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

Abstract

Mixed TMP-bases (TMP=2,2,6,6-tetramethylpiperidyl), such as TMPMgCl ⋅ LiCl, TMP₂ Mg ⋅ 2LiCl, TMPZnCl ⋅ LiCl and TMP₂ Zn ⋅ 2LiCl, are outstanding reagents for the metalation of functionalized aromatics and heterocycles. In the presence of Lewis acids, such as BF₃ ⋅ OEt₂ or MgCl₂ , 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 Cy₂ NLi, are also compatible with various Lewis acids, such as MgCl₂ ⋅ 2LiCl, ZnCl₂ ⋅ 2LiCl or CuCN ⋅ 2LiCl. Performing such metalations in continuous flow using commercial setups permitted practical and convenient reaction conditions.

Keywords: frustrated Lewis pairs; magnesium; metalation reactions; regioselectivity; zinc.

Scheme 1

BF₃ ⋅ OEt₂ triggered magnesiations of pyridines with TMPMgCl ⋅ LiCl (1).

Scheme 2

BF₃‐mediated metalation of aminated pyridines with TMPMgCl ⋅ LiCl (1).

Scheme 3

Full functionalization of 4‐cyanopyridine (23) using Zn‐ and Mg‐bases with or without BF₃ ⋅ OEt₂.

Scheme 4

Regioselective functionalization of quinine (29) using various protecting groups as well as the frustrated Lewis pair TMPMgCl ⋅ LiCl (1) and BF₃ ⋅ OEt₂.

Scheme 5

BF₃ ⋅ OEt₂ and bis‐Lewis acid 36‐mediated regioselective zincations of pyridazine (34).

Scheme 6

Selective magnesiations of pyrazolo[1,5‐a]pyridine (40) using TMPMgCl ⋅ LiCl (1) with or without BF₃ ⋅ OEt₂.

Scheme 7

Regioselective functionalization of 4‐arylated naphthyridine (48) by magnesiation with TMPMgCl ⋅ LiCl (1) in the presence or absence of BF₃ ⋅ OEt₂.

Scheme 8

Synthesis of key intermediate naphthyridines 55 and 58 for biological and material science application.

Scheme 9

MgCl₂‐triggered regioselective metalations of uridines using Zn‐ or Mg‐TMP bases.

Scheme 10

Regioselective zincations of chromone 67 or quinolone 68 with TMPZn‐bases 3 or 4 in the presence or absence of MgCl₂.

Scheme 11

Preparation of a natural flavone, isoflavones and quinolone by regioselective metalations.

Scheme 12

Regioselective metalation of thiochromone 69 and 2‐pyrones 83 and 86 using TMP‐bases 1 and 3.

Scheme 13

Regioselective metalations of various N‐heterocycles with TMP‐bases.

Scheme 14

Regioselective magnesiations of N‐aryl azoles with TMPMgBu and sBu₂Mg (105).

Scheme 15

Selective sequential ortho, ortho’‐functionalization of oxazoline 113 and 2‐aryl‐2H‐1,2,3‐triazole 117.

Scheme 16

Regioselective metalation via an in situ trapping metalation using ZnCl₂ ⋅ 2LiCl and TMPLi.

Scheme 17

Regioselective functionalizations of thiophene 125 using an in situ trapping with TMPLi and ZnCl₂ ⋅ 2LiCl.

Scheme 18

In situ trapping metalations of aromatics 129, 131  a‐c and heterocycle 134 with TMPLi in the presence of Lewis acids like ZnCl₂ ⋅ 2LiCl or LaCl₃ ⋅ 2LiCl.

Scheme 19

In situ trapping metalations in continuous flow with Cy₂NLi in the presence of zinc and magnesium halides at 0 °C and batch quenching with various electrophiles.