Formal aza-Michael additions to tropone: Addition of diverse aryl- and alkylamines to tricarbonyl(tropone)iron and [(C7H7O)Fe(CO)3]BF4

A formal aza-Michael addition to tropone by way of tricarbonyl(tropone)iron and/or the tetrafluoroborate salt formed via protonation of the complex is reported. Tricarbonyl(tropone)iron smoothly undergoes the direct aza-Michael reaction with unhindered aliphatic amines under solvent free conditions in good yields. Meanwhile, the known cationic complex [(C₇H₇O)Fe(CO)₃]BF₄ (whose reaction with a small number of nucleophiles was previously reported) undergoes addition with an even broader array of amine nucleophiles. Finally, it was discovered that protecting the aza-Michael adduct as a carbamate was necessary for oxidative demetallation of the complex.     

Salient features of the aza-Wacker cyclization reaction

The intramolecular aza-Wacker reaction has unparalleled potential for the site-selective amination of olefins, but it is perhaps underappreciated relative to other alkene oxidations. The first part of this review makes the distinction between classical and tethered aza-Wacker cyclization reactions and summarizes examples of the latter. The second portion focuses on developments in asymmetric aza-Wacker cyclization technology. The final part of the review summarizes applications of all classes of aza-Wacker cyclization reactions to natural product assembly.

The aza-Wacker cyclization reaction is a powerful strategy for alkene amination.     

Domino Michael/aza-Wittig reaction in the diastereoselective construction of spiro[azepane-4,3′-oxindoles]

A convenient synthetic strategy for the diastereoselective assembly of spiro[azepane-4,3′-oxindoles] was developed via a Staudinger/Michael/aza-Wittig/reduction/N-deprotection reaction sequence starting from PMB-protected oxindole-substituted ethylazides. The key step of the method is a domino self-catalytic Michael/aza-Wittig reaction wherein the phosphazene moiety acts first as the catalyst and then as the reactant, resulting in the formation of a seven-membered N-heterocycle.     

Diastereoselective scalable synthesis of 2,6-trans-Piperidines using an aza-Michael reaction

Highly efficient substrate and reagent controlled stereoselective synthesis of 2,6-trans-piperidine derivative (1) using an aza-Michael reaction is reported. This method was utilized to synthesize a variety of trans-piperidines on hundred-gram scales.     

Synthetic study of biphenylquinolizidine alkaloids I. Asymmetric total synthesis of lasubine I featuring organocatalyzed asymmetric intramolecular aza-Michael addition

A new procedure for the asymmetric total synthesis of lythraceous alkaloids with a 4-arylquinolizidine skeleton was developed, which involved an organocatalyzed asymmetric intramolecular aza-Michael addition.     

Phosphite mediated asymmetric N to C migration for the synthesis of chiral heterocycles from primary amines

A phosphite mediated stereoretentive C–H alkylation of N-alkylpyridinium salts derived from chiral primary amines was achieved. The reaction proceeds through the activation of the N-alkylpyridinium salt substrate with a nucleophilic phosphite catalyst, followed by a base mediated [1,2] aza-Wittig rearrangement and subsequent catalyst dissociation for an overall N to C-2 alkyl migration. The scope and degree of stereoretention were studied, and both experimental and theoretical investigations were performed to support an unprecedented aza-Wittig rearrangement–rearomatization sequence. A catalytic enantioselective version starting with racemic starting material and chiral phosphite catalyst was also established following our understanding of the stereoretentive process. This method provides efficient access to tertiary and quaternary stereogenic centers in pyridine systems, which are prevalent in drugs, bioactive natural products, chiral ligands, and catalysts.

N-Alkylpyridinium salt of chiral amines undergoes phosphite mediated stereoretentive migrations to generate chiral alkylpyridines. The role of phosphite on reactivity and stereoselectivity were examined to achieve a catalytic asymmetric version.     

Novel one-pot asymmetric cascade approach toward densely substituted enantioenriched α-methylene-γ-lactams

A novel one-pot asymmetric synthesis of densely substituted α-methylene-γ-lactams in favor of cis-isomer involving Zn-promoted aza-Barbier-type reaction has been well established. A wide array of α-methylene-γ-lactams were obtained in high yields with excellent diastereomeric ratios from 98:2 to >99:1 and good enantioselectivities. The synthetic potential of such α-methylene-γ-lactams was demonstrated by successfully oxidizing the phenol moiety to quinone in quantitative yield.     

A concise enantioselective synthesis of (+)-lentiginosine

A high yielding enantioselective synthesis of the indolizidine alkaloid, (+)-lentiginosine, has been described based on asymmetric aza-Cope rearrangement and the l-proline catalyzed α-aminooxylation of aldehydes. The strategy also makes use of ring-closing metathesis for the construction of piperidine core.     

Asymmetric synthesis of ABC tricyclic core in Daphniphyllum alkaloid 21-deoxy-macropodumine D

In this paper, we describe our efforts toward the asymmetric synthesis of Daphniphyllum alkaloid 21-deoxymacropodumine D which led to efficient preparation of a ABC tricyclic framework containing five consecutive stereocenters. This synthetic work features (1) utilization of an asymmetric conjugate addition to install the C5 all-carbon quaternary center, (2) an intramolecular aza-Michael addition followed by Pd-catalyzed α-alkenylation to build the bowl-shaped tricyclic core.     

Silica-gel-supported Ce(SO4)2·4H2O-mediated cyclization of 2′-amino and 2′-hydroxychalcones under solvent-free conditions

A simple, efficient, and environmentally friendly approach for the synthesis of flavones, aza-flavones, and aza-flavanones from corresponding 2′-hydroxy or 2′-aminochalcones has been developed. The reactions are successfully conducted in presence of silica-gel-supported Ce(SO₄)₂·4H₂O under solvent-free conditions.     

One-pot synthesis of cyclopentane-fused 5'-aryl-4-cycloalkylamino-2,2'-bipyridines via the aza-Diels–Alder/SNipso reactions

One-pot synthesis of cyclopentane-fused 5'-aryl-4- cycloalkylamino-2,2'-bipyridines based on the neat (200 °C) reaction of 3-(4-bromopyridin-2-yl)-1,2,4-triazines with enamines is reported. In the course of the transformation, consecutive aza-Diels–Alder reaction and nucleophilic substitution of bromine atom under the action of the liberating amine occur. The possibility of the solvent- and catalyst-free replacement of 4-positioned bromine atom in 2,2'-bipyridines by amino moieties was demonstrated.     

Asymmetric synthetic approach to a functionalized azabicyclo[3.3.1]nonane moiety of (+)-sarain A

This paper describes our efforts toward the asymmetric synthesis of sarain A which led to efficient preparation of a functionalized azabicyclo[3.3.1]nonane moiety. The key to the synthesis relied on a base-catalyzed asymmetric Diels-Alder cycloaddition to establish multiple stereocenters of a highly substituted cyclohexenone unit and a facile intramolecular aza-Michael addition to form the desired bicyclic system.     

Diastereoselective, large-scale synthesis of β-amino acids via asymmetric aza-Michael addition as α2δ ligands for the treatment of generalized anxiety disorder and insomnia

Scalable synthetic routes to β-amino acids 1 and 2 are presented. These two compounds, which bind to the α2δ subunit of calcium channels and have important medical applications, have been prepared on kilogram scale in our pilot plant through an improved synthesis that avoids the use of highly toxic reagents and hazardous chemistry present in the original Medicinal Chemistry route. The two chiral centers are introduced through asymmetric Michael and aza-Michael reactions with excellent diastereoselectivity.     

An improved synthesis of deuterated Schöllkopf’s bis-lactim ether and its use for the asymmetric synthesis of (R)-[α-2H]-phenylalanine methyl esters

Treatment of (S)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine with trifluoroacetic acid in MeOD results in regioselective deuteration at its C₆-position affording its corresponding (S)-[6-²H₂]-isotopomer in excellent yield with no loss of stereochemical integrity at its C₃-stereocentre. The lithium aza-enolate of this deuterated chiral template has been alkylated with a range of substituted benzyl bromides to afford (3S,6R)-[6-²H]-3-isopropyl-6-benzyl-bis-lactim ethers that were hydrolysed to afford their corresponding (R)-[α-²H]-phenylalanine methyl esters as hydrochloride salts in good yield.     

(N-Isocyanimino)triphenylphosphorane as an Efficient Reagent for the Synthesis of 1,3,4-Oxadiazoles from 3-Substituted Benzoic Acid Derivatives

The reaction of 3-substituted benzoic acid derivatives with (N-isocyanimino) triphenylphosphorane proceeds smoothly at room temperature to afford corresponding 1,3,4-oxadiazoles via an intramolecular aza-Wittig reaction in excellent yields under neutral conditions.     

Asymmetric epoxidation of chromenes catalyzed by chiral pyrrolidine SalenMn(III) complexes with an anchored functional group

Chiral pyrrolidine SalenMn(III) complexes with an anchored functional group at the N_aza‐substituent in the pyrrolidine backbone were synthesized, and used as catalysts for asymmetric epoxidation of substituted chromenes. The complex 1 with an anchored imidazole as acceptor could effectively catalyze epoxidation of substituted chromenes in the absence of expensive additive 4‐phenyl pyridine N‐oxide (PPNO) by the coordination of the anchored organic base to the central manganese ion. Complexes 2 and 3 with a quaternary ammonium salt unit at the N_aza‐substituent in the pyrrolidine backbone displayed higher activities than Jacobsen catalyst and the analogous complex 4 without anchored functional group in the aforementioned reaction. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of poly-substituted pyrroles starting from the Baylis-Hillman adducts

We synthesized poly-substituted pyrrole derivatives 4a-e, 7a-c and 10a-d from the reaction of phenacyl bromide and the aza-Baylis-Hillman adducts 1a-d or their rearranged derivatives 5a-e. The pyrroles were synthesized via the successive N-alkylation, Michael addition, elimination of p-toluenesulfinic acid and oxidative aromatization processes.     

Transition-metal-catalyzed cyclization reactions using vinyl and ethynyl benzoxazinones as dipole precursors

Vinyl and ethynyl benzoxazinones have recently received increasing attention from organic chemists because they are powerful tools for the construction of structurally diverse aza-heterocycles. A number of catalytic cyclization reactions have been developed that used these two reagents and required the presence of a transition-metal catalyst (i.e., palladium, iron, and copper). This review highlights the design and synthesis of these versatile reagents, and their applications as precursors for transition-metal-containing 1,4-dipoles in dipolar cyclizations and related cascade reactions. The general mechanisms and asymmetric inductions are briefly discussed as well.     

Ouroboros: Heterocycles closed by dative σ bonds and stabilized by π delocalization

Heteroarenes such as (aza and oxa)borines are increasingly important as synthetic targets and reagents. We map the intramolecular cyclization of saturated heterocyclic chains through dative bonding. A related set of planar unsaturated aza-, oxa-, and fluora-rings that feature dative σ bonding enhanced by π delocalization are identified. The systems have, in general, the formulae A′(CH₂)_mD′ and A′(CH)_mD′, where m?=?3 and 4, and A′ and D′ are acceptor and donor sites, respectively. In each case, the ring isomers, achievable via A′←D' internal coordination (in the manner of Kekulé’s ouroboros), are more stable than chains. Unsaturated aromatic rings examined herein include a oxadiborine with a hypervalent oxygen center and a dioxadiborine. They are isoelectronic with an azaborine, which was synthesized more recently, and benzene.     

The aza-Prins Cyclization of Unfunctionalized Olefins Promoted by NHC-Cu Complex and ZrCl4

The aza-Prins cyclization reaction catalyzed by ZrCl₄ and NHC (N-heterocyclic carbene) metal complexes is firstly reported. NHC-copper complexes as promoter and ZrCl₄ as chloride source are utilized under a mild condition, where homoallylic amines and aldehydes are successfully converted to piperidine derivatives in satisfactory yields and diastereoselectivity.