Regioselective Metalations of Pyrimidines and Pyrazines by Using Frustrated Lewis Pairs of BF₃⋅OEt₂ and Hindered Magnesium– and Zinc–Amide Bases

Preparation and Regioselective Metalation of Bis(trimethylsilyl)methyl‐Substituted Aryl Derivatives

“…Recently, the bis(silyl)methyl moiety has also been used for Wittig rearrangements and Prins cyclization 7. Also, we have shown that the pyrazine scaffold can be fully functionalized starting from a BTSM‐substituted pyrazine8 by using the magnesium base TMP 2 Mg ⋅ 2 LiCl ( 1 ; TMP=2,2,6,6‐tetramethylpiperidyl) 9. Herein, we report a simple way to introduce the BTSM substituent onto an aromatic system by using a Kumada–Corriu cross‐coupling reaction10 between (Me 3 Si) 2 CHMgBr ⋅ LiCl ( 2 )11 and various aryl bromides.…”

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

“…Thus, pyridylzinc pivalate 100 and 101, 50 obtained by the magnesiation of the corresponding azine and diazine 102 and 103 with TMPMg-Cl•LiCl (1) followed by the addition of Zn(OPiv) 2 , are treated with N-hydroxymorpholine benzoate in THF at 25 °C for 2 h, furnishing the aminated derivatives 104 and 105 in 91-95% yield (Scheme 19). 51 The performance of lateral zincations of pyridines has been achieved by using TMP 2 Zn•2LiCl•2MgCl 2 (81). Thus, the treatment of the cyanohydrine derivative 106 with TMP 2 Zn•2LiCl•2MgCl 2 (81) at 0 °C for 1 h provides the benzylic pyridylzinc derivative 107.…”

“…This zinc reagent can be acylated with cyclopropanecarbonyl chloride in the presence of 20% CuCN•2LiCl, affording, after tetrabutylammonium fluoride (TBAF) treatment, ketone 108 in 80% yield (Scheme 20). 52 Scheme 20 Lateral zincation of a pyridine cyanohydrine 106 using TMP 2 Zn•2LiCl•2MgCl 2 (81) The scope of azine zincations has been extended by performing a Barbier type zincation in which the metalation is performed with TMPLi in the presence of ZnCl 2 •2LiCl at low temperature. Thus, to a mixture of ZnCl 2 •2LiCl and the substrate pyridine 109, a THF solution of TMPLi (ca.…”

“…In some cases, this procedure may be performed by replacing TMPLi with the 100 times cheaper lithium biscyclohexylamide (Cy 2 NLi). 54 For example, the ethyl nicotinate 115 was metalated with Cy 2 NLi (1.5 equiv) at 0 °C within 40 s and further allylated under copper(I)-catalysis in batch, leading to the pyridine 128 in 88% yield (Scheme 25 (81)) in several cases allows a full functionalization of the pyridine scaffold. Thus, the treatment of 5-bromo-2chloropyridine (129) with TMPMgCl•LiCl (1) in THF (-40 °C, 3 h), followed by the addition of tosyl cyanide furnishes the regioselective product 130 in 68% yield.…”

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

“…The regioselective functionalization of heterocycles by metalation reactions is an important synthetic task. The bis(trimethylsilyl)methyl group (BTSM)1 pioneered by Snieckus2 has been used for the efficient regioselective metalation of aromatic substrates,3 as well as for that of a few heterocycles, such as pyrazines 4. Additionally, the BTSM group has recently found a number of applications in organic synthesis5 due to its unique synthetic features (steric hindrance combined with facile transformation).…”