Diastereoselective synthesis of trisubstituted piperidines: a versatile synthon for elaboration of uncommon poly(aza)heterocyclic structures

Hetero Michael addition on chiral β′-amino-α,β-unsaturated ketone furnished, after some structural modifications, β,β′-diaminoketals. Mannich type reaction of these diamines with an aldehyde led, with a high diastereoselectivity, to trisubstituted piperidines. Starting from a functionalized aldehyde and after subsequent deprotection of the amino group, an intramolecular Michael addition provided octahydro-2H-pyrrolo-[3,4-b]-pyridine, an uncommon framework found in compounds exhibiting biological activity.     

Synthesis of 2-keto-imidazoles utilizing N-arylamino-substituted N-heterocyclic carbenes

A new method for the synthesis of 2-aroyl-, 2-heteroaroyl-, and 2-cinnamoyl-substituted imidazoles in very good yields has been developed. The reaction employs novel nitrogen heterocyclic carbenes (NHCs), namely, N-arylamino-substituted NHCs, formed in situ from the corresponding imidazolium salts, and subsequent reaction with aromatic, heteroaromatic, and cinnamic aldehydes without utilizing transition metals or expensive specialized catalysts.     

Hydroacylation of activated ketones catalyzed by N-heterocyclic carbenes

N-heterocyclic carbenes derived from triazolium salts are effective catalysts between 10 and 15 mol % for the hydroacylation of activated ketones. The reducing equivalent is generated via the interaction of a nucleophilic carbene species and an aromatic aldehyde. The subsequent alcohol product can undergo an acylation event with the resulting acyl heteroazolium intermediate formed in situ between the NHC and the aldehyde. This unprecedented multiple bond-forming reaction can accommodate aromatic aldehydes as the hydride source and various electron-deficient ketones. Preliminary mechanistic evidence indicates that the reduction and acylation steps are sequential operations. The intramolecular variant of this organocatalytic reaction affords benzofuranones in good yield.     

Diastereoselective synthesis of highly substituted tetrahydropyran-4-ones

[reaction: see text] Aldol reactions of beta-ketoesters with aldehydes followed by a tandem Knoevenagel condensation, with a further equivalent of aldehyde, and intramolecular Michael addition produces single diastereomers of highly substituted tetrahydropyran-4-ones.     

Cyanosilylation of aldehydes catalyzed by N-heterocyclic carbenes

N-Heterocyclic carbenes produced in situ from salts of imidazolium, benzimidazolium, pyrido[1,2-c]imidazolium, imidazolinium, thiazolium, and triazolium catalyze the addition of trimethylsilylcyanide to aldehydes to yield cyanohydrin trimethylsilyl ethers. The use of C₂-symmetric imidazolidenyl carbene derived from (R,R)-1,3-bis[(1-naphthyl)ethyl]imidazolium chloride led to enantioselective cyanosilylation.     

Synthesis of pyrrolo[3,4-b]pyrroles and perhydrothiazolo[3′,4′-2,3]pyrrolo[4,5-c]pyrroles

The 1,3-dipolar cycloaddition reactions of various N-tethered alkenyl aldehydes with some cyclic and acyclic amino acids have been studied. Some key sulfonamides having strategically positioned aldehyde and olefinic tether have been synthesized and effectively subjected to intramolecular azomethine ylide cycloaddition reaction resulting in a series of pyrrolo[3,4-b]pyrrole and its N-1-C-2 derivatives, and a series of novel heterotricyclic compounds, perhydrothiazolo[3′,4′-2,3]pyrrolo[4,5-c]pyrroles, in good yields. The intramolecular cycloaddition reaction was found to be highly stereoselective to form only cis-fused cycloadducts in all cases.     

Chemoselective synthesis of xanthenes and tetraketones in a choline chloride-based deep eutectic solvent

A chemoselective synthesis of tetraketone and xanthene derivatives, by means of tandem Knoevenagel condensation and Michael addition in choline chloride-based deep eutectic solvents (DESs), is presented. The reaction of readily available aldehydes and active methylene compounds in malonic acid- and ZnCl₂-based DES gives various xanthenes derivatives with good to excellent yields under mild reaction conditions. On the other hand, tetraketones were synthesized in almost quantitative yields by simple condensation of an aldehyde and active methylene compounds in milder deep eutectic solvents of urea and SnCl₂. In addition, the reaction of other types of choline chloride-based DES leads to a mixture of tetraketone and xanthene.     

An investigation of the catalytic potential of mono- and dicationic imidazolium N-heterocyclic carbenes in the benzoin condensation

The catalytic potential of imidazolium salts in the benzoin condensation was investigated. Various aromatic aldehydes were tested in the benzoin condensation under the optimised protocol to afford α-hydroxyketones using N-heterocyclic carbenes derived from mono- and dicationic imidazolium salts. The products were obtained in good yields within short reaction times. Dicationic imidazolium salts with a long aliphatic chain between the imidazole rings were found to be more effective pre-catalysts for the benzoin condensation in comparison to the corresponding monocationic salts having the same aliphatic chain length.     

A convenient synthesis of substituted pyrazolidines and azaproline derivatives through highly regio- and diastereoselective reduction of 2-pyrazolines

The synthesis of substituted N-acetyl- and N-aroyl-2-pyrazolines via intramolecular Michael addition of alpha,beta-unsaturated hydrazones generated through olefination of phosphinyl and phosphonyl hydrazones with carbonyl compounds is reported. The regioselective reduction of the C-N double bond in these 2-pyrazolines using Superhydride (Et3BHLi) gives pirazolidine derivatives with excellent levels of cis-diastereoselectivity. These 2-pyrazolines can also be obtained in one-pot reaction from allenes, hydrazides, and aldehydes; and pyrazolidines, after reduction, from allenes, hydrazides, and aldehydes. This synthetic route was developed to provide a new approach to substituted azaproline derivatives in a diastereoselective fashion.     

A three component one-pot synthesis of N-amino-2-pyridone derivatives catalyzed by KF-Al2O3

Synthesis of 1,6-diamino-4-phenyl-3,5-dicyano-2-pyridone derivatives via a one-pot, three-component reaction of aryl aldehydes, malononitrile, and cyanoacetic hydrazide at room temperature using KF-Al₂O₃ as a recyclable catalyst have been developed. The reaction proceeds through the initial Knoevenagel condensation between aldehyde and malononitrile in the presence of KF-Al₂O₃ to form the benzylidene derivative which then undergoes Michael addition with cyanoacetic hydrazide followed by intramolecular cyclization of the resulting intermediate to produce the N-amino-2-pyridones in good to excellent yields. The structure of the synthesized compounds were characterized and established on the basis of their spectral data analysis and single-crystal XRD analysis.     

Facile and regioselective synthesis of functionalized benzenes via cascade reactions of 1,2-allenic ketones with 4-sulfonyl crotonates

An efficient and regioselective synthesis of functionalized benzenes via the cascade reactions of 1,2-allenic ketones with 4-sulfonyl crotonates under mild reaction conditions has been established. Mechanistically, the formation of the title compounds involves a cascade procedure consisting of an intermolecular regioselective Michael addition followed by an intramolecular condensation and aromatization. Compared with those of α,β-unsaturated aldehydes/ketones, the reactions of 1,2-allenic ketones with 4-sulfonyl crotonates demonstrated contrary regio-selectivity and distinct reaction conditions. Moreover, the functionalized benzene products obtained herein were found to be ready intermediates for the synthesis of fluorenone and anthracenone derivatives.     

Imidazole‐catalyzed Three‐component Cascade Reaction for the Facile Synthesis of Highly Substituted 3,4‐Dihydropyridin‐2‐one Derivatives

A novel one‐pot protocol for the synthesis of valuable 3,4‐dihydropyridin‐2‐ones from the condensation of aldehyde with cyanoacetamide and 1,3‐dicarbonyl compounds in the presence of imidazole was developed. A series of aldehydes and 1,3‐dicarbonyl compounds were employed to examine the scope of substrates for this protocol. This reaction proceeded through the formation of one ring and four new bonds (two C? C, one C? N, one C?C) via the sequence involving Knoevenagel condensation, Michael addition and intramolecular cyclization with moderate to excellent yields. All new compounds were characterized by IR, ¹H NMR, ¹³C NMR and HRMS.     

Reactions of dialkyl 4-bromo-2,2-dimethyl-3-oxohexane-1,6-dioates,-heptane-1,7-dioates with zinc and aromatic aldehydes

Zinc enolates generated from dimethyl 4-bromo-2,2-dimethyl-3-oxohexane-1,6-dioate and zinc reacted with aromatic aldehydes giving methyl 2,2-dimethyl-3-oxo-3-(5-oxo-2-aryltetrahydrofuran-3-yl)propanoates. The reaction of zinc enolates obtained from dimethyl 4-bromo-2,2-dimethyl-3-oxoheptane-1,7-dioate and zinc with aromatic aldehydes depending on the synthesis conditions led to the formation either methyl 2,2-dimethyl-3-oxo-3-(6-oxo-2-aryltetrahydropyran-3-yl)propanoates or 3-(5,5-dimethyl-4,6-dioxo-2-aryltetrahydropyran-3-yl)propanoates. The compounds synthesized formed as a single diastereomer of E-configuration.     

Studies on retro-[1,4] Brook rearrangement of 3-silyl allyloxysilanes. Observation of the formation of unusual 3,3-bissilyl enols

Detailed investigations of the retro-[1,4] Brook rearrangement of 3-silyl allyloxysilanes are described. Based on control experiments and NMR studies, rationalizations are proposed for the formation of 3,3-bissilyl enols, unusual compounds that are stable to acidic hydrolysis but that can be transformed into the corresponding aldehydes under basic hydrolysis conditions. These studies further show that the 3,3-bissilyl enolates can be O-alkylated by alkyl halides with complete chemoselectivity. This reaction provides a practical entry to various 3,3-bissilyl aldehydes and enol derivatives. As a demonstration of the synthetic utility of this approach, 3,3-bissilyl aldehyde was converted into bissilyl divinyl ketone, which can undergo an SiO₂-promoted Nazarov reaction to give cyclic β-silyl enone smoothly.     

N-heterocyclic carbene-catalyzed oxidation of unactivated aldehydes to esters

N-Heterocyclic carbenes catalyze the oxidation of unactivated aldehydes to esters with manganese(IV) oxide in excellent yield. The reaction proceeds through a transient activated alcohol, which when generated in situ allows for the selective oxidation of the aldehyde under mild conditions. These conditions successfully oxidize potentially epimerizable aldehydes and alcohols while preserving stereochemical integrity. A variety of ester derivatives can be synthesized with variation of the acylated alcohol as well as the unactivated aldehyde.     

Ambident Reactivity of Imidazolium Cations as Evidence of the Dynamic Nature of N-Heterocyclic Carbene-Mediated Organocatalysis

This work reveals ambident nucleophilic reactivity of imidazolium cations towards carbonyl compounds at the C2 or C4 carbene centers depending on the steric properties of the substrates and reaction conditions. Such an adaptive behavior indicates the dynamic nature of organocatalysis proceeding via a covalent interaction of imidazolium carbenes with carbonyl substrates and can be explained by generation of the H-bonded ditopic carbanionic carbenes.     

Direct enantioselective Michael addition of aldehydes to vinyl ketones catalyzed by chiral amines

Chiral amines such as (S)-2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine and the C(2)-symmetric (2S,5S)-2,5-diphenylpyrrolidine can catalyze the direct enantioselective Michael addition of simple aldehydes to vinyl ketones. The conditions for this organocatalytic reaction have been optimized and it has been found that the chiral amines catalyze the formation of optically active substituted 5-keto aldehydes in good yields and enantioselectivities, using aldehydes and, e.g., methyl vinyl ketone as starting compounds. Taking into account that the chiral amine can activate the aldehyde and/or the enone, the mechanism for the reaction has been investigated. On the basis of intermediate synthesis, nonlinear effect, and theoretical investigations, the mechanism for the catalytic direct enantioselective Michael addition of aldehydes to vinyl ketones is discussed.     

Nitrogen heterocycles by palladium-catalyzed cyclization of amino-tethered vinyl halides and ketone enolates

The scope and limitations of Pd(0)-catalyzed intramolecular coupling of amino-tethered vinyl halides and ketone enolates as a methodology for the synthesis of nitrogen heterocycles have been studied. This reaction constitutes a synthetic procedure to obtain bridged, condensed, and monocyclic nitrogen-containing compounds.     

The aza-Wittig reaction: an efficient tool for the construction of carbon-nitrogen double bonds

Recent advances in the aza-Wittig reaction of phosphazene derivatives with several carbonyl compounds are reviewed. Phosphazenes afford inter- and intramolecular aza-Wittig reactions with different compounds such as aldehydes, ketones, esters, thioesters, amides, anhydrides and sulfimides. One of the most important applications of this reaction is the synthesis of a wide range of acyclic and heterocyclic compounds, ranging from simple monocyclic compounds to complex polycyclic and macrocyclic systems.     

Syntheses of Polycyclic Natural Products Employing the Intramolecular Double Michael Reaction

The one-pot intramolecular double Michael reaction of compounds having two different α, β-unsaturated carbonyl groups to form polycyclic compounds can be carried out by three different methods: in the first the substrate is treated with lithium hexamethyldisilazide, in the second with chlorotrimethylsilane, triethylamine, and zinc chloride at an elevated temperature, and in the third with tert-butyldimethylsilyl trifluoromethanesulfonate and triethylamine. The reaction proceeds with complete regioselectivity and high stereoselectivity following a stepwise mechanism. Spiro-fused bicyclo[2.2.2]octane derivatives can be constructed with high stereoselectivity by the intromolecular double Michael reaction by using the first method. Enantiomerically pure atisine and the enantiomer of atisirene were synthesized stereoselectively by application of this methodology. The syntheses of steroids and angular triquinane-type sesquiterpenoids were possible with the second method. Heterocyclic compounds with a bridgehead nitrogen atom were obtained by the reaction of α, β-unsaturated amides following the second and third methods. The asymmetric synthesis of tylophorine with diastereofacial control was achieved by the intramolecular reaction according to the third method. The sulfur-mediated intramolecular double Michael reaction utilizing the third method produced trans-hydroindane derivatives. Furthermore, the intramolecular Michael-aldol reaction can be employed in synthesizing polycyclic systems with cyclobutane units by treatment with tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of triethylamine. The intermolecular double Michael reaction and related reactions will also be described.