Regioselective Magnesiations of Fluorinated Arenes and Heteroarenes Using Magnesium‐bis‐Diisopropylamide (MBDA) in Hydrocarbons

Abstract

We report a convenient preparation of a new and storable magnesium amide (iPr 2 N) 2 Mg (magnesiumbis-diisopropylamide; MBDA) which proved to be especially suitable for the non-cryogenic magnesiation of fluoro-substituted arenes and heteroarenes providing arylmagnesium amides (ArMgDA) or bis-heteroaryl magnesiums (HetAr) 2 Mg in hydrocarbons. Further reactions with electrophiles (aldehydes, ketones, allylic bromides, aryl halides (Negishi cross-coupling)) furnished a range of polyfunctional fluoro-substituted unsaturated building blocks. Several postfunctionalizations were described as well as NMR-studies confirming the dimeric structure of the base.

Alkali‐Metal‐Alkoxide Powered Zincation of Fluoroarenes Employing Zinc Bis‐Amide Zn(TMP)2

“…Knochel recently reported metalation of this substrate using a magnesium amide, which occurs preferentially ortho to the oxazoline unit, a substituent typically regarded as a very strong ortho-directing group in DoM chemistry. [46] The regioselectivity of these reactions was confirmed by the structural elucidation of the molecular structures of 2 k and 2 m which display almost identical structural motifs to that described for 2 a with K preferentially interacting with the ortho-F to the C which has undergone zincation (Figure 4 and Figure S1 in Supporting Information). Olefinic groups are also tolerated as a functional group as shown by the efficient zincation of 4-fluorostyrene in 3 h furnishing 2 n. While attempts to promote regioselective zincation of fluoropyridines at room temperature proved fruitless forming intractable black solids which could not be analyzed, pyridine is tolerated as a remote functional group under Next, electrophilic interception studies were carried out using potassium zincate 2 d, resulting from ortho-zincation of fluorobenzene (Scheme 2).…”

“…The same preference on regioselectivity was observed for 2‐(4‐fluorophenyl)‐4,4‐dimethyl‐4,5‐dihydroxazole where oxazoline bearing zincate 2 m was formed in a 93 % yield with regioselective zincation occurring ortho to the fluoro substituent. Knochel recently reported metalation of this substrate using a magnesium amide, which occurs preferentially ortho to the oxazoline unit, a substituent typically regarded as a very strong ortho ‐directing group in D o M chemistry [46] …”

Scalable Synthesis of 6-Chloro-1H-pyrazolo[3,4-b]pyrazine via a Continuous Flow Formylation/Hydrazine Cyclization Cascade

“…The high cost and unreliable availability of TMPMgCl·LiCl and its TMP precursor on industrial scale prompted us to explore alternative magnesium bases. A preliminary survey of cost-effective alternatives that included n -Bu 2 Mg, Turbo-Grignard reagent i -PrMgCl·LiCl, and ( i -Pr 2 N) 2 Mg , identified the less commonly employed base i -Pr 2 NMgCl·LiCl (MgDA) − to be optimal, giving comparable performance to TMPMgCl·LiCl in batch mode (vide infra). According to literature-known protocols, the synthesis of MgDA from diisopropylamine (DIPA) using i -PrMgCl·LiCl typically requires long reaction times of >1 h at room temperature. , To further elucidate the amine deprotonation kinetics and thus optimize consistent preparation of high-quality MgDA for use in flow reactions, we monitored its formation in situ by ReactIR and 1 H-NMR analysis (Figures S1–S3).…”

Main group metal-mediated strategies for C–H and C–F bond activation and functionalisation of fluoroarenes

“…Seminal advances in this aspect include Knochel's use of magnesium amides Mg(NR 2 ) 2 (NR 2 = N i Pr 2 , TMP; TMP = 2,2,6,6-tetramethylpiperidide) for regioselective C–H magnesiation of a wide range of substituted fluoroarenes producing bis-aryl magnesium intermediates MgAr F 2 (1) ( Scheme 2a ). 17 This methodology boasts an impressive substrate scope (including perfluoroarenes and fluoropyridines) and tolerates sensitive functional groups such ester, amide, azide and oxazoline functionalities. Remarkably, most of these reactions can be carried out at room temperature in toluene solutions.…”