In Situ Quench Reactions of Enantioenriched Secondary Alkyllithium Reagents in Batch and Continuous Flow Using an I/Li-Exchange.

We report a practical in situ quench (ISQ) procedure involving the generation of chiral secondary alkyllithiums from secondary alkyl iodides (including functionalized iodides bearing an ester or a nitrile) in the presence of various electrophiles such as aldehydes, ketones, Weinreb amides, isocyanates, sulfides, or boronates. This ISQ-reaction allowed the preparation of a broad range of optically enriched ketones, alcohols, amides, sulfides and boronic acid esters in typically 90-98 % ee. Remarkably, these reactions were performed at -78 °C or -40 °C in batch. A continuous flow set-up permitted reaction temperatures between -20 °C and 0 °C and allowed a scale-up up to a 40-fold without further optimization.

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.

Preparation and reactions of polyfunctional magnesium and zinc organometallics in organic synthesis.

Polyfunctional organometallics of magnesium and zinc are readily prepared from organic halides via a direct metal insertion in the presence of LiCl or a Br/Mg-exchange using iPrMgCl·LiCl (turbo-Grignard) or related reagents. Alternatively, such functionalized organometallics are prepared by metalations with TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl). The scope of these methods is described as well as applications in new Co- or Fe-catalyzed cross-couplings or aminations. It is shown that the use of a continous flow set-up considerably expands the field of applications of these methods and further allows the preparation of highly reactive organosodium reagents.

(2-Ethylhexyl)sodium: A Hexane-Soluble Reagent for Br/Na-Exchanges and Directed Metalations in Continuous Flow.

We report the on-demand generation of hexane-soluble (2-ethylhexyl)sodium (1) from 3-(chloromethyl)heptane (2) using a sodium-packed-bed reactor under continuous flow conditions. Thus, the resulting solution of 1 is free of elemental sodium and therefore suited for a range of synthetic applications. This new procedure avoids the storage of an alkylsodium and limits the handling of metallic sodium to a minimum. (2-Ethylhexyl)sodium (1) proved to be a very useful reagent and undergoes in-line Br/Na-exchanges as well as directed sodiations. The resulting arylsodium intermediates are subsequently trapped in batch with various electrophiles such as ketones, aldehydes, Weinreb-amides, imines, allyl bromides, disulfides and alkyl iodides. A reaction scale-up of the Br/Na-exchange using an in-line electrophile quench was also reported.

Continuous Flow Sodiation of Substituted Acrylonitriles, Alkenyl Sulfides and Acrylates.

The sodiation of substituted acrylonitriles and alkenyl sulfides in a continuous flow set-up using NaDA (sodium diisopropylamide) in EtNMe2 or NaTMP (sodium 2,2,6,6-tetramethylpiperidide)⋅TMEDA in n-hexane provides sodiated acrylonitriles and alkenyl sulfides, which are subsequently trapped in batch with various electrophiles such as aldehydes, ketones, disulfides and allylic bromides affording functionalized acrylonitriles and alkenyl sulfides. This flow-procedure was successfully extended to other acrylates by using Barbier-type conditions.

Continuous Flow Preparation of (Hetero)benzylic Lithiums via Iodine-Lithium Exchange Reaction under Barbier Conditions.

Herein we report the generation of benzylic lithiums via an iodine-lithium exchange reaction on benzylic iodides performed in continuous flow using tBuLi as the exchange reagent. The resulting benzylic lithium species are trapped in situ by carbonyl electrophiles under Barbier conditions, resulting in benzylic secondary and tertiary alcohols. This flow procedure further allows the generation of highly reactive heterobenzylic lithium compounds, which are difficult to generate under batch conditions. A general scale-up was possible without further optimization.

Preparation of Functionalized Aryl, Heteroaryl, and Benzylic Potassium Organometallics Using Potassium Diisopropylamide in Continuous Flow.

We report the preparation of lithium-salt-free KDA (potassium diisopropylamide; 0.6 m in hexane) complexed with TMEDA (N,N,N',N'-tetramethylethylenediamine) and its use for the flow-metalation of (hetero)arenes between -78 °C and 25 °C with reaction times between 0.2 s and 24 s and a combined flow rate of 10 mL min-1 using a commercial flow setup. The resulting potassium organometallics react instantaneously with various electrophiles, such as ketones, aldehydes, alkyl and allylic halides, disulfides, Weinreb amides, and Me3 SiCl, affording functionalized (hetero)arenes in high yields. This flow procedure is successfully extended to the lateral metalation of methyl-substituted arenes and heteroaromatics, resulting in the formation of various benzylic potassium organometallics. A metalation scale-up was possible without further optimization.

Synthesis of Chlorotrifluoromethylated Pyrrolidines by Electrocatalytic Radical Ene-Yne Cyclization.

The stereoselective synthesis of chlorotrifluoromethylated pyrrolidines was achieved using anodically coupled electrolysis, an electrochemical process that combines two parallel oxidative events in a convergent and productive manner. The bench-stable and commercially available solids CF3 SO2 Na and MgCl2 were used as the functional group sources to generate CF3. and Cl. , respectively, via electrochemical oxidation, and the subsequent reaction of these radicals with the 1,6-enyne substrate was controlled with an earth-abundant Mn catalyst. In particular, the introduction of a chelating ligand allowed for the ene-yne cyclization to take place with high stereochemical control over the geometry of the alkene group in the pyrrolidine product.

Diastereo- and Enantioselective Formal [3 + 2] Cycloaddition of Cyclopropyl Ketones and Alkenes via Ti-Catalyzed Radical Redox Relay.

We report a stereoselective formal [3 + 2] cycloaddition of cyclopropyl ketones and radical-acceptor alkenes to form polysubstituted cyclopentane derivatives. Catalyzed by a chiral Ti(salen) complex, the cycloaddition occurs via a radical redox-relay mechanism and constructs two C-C bonds and two contiguous stereogenic centers with generally excellent diastereo- and enantioselectivity.