Synthesis of Spirocyclic 1-Pyrrolines from Nitrones and Arynes through a Dearomative [3,3′]-Sigmatropic Rearrangement

A dearomative [3,3′]-sigmatropic rearrangement that converts N-alkenylbenzisoxazolines into spirocyclic pyrroline cyclohexadienones has been developed by using the dipolar cycloaddition of an N-alkenylnitrone and an aryne to access these unusual transient rearrangement precursors. This cascade reaction affords spirocyclic pyrrolines that are inaccessible through dipolar cycloadditions of exocyclic cyclohexenones and provides a fundamentally new approach to novel spirocyclic pyrroline and pyrrolidine motifs that are common scaffolds in biologically-active molecules. Diastereoselective functionalization processes have also been explored to demonstrate the divergent synthetic utility of the unsaturated spirocyclic products.     

Selective ortho C−H Cyanoalkylation of (Diacetoxyiodo)arenes through [3,3]‐Sigmatropic Rearrangement

We herein report a robust catalyst‐free cross‐coupling between ArI(OAc)₂ and α‐stannyl nitriles, aided by TMSOTf. The transformation introduces a cyanoalkyl group to the ortho position of ArI(OAc)₂ and simultaneously reduces the aryl iodine(III) to iodide, thus providing α‐(2‐iodoaryl) nitrile as the product. This transformation could be completed within 5 min at ?78 °C and features superb functional‐group tolerance and efficient scalability. DFT calculations indicate that the formation of a ketenimine(aryl)iodonium intermediate and subsequent [3,3]‐sigmatropic rearrangement are involved as key steps.     

New Synthesis of α′‐Hydroxydienones

Herein, attempted oxidation of selected allenols with PCC affording α′‐hydroxydienones rather than simple oxidation products is described. The formation of the products observed is rationalized via a series of sigmatropic shifts, followed by hydrolysis.     

An Asymmetric Redox Arylation: Chirality Transfer from Sulfur to Carbon through a Sulfonium [3,3]‐Sigmatropic Rearrangement

A general, asymmetric redox arylation of ynamides and thioalkynes with chiral sulfoxides is reported. This is the first example of a general 1,4‐chirality transfer from sulfur to a carbon stereocenter through a sulfonium [3,3]‐sigmatropic rearrangement. This reaction delivers α‐arylated thioesters and amides under mild conditions in an atom‐economical manner. The products are formed in high yields with enantiomeric ratios up to 99.5:0.5. Quantum chemical calculations suggest a mechanism for the chirality transfer from sulfur to carbon and explain the experimentally observed correlation of the enantioselectivity with both the catalyst and the substrate.     

Catalytic Asymmetric [2, 3]－Sigmatropic Rearrangement of Sulfur Ylides Generated from Carbenoids and Allenic 2－Methylphenyl Sulfide

The first investigation on catalytic asymmetric [2,3]-sigmatropic rearrangement of sulfur ylides generated from carbenoids and allenic phenyl sulfide was carried out. Up to 55% ee value was obtained.     

Direct Synthesis of Benzofuro[2,3‐b]pyrroles through a Radical Addition/[3,3]‐Sigmatropic Rearrangement/Cyclization/Lactamization Cascade

A straightforward synthetic method for the construction of benzofuro[2,3‐b]pyrrol‐2‐ones by a novel domino reaction through a radical addition/[3,3]‐sigmatropic rearrangement/cyclization/lactamization cascade has been developed. The domino reaction of O‐phenyl‐conjugated oxime ether with an alkyl radical allows the construction of two heterocycles with three stereogenic centers as a result of the formation of two C?C bonds, a C?O bond, and a C?N bond in a single operation, leading to pyrrolidine‐fused dihydrobenzofurans, which are not easily accessible by existing synthetic methods. Furthermore, asymmetric synthesis of benzofuro[2,3‐b]pyrrol‐2‐one derivatives through a diastereoselective radical addition reaction to a chiral oxime ether was also developed.     

Stereodivergent Synthesis of Tetrahydrofuroindoles through Pd‐Catalyzed Asymmetric Dearomative Formal [3+2] Cycloaddition

A stereodivergent synthesis of tetrahydrofuroindoles through palladium‐catalyzed asymmetric dearomative formal [3+2] cycloaddition of nitroindoles with epoxybutenes was developed. The polarity of the solvent was found to play a key role in the diastereoselectivity. In toluene, good to excellent yields (70–99 %), diastereoselectivity (87/13‐>95/5 d.r.), and enantioselectivity (85/15–94/6 e.r.) were obtained, regardless of the properties of the substituents on nitroindoles. In acetonitrile, tetrahydrofuroindoles of a different diastereoisomer were produced with good to excellent yields (75–98 %) and stereoselectivity (78/22–93/7 d.r., 93/7–99/1 e.r.). Mechanistic studies were conducted to illustrate the origin of the diastereodivergency. The kinetic experiments indicate that the rate‐determining step of this reaction is different in different solvents. ESI‐MS experiments also support the existence of key palladium complex intermediates and the catalytic cycle of the reaction.     

Synthesis of C2 Substituted Benzothiophenes via an Interrupted Pummerer/[3,3]‐Sigmatropic/1,2‐Migration Cascade of Benzothiophene S‐Oxides

Functionalized benzothiophenes are important scaffolds found in molecules with wide ranging biological activity and in organic materials. We describe an efficient, metal‐free synthesis of C2 arylated, allylated, and propargylated benzothiophenes. The reaction utilizes synthetically unexplored yet readily accessible benzothiophene S‐oxides and phenols, allyl‐, or propargyl silanes in a unique cascade sequence. An interrupted Pummerer reaction between benzothiophene S‐oxides and the coupling partners yields sulfonium salts that lack aromaticity and therefore allow facile [3,3]‐sigmatropic rearrangement. The subsequently generated benzothiophenium salts undergo a previously unexplored 1,2‐migration to access C2 functionalized benzothiophenes.     

Stereocontrolled Syntheses of Tetralone‐ and Naphthyl‐Type Lignans by a One‐Pot Oxidative [3,3] Rearrangement/Friedel–Crafts Arylation

The development of a stereoselective one‐pot oxidative [3,3] sigmatropic rearrangement/Friedel–Crafts arylation that provides enantioenriched benzhydryl compounds is reported. The utility of this new transformation is demonstrated by the concise synthesis of several tetralone‐ and naphthyl‐type lignan natural products, many of which display anti‐malarial activity.     

Generation and Rearrangement of N,O‐Dialkenylhydroxylamines for the Synthesis of 2‐Aminotetrahydrofurans

A new diastereoselective route to 2‐aminotetrahydrofurans has been developed from N,O‐dialkenylhydroxylamines. These intermediates undergo a spontaneous C?C bond‐forming [3,3]‐sigmatropic rearrangement followed by a C?O bond‐forming cyclization. A copper‐catalyzed N‐alkenylation of an N‐Boc‐hydroxylamine with alkenyl iodides, and a base‐promoted addition of the resulting N‐hydroxyenamines to an electron‐deficient allene, provide modular access to these novel rearrangement precursors. The scope of this de novo synthesis of simple nucleoside analogues has been explored to reveal trends in diastereoselectivity and reactivity. In addition, a base‐promoted ring‐opening and Mannich reaction has been discovered to covert 2‐aminotetrahydrofurans to cyclopentyl β‐aminoacid derivatives or cyclopentenones.     

Synthesis of Dispiro[indole‐3,2′‐pyrrolidine‐3′,2″‐pyrrolizine]‐1″,2(1H)‐diones via Azomethine Ylide 1,3‐Dipolar Cycloaddition

The 1,3‐dipolar cycloaddition of azomethine ylide generated in situ from isatin and sarcosine to 2‐arylmethylidene‐2,3‐dihydro‐1H‐pyrrolizin‐1‐ones afforded novel 1′‐methyl‐4′‐(aryl)‐1″H‐dispiro[indole‐3,2′‐pyrrolidine‐3′,2″‐pyrrolizine]‐1″,2(1H)‐diones in good yields. The structures of all the products were characterized thoroughly by NMR, infrared spectroscopy, mass spectrum, and elemental analysis.     

Diastereo‐ and Enantioselective Palladium‐Catalyzed Dearomative [3+2] Cycloaddition of 3‐Nitroindoles

Diastereo‐ and enantioselective cycloaddition of 3‐nitroindoles with vinyl aziridine was realized under Pd‐catalysis using commercially available Walphos as the ligand, affording pyrroloindolines in high yields with high diastereo‐ and enantioselectivities. The reaction can be scaled up to a gram scale and the reaction products are easily converted to amino pyrroloindoline and other pyrroloindoline derivatives.     

Catalytic Asymmetric Synthesis of Dihydropyrido[1,2‐a]indoles from Nitrones and Allenoates

An asymmetric method for the synthesis of dihydropyrido[1,2‐a]indoles from mixtures of nitrones and allenoates has been developed. This transformation showcases the use of squaramide catalysis in a complicated cascade system that has been shown to be highly sensitive to reaction conditions and substituent effects. The new method provides access to enantiomerically enriched dihydropyridoindoles from modular, non‐indole reagents. The optimization and scope of the new transformation is discussed in addition to initial mechanistic experiments that indicate the role of the catalyst.     

Construction of Biaryls from Aryl Sulfoxides and Anilines by Means of a Sigmatropic Rearrangement

An unprecedented S−N variant of the benzidine rearrangement for construction of biaryls has been developed. Aryl sulfoxides underwent dehydrogenative coupling with anilines by successive treatment with trifluoromethanesulfonic anhydride and trifluoromethanesulfonic acid to provide the corresponding 2-amino-2′-sulfanyl- and/or 4-amino-4′-sulfanylbiphenyls. Mechanistic studies indicate that the C−C-bond-forming sigmatropic rearrangement proceeds intramolecularly from dicationic S−N-tethered species.     

Regio‐ and stereospecific assembly of dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidines] from simple precursors using a one‐pot procedure: synthesis,spectroscopic and structural characterization,and a proposed mechanism of formation

The synthesis and characterization of three new dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine] compounds are reported, together with the crystal structures of two of them. (3RS,1′SR,2′SR,7a′SR)‐2′‐(4‐Chlorophenyl)‐1‐hexyl‐2′′‐sulfanylidene‐5′,6′,7′,7a′‐tetrahydro‐2′H‐dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine]‐2,4′′‐dione, C₂₈H₃₀ClN₃O₂S₂, (I), (3RS,1′SR,2′SR,7a′SR)‐2′‐(4‐chlorophenyl)‐1‐benzyl‐5‐methyl‐2′′‐sulfanylidene‐5′,6′,7′,7a′‐tetrahydro‐2′H‐dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine]‐2,4′′‐dione, C₃₀H₂₆ClN₃O₂S₂, (II), and (3RS,1′SR,2′SR,7a′SR)‐2′‐(4‐chlorophenyl)‐5‐fluoro‐2′′‐sulfanylidene‐5′,6′,7′,7a′‐tetrahydro‐2′H‐dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine]‐2,4′′‐dione, C₂₂H₁₇ClFN₃O₂S₂, (III), were each isolated as a single regioisomer using a one‐pot reaction involving l ‐proline, a substituted isatin and (Z)‐5‐(4‐chlorobenzylidene)‐2‐sulfanylidenethiazolidin‐4‐one [5‐(4‐chlorobenzylidene)rhodanine]. The compositions of (I)–(III) were established by elemental analysis, complemented by high‐resolution mass spectrometry in the case of (I); their constitutions, including the definition of the regiochemistry, were established using NMR spectroscopy, and the relative configurations at the four stereogenic centres were established using single‐crystal X‐ray structure analysis. A possible reaction mechanism for the formation of (I)–(III) is proposed, based on the detailed stereochemistry. The molecules of (I) are linked into simple chains by a single N—H…N hydrogen bond, those of (II) are linked into a chain of rings by a combination of N—H…O and C—H…S=C hydrogen bonds, and those of (III) are linked into sheets by a combination of N—H…N and N—H…S=C hydrogen bonds.