Preparation and Regioselective Magnesiation or Lithiation of Bis(trimethylsilyl)methyl‐Substituted Heteroaryls for the Generation of Highly Functionalized Heterocycles

Abstract

A wide range of bis(trimethylsilyl)methyl (BTSM)- substituted heteroaryl derivatives has been prepared by using Kumada-Corriu or Negishi cross-coupling reactions. The regioselective lithiation or magnesiation of these building blocks bearing a bulky BTSM group by using magnesium or lithium 2,2,6,6-tetramethylpiperidide bases followed by quenching reactions with different electrophiles provides various functionalized N-, O-, or S-heterocycles. Furthermore, the BTSM group can then be converted into formyl, methyl, or styryl groups to give access to a variety of highly functionalized heteroaromatics.

Recent Progress in Utilization of Functionalized Organometallic Reagents in Cross Coupling Reactions and Nucleophilic Additions

“…Klatt and co-workers 51 developed a simple procedure for the preparation of functionalized bis(trimethylsilyl)methyl (BTSM)-substituted heteroaryls from various heteroaryl halides and bis(trimethylsilyl)methyl magnesium bromide reagents catalyzed by palladium (Scheme 48). The reactions took place in mixed solvent (THF/toluene=1:1) at 50 °C.…”

Regioselective C–H Activation of Substituted Pyridines and other Azines using Mg- and Zn-TMP-Bases

“…The BF 3 -adduct 75 is exclusively metalated at position C6, providing, after a Negishi cross-coupling with an iodopyrimidine, the bis-azine 76 in 65% yield (Scheme 15). 43 Interestingly, 6-bromo-3-bis(trimethylsilylmethyl)pyridine (77) can be directly metalated by TMP 2 Mg•2LiCl (34) at 0 °C for 25 h, affording the magnesium derivative 78. Due to the steric hindrance of the silyl-substituent at position C3, no magnesiation occurs at position C2, and only a magnesiation is observed at position C5.…”

Aza-Peterson Olefinations: Rapid Synthesis of (E)-Alkenes

“…3,4 Bench stable bis(trimethylsilane) reagents have emerged as a milder method to access -silyl carbanions by activation with catalytic or stoichiometric amounts of Lewis bases (nBu 4 NF, nBu 4 NSiF 2 Ph 3 , CsF, KOSiMe 3 / nBu 4 NCl). [5][6][7][8][9][10] In most examples, strong bases are still required to synthesise these reagents. 5,[8][9][10] Alternatively, Knochel and co-workers have reported a palladium(0)-catalysed cross-coupling reaction from bis(trimethylsilyl)organometallic reagents and aryl bromides.…”

“…5,[8][9][10] Alternatively, Knochel and co-workers have reported a palladium(0)-catalysed cross-coupling reaction from bis(trimethylsilyl)organometallic reagents and aryl bromides. 6,7 Dependent on the electronics of the silicon reagent, alkenes can either be accessed directly (one step, Scheme 1a) or indirectly (two steps, Scheme 1b) -through isolation of -hydroxysilanes (Scheme 1b) and treatment under acidic (antielimination promoted by the -silicon effect) 11 or basic conditions (syn-elimination) to selectively give either the (E)-or (Z)-alkene. A long-standing issue for direct Peterson olefinations -using stabilised -silyl carbanions -is the lack of control over the stereoselectivity of the resulting olefin.…”