Gold Catalysis: Oxepines from γ‐Alkynylfurans

A ketal group in a furyl position affords arene oxides from γ‐alkynylfurans even with the simple gold(III) chloride (AuCl₃) catalyst. These can either undergo Diels–Alder reactions, isomerise to stable oxepines by an oxygen‐walk reaction or by the addition of water selectively be converted to phenols which differ in the position of the hydroxy group from the normal phenols formed in the gold‐catalysed phenol synthesis. With a phenyl substituent on the furan, the 2‐hydroxymethylpyridinato‐gold(III) complex, not the usual arene oxide but an oxepine is obtained, still the arene oxide can be trapped from the valence‐tautomeric equilibrium by a Diels–Alder reaction.     

Nitrones as Trapping Reagents of α,β‐Unsaturated Carbene Intermediates – [1,2]Oxazino[5,4‐b]indoles by a Platinum‐ Catalyzed Intermolecular [3+3] Cycloaddition

Some readily available Boc‐protected 2‐(3‐methoxy‐1‐propynyl)anilines and nitrones in platinum‐catalyzed reactions deliver [1,2]oxazino[5,4‐b]indoles. Twelve examples with yields of 41–95% are reported. Different substituents like nitro, trifluoromethyl, fluoro, bromo, and ester groups are tolerated. With regard to the mechanism, this reaction probably combines an initial intramolecular cyclization/elimination to vinylcarbenoid species and a subsequent stepwise intermolecular [3+3] cycloaddition with the nitrones.     

Gold‐Catalyzed Highly Diastereoselective Synthesis of Functionalized 3,4‐Disubstituted Butyrolactams via Phosphatyloxy or Carbonate Double Migrations

A gold‐catalyzed highly diastereoselective synthesis of functionalised 3,4‐disubstituted butyrolactams via phosphatyloxy or carbonate double migrations is reported, which is proposed to proceed by a tandem 1,3‐phosphatyloxy or carbonate migration and a “long‐range” 1,5‐phosphatyloxy or carbonate migration, which overall corresponds to a formal 1,6‐migration.     

Cationic Gold‐ and Silver‐Catalyzed Cycloisomerizations of Propargylic Ureas: A Selective Entry to Oxazolidin‐2‐imines and Imidazolidin‐2‐ones

A comparative study on transition metal‐catalyzed cycloisomerizations of propargylic ureas derived in situ from secondary propargylic amines and tosyl isocyanate was performed. The influence of catalytic system on the reaction outcome was thoroughly studied on two model examples resulting in the establishment of two selective protocols for both O‐ and N‐cyclizations. The application of cationic gold(I) catalysis generally resulted in a formation of oxazolidin‐2‐imines as major products while the application of silver(I) triflate selectively provided the corresponding imidazolidin‐2‐ones. An attempt to rationalize the observed chemoselectivity is described. The scope of both processes was demonstrated through the use of variously substituted secondary propargylic amines.     

Synthesis of Spiro[piperidine‐3,3′‐oxindoles] via Gold(I)‐Catalyzed Dearomatization of N‐Propargyl‐ and N‐Homoallenyl‐2‐bromotryptamines

N‐Propargyl‐ and N‐homoallenyl‐2‐bromo‐β‐tryptamines undergo gold(I)‐catalyzed dearomatizing cyclizations to afford 2‐bromospiroindolenines that are in situ hydrolyzed to furnish spirooxindoles in a one‐pot process. Tryptophane derivatives (R²=CO₂Et) led upon cyclization to chiral spirooxindoles in excellent diastereoselectivities.

     

Gold‐Catalyzed Efficient Formation of α,β‐Unsaturated Ketones from Propargylic Acetates

An efficient gold‐catalyzed method for the preparation of α,β‐unsaturated ketones from propargylic acetates has been developed. Under mild reaction conditions, β‐monosubstituted enones were formed mostly with excellent E‐selectivity. β,β‐Disubstituted enones can be prepared from propargylic acetates derived from ketones. The high efficiency and mild nature of this reaction render it a viable alternative for the synthesis of α,β‐unsaturated ketones.     

Synthesis and Structure of Highly Enantio‐ and Diastereoenriched 1‐Aza‐4‐oxa‐7‐thiabicyclo[3.3.0]octan‐8‐ones Derived from Acyl‐Substituted S‐Benzyl Thiocarbamates

A convenient method for the synthesis of the title compounds 4a,b, 3a,b via an intramolecular condensation of thiourethanes, derived from the acylation of enantioenriched α‐thio benzyllithium compounds, is reported. The structure of one of the major diastereomers was elucidated by a singlecrystal X‐ray analysis and compared to semiempirical calculations.     

Gold‐Catalyzed 5‐ and 6‐exo‐dig Selective Cyclizations of Alkynyl Silyl Enol Ethers: Efficient Method for [3+2] and [4+2] Annulations onto α,β‐Enones

An efficient method for the annulation of five‐ and six‐membered rings onto α,β‐enones is described via gold‐catalyzed 5‐ and 6‐exo‐dig selective cyclizations of alkynyl silyl enol ethers.     

Stereoselective Synthesis of Pyrroloquinolines by a Brønsted Acid Catalyzed [4+2]‐Heterocyclization of Indole‐7‐Carbaldehydes,Anilines and Electron‐Rich Alkenes

The pyrrolo[3,2,1‐ij]quinoline heterocyclic core is found in the structure of a variety of compounds with interesting applications and then, new efficient and flexible strategies to construct this skeleton are required. Here, a new diastereoselective tetrafluoroboric acid (HBF₄)‐catalyzed three‐component coupling reaction of 1H‐indole‐7‐carbaldehyde derivatives, anilines and electron‐rich alkenes to give pyrrolo[3,2,1‐ij]quinolines is described. The reaction involves an unusual [4+2]‐heterocyclization between an in situ formed imine and an alkene. The new catalytic method, where water is the only by‐product, is efficient, robust and flexible, and allows for multigram‐scale synthesis.

     

Gold(I)‐Catalyzed Regio‐ and Stereoselective 1,3‐Dipolar Cycloaddition Reactions of 1‐(1‐Alkynyl)cyclopropyl Oximes with Nitrones: A Modular Entry to Highly Substituted Pyrrolo[3,4‐d][1,2]oxazepines

An efficient approach for the synthesis of highly substituted pyrrolo[3,4‐d][1,2]oxazepines has been achieved by gold(I)‐catalyzed 1,3‐dipolar cycloaddition reactions of 1‐(1‐alkynyl)cyclopropyl oximes with nitrones in good to excellent yields as a single diastereomer. A complete chirality transfer was observed in this transformation.     

Efficient and Flexible Synthesis of Highly Functionalised 4‐Aminooxazoles by a Gold‐Catalysed Intermolecular Formal [3+2] Dipolar Cycloaddition

Oxazoles are important motifs within bioactive and functional materials. Complex, fully substituted and functionalised 4‐aminooxazoles are accessed by an efficient intermolecular reaction between an ynamide and an N‐acylpyridinium N‐aminide in the presence of a gold catalyst. The formal [3+2] dipolar cycloaddition employs a nucleophilic nitrenoid approach to access the 1,3‐N,O‐dipole character in a controllable fashion. The selectivity for a cycloaddition pathway provides a stark contrast against the indiscriminate reactivity of electrophilic acyl nitrenes. Protocols for the formation of acyl‐functionalised aminides are reported from accessible precursors including carboxylic esters and acids. The function of these aminides in the oxazole‐forming reaction has been explored and it is shown that substantial elaboration is accommodated despite proximity to the reactive centre. As a result functional oxazole‐based motifs, such as chiral oxazoles with biologically pertinent substitution patterns, are readily accessible. The use of ynamide types that are unexplored or little used in gold catalysis has been evaluated. Unusual all‐heteroatom substitution patterns around the oxazole are shown to be accessible using thio‐ynamides. The study shows that a close stoichiometry of reactants is suitable alongside relatively low loadings of the bench‐stable precatalysts in practically straightforward multi‐mmol scale reactions. The efficiency and flexibility of this regioselective intermolecular preparation is demonstrated in the ready synthesis of oxazoles with substantial structural and functional group variation.

     

Gold‐Catalyzed Regioselective Meyer–Schuster Rearrangement and Ring Expansion Cascade Leading to α‐Hydroxy‐α‐vinylcyclopentanones

Readily available cyclobutanols having a butyne‐1,4‐diol moiety underwent a sequential regioselective Meyer–Schuster rearrangement and 1,2‐shift, furnishing α‐hydroxy‐α‐vinylcyclopentanones. The reaction mechanism is consistent with the formation of an allenol intermediate that racemizes under the reaction conditions. Subsequent activation of the allenol leads to an enantio‐ and diastereoselective route to this scaffold.

     

Synthesis of Fully Substituted 3‐Formyl‐4‐iodofurans via a Gold(I)‐Catalyzed Oxidation/1,2‐Alkynyl Migration/Cyclization/Iodination Cascade

A highly efficient gold(I)‐catalyzed cascade reaction for the synthesis of fully substituted 3‐formyl‐4‐iodofurans has been developed. Mechanistic investigations indicate a reaction pathway that involves a direct iodination reaction of the organogold intermediate via functionalization of the Au C(sp²) bond, instead of a direct iodination of the 3‐formylfurans.

     

Gold(I)‐Catalyzed Reactions of 1‐(ortho‐Alkynylaryl)ureas: Highly Selective Heterocyclization and Synthesis of Mixed N,O‐Acetals

Readily available 1‐(ortho‐ethynylaryl)urea derivatives undergo a selective gold/silver {[AuCl(IPr)]/AgSbF₆} catalyzed N‐6‐exo‐dig or N‐5‐endo‐dig heterocyclization process in dimethylformamide (DMF) at 60 °C. Benzoxazine derivatives, i.e., the products of O‐6‐exo‐dig ring closure through the urea oxygen, could be observed under catalytic conditions only when the N‐3 basicity was substantially diminished, but were readily isolable in stoichiometric processes carried out at low temperature. The open chain amino O,O‐acetals and a series of new cyclic mixed N,O‐acetals containing the trifluoroethyl group were synthesized when the reactions were performed in ethanol or trifluoroethanol, respectively, as solvent. The procedure allows for an easy access to this versatile class of key intermediates in organic synthesis from simple starting materials. The effect of using either DMF or protic solvents on the course of the reactions is reported.

     

Copper‐Catalyzed Chloroamination of Alkynes: Highly Regio‐ and Stereoselective Synthesis of (E)‐β‐Chloro‐Enesulfonamides

An efficient copper catalysis system for the chloroamination of alkynes with chlorosulfonamide at room temperature is described, providing a highly regio‐ and stereoselective procedure for the synthesis of (E)‐β‐chloro‐enesulfonamides in moderate to good yields.     

Tandem Chemoselective 1,2‐/1,4‐Migration of the Thio Group in Keto Thioesters: An Efficient Approach to Substituted Butenolides

We report herein an efficient and mechanistically unique tandem chemoselective 1,2‐/1,4‐migration of the thio group in keto thioesters that provides substituted butenolides in moderate to excellent yields. Thus, α‐keto thioesters in the presence of stabilized phosphonate carbanions undergo tandem 1,2‐sulfur migration; whereas 1,4‐migration of the thio group has been achieved with the same thioesters after the treatment with Wittig reagents followed by BF₃⋅OEt₂‐catalyzed tandem reaction. The crossover experiments and the isolation of intermediates reveal a stepwise mechanism for both of these transformations.

     

Silica Supported Sodium Hydrogen Sulfate and Amberlyst‐15: Two Efficient Heterogeneous Catalysts for Facile Synthesis of Bis‐ and Tris(1H‐indol‐3‐yl)methanes from Indoles and Carbonyl Compounds[1]

Bis‐ and tris(1H‐indol‐3‐yl)methanes are synthesized in high yields by an electrophilic substitution reaction of indoles with carbonyl compounds under mild reaction conditions using two efficient heterogeneous catalysts, silica supported sodium hydrogen sulfate (NaHSO₄⋅SiO₂) and amberlyst‐15. The second catalyst can be reused.     

Using Conveniently Designed α‐Amino Ketones in Michael Reactions under Iminium Catalysis: Enantioselective Synthesis of γ‐Lactams and γ‐Amino‐δ‐keto Esters

The behaviour of aminoacetophenones as Michael donors in catalytic enantioselective Michael reactions with α,β‐unsaturated aldehydes under iminium activation has been studied. These compounds react with each other in the presence of catalytic amounts of a chiral secondary amine through a Michael/hemiaminal formation cascade process which proceeds with high yields and enantiocontrol. Elaboration of these adducts by oxidation allows the easy access to chiral disubstituted γ‐lactams and other synthetically useful chiral building blocks such as γ‐amino‐δ‐keto esters or β‐substituted δ‐oxoamides are accessible from the obtained adducts by simple transformations.     

Gold‐Catalyzed Redox Synthesis of Imidazo[1,2‐a]pyridines using Pyridine N‐Oxide and Alkynes

A mild, catalytic, atom economical synthesis of imidazo[1,2‐a]pyridines has been developed: catalytic dichloro(2‐pyridinecarboxylato)gold [PicAuCl₂] in the presence of an acid produces a range of imidazo[1,2‐a]pyridines in good yields starting from alkynes and 2‐aminopyridine N‐oxides. This strategy is mild and foreseen to be of particular use for the installation of stereogenic centers adjacent to the imidazo[1,2‐a]pyridine ring without loss of enantiomeric excess.

     

Solid‐Phase Synthesis of 3,4‐Dihydroquinoxalin‐2(1H)‐ones via the Cyclative Cleavage of N‐Arylated Carboxamides

We describe a practical (time‐efficient, with commercially available building blocks, user friendly reaction conditions, high purity of products) synthesis of pharmacologically relevant quinoxalinones with three points of diversification that takes advantage of solid‐phase synthesis and cyclative cleavage. Resin‐bound (S)‐2‐(N‐alkyl‐2‐nitrophenyl)sulfonamide‐3‐alkyl‐N‐(2‐hydroxyethyl)propanamides, which are accessible from Fmoc‐protected α‐amino acids, 2‐nitrobenzenesulfonyl chloride and alcohols, underwent base‐mediated N‐arylation. The reduction of the nitro group produced acyclic intermediates that were subjected to acid‐mediated cyclative cleavage to yield 3,4‐dihydroquinoxalin‐2(1H)‐ones.