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.     

A stereoselective synthesis of (2R,3S)-2-amino-3,4-dihydroxybutyric acid using an ether directed aza-Claisen rearrangement

A new approach for the stereoselective synthesis of (2R,3S)-2-amino-3,4-dihydroxybutyric acid, an α-amino acid from Lyophyllum ulmarium, has been accomplished using an ether directed aza-Claisen rearrangement. On investigation of optimal conditions for this key step it was shown for the first time that Au(I) can be used to catalyse this transformation.     

Tandem aza-Claisen rearrangement and ring-closing metathesis reactions: the stereoselective synthesis of functionalised carbocyclic amides

A one-pot, tandem process has been developed for the efficient synthesis of functionalised carbocyclic amides. A substituted cyclopentenyl trichloroacetamide was synthesised using a tandem thermal aza-Claisen rearrangement and RCM process, while an analogous cyclohexenyl trichloroacetamide was generated with high diastereoselectivity using a tandem MOM-ether directed metal-catalysed aza-Claisen rearrangement and RCM process.     

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.     

Total synthesis of N,O,O,O-tetraacetyl-d-ribo-phytosphingosine and its 2-epi-congener

Total synthesis of the natural d-ribo-phytosphingosine I and its 2-epimer III in the protected form was achieved through a common strategy. The aza-Claisen rearrangement of allylic thiocyanate (Z)-V incorporated the new stereogenic centre with nitrogen and the subsequent Wittig olefination constructed a non-polar side chain. Hydrogenation, followed by removal of protecting groups, completed the syntheses of I and III.     

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.     

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.     

Studies on the aza-Claisen rearrangement of 4,5-dihydroxylated allylic trichloroacetimidates: the stereoselective synthesis of (2R,3S)- and (2S,3S)-2-amino-3,4-dihydroxybutyric acids

Two new synthetic approaches, involving substrate directed aza-Claisen rearrangements and aza-Claisen rearrangements mediated by chiral Pd(II) catalysts, have been developed for the stereoselective synthesis of (2R,3S)-2-amino-3,4-dihydroxybutyric acid, a dihydroxylated α-amino acid from the edible mushroom, Lyophyllum ulmarium and its (2S,3S)-unnatural diastereomer.     

An easy access to pyrimidine-fused azocine derivatives by thiophenol-mediated radical cyclization via 8-endo-trig mode

An efficient route for the synthesis of eight-membered nitrogen heterocycles has been developed via a thiophenol-mediated intramolecular 8-endo-trig radical cyclization. The radical precursors were prepared using BF₃·Et₂O-catalyzed aza-Claisen rearrangement followed by the reaction with propargyl bromide. The alkenyl radicals are generated from thiophenol initiated by the benzoyl peroxide instead of commonly used AIBN for easy and facile isolation of the pure products.     

Aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a versatile strategy towards synthesis of isofagomine and related biologically important azasugars

Synthesis of isofagomine has been achieved by implementation of aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a key step. The above rearrangement has also been utilized in the synthesis of biologically important polyhydroxylated piperidine frameworks such as isogalactofagomine, ent-isogalactofagomine and their analogues and some other azasugars as glycosidase inhibitors.     

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.     

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.     

Synthesis of highly substituted dibenzoazocine derivatives by the aza-Claisen rearrangement and intramolecular Heck reaction via 8-exo-trig mode of cyclization

The synthesis of highly substituted dibenzo-azocine systems is still lacking. An efficient synthetic protocol utilizing the sequential aromatic aza-Claisen rearrangement followed by the implementation of the intramolecular Heck reaction as a key step has been developed for the synthesis of various dibenzo-azocine derivatives of biological relevance.     

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.     

Construction of an asymmetric quaternary carbon via an asymmetric aza-Claisen rearrangement and its application in the total synthesis of (+)-α-cuparenone

Excess lithium hexamethyldisilazide (LHMDS) with LiCl prompted the asymmetric aza-Claisen rearrangement of carboxamide and retarded the decomposition of its amide enolate. The addition of these two reagents was a key step that led to the total synthesis of (+)-α-cuparenone with a stereogenic quaternary center.     

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.     

Practical synthesis of 7-prenylindole

7-Prenylindole is a useful building block for natural product and natural product analogue synthesis. While there have been several past syntheses of 7-prenylindole, none of them is very practical for its preparation on scale. Using an aza-Claisen rearrangement as the key step, 7-prenylindole has been prepared in four steps from indoline in 62% overall yield.     

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.     

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 palladium(II)-catalysed aza-Claisen rearrangements: studies on the origin of the directing effect

Four new chiral δ-substituted allylic trichloroacetimidates have been synthesised to probe the origin of the high diastereoselectivity observed for the MOM-ether directed palladium(II)-catalysed aza-Claisen rearrangement. Rearrangement of these compounds has not only provided strong evidence for this directing effect but also that during the rearrangement both oxygen atoms from the MOM-ether are involved in coordinating to and directing the palladium(II) catalyst.