Multistep Continuous Flow Synthesis of Isolable NH2 -Sulfinamidines via Nucleophilic Addition to Transient Sulfurdiimide.

The growing interest in novel sulfur pharmacophores led to recent advances in the synthesis of some S(IV) and S(VI) motifs. However, preparation and isolation of uncommon primary sulfinamidines, the aza-analogues of sulfinamides, is highly desirable. Here we report a multistep continuous flow synthesis of poorly explored NH2 -sulfinamidines by nucleophilic attack of organometallic reagents to in situ prepared N-(trimethylsilyl)-N-trityl-λ4 -sulfanediimine (Tr-N=S=N-TMS). The transformation can additionally be realized under mild conditions, at room temperature, via a highly chemoselective halogen-lithium exchange of aryl bromides and iodides with n-butyllithium. Moreover, the synthetic potential of the methodology was assessed by exploring further manipulations of the products and accessing novel S(IV) analogues of celecoxib, tasisulam, and relevant sulfinimidoylureas.

Synthesis of γ-Lactams by Formal Cycloadditions with Ketenes.

The synthesis of γ-lactams is reported by a formal (3+2) cycloaddition between readily available ketenes and aziridines or a one-pot formal (2+1+2) cycloaddition using imines as aziridine precursors. The method is practical, is scalable, and affords high yields. It also offers a high level of regio- and diastereoselectivity on a wide range of substrates as well as a high stereoselectivity in the case of enantiopure aziridines.

Thermal [2 + 2]-Cycloaddition of Ketenes with Chiral Enol Ethers: Route to Densely Substituted Cyclobutanones.

Access to chiral polysubstituted cyclobutanones by [2 + 2]-cycloaddition of ketenes with chiral acyclic enol ethers is reported. A wide variety of easily accessible di- and monosubstituted ketenes were found to react with a very high degree of stereoselectivity with chiral, Stericol derived, acyclic enol ethers. This combination of simple reagents provides straightforward entry to highly substituted enantioenriched cyclobutanones.

Ynol Ethers: Synthesis and Reactivity.

Ynol ethers are highly valuable substrates offering a wide range of reactivity. These highly electron-rich heterosubstitued alkynes can be of great synthetic potential. In this mini-review, the different methods for the synthesis of ynol ethers are first presented, divided in three main approaches involving a ß-elimination, a carbene rearrangement and a direct oxidation of an alkyne. Their reactivity is then summarized underlying their synthetic utility. This non-exhaustive review aims at presenting the intrinsic reactivity of these compounds, still underexploited in synthesis.

Kinetic resolution in the [2+2] cycloaddition of ketenes: an experimental and theoretical study.

The kinetic resolution of Z and E olefins by [2+2] cycloaddition with ketenes allows the isolation of pure E olefin, as well as the synthesis of pure cis-cyclobutanones, starting from Z/E mixtures. A computational rationale for this kinetic difference is reported. The obtained difference of energy of activation matches with the experimental results.

Sulfinylimidates as chiral amide equivalents for irreversible, asymmetric aldol reactions.

A highly selective N-sulfinylimidate aldolization has been developed under mildly basic conditions leading to diastereopure products of high synthetic potential. The innate reversibility of this aldolization was suppressed by the use of titanium as the Lewis acid. An application of this methodology via the synthesis of a potential neurotransmitter reuptake inhibitor is illustrated.

Highly diastereoselective addition of alkoxyethynyl aluminium reagents to N-tert-butylsulfinyl aldimines.

The addition of dimethylaluminium alkoxyacetylides to Ellman's sulfinylimines is described. The reaction proceeds with excellent diastereoselectivity and high yield to produce oxygenated propargylamines in one step starting from simple dichloroenol ethers.

Asymmetric addition of alkoxy ethynyl anion to chiral N-sulfinyl imines.

The addition of lithiated ynol ethers to chiral N-sulfinyl imines proceeds in high yield and diastereoselectivity. The selectivity is completely reversed by the addition of boron trifluoride. These alkoxypropargyl sulfinamides can be reduced to afford enol ethers, selectively oxidized to busyl derivatives, or the ynol ether can be hydrolyzed to afford ß-amino esters.

A Diels-Alder-based total synthesis of (-)-kainic acid.

An efficient synthesis of (-)-kainic acid, through a high-pressure-promoted Diels-Alder cycloaddition of a vinylogous malonate derived from 4-hydroxyproline, is described. The bicyclic adduct could be converted into the natural product with complete stereocontrol.

Sequential Rh(I)/Pd-catalyzed 1,4-addition/intramolecular allylation: stereocontrolled construction of gamma-butyrolactones and cyclopropanes.

The rhodium-catalyzed conjugate addition of functionalized vinyltin reagents to alkylidene Meldrum's acids, followed by Pd-catalyzed intramolecular allylation, is a direct entry into vinyl-substituted gamma-lactones via O-alkylation and vinylcyclopropanes via C-alkylation.