Thionium ion

A more recent approach, which also profits from the synthetic versatility of stabilized thionium ions, has been elaborated by Berard and Piras [22]. These authors observed that the cyclobutane thionium ions 1-76 obtained from the cyclopropyl phenyl sulfides 1-75 by treatment with pTsOH under anhydrous conditions can be trapped by an adjacent electron-rich aromatic ring to give the chromane derivatives 1-77 in good to excellent yields (Scheme 1.20). As expected, 1-77 were obtained as single diastereoisomers with a ds-orientation of the methyl and the phenylthio group as a consequence of steric constraints. 

Finally, a sequence consisting of thionium ion formation, thionium ion trapping, an aromatic substitution, and an alkylation, as elaborated by Padwa and coworkers, will be discussed [462]. Since several related sequences have already been mentioned in the foregoing sections, only the total synthesis of ( )-jamtine N-oxide (2-916) will be discussed here (Scheme 2.204). This natural product is an alkaloid from the shrub Cocculus hirsutus, which is commonly found in Pakistan [463]. 

The intramolecular Pummerer reaction has been applied to the synthesis of simple quinolizidine alkaloids like lupinine <2000JOC2368>, and also to arenoquinolizine alkaloids. Thus, the 2-(2-piperidyl)indole 284 was converted to indolo[2,3- ]quinolizidine 287 following a protocol that has as the key step the regioselective cyclization onto the indole 3-position of a thionium ion generated by Pummerer reaction from the appropriately substituted compound... 

Cyclisation of an NH amide toward a cyclic thionium ion was described for the synthesis of a tetrahydropyrrolo-[l,2-tf]pyrimidine-2,6(l//,7//)-dione 351. Compound 349 was transformed to 351 in two steps. The first one is the formation of a transient alkylthio-substituted lactam 350 from amidothioacetal 349 in the presence of dimethyl-(methylthio)sulfonium tetrafluoborate (DMTSF) followed by intramolecular cyclization <2000JOC235>. 

Two step synthesis of medium-ring ethers through the intermediacy of thionium ions followed by sulfide reduction. 

As mentioned in Section 10.1.2, Padwa and co-workers (40,41) employed the Pummerer reaction to generate and trap isomtinchnones. This group (190,191) has now adapted the intramolecular version of this tactic to the synthesis of several alkaloids of the pyridine, quinolizidine, and clavine classes. In each case, a 2-pyridone serves as the keystone intermediate. For example, Kuethe and Padwa (190) employed this Pummerer reaction of imidosulfoxides that contain tethered iz-bonds in a formal synthesis of the frog alkaloid ( )-pumiliotoxin C. They also used this methodology to synthesize the azafluorenone alkaloid onychine (295) (Scheme 10.42) (191). Generation of the thionium ion 291 under standard... 

Addition of allyltins to thioketals.2 The reagent can convert dimethyl thio-ketals to a thionium ion, >=SCH3, which can react with a nucleophile such as an allyltin. 

Scheme 48) <1998TL4761>. Further examples of this strategy were also reported <2000JOC2684>. A thionium ion-promoted Mannich reaction of the amide 39 upon treatment with dimethyl(methylthio)sulfonium tetrafluoro-borate yields the extended tetrahydroisoquinoline in excellent yield (Equation 105) <2000JOC235>. 

One mechanistic possibility for this thioacetalation reaction invokes furanoside ring-opening of 17, initiated by complexation with boron trifluoride etherate (Scheme 12.9). Oxonium ion 28 could then get intercepted by the ethanethiol to produce 29. After further complexation with BF3, in the manner shown, thionium ion formation can again occur to give 30, which can then engage in yet another nucleophilic addition with the ethanethiol to produce 31 after protonation. 

Several related methods for the preparation of differentially substituted 5-thio-2,3-trisubstituted furans were developed, which involved the formation of a thionium ion and the cyclization of this reactive intermediate into the tethered carbonyl group <02JOC1595>. 

The finding that thionium ions may serve as electrophiles in electrophilic substitution chemistry has greatly extended the synthetic range of the Pummerer reaction. Padwa and Kuethe used intramolecular versions of this process in the preparation of nitrogen-containing heterocycles. Vinyl amido sulfoxide 217 underwent an additive Pummerer reaction, on treatment with triflic anhydride, to yield product 220 (Scheme 56).123 The critical step in this transformation involves a... 

For the intramolecular vinylogous Pummerer reaction pathway, an electrophilic thionium ion intermediate (222) is formed by y-proton loss from 221 followed by sulfoxide S-O bond scission. This unsaturated thionium ion (222) is then intercepted by a nucleophile at the y-position to yield a vinyl sulfide product (223) (Fig. 11). 

Sequential reduction and cyclisation of a-alkenoyl-a-carboxyl ketene dithioacetals 38 affords 6-substituted 3-ylidene-3,6-dihydropyran-2-ones an intermediate thionium ion is invoked. Further reactions of the products are described <07JOC4401>. 

A convenient method for the synthesis of annulated 2-alkylthio-5-aminofurans has been described by Padwa et al. The reaction sequence involves the formation of a thionium group from readily available dithioacetals upon treatment with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF). The thionium ion undergoes cyclization with the 7-carbonyl group followed by an elimination step to yield the 2,3,5-trisubstituted furans in good to excellent yields (Equation 29) <2002JOC1595>. The alkylthioaminofuran reaction products can be utilized to constmct polyclic frameworks of natural products in a subsequent Diels-Alder reaction. 

Creation of the 8-membered ring 3 3 of IhxoL by an intramolecular directed aldol reaction failed when the thionium ion intermediate 3 2 underwent intramolecular hydride transfer from a neighbouring p-methoxy benzyl ether instead [Scheme 1.38]. Loss of p-methoxybenzaldehyde and hydrolysis of the enol silane occurred on workup to give the hemiacetal 38,5 in 48% yield. Benzyl ethers can also transfer hydride to proximate carbocationic intermediates.71... 

We have already stressed that acetals are far more susceptible to hydrolysis than thioacetals and Scheme 2.62 attests to the assertion.133-135 The high acid stability of 55-acetals compared with 0,0-acetals may be attributed to the lower Bronsted basicity of sulfur compared with oxygen and the barrier to formation of a thionium ion with its bond. The large number of methods that... 

LTA reacts with enol sulfides,to produce thionium ions, e.g. (106), and thence all)dic acetates (107) or bisacetoxylated products (10, in good yields. Presumably either of Aese compounds could be hydrolyzed to the a-acetoxy ketone. 

Figure 5 Diastereoselectivity in nucleophilic additions to chiral thionium ions...

Inter- and Intra-molecular Reactions ofa-Acyloxy Sulfides or their Thionium Ion Precursors with Nucleophiles... 

In many respects the Pummeter reaction can be regarded as the sulfur version of the Polonovski reaction (and vice versa), and by analogy to the Polonovski reaction the central intermediate is a sulfur-stabilized carbocation (thionium ion). Although the existence of this species is only transient, it reacts to give a number of different products, e.g. a-acetoxy sulfides, vinyl sulfides, cationic cyclization products, etc., depending upon the sulfoxide structure and reaction conditions. Other reaction pathways ate specific to the Pummerer reaction as a result of sulfur s ability to expand its valence shell (additive Pum-merer reactions). A moderate degree of asymmetric induction is also observed in certain Pummerer reactions, where optically pure sulfoxides are substrates. 

Non-nucleophilic activating agents, such as p-toluenesulfonic acid, are generally used to generate the intermediate thionium ions. The use of trifluoroacetic anhydride in the Pummerer step of the kopsanone synthesis is feasible, since at elevated temperatures an equilibrium is established between the thionium ion and trifluoroacetoxy sulfide intermediates. Trifluoroacetic anhydride in combination with a Lewis acid can also be used. Under these latter conditions efficient intermolecular reactions of acylthionium ions with aromatic systems are observed. ... 

The additive Pummerer reaction is a reaction in which displacement of the acyloxy group in the initially formed acyloxysulfonium salt by an internal nucleophile occurs to give a new positively charged sulfur species (Scheme 33). A number of pathways are open for the subsequent reaction of intermediate (138), including elimination of the proton a to the sulfur to give a thionium ion (pathway a), displacement of the sulfur from the a -carbon by an external nucleophile (pathway b), elimination of a 3-proton with formation of an alkene and (139) (pathway c) and loss of a proton fimm the carbon atom a to Nu with formation of (140 pathway d). 

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