Synthesis and Transformations of NH-Sulfoximines.

Recent years have seen a marked increase in the occurrence of sulfoximines in the chemical sciences, often presented as valuable motifs for medicinal chemistry. This has been prompted by both pioneering works taking sulfoximine containing compounds into clinical trials and the concurrent development of powerful synthetic methods. This review covers recent developments in the synthesis of sulfoximines concentrating on developments since 2015. This includes extensive developments in both S-N and S-C bond formations. Flow chemistry processes for sulfoximine synthesis are also covered. Finally, subsequent transformations of sulfoximines, particularly in N-functionalization are reviewed, including N-S, N-P, N-C bond forming processes and cyclization reactions.

Synthesis of glycosyl sulfoximines by a highly chemo- and stereoselective NH- and O-transfer to thioglycosides.

A synthesis of unprecedented and stable glycosyl sulfoximines is reported. The developed strategies represent the first example of highly stereoselective sulfoximine formation directly from thioglycosides. This synthetic protocol has been tested on several ß-thioglycosides bearing different aromatics and alkyls as S-substituents, and bearing glucose, mannose and galactose as glycosyl units. The process has been extended to a lactose derived thioglycoside and to a glucose derived sulfenamide. The process was chemo- and stereoselective, and X-ray analysis confirmed the structure and provided stereochemical information on the configuration at the sulfur atom. A model for the stereochemical outcome is proposed based on the steric environment of the sulfide.

Fluoro-Substituted Methyllithium Chemistry: External Quenching Method Using Flow Microreactors.

The external quenching method based on flow microreactors allows the generation and use of short-lived fluoro-substituted methyllithium reagents, such as fluoromethyllithium, fluoroiodomethyllithium, and fluoroiodostannylmethyllithium. Highly chemoselective reactions have been developed, opening new opportunities in the synthesis of fluorinated molecules using fluorinated organometallics.

Synthesis of Sulfonimidamides from Sulfenamides via an Alkoxy-amino-λ6 -sulfanenitrile Intermediate.

Sulfonimidamides are intriguing new motifs for medicinal and agrochemistry, and provide attractive bioisosteres for sulfonamides. However, there remain few operationally simple methods for their preparation. Here, the synthesis of NH-sulfonimidamides is achieved directly from sulfenamides, themselves readily formed in one step from amines and disulfides. A highly chemoselective and one-pot NH and O transfer is developed, mediated by PhIO in iPrOH, using ammonium carbamate as the NH source, and in the presence of 1 equivalent of acetic acid. A wide range of functional groups are tolerated under the developed reaction conditions, which also enables the functionalization of the antidepressants desipramine and fluoxetine and the preparation of an aza analogue of the drug probenecid. The reaction is shown to proceed via different and concurrent mechanistic pathways, including the formation of novel S≡N sulfanenitrile species as intermediates. Several alkoxy-amino-λ6 -sulfanenitriles are prepared with different alcohols, and shown to be alkylating agents to a range of nucleophiles.

Straightforward chemo- and stereoselective fluorocyclopropanation of allylic alcohols: exploiting the electrophilic nature of the not so elusive fluoroiodomethyllithium.

An unprecedented direct fluorocyclopropanation of allylic alcohols is reported. This simple method involves the not so elusive fluoroiodomethyllithium, a carbenoidic intermediate that under the developed conditions discloses its electrophilic nature. Gratifyingly, the reaction turned out to be highly chemo- and stereoselective, and DFT calculations provided insights into the structure and nature of this new type of carbenoid.

Modular and Chemoselective Strategy for the Direct Access to α-Fluoroepoxides and Aziridines via the Addition of Fluoroiodomethyllithium to Carbonyl-Like Compounds.

An expeditious, high-yielding synthesis of rare α-fluoroepoxides and α-fluoroaziridines through the addition of the unkown fluoroiodomethyllithium (LiCHIF)-formed via deprotonation the commercially available fluoroiodomethane with a lithium amide base-to carbonyl-like compounds is documented. The ring-closure reactions, leading to α-fluorinated three-membered heterocycles, rely on the diversely reactive C-I and C-F bonds. Excellent chemoselectivity was observed in the presence of highly sensitive functionalities-aldehyde, ketone, nitrile, alkene-which remained untouched during the homologation sequence.

Highly Chemoselective NH- and O-Transfer to Thiols Using Hypervalent Iodine Reagents: Synthesis of Sulfonimidates and Sulfonamides.

Aryl thiols can be selectively converted to sulfonimidates or sulfonamides with three new S-X connections being made selectively in one pot. Using hypervalent iodine reagents in the presence of ammonium carbamate, NH- and O-groups are transferred under mild and practical conditions. Reducing the loading of ammonium carbamate changed the product distribution, converting the sulfonimidate to the sulfonamide. Studies into the possible intermediate species are presented, suggesting that multiple pathways may be possible via sulfinate esters, or related intermediates, with each species forming the same products.

Synthesis of NH-sulfoximines from sulfides by chemoselective one-pot N- and O-transfers.

Direct synthesis of NH-sulfoximines from sulfides has been achieved through O and NH transfer in the same reaction, occurring with complete selectivity. The reaction is mediated by bisacetoxyiodobenzene under simple conditions and employs inexpensive N-sources. Preliminary studies indicate that NH-transfer is likely to be first, followed by oxidation, but the reaction proceeds successfully in either order. A wide range of functional groups and biologically relevant compounds are tolerated. The use of AcO15NH4 affords 15N-labeled compounds.