Thionium Ion Research Articles

Studies on the synthesis of Strychnos indole alkaloids from 2-(3-indolyl)piperidine derivatives. A new synthetic entry to the indolo[3,2-a]quinolizidine system

The attempted elaboration of the pentacyclic skeleton of Strychnos indole alkaloids by a Pummerer-initiated sequential closure of C and E rings from a 2-(3-indolyl)piperidine-4-acetate derivative bearing a 2-(phenylsulfinyl)ethyl chain on the piperidine nitrogen is described. An indolo(3,2-a)quinolizidine, resulting from the direct attack of the intermediate thionium ion on the 2 position of the heterocycle, is obtained instead.

Synthesis of New Heterocycles Through a Cation‐Driven Tandem Ring‐Enlargement—Annulation Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantioselective total synthesis of (-)-strychnine using the catalytic asymmetric Michael reaction and tandem cyclization.

The enantioselective total synthesis of (-)-strychnine was accomplished through the use of the highly practical catalytic asymmetric Michael reaction (0.1 mol % of (R)-ALB, more than kilogram scale, without chromatography, 91% yield and >99% ee) as well as a tandem cyclization that simultaneously constructed B- and D-rings (>77% yield). Moreover, newly developed reaction conditions for thionium ion cyclization, NaBH3CN reduction of the imine moiety in the presence of Lewis acid to prevent ring opening reaction, and chemoselective reduction of the thioether (desulfurization) in the presence of exocyclic olefin were pivotal to complete the synthesis. The described chemistry paves the way for the synthesis of more advanced Strychnos alkaloids.

A New Method for the Preparation of 2‐Thio Substituted Furans by Methylsulfanylation of γ‐Dithiane Carbonyl Compounds.

AbstractFor Abstract see ChemInform Abstract in Full Text.

ChemInform Abstract: Stereoselective Additions of Chiral (E)‐Crotylsilanes to Thionium Ions: Asymmetric Synthesis of Homoallylic Thioethers.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of new heterocycles through a cation-driven tandem ring-enlargement-annulation reaction.

[reaction: see text] The thionium ion, generated through a cyclopropylcarbinyl-cyclobutyl ring expansion, is, for the first time, intramolecularly intercepted by activated aromatic rings to generate new versatile 2a-methyl-8b-(phenylsulfanyl-1,2a,3,8b-tetrahydro-2H-cyclobuta[c]chromenes.

Pd(0)-catalyzed cross-coupling reactions of 2-indolylzinc halides. A convenient route to indolo[2,3-a]quinolizidines

The generation of 4-, 5-, and 6-methoxy-3-indolylzinc chlorides 3a-c and their Pd(0)-catalyzed cross-coupling reactions with 2-halopyridines to give 4-, 5-, and 6-methoxy substituted 2-(2- pyridyl)indoles 4a-c is reported. 2-(2-Pyridyl)indole 8 is converted to indolo(2,3-a)quinolizidine 15. The key step is the regioselective cyclization on the indole 3-position of a thionium ion generated by Pummerer reaction from an appropriately substituted 2-(2-piperidyl)indole.

Stereoselective additions of chiral (E)-crotylsilanes to thionium ions: asymmetric synthesis of homoallylic thioethers.

Stereochemically well-defined homoallylic thioethers 3 are synthesized via Lewis acid promoted condensation reaction between chiral organosilane reagents 2 and in situ generated thionium ions. The stereochemical course of the reaction is consistent with earlier reports concerning crotylsilations of oxonium ions.

A new method for the preparation of 2-thio substituted furans by methylsulfanylation of gamma-dithiane carbonyl compounds.

Several related methods for the preparation of differentially substituted 2-thiofurans are described. The general procedure involves the formation of a thionium ion from a gamma-dithianyl substituted carbonyl compound followed by cyclization of this reactive intermediate onto the tethered carbonyl group. Two methods for thionium ion generation were explored. One of these involved an acid-catalyzed reaction of beta-ketenedithioacetals, prepared from the condensation of 2,2-bis(methylsulfanyl)acetaldehyde with a variety of ketones. Cyclization followed by loss of methane thiol gave 2-thiofurans 17, 18 and 23, 24 in 70-90% yield. Attempts to prepare 5-heteroatom substituted 2-thiofurans from the corresponding beta-ketenedithioacetal amides or esters were unsuccessful, leading to 1,2-thio rearranged products. A more successful route involved the reaction of beta-acetoxy-gamma-thianyl carbonyl compounds with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF). Treatment of the dithiane with this reagent resulted in the smooth generation of a thionium ion. Cyclization followed by loss of acetic acid afforded thiofurans 17, 18, 23, 47-49, 51, and 61-64 in 40-100% yield. The N-butenyl substituted thioamido furan furnished a rearranged hexahydropyrroloquinolin-2-one in high yield when heated at 110 degrees C.

Using the Pummerer Cyclization−Deprotonation−Cycloaddition Cascade of Imidosulfoxides for Alkaloid Synthesis

The Pummerer reaction of imidosulfoxides bearing tethered alkenyl groups has been employed for the synthesis of several alkaloids. The required imidosulfoxides necessary for the cascade sequence were easily obtained by heating the appropriate amide with (ethylsulfeny)acetyl chloride followed by sodium periodate oxidation. The initially formed thionium ion, obtained by treating the imidosulfoxide with acetic anhydride and p-toluenesulfonic acid, reacts with the neighboring imido group, and the resulting oxonium ion undergoes subsequent deprotonation to produce an isomünchnone dipole. This mesoionic betaine intermediate undergoes ready intramolecular dipolar cycloaddition across the neighboring pi-bond. Exposure of the resulting cycloadducts to additional acetic anhydride leads to ring opening and formation of a 5-acetoxy-substituted 2(1H)-pyridone. This six-ring heterocyclic system constitutes a valuable building block for the synthesis of a variety of pyridine, quinolizidine, and clavine alkaloids. The cyclization-deprotonation-cycloaddition cascade has been successfully applied to the synthesis of the naturally occurring alkaloids onychnine, dielsiquinone, (+/-)-lupinine, (+/-)-anagyrine, (+/-)-pumiliotoxin C, and (+/-)-costaclavine.

Synthesis of Nitrogen Heterocycles Using the Intramolecular Pummerer Reaction

The Pummerer rearrangement has been widely studied and has received considerable attention as a synthetically useful process. a-Acyl thionium ions generated from a-acyl sulfoxides under Pummerer conditions are powerful electrophiles, reacting efficiently with nucleophilic carbon species. Bimolecular addition of the cation to various carbon-carbon double bonds is well known. In the realm of natural product synthesis, most success has been achieved using intramolecular Friedel-Crafts cyclization of the Pummerer thionium ion intermediate. Interception of the Pummerer intermediate by heteronucleophiles represents an extremely important variation which has been used for the synthesis of numerous nitrogen containing heterocycles. The present article also describes various applications of the domino Pummerer (slash) N-acyliminium ion cyclization cascade. The successful synthesis of a number of alkaloids by this sequence of reactions reveals the usefulness and importance of this unique domino cascade.XXXYYYZ ZZ Keywords: Intramolecular Pummerer Reaction, Cyclization, Heteroaromatic Nucleophiles, Pyrrole cyclization, Target syntheses, Pummerer Intermediates, Additive, Vinylogous pummerer chemistry, Tandem cyclization of pumerer intermediates, Intramolecular heteroatom trapping, Diels Alder cyclizations, Dipolar cycloaditions

Studies dealing with thionium ion promoted mannich cyclization reactions.

Treatment of several amido-substituted thioacetals with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) produces synthetically useful thionium ions that are intercepted by the adjacent nitrogen atom to afford both five- and six-membered alkylthio-substituted lactams as transient intermediates. Further reaction of the alkylthio-substituted lactam with DMTSF generates an N-acyliminium ion, which undergoes cyclization with the tethered aromatic ring to produce an azapolycyclic ring system. Related cyclization sequences occur when amido thioacetals possessing simple olefinic tethers were used. The overall procedure represents an efficient one-pot approach toward various nitrogen-containing ring systems. The cyclization reaction was employed for a synthesis of the core skeleton of the erythrina alkaloid family.

Synthesis of methoxy-2-quinolones via pummerer-type cyclization of N-aryl-N-methyl-3-(phenylsulfinyl)propionamides.

The thionium ions 10 generated by Pummerer reaction of N-aryl-N-methyl-3-(phenylsulfinyl)propionamides 4 caused not only an electrophilic cyclization reaction producing 2-quinolones 8, but also the formation of the vinyl sulfides 5 and 6 in favor of the latter reaction. On the other hand, the treatment of the vinyl sulfides 5 and 6 with p-toluenesulfonic acid induced cyclization to afford the 2-quinolones 8 in excellent to moderate yields, depending on the electronic properties of the aromatic ring, thus providing a convenient method for the synthesis of methoxy-2-quinolones.

Methylsulfenylation of thioacetals as a method for synthesizing 2-thio-substituted furans.

[formula: see text] The dimethyl(methylthio)sulfonium tetrafluoroborate induced cyclization of various bis(methylsulfanyl) carbonyl compounds is described. The reaction proceeds by methylthiolation of the thioacetal group to give a thionium ion which undergoes subsequent cyclization with the neighboring carbonyl group. This is followed by an elimination reaction to furnish the furan ring.

Additive and Vinylogous Pummerer Reactions of Amido Sulfoxides and Their Use in the Preparation of Nitrogen Containing Heterocycles

The α-thiocarbocation generated from the Pummerer reaction of N-methyl-N-phenyl-2-[2-(toluene-4-sulfinyl)phenyl]acetamide undergoes Friedel−Crafts reaction at the γ-carbon with the tethered aromatic ring. Reductive removal of the phenylthio group from the resulting product using Raney nickel occurs in high yield, and the overall reaction represents a new method for the synthesis of a variety of 3-phenyl-substituted oxindoles. Treatment of the related N-benzyl-N-alkyl amido sulfoxide system with trifluoroacetic anhydride affords tetrahydroisoquinolone derivatives. The product distribution encountered coincides with the rotamer population of the starting amide. When the N-benzyl-N-methyl amide is used, only the normal Pummerer product is formed. In this case, the thionium ion is generated in the wrong conformation for π-cyclization to occur. The corresponding N-tert-butyl amido system, however, exists in a geometric orientation which places the benzylic group in the crucial conformation necessary for π-cyclization, and consequently, the reaction proceeds smoothly. Related cyclization reactions occur in good yield with the corresponding furanyl and cyclohexenyl N-tert-butyl amido sulfoxides. The additive Pummerer reaction of 3-phenylsulfinyl-N-benzyl-N-tert-butylacrylamide gave products derived from both 5- and 6-exo trig cyclizations. Intramolecular electrophilic aromatic substitution via six-membered ring closure ultimately afforded a dihydropyridone. The competitive process involving ipso attack of the aromatic ring on the thionium ion generates a spiro cyclohexadienyl cation that undergoes fragmentation of the adjacent σ-bond. The resulting acyl iminium ion is converted to N-tert-butyl-2-phenyl-3-phenylsulfinylacrylamide upon aqueous workup. Only cyclizations leading to five-membered rings occur with the corresponding indolyl and alkenyl N-tert-butyl amido sulfoxides.

ChemInform Abstract: Stereoselective Synthesis of a Bicyclic Ketooxetane via a Thionium Ion‐ Mediated Cyclization Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthetic Efforts toward Akuammiline Alkaloids from Tetracyclic 6,7-Seco Derivatives

The addition of enolates derived from indole-3-acetic esters 1−3 to pyridinium salts 4, 23, and 24, followed by acid cyclization of the resulting 1,4-dihydropyridines, leads to tetrahydro-1,5-methanoazocino[3,4-b]indoles 5−7, 25−27, which have been subsequently elaborated into 4E-ethylidene(or 4α-ethyl)-hexahydro-1,5-methanoazocino[3,4-b]indoles. Closure of the six-membered C ring of akuammiline alkaloids by formation of C-6/C-7 bond from appropriately N(b)-substituted derivatives of these tetracyclic ABDE substructures has been extensively investigated. In the N-unsubstituted indole series, both cyclization of thionium ions generated either by Pummerer reaction from sulfoxide 16 or by DMTSF treatment of dithioacetal 36 and photocyclization of chloroacetamide 47 occur upon the indole nitrogen to give pentacycles 18, 38, and 49, respectively. When the indole nitrogen is blocked by a substituent, the thionium ions derived from sulfoxides 17 and 43 and dithioacetals 37 and 44 do not cyclize and lead to different products depending on the reaction conditions, whereas chloroacetamides 48 and 51 undergo a reductive photodehalogenation. Attempted radical cyclization of seleno derivatives 53, 55, and 56 under a variety of conditions gives the corresponding reduced products. Finally, attempted photoisomerization of 1-acylindole 62 leads to the N(b)-methyl tetracycle 63.

Total Synthesis of (+/-)-Deethylibophyllidine: Studies of a Fischer Indolization Route and a Successful Approach via a Pummerer Rearrangement/Thionium Ion-Mediated Indole Cyclization.

The total synthesis of (+/-)-deethylibophyllidine is described, proceeding in eight steps from 4-(methoxyphenyl)ethylamine in 5% overall yield (Scheme 6). In terms of sequential annulation, the strategy involves the following operations: E --> DE --> ABDE --> ABCDE (Scheme 1). The key steps in the synthesis are the stereoselective formation of octahydroindol-6-ones by acid treatment of dihydroanisole derivatives, the regioselective Fischer indolization to obtain octahydropyrrolo[3,2-c]carbazoles, and the tandem process consisting of Pummerer rearrangement upon a beta-amino sulfoxide and thionium ion cyclization upon a beta-indole position of a 2,3-disubstituted indole to generate the quaternary spiro center. Attempts to effect the construction of the pentacyclic framework by means of Fischer indolization of the octahydropyrrolo[3,2,1-hi]indol-6-one resulted in failure (Scheme 2).

Neighboring‐Group Participation in the Gas Phase. Loss of benzaldehyde from [(benzyloxy)methyl]dialkylsilyl‐substituted 1,3‐dithianes

Abstract[(Benzyloxy)methyl]dialkylsilyl‐substituted 1,3‐dithianes show in CI‐MS an abundant loss of benzaldehyde from the [M + H]+ quasi‐molecular ion. The fragmentation is explained with an intramolecular redox process, where a hydride is proposed to be transferred from the benzyl position to a neighboring thionium ion. This would form a particle that could readily lose benzaldehyde as a neutral fragment. The CI‐MS results provide an explanation for the unusual instability of (benzyloxy)methyl‐substituted silanes towards acids. In fact, the formation of benzaldehyde was established in the decomposition of a (benzyloxy)methyl‐substituted acylsilane in the presence of Lewis or Brønsted acids and ethanethiol. The CI‐MS study, therefore, represents a useful method to recognize unusual reactions that are – or might be – important in solution.

The potential utility of homoacylation through the pummerer rearrangement‐intermediates. A direct approach to the 1‐benzene‐sulfonyl‐4‐keto‐8‐methoxy‐1,2,2a,3,4,5‐hexahydrobenz‐[cd]indole via intra‐homoacylation

AbstractA convenient synthesis of tricyclic ketone 7 is described based on an intra‐homoacylation via a Pummerer intermediate. The indole 3, was both annelated and functionalized for the next step through its protected indoline 4 using the single reagent dimsyllithium. The produced sulfoxide 5 generated the thionium ion intermediate upon treatment with trifluoroacetic anhydride, which subsequently underwent intramolecular cyclization to ketone 6 in the presence of a Lewis acid.