Regioselective Magnesiation and Zincation Reactions of Aromatics and Heterocycles Triggered by Lewis Acids

Mixed TMP‐bases (TMP=2,2,6,6‐tetramethylpiperidyl), such as TMPMgCl ⋅ LiCl, TMP(2)Mg ⋅ 2LiCl, TMPZnCl ⋅ LiCl and TMP(2)Zn ⋅ 2LiCl, are outstanding reagents for the metalation of functionalized aromatics and heterocycles. In the presence of Lewis acids, such as BF(3) ⋅ OEt(2) or MgCl(2), the metalation scope of such bases was dramatically increased, and regioselectivity switches were achieved in the presence or absence of these Lewis acids. Furthermore, highly reactive lithium bases, such as TMPLi or Cy(2)NLi, are also compatible with various Lewis acids, such as MgCl(2) ⋅ 2LiCl, ZnCl(2) ⋅ 2LiCl or CuCN ⋅ 2LiCl. Performing such metalations in continuous flow using commercial setups permitted practical and convenient reaction conditions

Transition‐Metal Free Electrophilic Aminations of PolyfunctionalO‐2,4,6‐Trimethylbenzoyl Hydroxylamines with Zinc and Magnesium Organometallics

We reported a new electrophilic amination of various primary, secondary and tertiary alkyl, benzylic, allylic zinc and magnesium organometallics with O-2,4,6-trimethylbenzoyl hydroxylamines (O-TBHAs) in 52–99 % yield. These O-TBHAs displayed an excellent long-term stability and were readily prepared from various highly functionalized secondary amines via a convenient 3 step procedure. The amination reactions showed remarkable chemoselectivity proceeding without any transition-metal catalyst and were usually complete after 1–3 h reaction time at 25 °C. Furthermore, this electrophilic amination also provided access to enantioenriched tertiary amines (up to 88 % ee) by using optically enriched secondary alkylmagnesium reagents of the type s-AlkylMgCH2SiMe3

Stereoselective Csp3−Csp2 Cross‐Couplings of Chiral Secondary Alkylzinc Reagents with Alkenyl and Aryl Halides

We report palladium‐catalyzed cross‐coupling reactions of chiral secondary non‐stabilized dialkylzinc reagents, prepared from readily available chiral secondary alkyl iodides, with alkenyl and aryl halides. This method provides α‐chiral alkenes and arenes with very high retention of configuration (dr up to 98:2) and satisfactory overall yields (up to 76 % for 3 reaction steps). The configurational stability of these chiral non‐stabilized dialkylzinc reagents was determined and exceeded several hours at 25 °C. DFT calculations were performed to rationalize the stereoretention during the catalytic cycle. Furthermore, the cross‐coupling reaction was applied in an efficient total synthesis of the sesquiterpenes (S)‐ and (R)‐curcumene with control of the absolute stereochemistry

Exploiting Coordination Effects for the Regioselective Zincation of Diazines Using TMPZnX⋅LiX (X=Cl, Br)

A new method for regioselective zincations of challenging N-heterocyclic substrates such as pyrimidines and pyridazine was reported using bimetallic bases TMPZnX⋅LiX (TMP=2,2,6,6-tetramethylpiperidyl; X=Cl, Br). Reactions occurred under mild conditions (25-70 °C, using 1.75 equivalents of base without additives), furnishing 2-zincated pyrimidines and 3-zincated pyridazine, which were then trapped with a variety of electrophiles. Contrasting with other s-block metalating systems, which lack selectivity in their reactions even when operating at low temperatures, these mixed Li/Zn bases enabled unprecedented regioselectivities that cannot be replicated by either LiTMP nor Zn(TMP)2 on their own. Spectroscopic and structural interrogations of organometallic intermediates involved in these reactions have shed light on the complex constitution of reaction mixtures and the origins of their special reactivities

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 degrees C or -40 degrees C in batch. A continuous flow set-up permitted reaction temperatures between -20 degrees C and 0 degrees C and allowed a scale-up up to a 40-fold without further optimization

Calculation-Driven Regioselective Functionalization of the Imidazo[1,2-a]pyrazine Scaffold via Zinc and Magnesium Organometallic Intermediates

Straightforward calculations such as determinations of pKa values and N-basicities have allowed the development of a set of organometallic reactions for the regioselective functionalization of the underexplored imidazo[1,2 a]pyrazine. Thus, regioselective metalations of 6 chloroimidazo[1,2-a]pyrazine using TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl) such as TMPMgCl∙LiCl and TMP2Zn∙2MgCl2∙2LiCl provided Zn- and Mg-intermediates, that after quenching with various electrophiles gave access to polyfunctionalized imidazopyrazine heterocycles. Additionally, the use of TMP2Zn∙2MgCl2∙2LiCl as base for the first metalation allowed an alternative regioselective metalation. Nucleophilic additions at position 8 as well as selective Negishi cross-couplings complete the set of methods for selectively decorating this heterocycle of the future