Continuous Flow Preparation of Benzylic Sodium Organometallics.

We report a lateral sodiation of alkyl(hetero)arenes using on-demand generated hexane-soluble (2-ethylhexyl)sodium (1) in the presence of TMEDA. (2-Ethylhexyl)sodium (1) is prepared via a sodium packed-bed reactor and used for metalations at ambient temperature in batch as well as in continuous flow. The resulting benzylic sodium species are subsequently trapped with various electrophiles including carbonyl compounds, epoxides, oxetane, allyl/benzyl chlorides, alkyl halides and alkyl tosylates. Wurtz-type couplings with secondary alkyl halides and tosylates proceed under complete inversion of stereochemistry. Furthermore, the utility of this lateral sodiation is demonstrated in the synthesis of pharmaceutical relevant compounds. Thus, fingolimod is prepared from p-xylene applying the lateral sodiation twice. In addition, 7-fold isotopically labeled salmeterol-d7 and fenpiprane as well as precursors to super linear alkylbenzene (SLAB) surfactants are prepared.

Cobalt(II) Porphyrin-Catalyzed Intramolecular Cyclopropanation of N-Alkyl Indoles/Pyrroles with Alkylcarbene: Efficient Synthesis of Polycyclic N-Heterocycles.

A protocol on chemoselective cobalt(II) porphyrin-catalyzed intramolecular cyclopropanation of N-alkyl indoles/pyrroles with alkylcarbenes has been developed. The reaction enables the rapid construction of a range of nitrogen-containing polycyclic compounds in moderate to high yields from readily accessible materials. These N-containing polycyclic compounds can be converted into a variety of N-heterocycles with potential synthetic and biological interest. Compared to their N-tosylhydrazone counterparts, the use of bulky N-2,4,6-triisopropylbenzenesulfonyl hydrazones as carbene precursors allows cyclopropanation to occur under milder reaction conditions.

Ruthenium-porphyrin-catalyzed diastereoselective intramolecular alkyl carbene insertion into C-H bonds of alkyl diazomethanes generated in situ from N-tosylhydrazones.

With a ruthenium-porphyrin catalyst, alkyl diazomethanes generated in situ from N-tosylhydrazones efficiently underwent intramolecular C(sp(3))-H insertion of an alkyl carbene to give substituted tetrahydrofurans and pyrrolidines in up to 99% yield and with up to 99:1 cis selectivity. The reaction displays good tolerance of many functionalities, and the procedure is simple without the need for slow addition with a syringe pump. From a synthetic point of view, the C-H insertion of N-tosylhydrazones can be viewed as reductive coupling between a C=O bond and a C-H bond to form a new C-C bond, since N-tosylhydrazones can be readily prepared from carbonyl compounds. This reaction was successfully applied in a concise synthesis of (±)-pseudoheliotridane.

Ruthenium porphyrin catalyzed three-component reaction of diazo compounds, nitrosoarenes, and alkynes: an efficient approach to multifunctionalized aziridines.

A ruthenium porphyrin catalyzed three-component reaction of diazo compounds, nitrosoarenes, and alkynes gives multifunctionalized aziridines in good to high yields and with moderate to high diastereoselectivity.

Diastereoselective ruthenium porphyrin-catalyzed tandem nitrone formation/1,3-dipolar cycloaddition for isoxazolidines. Synthesis, in silico docking study and in vitro biological activities.

Ruthenium porphyrin catalyzes tandem nitrone formation/1,3-dipolar cycloaddition of diazo compounds, nitrosoarenes and alkenes to form isoxazolidines in good to high yields and with excellent regio-, chemo- and diastereo-selectivities. A broad substrate scope of alkenes is applicable to this protocol and various functional groups are compatible with the reaction conditions. In silico analysis and in vitro biological experiments revealed that some of the new isoxazolidines synthesized in this work could act as leukotriene A4 hydrolase inhibitors.