A tandem aza-Claisen rearrangement and ring closing metathesis reaction for the synthesis of cyclic allylic trichloroacetamides

A one-pot tandem palladium(II)-catalyzed aza-Claisen rearrangement and ring closing metathesis process has been developed for the efficient synthesis of cyclic allylic trichloroacetamides. The use of chiral Pd(II) catalysts such as (S)-COP-Cl during the rearrangement stage results in the preparation of these compounds in excellent yields and in high enantiomeric excess.     

Stereoselective synthesis of functionalised carbocyclic amides: construction of the syn-(4aS,10bS)-phenanthridone skeleton

A new synthetic approach has been developed for the preparation of 7-deoxypancratistatin analogues bearing a syn-(4aS,10bS)-phenanthridone ring junction. A one-pot tandem process involving a substrate-directed Overman rearrangement and ring closing metathesis reaction was developed for the stereoselective synthesis of a carbocyclic allylic trichloroacetamide. Conversion to a 6-bromopiperonyl amide, followed by a Heck reaction generated a homoallylic alcohol and completed the syn-(4aS,10bS)-phenanthridone carbon skeleton. Stereoselective epoxidation and dihydroxylation of the syn-(4aS,10bS)-phenanthridone framework was then investigated leading to the preparation of new analogues of 7-deoxypancratistatin.     

N-allyl-N-sulfonyl ynamides as synthetic precursors to amidines and vinylogous amidines. An unexpected N-to-C 1,3-sulfonyl shift in nitrile synthesis

A detailed study of amidine synthesis from N-allyl-N-sulfonyl ynamides is described here. Mechanistically, this is a fascinating reaction consisting of diverging pathways that could lead to deallylation or allyl transfer depending upon the oxidation state of palladium catalysts, the nucleophilicity of amines, and the nature of the ligands. It essentially constitutes a Pd(0)-catalyzed aza-Claisen rearrangement of N-allyl ynamides, which can also be accomplished thermally. An observation of N-to-C 1,3-sulfonyl shift was made when examining these aza-Claisen rearrangements thermally. This represents a useful approach to nitrile synthesis. While attempts to render this 1,3-sulfonyl shift stereoselective failed, we uncovered another set of tandem sigmatropic rearrangements, leading to vinyl imidate formation. Collectively, this work showcases the rich array of chemistry one can discover using these ynamides.     

A new entry to the phenanthridine ring system

A new synthesis of phenanthridine derivatives having three-point diversity has been developed based on the sequential application of three-atom economic processes viz. aza-Claisen rearrangement, ring-closing enyne metathesis and Diels–Alder reaction as key steps. An unexpected isomerisation was observed during aza-Claisen rearrangement of N-allylanilines which may open up new opportunities in heterocyclic synthesis.     

A stereo-controlled access to functionalized macrolactams via an aza-Claisen rearrangement

A novel and stereo-controlled method for the preparation of functionalized macrolactams was developed. The process involves stereoselective enol ether formation, followed by an azacyclic ring expansion via an aza-Claisen rearrangement. Herewith, we describe a systematic investigation of an aza-Claisen rearrangement-induced ring expansion of azacycles prepared by appending E/Z-enol ethers to the medium-sized lactams as well as the stereochemical outcome. In addition, the strategy was successfully applied to the total synthesis of fluvirucinine A(1) and 3-epi-fluvirucinine A(1). This method offers an attractive alternative to the intramolecular amide-aldol reaction for the elaboration of β-alkoxy-α-substituted motifs.     

An Efficient Synthesis of de novo Imidates via Aza-Claisen Rearrangements of N-Allyl Ynamides

A novel thermal 3-aza-Claisen rearrangement of N-allyl ynamides for the synthesis of α-allyl imidates is described. Also, a sequential aza-Claisen, Pd-catalyzed Overman rearrangement is described for the synthesis of azapine-2-ones.     

Aromatic Aza-Claisen Rearrangement of Arylpropargylammonium Salts Generated in situ from Arynes and Tertiary Propargylamines

The charge-accelerated aza-Claisen rearrangement of ammonium salts serves as a key step in the construction of complex nitrogen-containing molecules. However, much less attention has been paid to the aromatic aza-Claisen rearrangement than to the aliphatic one. Herein, we report an unprecedented aromatic aza-Claisen rearrangement of arylpropargylammonium salts, generated in situ from arynes and tertiary propargylamines, delivering structurally diverse 2-propargylanilines in moderate to good yields with high regioselectivity. This rearrangement proceeds in the absence of strong bases or transition metals, is compatible with moisture and air, tolerates a wide variety of functional groups, and is amenable to forming 11- to 13-membered heterocycles with a triple bond. The 2-propargylaniline products were treated with aluminum chloride in ethanol to afford multisubstituted indoles in moderate to excellent yields. Finally, a series of deuterium-labeling experiments was performed to elucidate the reaction mechanism.     

Ether-directed, stereoselective aza-Claisen rearrangements: synthesis of the piperidine alkaloid, alpha-conhydrine

[reaction: see text] A new approach for the stereoselective synthesis of the piperidine alkaloid (+)-alpha-conhydrine and its pyrrolidine derivative has been developed using a palladium(II)-catalyzed, MOM-ether-directed aza-Claisen rearrangement and ring-closing metathesis to effect the key steps.     

A new palladium(II)-catalyzed [3,3] aza-Claisen rearrangement of 3-allyloxy-5-aryl-1,2,4-oxadiazoles

A new efficient palladium(II)-catalyzed [3,3] aza-Claisen, formal sigmatropic rearrangement of 3-allyloxy-5-aryl-1,2,4-oxadiazoles was developed. The mechanism was studied by analyzing the regiochemical and stereochemical course of the reaction. The results obtained indicated the intervention of a cationic pallada-cycle similar to the one postulated for the Cope rearrangement of 1,5-dienes.     

Scope and limitations of ether-directed, metal-catalysed aza-Claisen rearrangements; improved stereoselectivity using non-coordinating solvents

In an effort to understand and enhance the stereochemical outcome of the MOM-ether directed rearrangement of allylic trichloroacetimidates we have investigated various reaction conditions for this process. A range of Pd(ii) and other metal catalysts have been shown to effectively catalyse the rearrangement providing the subsequent allylic amides in high selectivity (up to 11 : 1 ratio of diastereomers). The replacement of THF as a solvent in this reaction with non-coordinating solvents such as toluene has led to an enhancement of the directing effect resulting in a significant increase in the diastereoselective outcome (15 : 1 ratio). The reaction was also carried out for the first time, using a highly coordinating ionic solvent which disrupts binding of the Pd(ii)-catalyst to the MOM-ether yielding the allylic amide in only moderate diastereoselectivity. These results provide further evidence for the ether directed aza-Claisen rearrangement of allylic trichloroacetimidates.     

Preparation of bis[palladacycles] and application to asymmetric aza-Claisen rearrangement of allylic imidates

A variety of optically active bis[palladacycles] 1–3 were prepared from ferrocene. The synthetic application of these chiral catalysts in asymmetric aza-Claisen rearrangement of allylic imidates was carried out with high enantioselectivity.     

Total Synthesis of (+)-okaramine J featuring an exceptionally facile N-reverse-prenyl to C-prenyl aza-Claisen rearrangement

[reaction: see text] The convergent total synthesis of (+)-okaramine J was achieved in a longest linear sequence of 12 steps from l-tryptophan tert-butyl ester. A key reaction was the acid-catalyzed room-temperature aza-Claisen rearrangement of a N-reverse-prenylated hexahydro[2,3-b]pyrroloindole to a C-prenylated derivative.     

Carbocyclization cascades of allyl ketenimines via aza-Claisen rearrangements of N-phosphoryl-N-allyl-ynamides

A series of carbocyclization cascades of allyl ketenimines initiated through a thermal aza-Claisen rearrangement of N-phosphoryl-N-allyl ynamides is described. Interceptions of the cationic intermediate via Meerwein-Wagner rearrangements and polyene-type cyclizations en route to fused bi- and tricyclic frameworks are featured.     

Achiral auxiliary-assisted chiral transfer via microwave-accelerated aza-Claisen rearrangement: a short synthesis of (+)-1-hydroxyquinolizidinone

A short and efficient synthesis of (+)-1-hydroxyquinolizidinone as an advanced core intermediate for the syntheses of (+)-epiquinamide, (+)-homopumiliotoxin, and (+)-lupinine is described. The key feature of our strategy includes a sequential chiral transfer using an achiral phenylsulfide auxiliary via microwave-accelerated aza-Claisen rearrangement of the unexplored N-thiophenoxyacetyl-α-vinyl piperidine substrate and the oxone-induced transannulation.     

Asymmetric Total Synthesis of Fluvirucinine A(1)

Diastereoselective vinyl addition to an amide carbonyl group and amide enolate induced aza-Claisen rearrangement are the key steps in the first asymmetric total synthesis of fluvirucinine A(1) (1), the aglycon of fluvirucin A(1). Fluvirucins are a class of macrolactam antibiotics produced by actinomycete strains that show promising biological properties.     

Enantioselective, NHC-Catalyzed Annulations of Trisubstituted Enals and Cyclic N-Sulfonylimines via α,β-Unsaturated Acyl Azoliums

All aboard please! A new reaction of enals and cyclic sulfonylimines, as the nucleophiles(!), is the first highly enantioselective NHC-catalyzed annulation of trisubstituted enals. The catalytically generated α,β-unsaturated acyl azolium undergoes a reaction with the enamine tautomer of the imine via an aza-Claisen rearrangement as the key C?C bond-forming step. High yields and enantioselectivities were achieved using β-, α,β-, and β,β'-substituted enals.     

Synthesis of [5,6]-fused pyridocoumarins through aza-Claisen rearrangement of 6-propargylaminocoumarins

[5,6]-Fused pyridocoumarins are prepared through aza-Claisen rearrangement and subsequent in situ cyclization of 6-propargylaminocoumarins under microwave irradiation in the presence of boron trifluoride diethyl etherate in N,N-dimethylformamide. During this process demethoxycarbonylation is observed in the corresponding 4-carbomethoxycoumarin derivatives.     

Enantioselective synthesis of lyxo-(2R,3R,4R)-C18-phytosphingosine using double stereodifferentiation

lyxo-C₁₈-Phytosphingosine can be synthesized by the cis-dihydroxylation of an (E)-allylic trichloroacetamide obtained by an Overman rearrangement. A double stereodifferentiation using AD-mix-β and an enantiomerically enriched (S)-allylic trichloroacetamide allowed the first synthesis of lyxo-(2R,3R,4R)-C₁₈-phytosphingosine with high diastereoselectivity (de=94%) and excellent enantioselectivity (ee=93%). This sphingosine was fully characterized by the physical and spectral data of the corresponding tetraacetate.     

Stereoselective beta-hydroxy-alpha-amino acid synthesis via an ether-directed, palladium-catalysed aza-Claisen rearrangement

A highly diastereoselective synthesis of (2S,3S)-beta-hydroxy-alpha-amino acids has been developed from enantiopure alpha-hydroxy acids using a MOM-ether-directed, palladium(II)-catalysed, aza-Claisen rearrangement of allylic acetimidates to effect the key step. This highly stereoselective process gave allylic amides in diastereomeric ratios of up to 14 : 1. Problems associated with the isolation of 1,3-products (anti-Claisen) from sterically demanding substrates via an insitu palladium(0)-catalysed rearrangement process were overcome by the addition of a re-oxidant, p-benzoquinone, leading to cleaner reactions and improved yields of the 3,3-products (Claisen). The target beta-hydroxy-alpha-amino acids are an important class of natural products that are also components of more complex organic compounds with significant biological properties.     

An expedient approach for the synthesis of pyrrolo[3,2-d]pyrimidines (9-deazaxanthines) and furo[3,2-d]pyrimidine via radical cyclization

A new efficient route for the synthesis of substituted 9-deazaxanthines in excellent yields via aza-Claisen rearrangement followed by radical cyclization has been achieved. This methodology has also been applied to the synthesis of furo[3,2-d]pyrimidine.