Superbasic System Research Articles

Aza-Favorsky reaction with regioisomeric C- and N-linked 1,4-bis(imino)benzenes: Synthetic and reactivity dissimilarities

Structurally analogous C- and N-linked 1,4-bis(imino)-functionalized benzenes react with acetylenes in the KOBut/ DMSO superbase system to give the corresponding bis-(propargylamino)-containing derivatives in 62–82% yields (C-linking) or 38–42% yields (N-linking). In the latter case, with phenylacetylene, the yields of mono- and bisadducts were 32 and 38%, respectively. The observed dissimilarities between both bisimine chemotypes in the reactivity and synthetic outcomes imply the long-range adverse repulsive interaction between nitrogen anionic center and the second nitrogen atom in the N-linked 1,4-bis(imino) benzenes.

A Short‐Cut to Substituted Fused Pyrrolo[2,1‐c][1,4]oxazines: A Hybrid Theoretical and Experimental Study

AbstractThe effect of substituents in the pyrrole ring and at the triple bond on the formation of fused pyrrolooxazines from 1H‐pyrrol‐2‐ylmethanols and propargyl chlorides has been theoretically and experimentally studied. The energy characteristics of the reaction are evaluated using quantum‐chemical calculations (CBS‐Q//B3). A one‐pot transition metal‐free synthesis of substituted 3‐methyl‐1H‐pyrrolo[2,1‐c][1,4]oxazines in good yields has been implemented in the superbasic system NaOH/DMSO.

Triton-X-100 as an Organic Catalyst for One-Pot Synthesis of Arylmethyl-H-phosphinic Acids from Red Phosphorus and Arylmethyl Halides in the KOH/H2O/Toluene Multiphase Superbase System

Triton-X-100, a polyethylene glycol 4-(tert-octyl)phenyl ether, has been found to be an active micellar organic catalyst for the one-pot selective synthesis of arylmethyl-H-phosphinic acids in up to 65% yields by the direct phosphinylation of arylmethyl halides with red phosphorus in the KOH/H2O/toluene multiphase superbase system. The catalyst demonstrates a good recyclability. As a result, an expeditious method for the chemoselective synthesis of arylmethyl-H-phosphinic acids—versatile sought-after organophosphorus compounds—has been developed. The synthesis is implemented via direct alkylation/oxidation of red phosphorus with arylmethyl halides, promoted by superbase hydroxide anions using Triton-X-100 (a commercial off-the-shelf organic recyclable micellar catalyst). The reaction comprises the hydroxide anions-assisted disassembly of Pred 3D polymer molecules triggered by the separation from the potassium cation in ordinary crown-like micelles to produce polyphosphide anions in aqueous phase. Further, polyphosphide anions are alkylated with arylmethyl halides in organic phase in the presence of the catalytic Triton-X-100 reverse micelles and alkylated polyphosphide species undergo the double hydroxylation. The advantages of the strategy developed include chemoselectivity, benign and accessible starting reagents, catalyst recyclability, and facile one-pot implementation.

Acetylene-driven multi-molecular assemblies of high complexity: imidazo[1,2-a]pyridines and 5-chloro-N-[2-(imidazo[1,2-a]pyridin-6-yl)vinyl]pyridin-2-amine

Acetylene reacts with 2-aminopyridines in the superbase system KOBut/DMSO (the initial acetylene pressure ∼8 atm, 80 °C, 5 min) to give 2,3-dimethylimidazo[1,2-α]-pyridines in up to 60% yields. In the case of 2-amino-5-chloropyridine, along with ‘normal’ product, (Z)-5-chloro- N-[2-(2,3-dimethylimidazo[1,2-α]pyridin-6-yl)vinyl]pyridin-2-amine is formed in 40% yield. These multi-molecular assemblies involve parallel nucleophilic addition of N-centered anions to the triple bond and ethynylation of the forming C=N bond.

Diversifying the superbase-catalyzed C=N bond ethynylation: triaryl-1-pyrrolines and triaryl-1H-pyrroles from N-benzyl aldimines and arylacetylenes

N-Benzyl aldimines react with arylacetylenes in the presence of ButOK/DMSO superbase system to afford 2,3,5-triaryl-1-pyrrolines as two tautomers with 1,2- and 1,5-location of the double bond, both being the trans-diastereomers. This version of the C=N bond ethynylation differs from the previous one with N-benzyl ketimines. The oxidation of the pyrroline tautomeric mixtures without their isolation gives 2,3,5-triaryl-1H-pyrroles.

Superbase-Mediated gem-Difluoroalkenylations of Sulfoximines.

At ambient temperature, deprotonated sulfoximines react with 1-trifluoromethylalkenes to provide either N- or C-gem-difluoroalkenylated products. The reaction site depends upon the N substituent of the starting material. The optimal conditions involve the use of a superbasic system NaOH in dimethyl sulfoxide. The reactions are characterized by a broad substrate scope and medium to high yields. Scale-up experiments of both the N- and C-gem-difluoroalkenylations proceeded well. Treatment of a N-difluoroallyl sulfoximine with an aryl thiol under dioxygen afforded the corresponding oxygenated addition product.

Synthesis of Diorganylphosphine Oxides Bearing Hetarylalkyl Moieties and Study of Their Antimicrobial Activities

AbstractTertiary phosphine oxides have been synthesized by the reaction of secondary phosphine oxides with diverse hetarylmethylchlorides (pyridines, imidazoles, pyrazole) in the superbasic systems CsF/NaOH/DMF/4 Å MS or NaOH/DMSO/4 Å MS at 23–25 °C. It is found that a tertiary phosphine oxide bearing the imidazole fragment possess the pronounced antimicrobial activity.

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

Semistabilized diazatrienyl anions are generated by the reaction of 2-pyridylarylimines with arylacetylenes in superbase systems MOtBu (M = Li, Na, K)/DMSO at ambient temperature for 15 min. The initial intermediate N-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 (Z)-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*).

Access to α,α-dithioketones through direct di-sulfenylation of methyl ketones mediated by KOH-DMSO system

A direct di-sulfenylation of methyl ketones with disulfides mediated by KOH-DMSO superbase system has been developed. This reaction provides an efficient route to α,α-dithioketones, which has the advantages of readily available non-prefunctionalized substrates, good functional group tolerance, excellent yields as well as high selectivity. In a single operation, two CS bonds are simultaneously built on the same carbon atom under mild reaction conditions.

SUPERBASES IN ORGANIC SYNTHESIS

In this concise review, an emphasis is laid on the important role of superbases as catalysts and reagents in organic synthesis that so far remain underestimated. Diverse approaches to understand the superbasicity phenomenon are considered and the definition of superbase is given. Typical compositions of most widespread superbase systems are systematized and tabulated. The representative classic organic reactions assisted by superbases are surveyed.

Self-Assembly of N-Phenyl-2,5-dimethylpyrrole from Acetylene and Aniline in KOH/DMSO and KOBut/DMSO Superbase Systems: A Quantum-Chemical Insight.

By employing the contemporary B2PLYP(D3)/6-311+G**//B3LYP/6-31+G* method of quantum chemistry, we unraveled the mechanism of a recently discovered cascade assembly of N-phenyl-2,5-dimethylpyrrole from one molecule of aniline and three molecules of acetylene activated by KOH/DMSO and KOBut/DMSO superbase systems. For the established mechanism, we compare and analyze the activity of these two superbases. The reaction is found to be activated by the interaction of aniline with acetylene, and the barrier associated with this interaction turns out to be the limiting one. Another barrier close in value to the limiting one is found along the cascade assembly pathway and relates to ethynylation of N-but-3-yn-2-yl-aniline by the ethynide ion. The cascade reaction turns out to be selective with respect to propyne-allene rearrangements. The alternative mechanism of N-phenyl-2,5-dimethylpyrrole self-assembly, which involves a preliminary stage of acetylene oligomerization, is shown to be kinetically less favorable.

Synthesis of 3,5-Disubstituted 1,2,4-Oxadiazoles from Amidoximes and Aldehydes in the Superbasic System NaOH/DMSO

A new procedure has been proposed for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles by reaction of amidoximes with aldehydes in the superbasic system NaOH/DMSO at room temperature. The scope of the proposed procedure has been demonstrated by 15 syntheses from various amidoximes and aromatic aldehydes with 27–76% yields. The procedure is inapplicable to aliphatic aldehydes.

Thermodynamics and isomerism of products and intermediates of a one-pot superbase-promoted assembly of tetracyclic frontalin derivatives: A quantum chemical study

Tetracyclic frontalin derivatives are used as precursors of drugs for the therapy and prevention of HIV infections and cancer, as well as antibiotics with a wide spectrum of antibacterial action. A recently proposed method of the preparation of tetracyclic frontalin derivatives from two cycloaliphatic ketone molecules and two acetylene molecules in a superbasic catalytic system KOH/DMSO has opened up an elegant and direct approach to the design of these classes of biologically active compounds. In this work, we carried out a quantum-chemical study of isomerism and thermodynamic stability of intermediates and product of the reaction underlying the aforementioned approach. Particular attention was paid to the issues of diastereomerism and violation of diastereoselectivity of the reaction when replacing alkylaromatic or dialkyl ketones by cycloaliphatic ketones in the reactions with acetylene. Based on the results we propose a possible reason for the experimentally observed formation of a mixture of diastereomers of 14,16-dioxatetracyclohexadecane in the cascade assembly of two cyclohexanone molecules and two acetylene molecules. It is shown that the observed ratio of the 14,16-dioxatetracyclohexadecane diastereomers correlates with the equilibrium ratio of cascade assembly intermediates, the semiketal anion diastereomers.

Calcium Carbide as Acetylene Source in Cascade Assemblies of Hydroxypyrrolines and 3H‐Pyrroles from Ketoximes

AbstractTwo types of rare five‐membered aza‐heterocycles, namely 3,3‐disubstituted‐3H‐pyrroles and 5‐hydroxypyrrolines, were synthesized from calcium carbide and available sec‐alkyl (het)aryl ketoximes in the MOH/DMSO (M=Na, K) superbase systems. In contrast to the known procedures implemented with acetylene gas, the modified method is expedient and much safer that makes these intriguing aza‐heterocycles accessible for any laboratory without facilities working with acetylene gas.

Quantum‐chemical models of KOH(KOBut)/DMSO superbasic systems and mechanisms of base‐promoted acetylene reactions

AbstractThe mechanisms of fundamental base‐promoted acetylene reactions, namely, nucleophilic addition to the triple C ≡ C bond (vinylation) and nucleophilic addition of acetylenic carbanion to a carbonyl group (ethynylation), are addressed using three models of different complexity—pentasolvate, monosolvate, and anionic—which describe the catalytic superbasic systems MOH(OBut)/DMSO (suspensions of alkali hydroxides or tert‐butoxides in dimethyl sulfoxide). The above acetylene reactions and sequential transformations of reagents arranged by the superbasic center are modeled within the framework of the most complete pentasolvate model, in which the superbase is represented by the KOH·5DMSO (KOBut·5DMSO) complexes. We have developed approaches to the construction of simplified models (monosolvate and anionic) to describe transformations in complex systems. The mechanisms of cascade assemblies of 6,8‐dioxabicyclo[3.2.1]octanes, cyclopentenones, and furan cycles from ketones and acetylenes in the superbasic environment are investigated using a uniform B2PLYP/6‐311+G**//B3LYP/6‐31+G* approach, and the energy profiles of these different carbo‐ and heterocycles are analyzed.

Transition‐Metal‐Free Reverse Reactivity of (2‐Alkynyl)‐Arylaldimines: Assembly of Functionalized Amino‐Indinones

AbstractTransition‐metal‐free regioselective synthesis of functionalized amino‐indenones by the reaction of ortho‐alkynylaldehydes with a broad range of primary amines by intramolecular cyclization has been described. The designed reaction proceeds through KOH‐mediated Prins‐type cyclization and DMSO‐promoted oxidation of the cyclopent‐2‐en‐1‐one system. The proposed mechanism and role of solvent were well supported by control experiments. For the first time, we have disclosed the reverse reactivity of (2‐alkynyl)‐arylaldimines in a super basic system.

Superbase‐Assisted Selective Synthesis of Triarylphosphines from Aryl Halides and Red Phosphorus: Three Consecutive Different SNAr Reactions in One Pot

Aryl halides, ArX (Ar = Ph, 2‐, 3‐ and 4‐Tol, 1‐ and 2‐Np, 4‐C6H4CONH2; X = F, Cl, Br), rapidly and exothermically (100–180 °C, 0.5–2 h) react with red phosphorus in superbase systems KOH/L, where L is a polar nonhydroxylic complexing solvent (ligand), such as NMP, DMSO, HMPA, to afford the corresponding triarylphosphines (Ar3P) in up to 74 % yield (for X = F). Thus, three consecutive reactions of SNAr (aromatic nucleophilic substitution) to form the three C(sp2)–P bonds are realized in one pot. The synthesis is mostly chemoselective (with rare exception): neither mono‐ nor diphosphines have been isolated. The best results were attained when aryl fluorides were treated with red phosphorus (Pn) in the KOH/NMP superbase system. This environmentally friendly, PCl3‐free synthesis of Ar3P from available starting materials opens an easy and straightforward access to triarylphosphines, which are important ligands, synthetic auxiliaries, and components of high‐tech‐ and medicinally oriented complexes.

Transition metal-free regioselective access to 9,10-dihydroanthracenes via the reaction of anthracenes with elemental phosphorus in the KOH/DMSO system

Anthracene and its 9- or 9,10-substituted (Me, Ph, Cl, Br) derivatives react with red phosphorus (Pn) in the KOH/DMSO superbase system at 85–120 °C to afford 9,10-dihydroanthracenes in good to excellent yields, thus providing simple and clean access to these extensively used dihydroaromatics.

First Example of the Aza-Favorskii Reaction. Ethynylation of C=N Bond in the Superbasic System t-BuOK–DMSO

Direct ethynylation of ketimines with alkynes in the superbasic system t-BuOK–DMSO has been accomplished for the first time using the reaction of (E)-N,1-diphenylethan-1-imine with 3-ethynylaniline as an example.

Transition‐Metal‐Free Addition of Acetylenes to Ketimines: the First Base‐Catalyzed Ethynylation of the C=N Bond

A one‐pot transition metal‐free synthesis of propargylamines in good to excellent yield from ketone‐derived imines and aryl‐ and hetarylacetylenes in the presence of KOBut/DMSO superbase system (40 °C, 10 min) has been developed. The reaction involves a nucleophilic addition of acetylenic carbanions to the C=N bond, thus for the first time featuring the aza‐Favorsky reaction.