Pummerer-type Reaction Research Articles

Acyl Azolium-Photoredox-Enabled Synthesis of β-Keto Sulfides.

α-Heteroatom functionalization is a key strategy for C-C bond formation in organic synthesis, as exemplified by the addition of a nucleophile to electrophilic functional groups, such as iminium ions; oxocarbenium ions; and their sulfur analogues, sulfenium ions. We envisioned a photoredox-enabled radical Pummerer-type reaction realized through the single-electron oxidation of a sulfide. Following this oxidative event, α-deprotonation would afford α-thio radicals that participate in radical-radical coupling reactions with azolium-bound ketyl radicals, thereby accessing a commonly proposed mechanistic intermediate of the radical-radical coupling en route to functionalized additive Pummerer products. This system provides a complementary synthetic approach to highly functionalized sulfurous products, including modification of methionine residues in peptides, and beckons further exploration in C-C bond formations previously limited in the standard two-electron process.

Synthesis of 4-Selenothreofuranose Derivatives via Pummerer-Type Reactions of trans-3,4-Dioxygenated Tetrahydroselenophenes Mediated by a Selenonium Intermediate.

Selenosugars are interesting targets of organic synthesis as they would possess potential biological activities. However, 4-selenotherofuranose derivatives, which have trans configuration for the two dihydroxy substituents at the 2,3-positions and a glycoside bond at the anomeric position, are not available in the current selenosugar library. In this study, racemic 4-selenothreofuranose derivatives were synthesized from trans-3,4-dioxygenated tetrahydroselenophenes in 77–99% yields with the α/β selectivity about 7:3 via oxidation and subsequent seleno-Pummerer rearrangement. The acetoxy group introduced at the anomeric position was then substituted with various nucleophiles, including activated 6-chloropurine, which afforded 4′-selenothreonucleoside derivatives, in the presence of BF3·OEt2 or TMSOTf. The stereochemistry of the selenosugar products was established by 1H NMR spectroscopy as well as X-ray analysis. The similar α/β selectivity observed in the latter glycosylation reaction to that in the former seleno-Pummerer rearrangement suggested the mediation of a common selenonium intermediate (−Se+=C<). It was also suggested that an unexpected interaction between the ester protecting group at the 3-position of the selenofuranose ring and the anomeric carbon atom decreases the α/β selectivity.

Synthesis of N-alkylated 2-pyridones through Pummerer type reactions of activated sulfoxides and 2-fluoropyridine derivatives.

N-Alkylated 2-pyridone products were obtained in good to excellent yields through a one-pot procedure involving either normal or interrupted Pummerer reactions between triflic anhydride activated sulfoxides and 2-fluoropyridine derivatives, followed by hydrolysis. This is a rare case that uses 2-fluoropyridine as a nucleophile in Pummerer type reactions.

Sulfur-directed metal-free and regiospecific methyl C(sp3)–H imidation of thioanisoles

Regiospecific and direct imidation of the methyl C(sp3)–H bond of thioanisoles is realized under mild and metal-free conditions with N-fluorobis(benzenesulfonyl)imide as an oxidant and nitrogen source. Proposed mechanism suggests that thionium ion intermediates and a Pummerer-type reaction are involved. The imidation has advantages such as high step-economy, excellent functionality tolerance, and regiospecificity, giving structurally diverse imidation products.

Copper-catalyzed Pummerer type reaction of α-thio aryl/heteroarylacetates: Synthesis of aryl/heteroaryl α-keto esters

A copper catalyzed Pummerer type reaction of α-thio aryl/heteroarylacetates is described for the first time. This transformation represents a new route to synthesize α-keto esters, which are important intermediates for pharmaceuticals and organic synthesis. The reaction proceeds via in situ generation of a thionium ion that undergoes hydrolysis to furnish α-keto esters in synthetically viable yields (up to 82%).

ChemInform Abstract: Synthesis of 2‐Alkylidene‐3,1‐benzoxathiin‐4‐ones by the Pummerer Type Reaction

AbstractReview: 3 refs.

Synthesis of 2-Alkylidene-3,1-Benzoxathiin-4-Ones by the Pummerer Type Reaction

GRAPHICAL ABSTRACT

ChemInform Abstract: A Novel NH4OAc and CuBr(PPh3)3‐Induced Intermolecular Pummerer‐Type Reaction Between Free (NH)‐Indoles and Dimethylsulfoxide: Facile Synthesis of 3‐Methylthiomethyl Substituted Indoles.

Abstract A novel NH4OAc/CuBr(PPh3)3-induced intermolecular Pummerer-type reaction between free (NH)-indoles and dimethylsulfoxide is first reported, which offers the 3-methylthiomethyl substituted indoles conveniently and efficiently.

A novel NH 4OAc and CuBr(PPh 3) 3-induced intermolecular Pummerer-type reaction between free (NH)-indoles and dimethylsulfoxide: facile synthesis of 3-methylthiomethyl substituted indoles

A novel NH 4OAc/CuBr(PPh 3) 3-induced intermolecular Pummerer-type reaction between free (NH)-indoles and dimethylsulfoxide is first reported, which offers the 3-methylthiomethyl substituted indoles conveniently and efficiently.

Hypervalent Iodine(III) Reagent Mediated Synthesis of 2‐Methylbenzofuran Derivatives by Pummerer‐type Reaction in Ionic Liquid

AbstractAn efficient route for the synthesis of 2‐methylbenzofuran derivatives utilizing hypervalent iodine(III) reagent and a‐(methylthio)acetone via Pummerer‐type reaction in ionic liquid is described.

Accidental discovery of a ‘longer-range’ vinylogous Pummerer-type lactonization: formation of sulindac sulfide lactone from sulindac

Unexpected formation of sulindac sulfide lactone occurred when sulindac was treated with oxalyl chloride and triethylamine. Structurally analogous sulindac sulfide and indomethacin did not undergo such lactonization under similar reaction conditions. We believe that the sulfoxide function in sulindac plays a pivotal role possibly via a ‘longer-range’ vinylogous Pummerer-type reaction as a driving force for the observed lactonization. The structure of the lactone was confirmed by single crystal X-ray analysis.

ChemInform Abstract: Highly Enantioselective Construction of a Quaternary Carbon Centre by the Pummerer Type Reaction: A Total Synthesis of (-)-Sibirine.

Highly enantioselective quaternary carbon formation (96% enantiomeric excess) is achieved by the Pummerer-type reaction of a chiral vinylic sulphoxide with allylmagnesium bromide; this method is applied to the synthesis of (–)-sibirine.

ChemInform Abstract: New Carbon-Carbon Bond Formation by the Pummerer Type Reaction of Vinylic Sulfoxides with Allylmagnesium Bromide.

ChemInform Abstract: New Carbon-Carbon Bond Formation by the Pummerer Type Reaction of Vinylic Sulfoxides with Allylmagnesium Bromide.

ChemInform Abstract: Synthesis of Aspidospermidine Alkaloids from 1,2,3,4-Tetrahydrocarbazole: Total Stereoselective Synthesis of (.+-.)-18-Noraspidospermidine.

Abstract The reactivity of the 1,2,3,4-tetrahydrocarbazol-4-one derivatives has been analysed and applied to the synthesis of (±)-18-noraspidospermidine (1b). This was synthesised, starting from 4-(1′,3′-dioxolan-2′-yl)cyclohexanone which was successively transformed to 3-methyl-3-(3′-nitropropyl)-1,2,3,4-tetrahydrocarbazol-4-one and to the imine tetracycle 13 by means of nickel boride catalyst. The reduction of 13 to the natural cis D ring junction was carried out with the LiAlH 4 AlCl 3 system. The construction of the E-ring was carried out by a Pummerer type reaction from thecis-7-tosyl-1-phenylthioacetamide derivative 17 by oxidation followed by intramolecular cyclisation, desulfurization and reduction to 1b.

グリコシド結合形成反応の開発と新規生物活性ヌクレオシド誘導体合成への展開

Nucleoside antimetabolites act an important role in the fields of cancer and viral chemotherapies. To search new agents effective for tumor and virus, many attempts were made for synthesizing novel nucleoside derivatives. Construction of the glycosidic bond is a key reaction to synthesize new nucleoside derivatives. We have been focused the synthesis of novel biologically active nucleoside derivatives by developing novel “glycosylation” reactions. Our first successful example was the synthesis of 4′-thionucleoside by using the Pummerer-type thioglycosylation reaction. As a result, we found potent antineoplastic nucleoside, 4′-thioFAC, and some novel 4′-thionucleosides possessing antiherpes virus activities. Secondary, we developed a new entry to isonucleosides in which the Mitsunobu reaction with neighboring sulfur assistance was employed as a nucleobase introducing reaction. We also developed a conceptually new method for synthesizing carbocyclic nucleosides based on hypervalent iodine chemistry. The mechanism of this oxidative coupling reaction was investigated.

Formation of N-heterocycles by the reaction of thiols with glyoxamides: exploring a connective Pummerer-type cyclisation

The reaction of thiols with glyoxamides provides a convenient method for the generation of thionium ions and the initiation of Pummerer-type reactions. When the glyoxamides contain tethered aromatic nucleophiles, N-heterocycles are formed by a thionium ion cyclisation. The scope and mechanism of the connective Pummerer-type process has been investigated using a range of thiols, Lewis acids and both mono- and bis-glyoxamides. The utility of the process has been illustrated in a synthesis of the indoloquinoline natural product, neocryptolepine.

Pummerer-type reactions in the (2-methylsulfanyl-2-phosphonyl) thiopyran 1-oxide series

Two (3,6-dihydro-2-methylsulfanyl-2 H-thiapyran-2-yl)phosphonate derivatives have been chemoselectively oxidized on the thiopyran sulfur. The obtained allylic six-membered cyclic sulfoxides 2a and 2b were reacted under Pummerer reaction conditions leading to new thiopyran derivatives ( 4a and 6b, respectively). In both studied cases, the nucleophilic attack of β,γ-unsaturated thionium ion intermediate took place regioselectively at the γ-position (even when occupied by a methyl substituent like in 2b). An unexpected second product 7b was however obtained from substrate 2b (having the dimethyl-substituted double bond). Dephosphorylation of 7b under basic conditions led to an original conjugated tri-unsaturated trifluromethylcarbonyl thiopyran product ( 8b). These results represent new original examples of the Pummerer reaction.

C−H Bond Oxidation Initiated Pummerer- and Knoevenagel-Type Reactions of Benzyl Sulfide and 1,3-Dicarbonyl Compounds

A novel Pummerer-type reaction was developed via o-chloranil-mediated C-H bond oxidation. The reaction provides a simple and efficient method to construct sulfide derivatives. A Knoevenagel-type reaction was also achieved via multiple C-H bonds activation under neutral reaction conditions.

Total Synthesis of (±)‐γ‐Rubromycin on the Basis of Two Aromatic Pummerer‐Type Reactions

Double or nothing: In a convergent synthesis of the title compound, a potent inhibitor of human telomerase, two different aromatic Pummerer-type reactions were employed to construct the pivotal bisbenzannelated spiroketal skeleton from the two fragments shown in the scheme. This methodology offers convenient access to a wide range of substituted bisbenzannelated spiroketals from naphthol derivatives. MOM=methoxymethyl.

Synthesis of 2′,4′-BNACOC bearing a purine nucleobase

Recently, we have synthesized pyrimidine derivatives of 2',4'-BNA(COC) monomer, the sugar conformation of which was restricted in N-form by a seven-membered bridged structure. The oligonucleotides containing these monomers showed high affinity with complementary single-stranded RNA and significant resistance to nuclease degradation. For an application to antisense methodology, it is important to synthesize 2',4'-BNA(COC) monomers bearing a purine nucleobase. However, the formation of methyleneoxymethylene (COC) linkage in the purine derivatives failed under the acidic conditions used for the synthesis of 2',4'-BNA(COC) with pyrimidine nucleobases. After several examinations, we successfully achieved the synthesis of 2',4'-BNA(COC) monomers bearing a purine nucleobase via the formation of COC linkage using Pummerer-type reaction.