General electrochemical Minisci alkylation of N-heteroarenes with alkyl halides.

Herein, we report, a general, facile and environmentally friendly Minisci-type alkylation of N-heteroarenes under simple and straightforward electrochemical conditions using widely available alkyl halides as radical precursors. Primary, secondary and tertiary alkyl radicals have been shown to be efficiently generated and coupled with a large variety of N-heteroarenes. The method presents a very high functional group tolerance, including various heterocyclic-based natural products, which highlights the robustness of the methodology. This applicability has been further proved in the synthesis of various interesting biologically valuable building blocks. In addition, we have proposed a mechanism based on different proofs and pieces of electrochemical evidence.

Unlocking the direct photocatalytic difluoromethylation of C[double bond, length as m-dash]N bonds.

The current study presents a direct CF2H radical addition to C[double bond, length as m-dash]N bonds predicated on the photocatalytic activation of commercially available zinc difluoromethanesulfinate. The mild conditions in place lead to impressive structural diversity, as quinoxalinones and dibenzazepines, among others, are successfully functionalized.

Intramolecular Homolytic Substitution Enabled by Photoredox Catalysis: Sulfur, Phosphorus, and Silicon Heterocycle Synthesis from Aryl Halides.

Aryl radical generation and manipulation constitutes a long-standing challenge in organic synthesis. Photocatalytic single-electron reduction of aryl halides has been established as a premier activation pathway to reach these intermediates. The current study integrates the conceptual simplicity of the classical intramolecular homolytic substitution with the practicality of the modern photocatalytic approach. Predicated on an efficient metal-free dehalogenation of aryl halides under mild organo-photoredox conditions, sulfur, phosphorus, and silicon heteroatoms capture the C(sp2)-centered radical in an intramolecular fashion.

Reformatsky Reaction to Alkynyl N- tert-Butanesulfinyl Imines: Lewis Acid Controlled Stereodivergent Synthesis of ß-Alkynyl-ß-Amino Acids.

A highly diastereoselective Refortmatsky reaction to N- tert-butanesulfinyl propargylaldimines and ketimines is presented. The reaction proceeded with excellent yields and diastereoselectivities provided by the sulfinyl group in the presence of Me3Al. The use of TBSOTf as a Lewis acid promoter switched the sense of the stereoinduction. Thus, this methodology allowed the stereodivergent asymmetric synthesis of ß-alkynyl ß-amino acid derivatives, from the same sulfinyl configuration, by simply changing the Lewis acid promoter.

Asymmetric radical alkylation of N-sulfinimines under visible light photocatalytic conditions.

In this communication, a new photocatalytic strategy for the addition of alkyl-radical derivatives to N-sulfinimines with complete diastereoselectivity and moderate to good yields is presented. This is the first asymmetric photocatalytic addition to N-sulfinimines under visible light irradiation with smooth conditions and functional group tolerance.

Stereochemical aspects and the synthetic scope of the S(H)i at the sulfur atom. Preparation of enantiopure 3-substituted 2,3-dihydro-1,2-benzoisothiazole 1-oxides and 1,1-dioxides.

Intramolecular homolytic substitution (SHi) on the sulfur atom at acyclic N-(o-bromobenzyl)sulfinamides takes place with a complete inversion of the configuration and provides an excellent tool to connect N-tert-butanesulfinylimines with enantiopure 3-substituted benzo-fused sulfinamides (1,2-benzoisothiazoline 1-oxides) and the related pharmacologically relevant sulfonamides.

Intermolecular alkyl radical additions to enantiopure N-tert-butanesulfinyl aldimines.

The sulfinyl group in (R)-N-tert-butanesulfinyl aldimines provides efficient control of the stereoselectivity in the intermolecular reactions with alkyl radicals. The methodology is applicable to aryl, heteroaryl, benzyl, and alkynyl imines, even those containing CN, CO2Me, COR, and OH groups. The best results are attained with hindered radicals (tertiary and secondary ones) without C═N bond reduction. This reaction complements the well-established organometallic additions to N-sulfinyl aldimines to obtain enantiomerically pure functionalized α-branched primary amines.

Stereocontrolled fluorobenzylation of vinyl sulfones and α,ß-unsaturated esters mediated by a remote sulfinyl group. Synthesis of functionalized enantiomerically pure benzylic fluorides.

A sulfinyl group in an ortho position confers enough chemical and configurational stability to monofluorobenzylcarbanions to evolve in a completely stereoselective way in their reactions with ß-substituted vinyl sulfones and α,ß-unsaturated esters. Reactions afford easily separable mixtures of two epimers differing in the configuration of the center derived from the Michael acceptor (up to 98% de). They can be easily converted into enantiomerically pure γ-fluorinated γ-phenylsulfones and γ-phenylesters bearing two chiral centers.

Remote stereocontrol mediated by a sulfinyl group: synthesis of allylic alcohols via chemoselective and diastereoselective reduction of gamma-methylene delta-ketosulfoxides.

The efficiency of the sulfinyl group as a remote controller of the chemoselectivity and diastereoselectivity of the reduction of alpha, beta-unsaturated alpha-[2-(p-tolylsulfinyl)phenyl] substituted ketones 1 has been demonstrated in reactions carried out under NaBH4 in the presence of Yb(OTf)3 as the chelating agent. The starting unsaturated ketones have been prepared from the corresponding 2-(p-tolylsulfinyl) benzyl alkyl (and aryl) ketones 2 by insertion of the methylidene group under modified Mannich conditions, exploiting ultrasound irradiation to obtain the aminomethylation adducts and silica gel treatment to produce its complete elimination. Desulfinylation of the reduction products yielded the corresponding vinyl carbinols with high enantiomeric purity.

Efficient trans-selectivity in the cyclocondensation of (S)-2-[2-(p-tolylsulfinyl)phenyl]acetaldehyde with activated dienes catalyzed by Yb(OTf)3.

Reactions of (S)-2-[2-(p-tolylsulfinyl)phenyl]acetaldehyde 1 with Danishefsky's and related dienes took place in the presence of Yb(OTf)3 in a completely stereoselective manner, mediated by a remote sulfinyl group (1,5-asymmetric induction), to afford the corresponding 2,3-dihydro-4H-pyran-4-ones. These reactions followed a stepwise mechanism, as was corroborated by isolation of the corresponding intermediates, with a high level of trans-selectivity for 4-methyl-substituted dienes. Treatment of the adducts with Raney Ni provided concomitant cleavage of the C-S bond and reduction of the conjugated carbonyl grouping.

Remote stereocontrol by sulfinyl groups: reduction of delta-ketosulfoxides.

The reduction of delta-ketosulfoxides constitutes the first evidence of the efficiency of the sulfinyl group to control the stereoselectivity of 1,5-asymmetric induction processes. The use of DIBAL/Yb(OTf)3 or L-Selectride as the reducing agents provides delta-hydroxysulfoxides with the opposite configuration at the hydroxylic carbon in a highly stereoselective way.