quantum-chemical analysis (B2PLYPD/6-311+G**//B3LYP/6-31+G*).

Diastereomerically pure rarely functionalized alkenoyl dihydropyrans, 1,6-diketones, and cyclopentanes from acetylene gas and ketones.

Pure ()-alkenoyl dihydropyrans are stereoselectively assembled from 2-acetyl-3,4-dihydropyrans (products of one-pot self-organization of acetylene gas and ketones) and aromatic aldehydes (52-86% yields). Furthermore, ()-alkenoyl dihydropyrans undergo ring opening (acid hydrolysis) to afford 5-hydroxy-1,6-diketones (44-67% yields) and acetyl-2-()-styryl-2,3-dihydroxycyclopentanes (19-32% yields), both as single diastereomers.

Regio- and stereoselective base-catalyzed assembly of 6-methylene-5-oxaspiro[2.4]heptanones from alkynyl cyclopropyl ketones.

6-Methylene-5-oxaspiro[2.4]heptanones have been synthesized base-catalyzed dimerization of available alkynyl cyclopropyl ketones. The reaction proceeds effectively in the presence of the -BuOK/-BuOH/THF catalytic system at room temperature to afford the desired spirocycles in a regio- and stereoselective manner.

Synthesis of Pyrrolo[2,1-]isoquinolinium Salts from 1-Pyrrolines and Alkynes via Rhodium-Catalyzed C-H Functionalization/N-Annulation Tandem Reaction.

A convenient synthesis of pyrrolo[2,1-]isoquinolinium salts from 1-pyrrolines and alkynes through rhodium-catalyzed C-H functionalization/N-annulation tandem reaction is described. The protocol features a good substrate tolerance, mild reaction conditions, and high yields of target products. Exploration of the alkyne scope unexpectedly revealed a novel labile functional group-promoted rhodium-catalyzed C-H functionalization/C-annulation/elimination cascade reaction of 1-pyrrolines with electron-deficient alkynes.

Multimolecular Self-Organization of 1-Acetyl-1,3-bis(haloarylamines) in KOH/DMSO System: From Acetylene Gas and -Halo Arylamines toward a Higher Molecular Complexity and Diversity.

An unprecedented self-organization of three molecules of acetylene, two molecules of -halo arylamine, and one molecule of water to 1-acetyl-1,3-bis(haloarylamines) in the KOH/DMSO system has been discovered. These high-value 1,3-bis(arylamines) are capable of acting as efficient "platform molecules" to provide one-pot access to hexahydropyrrolo[3,2-]indoles, 3-haloarylamino-pyrrolidines, benzyliden piperidinols, and other functionalized diamines.

Base-Catalyzed [3 + 2] Cycloaddition of Benzyl Ketimines to Arylacetylenes Followed by Oxidation: A One-Pot Access to Polyarylated 2-Pyrroles via Intermediate Pyrrolines.

-Benzyl ketimines undergo [3 + 2] cycloaddition with arylacetylenes in the KOBu/DMSO solution to 2,3,5-triarylpyrrolines, which are oxidized (chloranil, DDQ) in situ to 2,3,5-triaryl-2-pyrroles in 53-71% yields. The intermediate 1-pyrrolines can be isolated in 31-91% yields and separately oxidized to the corresponding 2-pyrroles.

Aldol Condensation Superbase-Catalyzed Addition of Ketones to Acetylenes: A Quantum-Chemical and Experimental Study.

The mechanism of aldol condensation of ketones in KOH/DMSO superbasic media has been investigated using the B2PLYP(D2)/6-311+G**//B3LYP/6-31+G* quantum-chemical approach. It is found that the interaction of three ketone molecules resulting in the formation of the cyclohex-2-enone structure [isophorone or 3,5-dicyclohexyl-5-methylspiro(5.5)undec-2-en-1-one] is thermodynamically more favorable than the interaction of two, three, or four molecules of ketone, resulting in the formation of linear products of the condensation.

Regiocontrolled synthesis of 2,4,6-triarylpyridines from methyl ketones, electron-deficient acetylenes and ammonium acetate.

A novel one-pot two-step approach for the synthesis of 2,4,6-triarylpyridines via t-BuOK/DMSO-promoted C-vinylation of a variety of methyl ketones with electron-deficient acetylenes (alkynones) followed by a cyclization of the in situ generated unsaturated 1,5-dicarbonyl species with ammonium acetate has been developed. This approach possesses competitive advantages such as high regioselectivity, available starting materials and the absence of transition-metal catalysts, oxidants and undesirable byproducts. A wide synthetic utility of the developed approach was demonstrated by the synthesis of trisubstituted, tetrasubstituted and fused pyridines.

Hydrazides in the reaction with hydroxypyrrolines: less nucleophilicity - more diversity.

Expedient protocols for the synthesis of three types of highly functionalized azaheterocyclic scaffolds (dihydropyridazines, tetrahydropyridazines, and partially saturated tricyclic systems) from readily available hydroxypyrrolines and hydrazides are described. The directions of the transformation of a common initial intermediate, namely a Brønsted acid-activated hydroxypyrroline, depend on the reaction conditions and the structure of the hydrazides.

Retrosynthetic Analysis of α-Alkenyl-β-Diketones: Regio- and Stereoselective Two-Step Synthesis of Highly Arylated Representatives from Acetylenes, Ketones, and Acyl Chlorides.

Highly arylated α-alkenyl-β-diketones are synthesized a two-step sequence consisting of () potassium -butoxide/DMSO-catalyzed ()-stereoselective C-H functionalization of ketones with acetylenes followed by () magnesium bromide etherate/DIPEA-soft enolization of the formed β,γ-unsaturated ketones and regioselective acylation with acyl chlorides. The method is compatible with a broad range of substrates and shown to be applicable as an intermediate stage in the construction of polyarylated heterocycles.

Oxaazabicyclooctene Oxides, Another Type of Bridgehead Nitrones: Diastereoselective Assembly from Acetylene Gas, Ketones, and Hydroxyl Amine.

Unique bridgehead nitrones, 8-oxa-6-azabicyclo[3.2.1]oct-6-ene 6-oxides, have been assembled diastereoselectively via acetyldihydropyrans, products of one-pot self-organization of two molecules of ketones and two molecules of acetylene, which after oximation undergo acid-catalyzed ring closure.

KOBu/DMSO-Mediated α-C-H Vinylation of -Benzyl Ketimines with Acetylene Gas: Stereoselective Synthesis of (,)-2-Azadienes.

Several imines, readily derived from aryl methyl ketones and benzylamines, react with acetylene gas in KOBu/DMSO system to afford 2-azadienes stereoselectively. This new C-C bond constructing reaction involves, instead of the expected ethynylation of the C═N bond, the addition of azaallyl anions to the triple bond of acetylene.

Transition-Metal-Free Superbase-Catalyzed C-H Vinylation of Aldimines with Acetylenes to 1-Azadienes.

Aldimines react with aryl- and hetarylacetylenes in the presence of KOBu/dimethyl sulfoxide (DMSO) or NaOBu/DMSO systems under exceptionally mild conditions (14 °C, 1 h) to afford C-H-vinylated products, 1-azadienes of configuration relative to the C-C bond, in up to 72% yield. Vinylation involves the unprecedentedly fast multiposition proton transfer in the intermediate adducts of acetylene to the C═N bond. This new Csp-Csp bond-forming reaction opens a straightforward pot-, atom-, step-, and energy-economic access to synthetically valuable 1-azadienes.

Toward Acetylene Renaissance: Functionally Rich N-Aminoindoles from Acetylene Gas, Ketones, and Hydrazines in Two Steps.

A straightforward acetylene-based scalable strategy for the synthesis of highly functionalized N-aminoindoles has been discovered. This pot-, atom-, step-, and energy-economic strategy includes two simple stages: (i) a one-pot multimolecular (2 + 2) diastereoselective assembly of 6,8-dioxabicyclo[3.2.

Acetylene-based two-step diastereoselective synthesis of bridgehead dihydro-oxadiazines using ketones and hydrazine as the only reactants.

Pharmaceutically related bridgehead dihydro-1,3,4-oxadiazines are synthesized in up to 94% yield by the acid-catalyzed diastereoselective reaction of hydrazine hydrate with 6,8-dioxabicyclo[3.2.1]octanes (6,8-DOBCOs), the products of the superbase-promoted self-organization of acetylene with ketones.

Exploring Acetylene Chemistry: A Transition Metal-Free Route to Dienyl 6,8-Dioxabicyclo[3.2.1]octanes from Ketones and Acetylenes.

Dienyl derivatives of 6,8-dioxabicyclo[3.2.1]octanes, closely related to naturally abundant molecules, have been synthesized from 2-acetyl-3,4-dihydropyrans (readily available from ketones and acetylene in two steps), which further add to aryl(hetaryl)acetylenes in the KOBu/DMSO superbase system (105 °C, 1.

Acetylenes in the Superbase-Promoted Assembly of Carbocycles and Heterocycles.

In this Account, we briefly discuss the recently discovered and rapidly developing superbase-promoted self-organization reactions of several equivalents of acetylenes and ketones to afford complex compounds that represent promising synthetic building blocks common in natural products. Notably, acetylenes play a special role in these reactions because of their dual (acting as an electrophile and a nucleophile) and flexible reactivity. These unique properties of acetylenes are elegantly expressed in superbasic media, where acetylenes are more deprotonated and their electrophilicity increases as a result of complexation with alkali metal cations, with simultaneous enhancement of the nucleophilic reactants due to desolvation.

Nucleophilic Addition of Ketones To Acetylenes and Allenes: A Quantum-Chemical Insight.

A CBS-Q//B3 based study has been carried out to elucidate the mechanism of the KOH/DMSO superbase catalyzed ketones nucleophilic addition to alkyl propargyl and alkyl allenyl ethers yielding, along with (Z)-monoadducts, up to 26% of unexpected (E)-diadducts. The impact of different substrates (alkynes versus allenes) on the reaction mechanism has been discussed in detail. Along with the model reaction of acetone addition to propyne and allene, the addition of acetone and acetophenone to methyl propargyl and methyl allenyl ethers is considered.

Decorated Cyclopentadienes from Acetylene and Ketones in Just Two Steps.

The products of the one-pot assembly of acetylene and ketones in the KOH/DMSO system, 7-methylene-6,8-dioxabicyclo[3.2.1]octanes, undergo an acid-catalyzed (CFCOOH, room temperature) rearrangement to rarely substituted cyclopentadienes in good-to-excellent yields.

A One-Pot Synthesis of 2-Aminopyrimidines from Ketones, Arylacetylenes, and Guanidine.

The three-component reaction of ketones, arylacetylenes, and guanidine catalyzed by the KOBu/DMSO system leads to 2-aminopyrimidines in up to 80% yield. Depending on structure of the starting ketones, the aromatization of intermediate dihydropyrimidines occurs either with loss of hydrogen molecules or methylbenzenes. The latter process takes place in the ketones, in which one of the substituents is not a methyl group.