Cyclic Sulfinamides.

The literature on cyclic sulfinamides (put simply, sultims) published from 1989 to 2022 has been summarized and reviewed. The information is divided into two sections: the analysis of synthetic methods on the preparation of cyclic sulfinamides and the discussion of the chemical properties of cyclic sulfinamides focusing on their reactions and applications. The survey of the reaction conditions, provided in the most detailed way, and a critical view of the reaction mechanisms add an extra dimension to the text. The data presented will be useful to specialists in different areas, especially those who work in the field of synthetic organic and pharmaceutical chemistry.

Monoterpene Thiols: Synthesis and Modifications for Obtaining Biologically Active Substances.

Monoterpene thiols are one of the classes of natural flavors that impart the smell of citrus fruits, grape must and wine, black currants, and guava and are used as flavoring agents in the food and perfume industries. Synthetic monoterpene thiols have found an application in asymmetric synthesis as chiral auxiliaries, derivatizing agents, and ligands for metal complex catalysis and organocatalysts. Since monoterpenes and monoterpenoids are a renewable source, there are emerging trends to use monoterpene thiols as monomers for producing new types of green polymers. Monoterpene thioderivatives are also known to possess antioxidant, anticoagulant, antifungal, and antibacterial activity. The current review covers methods for the synthesis of acyclic, mono-, and bicyclic monoterpene thiols, as well as some investigations related to their usage for the preparation of the compounds with antimicrobial properties.

A Sulfoxide Reagent for One-Pot, Three-Component Syntheses of Sulfoxides and Sulfinamides.

Sulfoxides and sulfinamides represent versatile sulfur functional groups found in ligands, chiral auxiliaries, and bioactive molecules. Canonical two-component syntheses, however, rely on substrates with a preinstalled C-S bond and impede efficient and modular access to these sulfur motifs. Herein is presented the application of an easily prepared, bench-stable sulfoxide reagent for one-pot, three-component syntheses of sulfoxides and sulfinamides. The sulfoxide reagent donates the SO unit upon the reaction with a Grignard reagent (RMgX) as a sulfenate anion (RSO- ). While subsequent trapping reactions of this key intermediate with carbon electrophiles provide sulfoxides, a range of tertiary, secondary, and primary sulfinamides can be prepared by substitution reactions with electrophilic amines. The syntheses of sulfinamide analogs of amide- and sulfonamide-containing drugs illustrate the utility of the method for the rapid preparation of medicinally relevant molecules.

Hydroxylamine-Derived Reagent as a Dual Oxidant and Amino Group Donor for the Iron-Catalyzed Preparation of Unprotected Sulfinamides from Thiols.

An iron catalyzed reaction for the selective transformation of thiols (-SH) to sulfinamides (-SONH2 ) by a direct transfer of -O and free -NH2 groups has been developed. The reaction operates under mild conditions using a bench stable hydroxylamine derived reagent, exhibits broad functional group tolerance, is scalable and proceeds without the use of any precious metal catalyst or additional oxidant. This novel, practical reaction leads to the formation of two distinct new bonds (S=O and S-N) in a single step to chemoselectively form valuable, unprotected sulfinamide products. Preliminary mechanistic studies implicate the role of the alcoholic solvent as an oxygen atom donor.

Efficient Synthesis of Cyclic Sulfoximines from N-Propargylsulfinamides through Sulfur-Carbon Bond Formation.

Cyclic sulfoximines were readily synthesized by the cyclization of N-propargylsulfinamides without using expensive and toxic metal catalysts. This cyclization proceeded without loss of optical purity of chiral sulfinamides through the unusual sulfur-carbon bond formation promoted by an inexpensive inorganic base. This stereospecific cyclization offers a general approach to the asymmetric synthesis of chiral cyclic sulfoximines as an emerging heterocycle in medicinal chemistry.

Asymmetric Synthesis of Chiral Sulfoximines through the S-Alkylation of Sulfinamides.

Innovation in drug discovery critically depends on the development of new bioisosteric groups. Chiral sulfoximines, which contain a tetrasubstituted sulfur atom that bears one nitrogen, one oxygen, and two different carbon substituents, represent an emerging chiral bioisostere in medicinal chemistry. Chiral sulfoximines are conventionally prepared by a stereospecific nitrene transfer reaction to chiral sulfoxides; however, the number of readily available chiral sulfoxides remains limited. Herein, we report the asymmetric synthesis of a class of hitherto difficult-to-access chiral sulfoximines with two structurally similar alkyl chains. Our synthetic approach is based on the sulfur-selective alkylation of easily accessible chiral sulfinamides with commercially available reagents under simple and safe conditions. This stereospecific S-alkylation offers a general and scalable approach to the asymmetric synthesis of chiral sulfoximines, which represent important substructures in bioactive molecules.

Diastereoselective Aza-Mislow-Evans Rearrangement of N-Acyl tert-Butanesulfinamides into α-Sulfenyloxy Carboxamides.

A diastereoselective [2,3] rearrangement of O-silyl N-sulfinyl N,O-ketene acetals derived from chiral N-acyl tert-butanesulfinamides was developed, giving α-sulfenyloxy carboxamides with excellent enantioselectivity. Enolization and subsequent silylation of N-acyl tert-butanesulfinamides initiate this aza variant of the Mislow-Evans rearrangement, in which the chirality at the sulfur atom in the rearrangement precursors is faithfully transferred to the α-carbon stereocenter of the products. The Ellman sulfinamide, often used as a chiral ammonia equivalent, can serve in this rearrangement as a chiral precursor for the asymmetric synthesis of α-oxygen-functionalized carboxamides.

A New, Practical One-Pot Synthesis of Unprotected Sulfonimidamides by Transfer of Electrophilic NH to Sulfinamides.

Unprotected tertiary sulfonimidamides have been prepared in good to excellent yields in a one-pot transformation from tertiary sulfinamides through NH transfer. The reaction is mediated by commercially available (diacetoxyiodo)benzene and ammonium carbamate in methanol under convenient conditions. A wide range of functional groups are tolerated and initial results indicate that the NH transfer is stereospecific. A small molecule X-ray analysis of NH sulfonimidamide 2 a and its behavior in selected in vitro assays in comparison to the matched sulfonamide are also reported. This new reaction provides a safe, short and efficient approach to sulfonimidamides, which have been the subject of recent, growing interest in the life sciences.

Catalytic Nitrene Transfer To Alkynes: A Novel and Versatile Route for the Synthesis of Sulfinamides and Isothiazoles.

A novel transformation is reported for the reaction of terminal or internal alkynes with the nitrene precursor PhI=NTs (Ts=p-toluenesulfonyl) in the presence of catalytic amounts of TpBr3 Cu(NCMe) (TpBr3 =hydrotris(3,4,5-tribromo-pyrazolylborate). Two products containing an imine functionality have been isolated from the reaction mixtures, identified as sulfinamides and isothiazoles. The former correspond to the formal reduction of the sulfone group into sulfoxide, whereas the latter involves the insertion of an alkyne carbon atom into the aromatic ring of the N-tosyl moiety.

Metal-Free Cross-Coupling of Arylboronic Acids and Derivatives with DAST-Type Reagents for Direct Access to Diverse Aromatic Sulfinamides and Sulfonamides.

We have developed a simple and convenient method for the cross-coupling of arylboronic acids and their derivatives with DAST-type reagents under mild and metal-free conditions to directly afford sulfinamides in moderate to good yields. Moreover, sulfonamides were obtained after a simple oxidation reaction. The reaction mechanism was investigated by (18) O-labeling experiments, and the synthetic utility was demonstrated by the sulfoxidation of natural products.

Access to Highly Functionalized Sulfonated Cyclopentanes by Acid-Promoted Rauhut-Currier Reaction with Sulfinamides.

An unexpected acid-mediated cascade reaction induced by conjugate addition of sulfinamides to dienediones has been developed. This highly efficient Rauhut-Currier reaction enables the rapid, high-yielding construction of sulfonated cyclopentanes with three contiguous stereogenic centers in a single operation starting from simple sulfinamides. This process constitutes the first example of sulfinamide-promoted cycloisomerization.

Rational Design of Insecticidal Isoxazolines Containing Sulfonamide or Sulfinamide Structure as Antagonists of GABA Receptors with Reduced Toxicities to Honeybee and Zebrafish.

To develop highly effective, nontarget organism-friendly insecticides based on the isoxazoline scaffold, we rationally designed and synthesized 25 isoxazoline derivatives containing sulfonamides and sulfinamides. Their insecticidal activities against the diamondback moth (Plutella xylostella), fall armyworm (Spodoptera frugiperda), beet armyworm (Spodoptera exigua), and Spodoptera litura Fabricius (S. litura) were evaluated. The trifluoromethyl sulfinamide-containing compound 7w displayed excellent activities with LC50 values being 0.09, 0.84, 0.87, and 0.68 mg/L against P. xylostella, S. frugiperda, S. exigua, and S. litura, respectively, which were superior to fluxametamide (LC50 = 0.09, 1.24, 1.10, and 0.65 mg/L, respectively) and maintained at the same order of magnitude LC50 values as fluralaner (LC50 = 0.02, 0.17, 0.12, and 0.19 mg/L, respectively). Importantly, compound 7w showed a medium toxicity level of acute toxicity to honeybee (LD50 = 2.22 µg/adult), which is significantly lower than the fluralaner (high toxicity level, LD50 = 0.09 µg/adult). Acute toxicity experiments with zebrafish (Danio rerio) indicated that compound 7w was safe with the LC50 value being 42.4 mg/L (low toxicity level). Furthermore, electrophysiological experiments and molecular docking studies preliminarily verified that compound 7w acts on the insect GABA receptor, and the theoretical calculations explained that the sulfinamide structure may play an important role in exhibiting biological activities. The above results suggest that compound 7w could be employed as a potentially highly effective, environmentally friendly insecticide to control multiple agricultural pests.

Chromatographic enantioseparation of chiral sulfinamide derivatives on polysaccharide-based chiral stationary phases.

Chiral sulfinamides are increasingly recognizedfor their extensive potential applications in chemistry, medicine and material science, yet chromatographic study on these compounds is seldom. In this article, we describe the enantioseparation of twelve closely related chiral sulfinamide derivatives on polysaccharide-based chiral stationary phases (CSPs). We investigated the factors affecting separation, such as the types of chiral columns, the concentration of polar alcohol and the column temperature. The acyclic sulfinamide derivatives-with the exception of a cyclic sulfinamide compound-were effectively resolved with a Chiralcel OD-H column and a mixture of n-hexane:isopropyl alcohol (90:10) as the mobile phase. All compounds except N-benzylidene-2-methylpropane-2-sulfinamide are baseline resolved on the Chiralpak AD-H column, but only eight compounds are resolved on a Chiralpak AS-H column under the given chromatographic conditions. This study offers valuable guidance for future chiral HPLC studies related to chiral sulfinamides.

Stereoselective Nucleophilic Trifluoromethylation of N-(tert-Butylsulfinyl)imines by Using Trimethyl(trifluoromethyl)silane.

A very general reaction is presented to achieve the nucleophilic transfer of "CF3 " to chiral N-(tert-butylsulfinyl)imines in high yield and high stereoselectivity. Tetrabutylammonium difluorotriphenylsilicate (TBAT) functions as a fluoride source, and aromatic, heterocyclic, and aliphatic sulfinylimines react smoothly. The high stereoselectivity suggests that the reaction proceeds through an open transition state. TMS=trimethylsilyl.