Sulfur dioxide mediated one-pot, three- and four-component syntheses of polyfunctional sulfonamides and sulfonic esters: study of the stereoselectivity of the ene reaction of sulfur dioxide

The ene reaction of sulfur dioxide with enoxysilanes or with allylsilanes generates silyl sulfinates that can be brominated (Br(2) or NBS) or chlorinated (NCS or Cl(2)) to produce the corresponding sulfonyl halides. They react with primary and secondary amines or alcohols to give the corresponding sulfonamides and sulfonic esters, respectively. The hetero-Diels-Alder addition of sulfur dioxide to 1-oxy- or 1,3-dioxy-1,3-dienes generates zwitterions that add to enoxysilanes or allylsilanes giving silyl sulfinates that can be converted in situ into polyfunctional sulfonamides or sulfonic esters. This realizes quick access to libraries of complicated sulfonamides and sulfonic esters applying one-pot, three- and four-component methods.     

Visible-light-promoted oxidative difunctionalization of alkenes with sulfonyl chlorides to access β-keto sulfones under aerobic conditions

A mild, practical and efficient strategy to prepare β-keto sulfones has been developed by visible light promoted reactions. This reaction involves Ir(ppy)₂(dtbbpy)PF₆ catalyzed direct funcationalization of alkenes with sulfonyl chlorides under mild conditions. Air was used as oxidant without any additives. The transformation affords the corresponding products in moderate to high yields.     

Development of a new carbon-carbon bond forming reaction. new organic chemistry of sulfur dioxide. Asymmetric four-component synthesis of polyfunctional sulfones.

At low temperature 1-alkoxy-1,3-dienes add to sulfur dioxide activated by a Lewis or Br?nstedt acid and generate zwitterionic intermediates that can be quenched by enoxysilanes. The resulting beta,gamma-unsaturated silyl sulfinates can be desilylated and reacted with methyl iodide to provide polyfunctional sulfones. Exploratory studies of this four-component synthesis of sulfones are reported. Enantiomerically pure derivatives containing up to three new stereogenic centers can be obtained using enantiomerically pure (E,E)-1-alkoxy-2-methylpenta-1,3-dienes derived from alpha-methyl benzyl alcohols, including the Greene's chiral auxiliary. The stereochemistry of the reactions is consistent with a mechanism involving the suprafacial hetero-Diels-Alder addition of sulfur dioxide to the 1-alkoxy-1,3-dienes that are rapidly ionized into zwitterionic intermediates.     

Palladium-catalyzed conversion of beta,gamma-unsaturated silyl sulfinates into (E)-alkenes: asymmetric synthesis of polypropionate fragments

At low temperature, 1-alkoxy-1,3-dienes add to sulfur dioxide activated by a Lewis or protic acid generating zwitterionic intermediates that can be quenched by enoxysilanes. The resulting beta,gamma-unsaturated silyl sulfinates can be desilylated by 1:1 Pd(OAc)(2)/PPh(3) catalyst, liberating the corresponding beta,gamma-unsaturated sulfinic acids that undergo smooth and highly stereoselective retro-ene eliminations of sulfur dioxide. The method has been applied to generate enantiomerically pure polypropionate fragments.     

Synthesis and Applications of Silyl 2‐Methylprop‐2‐ene‐1‐sulfinates in Preparative Silylation and GC‐Derivatization Reactions of Polyols and Carbohydrates

Trimethylsilyl, triethylsilyl, tert‐butyldimethylsilyl, and triisopropylsilyl 2‐methylprop‐2‐ene‐1‐sulfinates were prepared through (CuOTf)₂?C₆H₆‐catalyzed sila‐ene reactions of the corresponding methallylsilanes with SO₂ at 50 °C. Sterically hindered, epimerizable, and base‐sensitive alcohols gave the corresponding silyl ethers in high yields and purities at room temperature and under neutral conditions. As the byproducts of the silylation reaction (SO₂+isobutylene) are volatile, the workup was simplified to solvent evaporation. The developed method can be employed for the chemo‐ and regioselective semiprotection of polyols and glycosides and for the silylation of unstable aldols. The high reactivity of the developed reagents is shown by the synthesis of sterically hindered per‐O‐tert‐butyldimethylsilyl‐α‐d ‐glucopyranose, the X‐ray crystallographic analysis of which is the first for a per‐O‐silylated hexopyranose. The per‐O‐silylation of polyols, hydroxy carboxylic acids, and carbohydrates with trimethylsilyl 2‐methylprop‐2‐ene‐1‐sulfinate was coupled with the GC analysis of nonvolatile polyhydroxy compounds both qualitatively and quantitatively.     

Functional group divergence and the structural basis of acridine photocatalysis revealed by direct decarboxysulfonylation

The reactivity of the sulfonyl group varies dramatically from nucleophilic sulfinates through chemically robust sulfones to electrophilic sulfonyl halides—a feature that has been used extensively in medicinal chemistry, synthesis, and materials science, especially as bioisosteric replacements and structural analogs of carboxylic acids and other carbonyls. Despite the great synthetic potential of the carboxylic to sulfonyl functional group interconversions, a method that can convert carboxylic acids directly to sulfones, sulfinates and sulfonyl halides has remained out of reach. We report herein the development of a photocatalytic system that for the first time enables direct decarboxylative conversion of carboxylic acids to sulfones and sulfinates, as well as sulfonyl chlorides and fluorides in one step and in a multicomponent fashion. A mechanistic study prompted by the development of the new method revealed the key structural features of the acridine photocatalysts that facilitate the decarboxylative transformations and provided an informative and predictive multivariate linear regression model that quantitatively relates the structural features with the photocatalytic activity.

Carboxylic acids can now serve as a single point of entry to several sulfonyl functional groups by a one-step organophotocatalytic sulfonylation, revealing structural effects that enable the photocatalysis.     

Sulfated zirconia (SO4/ZrO2) as a reusable solid acid catalyst for the Mannich-type reaction between ketene silyl acetals and aldimines

Sulfated zirconia (SO₄/ZrO₂) catalyzed Mannich-type reactions of ketene silyl acetals and aldimines proceeded smoothly at room temperature to afford β-amino esters in good to high yields. In addition, the heterogeneous solid acid catalyst SO₄/ZrO₂ was easily recovered from the reaction mixture and then reused without significant loss of effectiveness.     

Divergent reactivity of sulfinates with pyridinium salts based on one- versus two-electron pathways

One of the main goals of modern synthesis is to develop distinct reaction pathways from identical starting materials for the efficient synthesis of diverse compounds. Herein, we disclose the unique divergent reactivity of the combination sets of pyridinium salts and sulfinates to achieve sulfonative pyridylation of alkenes and direct C4-sulfonylation of pyridines by controlling the one- versus two-electron reaction manifolds for the selective formation of each product. Base-catalyzed cross-coupling between sulfinates and N-amidopyridinium salts led to the direct introduction of a sulfonyl group into the C4 position of pyridines. Remarkably, the reactivity of this set of compounds is completely altered upon exposure to visible light: electron donor–acceptor complexes of N-amidopyridinium salts and sulfinates are formed to enable access to sulfonyl radicals. In this catalyst-free radical pathway, both sulfonyl and pyridyl groups could be incorporated into alkenes via a three-component reaction, which provides facile access to a variety of β-pyridyl alkyl sulfones. These two reactions are orthogonal and complementary, achieving a broad substrate scope in a late-stage fashion under mild reaction conditions.

Divergent reactions of sulfinates with pyridinium salts were developed by controlling the one- versus two-electron reaction manifolds.     

Alkenylation of C(sp3)−H Bonds by Zincation/Copper‐Catalyzed Cross‐Coupling with Iodonium Salts

α‐Vinylation of phosphonates, phosphine oxides, sulfones, sulfonamides, and sulfoxides has been achieved by selective C?H zincation and copper‐catalyzed C(sp³)?C(sp²) cross‐coupling reaction using vinylphenyliodonium salts. The vinylation transformation proceeds in high efficiency and stereospecificity under mild reaction conditions. This zincative cross‐coupling reaction represents a general alkenylation strategy, which is also applicable for α‐alkenylation of esters, amides, and nitriles in the synthesis of β,γ‐unsaturated carbonyl compounds.     

The reactions of perfluoroalkanesulfonyl bromide with hetero-atom substituted olefinic bonds

Perfluoroalkanesulfonyl bromides reacted with vinyl bromide, vinyl acetate and trimethyl vinyl silane to give the corresponding adducts with the evolution of SO₂. Perfluoroalkanesulfonyl bromide reacted with trimethyl silyl enol ether followed by hydrolysis to give the corresponding α-bromoketones and perfluoroalkanesulfinic acid. However, perfluoroalkanesulfonyl chlorides reacted with trimethyl silyl enol ether of pinacolone on UV irradiation to give the corresponding α-perfluoroalkyl derivatives of pinacolone. Under mild condition, perfluoroalkanesulfonyl bromide also brominated phenol and anisole to give the corresponding p-bromo derivatives. Sodium α, α-dichlorotrifluoroethanesulfinate reacted with bromine in water at 25°C to form α, α-dichlorotrifluoroethanesulfonyl bromide which was thermally less stable than but similar in reactivity to perfluoroalkanesulfonyl bromide.     

Multicomponent Reductive Cross-Coupling of an Inorganic Sulfur Dioxide Surrogate: Straightforward Construction of Diversely Functionalized Sulfones

Conventionally, sulfones are prepared by oxidation of sulfides with strong oxidants. Now, a multicomponent reductive cross-coupling involving an inorganic salt (sodium metabisulfite) for the straightforward construction of sulfones is disclosed. Both intramolecular and intermolecular reductive cross-couplings were comprehensively explored, and diverse sulfones were accessible from the corresponding alkyl and aryl halides. Intramolecular cyclic sulfones were systematically obtained from five- to twelve-membered rings. Naturally occurring aliphatic systems, such as steroids, saccharides, and amino acids, were highly compatible with the SO₂-insertion reductive cross-coupling. Four clinically applied drug molecules, which include multiple heteroatoms and functional groups with active hydrogens, were successfully prepared via a late-stage SO₂ insertion. Mechanistic studies show that alkyl radicals and sulfonyl radicals were both involved as intermediates in this transformation.     

Silver(I)‐Promoted Radical Sulfonylation of Allyl/Propargyl Alcohols: Efficient Synthesis of γ‐Keto Sulfones

An efficient Ag₂CO₃‐promoted sulfonylation of allyl/propargyl alcohols with sodium sulfinates has been developed. The reaction tolerates a wide range of functional groups to deliver γ‐keto sulfones in high yields (up to 93 %). Propargyl alcohols furnished trimerization product 1,3,5‐triaroylbenzenes in the presence of sodium methanesulfinate under the standard conditions. A mechanism involving a sulfonyl radical was suggested.     

Synthesis of β‐Keto Sulfones by a Catalyst‐Free Reaction of Aryldiazonium Tetrafluoroborates,Sulfur Dioxide,and Silyl Enol Ethers

A green approach for the generation of β‐keto sulfones through a reaction of aryldiazonium tetrafluoroborates and sulfur dioxide with silyl enol ether under catalyst‐ and additive‐free conditions has been realized. This reaction proceeds efficiently at room temperature and goes to completion in half an hour. During the reaction process, aryldiazonium tetrafluoroborate is treated with DABCO ⋅ (SO₂)₂ (DABCO=1,4‐diazabicyclo[2.2.2]octane) to provide a sulfonyl radical as the key intermediate, which then initiates the transformation. Oxidants or metal catalysts are avoided, and the presence of DABCO also plays an important role in the reaction.     

An Improved Synthesis of Vinyl- and β-Iodovinyl Sulfones by a Molecular Iodine-Mediated One-Pot Iodosulfonation-Dehydroiodination Reaction

An improved one-pot method to synthesize vinyl sulfones from unsaturated systems by using molecular iodine/sodium arenesulfinate/sodium acetate as reagents was described. Vinyl sulfones derived from styrene derivatives were generally obtained in good to excellent yields except for those bearing strong electron releasing substituent. Aliphatic alkenes and activated alkenes gave the corresponding vinyl sulfone products in moderate to good yields. Arylacetylenes yielded the respective β-iodovinyl sulfones in good yields while low yield was observed with aliphatic terminal alkyne. The potentials of the method entail simplicity, short reaction time, non-anhydrous reaction conditions, employing inexpensive, non-metallic reagent and integrating two reactions that are commonly accomplished separately into a single operation.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Reaction of β-trifluoroethoxy vinamidinium salts with carbon nucleophiles

β-Trifluoroethoxy vinamidinium salts 1 reacted smoothly with various types of the carbanions, generated by treatment of ketones, esters, amide and nitriles with LDA, to give the corresponding trifluoroethoxylated multifunctional dienamine derivatives 3 in moderate to good yields. On the other hand, the reaction of 1 with lithium acetylide and other carbanions derived from methyl compounds bearing sulfonyl, sulfinyl, and phosphonyl groups produced the corresponding α,β-unsaturated aldehydes 5 in good yields.     

DIMETHYL METHYLPHOSPHONATE AS METHYLATING REAGENT

Abstract

The methylating properties of dimethyl methylphosphonate have been investigated. Aromatic mono- and polycarboxylic acids were converted into their methyl esters by heating with dimethyl methylphosphonate. Similarly phenols or amines gave their respective O- or N-methyl derivatives. The sodium salts of sulfinic acids also reacted yielding sulfones in high yield.     

Polymer-supported glyoxylate and alpha-imino acetates. Versatile reagents for the synthesis of alpha-hydroxycarboxylic acid and alpha-amino acid libraries

Polymer-supported glyoxylate.monohydrate (3) and alpha-imino acetates (7) have been readily prepared from chloromethylated resin via two or three steps. The ene reactions of 3 with alkenes were successfully performed in the presence of Yb(OTf)3 (50 mol %) to afford, after cleavage from the polymer support, the corresponding alpha-hydroxycarboxylic acid esters in good yields. The reactions of 7 with silyl enolates, Danishefsky's diene, and alkenes also proceeded smoothly in the presence of Sc(OTf)3 (20 mol %) to give the corresponding alpha-amino acid, pyridone, and tetrahydroquinoline derivatives, respectively, in good yields.     

Multicomponent Reductive Cross‐Coupling of an Inorganic Sulfur Dioxide Surrogate: Straightforward Construction of Diversely Functionalized Sulfones

Conventionally, sulfones are prepared by oxidation of sulfides with strong oxidants. Now, a multicomponent reductive cross‐coupling involving an inorganic salt (sodium metabisulfite) for the straightforward construction of sulfones is disclosed. Both intramolecular and intermolecular reductive cross‐couplings were comprehensively explored, and diverse sulfones were accessible from the corresponding alkyl and aryl halides. Intramolecular cyclic sulfones were systematically obtained from five‐ to twelve‐membered rings. Naturally occurring aliphatic systems, such as steroids, saccharides, and amino acids, were highly compatible with the SO₂‐insertion reductive cross‐coupling. Four clinically applied drug molecules, which include multiple heteroatoms and functional groups with active hydrogens, were successfully prepared via a late‐stage SO₂ insertion. Mechanistic studies show that alkyl radicals and sulfonyl radicals were both involved as intermediates in this transformation.     

Sulfur dioxide mediated one-pot, four-component synthesis of polyfunctional sulfones and sulfonamides, including medium-ring cyclic derivatives

In previous papers (Synthesis2002, 232 and J. Org. Chem.2004, 69, 6413), we have shown that the hetero-Diels-Alder addition of sulfur dioxide to 1-oxy or 1,3-dioxy-1,3-dienes generates zwitterions that add to enoxysilanes or allylsilanes giving silyl sulfinates that can be converted in the same pot into polyfunctional sulfones, sulfonamides or sulfonic esters. We are presenting further applications of this method, including the synthesis of new medium-size heterocyclic systems of the type tetrahydro-2H-thiocines and hexahydro-1,2-thiazonine.     

Catalytic Regio‐ and Enantioselective [4+2] Annulation Reactions of Non‐activated Allenes by a Chiral Cationic Indium Complex

Regio‐ and enantioselective [4+2] annulation between β,γ‐unsaturated α‐keto esters and non‐activated allenes was achieved by using a chiral cationic indium(III)/phosphate catalyst. The reaction affords the corresponding C3‐selective dihydropyrans in good yields and with high enantioselectivity (up to 99 % ee ).