Pummerer-type Rearrangement Research Articles

Facile Cleavage of Activated Ketones: An Access to Thioethers via In Situ Generation of Anhydrides by Pummerer-Type Rearrangement.

Herein, we report an oxygen insertion in activated ketones from simple inorganic carbonates for the synthesis of symmetric aromatic anhydrides. For the first time, Li2CO3 acts as an oxygen source and the in situ generated symmetric aromatic anhydrides undergo Pummerer-type rearrangement to access α-benzoyloxy-thioethers. Attractively, this protocol occurs under metal-, ligand-, and oxidant-free conditions and is compatible with a wide range of substrates. Control experiments reveal the reaction pathway.

Synthesis of Highly Functionalized Pyridines: A Metal-Free Cascade Process

Herein, we report a new process for the synthesis of highly functionalized pyridines based on a tandem Pummerer-type rearrangement, aza-Prins cyclization, and elimination-induced aromatization. This formal [5+1] cyclization provides pyridines in good yields with easily accessible starting materials. The synthetic potential of our new method is further demonstrated in the modification of the frameworks of BINOL and some natural products.

An Umpolung Oxa-[2,3] Sigmatropic Rearrangement Employing Arynes for the Synthesis of Functionalized Enol Ethers.

An oxa-[2,3] sigmatropic rearrangement involving arynes is reported featuring the umpolung of ketones, where the C═O bond polarity is reversed. The in situ-generated sulfur ylides from β-keto thioethers and arynes undergo efficient rearrangement allowing the facile and robust synthesis of functionalized enol ethers in high yields and excellent functional group compatibility. Preliminary mechanistic studies rule out the possibility of Pummerer-type rearrangement operating in this case.

Rapid Assembly of Tetrasubstituted Furans via Pummerer-Type Rearrangement.

Despite the many methods available for the synthesis of furans, few methods remain that allow for the custom-made assembly of fully substituted furans. Here we report a powerful protocol to rapidly construct tetrasubstituted, orthogonally functionalized furans under mild reaction conditions. The developed method involves the regioselective ring-opening of readily available 2,5-dihydrothiophenes followed by an oxidative cyclization to provide the heterocycle. The selective oxidation at sulfur is promoted by N-chlorosuccinimide as an inexpensive reagent and proceeds at ambient temperature in high yield within 30 min. The obtained furans serve as exceptionally versatile intermediates and were shown to participate in a series of valuable postmodifications. The fate of the initial sulfonium intermediate was investigated by mechanistic experiments, and computational studies revealed the existence of an unprecedented Pummerer-type rearrangement. The potential for organic synthesis is highlighted by the total synthesis of bisabolene sesquiterpenoids (pleurotins A, B, and D).

Recent Advances in Synthesis of Chiral Thioethers.

Chiral thioethers is an important class of organosulfur molecules with extensive applications, especially in the field of medicine and organic synthesis. This review discusses the recent progress of synthesis of enantioenriched chiral thioethers and hopes to be helpful for related research in the future. It is summarized from organosulfur compounds-participating organic reaction types, including nucleophilic substitution, cross coupling, sulfa-Michael addition, sulfenylation, asymmetric allylic reaction, asymmetric Doyle-Kirmse reaction, Pummerer-type rearrangement, Smiles rearrangement,[2,3] Stevens and Sommelet-Hauser rearrangement.

Asymmetric Synthesis of 2'-C-Methyl-4'-selenonucleosides as Anti-Hepatitis C Virus Agents.

In search of a new template for anti-hepatitis C virus (HCV) agents, we designed and synthesized the 2'-C-methyl-4'-selenopyrimidine and -purine nucleosides and their phosphoramidate prodrugs to replace a furanose oxygen of anti-HCV nucleos(t)ides with a selenium atom on the basis that selenium is a chemical isostere of oxygen. These nucleosides are expected to show different physicochemical properties such as better lipophilicity which might enhance the penetration across cell membranes and the conformational constraint induced by a bulky selenium atom in the sugar ring. The 2'-C-methyl-4'-selenopyrimidine and -purine nucleosides 8 and 9 were synthesized from 2-C-methyl-d-ribono-γ-lactone (14) via construction of 2-C-methyl-d-selenosugar 18 through C-4 epimerization and SN2 cyclization with Se2- as key steps. The key 4'-selenosugar was converted to the 2'-C-methyl-4'-selenopyrimidine and -purine nucleosides using Pummerer-type rearrangement and Vorbrüggen glycosylation, respectively. In addition, the ProTide strategy has been applied to synthesize the adenine and uracil phosphoramidate derivatives 10a and 10b to overcome the limitations associated with parent nucleosides such as inefficient conversion to their corresponding 5'-monophosphate form and poor cellular uptake. The regio- and stereochemistry of 4'-selenonucleosides were confirmed by 2D NOESY NMR spectroscopy and X-ray crystallography. None of the final pyrimidine and purine nucleosides and their prodrugs exhibited significant anti-HCV activity up to 100 μM.

Facile synthesis of methylthiomethyl esters through Pummerer-type rearrangement of carboxylic acids and DMSO under metal-free conditions

A green and cost-effective Pummerer-type rearrangement between readily accessible carboxylic acids and DMSO has been achieved under metal-free conditions in satisfactory to excellent yields. The transformation for the synthesis of valuable methylthiomethyl esters is shown to be a convenient strategy for various (hetero)aromatic acids, α,β-unsaturated carboxylic acids and saturated alkyl carboxylic acids with good functional group tolerance.

Post-transition state bifurcations induce dynamical detours in Pummerer-like reactions.

A post-transition state bifurcation (PTSB) involved in a Pummerer-type rearrangement is characterized using density functional theory (DFT) calculations on potential energy stationary points and direct dynamics simulations. A sensitivity of the ratio of products produced via this PTSB to solvent dielectric constant is revealed and implications of such a dependence for selectivity control of organic reactions are discussed.

Catalyst-Free Three-Component Tandem CDC Cyclization: Convenient Access to Isoindolinones from Aromatic Acid, Amides, and DMSO by a Pummerer-Type Rearrangement.

A catalyst-free multicomponent CDC reaction is rarely reported, especially for the intermolecular tandem CDC cyclization, which represents an important strategy for constructing cyclic compounds. Herein, a three-component tandem CDC cyclization by a Pummerer-type rearrangement to afford biologically relevant isoindolinones from aromatic acids, amides, and DMSO, is described. This intermolecular tandem reaction undergoes a C(sp(2) )-H/C(sp(3) )-H cross-dehydrogenative coupling, C-N bond formation, and intramolecular amidation. A notable feature of this novel protocol is avoiding a catalyst and additive (apart from oxidant).

ChemInform Abstract: From Amino Acids to Fluorine‐Containing Carbohydrates: De novo Synthesis of 2‐Amino‐4‐fluoroxylose and ‐lyxose.

Fluorine-containing amino sugars are highly interesting synthetic targets owing to their promising applications in medicinal chemistry. However, only a few concise approaches for their preparation are described. Herein, we wish to report on a titanium-mediated aldol addition strategy for the preparation of 2-amino-2,4-dideoxy-4-fluoropentoses. Our earlier reports on the application of serine- and threonine-derived aldehydes in this reaction are now complemented by the corresponding cysteine analogues. Furthermore, a new deprotection sequence for the fluorohydrin aldol products has been developed by applying a photochemical Pummerer-type rearrangement followed by acidic cleavage of the monothioacetals obtained, finally furnishing 2-acetamido-2,4-dideoxy-4-fluoro-D-xylose and -lyxose in a four-step synthetic sequence. Moreover, we found that the cysteine-derived aldehydes behave differently in aldol reactions compared with their serine and threonine analogues.

ChemInform Abstract: Tandem Pummerer-Type Rearrangement and Nickel-Catalyzed Alkylative Olefination of the Cyclic Dithioacetal S-Oxides of Aromatic Aldehydes with Grignard Reagents.

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Synthesis and Anti-HIV Activity of d- and l-Thietanose Nucleosides

Various D- and L-thietanose nucleosides were synthesized from D- and L-xylose. The four-membered thietane ring was efficiently synthesized by the cyclization of 1-thioacetyl-3-mesylate (4/38) under basic conditions. Condensation with various heterocyclic bases was conducted via Pummerer-type rearrangement to afford various nucleoside derivatives. Among the synthesized nucleosides, D-uridine (23), D-cytidine (24), D-5-fluorocytidine (25), and L-cytidine (52) analogues showed moderate anti-HIV activity, with EC50 = 6.9, 1.3, 5.8, and 14.1 microM, respectively. However, these four nucleoside analogues are cytotoxic in peripheral blood mononuclear and CEM cells. The other nucleosides are neither active nor cytotoxic. Interestingly, the oxetanocin A analogue 33 was not active. Comparison of the minimized reverse transcriptases (RTs) complexed with the corresponding triphosphates of the cytidine analogue 24 and the adenosine analogue 33 by molecular modeling studies showed that there is no difference in the binding mode of the triphosphate of the cytidine analogue 24 to the active site of HIV-1 RT from that of the triphosphate of the adenosine analogue 33. Modeling studies on the initial monophosphorylation step by deoxycytidine kinase showed that the catalytic efficiency of phosphorylation through a nucleophilic attack of the 4'-hydroxyl group of thietanose on the gamma-phosphate of ATP is diminished in the case of L-cytidine analogue (52) due to the increased distance between the 4'-hydroxyl group and the gamma-phosphate.

ChemInform Abstract: Domino Michael-Seleno Pummerer Type Reaction (Additive Seleno Pummerer Reaction).

Domino Michael–seleno Pummerer type reaction (additive seleno Pummerer type rearrangement) has been realised by the reaction of 1,3-dicarbonyl compounds with vinyl selenoxides in the presence of amine and chlorosilane.

Domino Michael–seleno Pummerer type reaction (additive seleno Pummerer reaction)

Domino Michael–seleno Pummerer type reaction (additive seleno Pummerer type rearrangement) has been realised by the reaction of 1,3-dicarbonyl compounds with vinyl selenoxides in the presence of amine and chlorosilane.

Facile Synthesis of α-Fluoroalkyl Sulfides under the Oxidative Desulfurization–Fluorination Conditions

Abstract Upon treatment with n-Bu4NH2F3 and 1,3-dibromo-5,5-dimethylhydantoin, various organic sulfides underwent a Pummerer-type rearrangement, followed by fluorination, to give α-fluoro sulfides. The fluoro-Pummerer rearrangement, when applied to RCH(SMe)CF2SMe, gave trifluoro sulfides RCF(SMe)CF2SMe. When an HF-pyridine reagent was used as the fluorinating agent, an oxidative desulfurization–fluorination reaction occurred depending on the structure of the substrates.

σ-Delocalized Hexakis(methylthio)benzene Dication: A Possible Intermediate of Pummerer-type Rearrangement of Monooxide of Hexakis(methylthio)benzene

Abstract The Pummerer-type rearrangement of monooxide of hexakis(methylthio)benzene with H2SO4 or (CF3SO2)2O gives the cyclic methylsulfonium salt. A σ-delocalized hexathia dication is proposed as an intermediate.

Radical β-addition to acyclic α-(arylsulfinyl) enones: Pummerer-type rearrangement

The reaction of (S,E)-3-(p-tolylsulfinyl)pent-3-en-2-one with an isopropyl radical, generated from isopropyl iodide and triethylborane, gives the non-stereoselective addition product and an unexpected α-(arylsulfanyl) enone which is formed through a radical addition and subsequent Pummerer-type rearrangement. The formation of the α-(arylsulfanyl) enone depends upon the additives used as well as the aryl group on the sulfur.

Isolation of the Quinone Mono O,S‐Acetal Intermediates of the Aromatic Pummerer‐Type Rearrangement of p‐Sulfinylphenols with 1‐Ethoxyvinyl Esters

A versatile synthetic building block and evidence for the mechanism of the Pummerer-type rearrangement have been obtained in the form of the acetal intermediate B, isolated in the reaction of p-sulfinylphenols 1 to p-quinones 2 induced by acid anhydrides. Thus, a method is now also available for the efficient preparation of quinone monoacetals under nonoxidative conditions.

Synthesis of N-Cbz-fluoropyruvaldehyde N, S-ketals: construction of highly stereoselective and high yielding synthetic reactions using multivariate modelling and design

The synthesis of ( R)-fluoropyruvaldehyde- N, S-ketals via a tandem self-immolative Pummerer-type rearrangement of enantiopure ( R)- α-fluoroalkyl-β-sulfinylenamines has been studied using statistical experimental design and multivariate modelling. By this study a procedure has been established which simultaneously gives excellent enantioselectivity and synthetically useful yields. The improvement of the ee of the trifluoro derivative was from 69% to 82%. The optimised procedure has been scaled up (10 fold) and extended to the corresponding difluoro and chlorodifluoro derivatives, with similarly good results. The chemometric analysis, along with a crossover experiment, strongly supports the hypothesis of a strictly intramolecular process, according to the previously proposed mechanism.

Some Recent Advances in Pummerer-type Reactions

A highly enantiomeric excess in an asymmetric Pummerer-type rearrangement of chiral, non-racemic sulfoxides using O-silylated ketene acetal and the first successful Pummerer-type rearrangement on aromatic rings, are described.