Directed Manganation of Functionalized Arenes and Heterocycles Using tmp₂Mn⋅2 MgCl₂⋅4 LiCl

Abstract

The metalation of arenes and heterocycles is of considerable interest, since it allows direct functionalization of an unactivated CÀH bond by the stoichiometric formation of an organometallic intermediate. Whereas the lithiation of unsaturated organic substrates has been extensively used, [1] the search for metalation procedures that are compatible with more functional groups and proceed at close to room temperature has been the subject of considerable efforts. In this regard, the development of various "ate" bases has been very promising. [2,3] Also, the use of sterically hindered metallic amides complexed by LiCl of the type tmp n M 1 ·x M 2 X m ·y LiCl (tmp = 2,2,6,6-tetramethylpiperidyl; M 1 = Mg, [4] Zn, [5] Al; [6] M 2 = Mg) has led to highly chemoand regioselective metalations. The presence of LiCl was essential since it increases the solubility of these metallic bases and enhances their kinetic basicity by lowering their aggregation states. [7] The preparation of transition-metal amides has been envisioned, as transition metals display reactivity patterns not accessible for main-group elements.[8] Especially manganese, owing to its low price, moderate toxicity, and versatile reactivity, is of synthetic interest.[9] Herein, we report a new manganese base [10] that shows a unique chemoselectivity and reactivity, allowing the efficient formation of CÀC and CÀN bonds. Furthermore, the convenient metalation conditions make it a very practical base for synthetic applications. Thus, the addition of commercially available tmmpMgCl·LiCl (2; 2.0 equiv) to MnCl 2 ·2 LiCl [11] (1 equiv) at 0 8C with subsequent stirring at 25 8C for 3 h provides the manganese amide 3 as a 0.5 m solution in THF (Scheme 1). The base 3 has an excellent thermal stability and can be stored at 25 8C for more than eight weeks without appreciable decomposition. Preliminary experiments show immediately that the new Mn base has a very different reactivity than the Mg base 2. Thus, whereas the reaction of 2 with 2-phenyl-1,3,4-oxadiazole (4) provides only ring fragmentation products (PhCN and NCOMgCl), its metalation with 3 furnishes cleanly the corresponding diheteroaryl manganese reagent, which smoothly adds to benzaldehyde, thus providing the alcohol 5 in 77 % yield (Scheme 1).Remarkably, we found that a range of functionalized aromatic substrates are readily manganated under convenient reaction conditions (0-25 8C). Thus, methyl 4-bromobenzoate (6 a) reacts with 3 (0.6 equiv) within 3.5 h at 25 8C, furnishing the diaryl manganese reagent 7 a without cleavage of the sensitive methyl ester function. Copper(I)-catalyzed acylation using CuCN·2 LiCl [12] (20 mol %) and 2-thienoyl chloride (1.2 equiv) provides the ketone 8 a in 77 % yield. The highly functionalized benzophenone derivative 6 b is converted to the corresponding manganese species 7 b by the reaction with 3 (0.6 equiv, 25 8C, 2 h). Cu I -catalyzed allylation with 3-bromocyclohexene (1.2 equiv) provides the polyfunctional benzophenone 8 b in 74 % yield (Scheme 2).Subsequent palladium...

Praktische kontinuierliche Durchfluss‐Abfangmetallierungen funktionalisierter Arene und Heteroarene mit TMPLi in Gegenwart von Mg‐, Zn‐, Cu‐ oder La‐Halogeniden

“…Dieses wird folglich immer von Standardbasen wie TMPMgCl·LiCl oder (TMP) 2 Mn· 2MgCl 2 ·4 LiCl deprotoniert. [10] Unter den hier beschriebenen Reaktionsbedingungen ist die starke Base TMPLi jedoch in der Lage,i nk inetisch kontrollierter Weise das Proton von Position 6z ua bstrahieren, sodass nach Negishi-Kreuzkupplung oder Kupfer-vermittelter Acylierung die trisubstituierten Arene (2d,e)i n7 3b zw.7 0% Ausbeute gebildet werden (Nr. 3und 4).…”

Practical Continuous‐Flow Trapping Metalations of Functionalized Arenes and Heteroarenes Using TMPLi in the Presence of Mg, Zn, Cu, or La Halides

“…This position is therefore always deprotonated with standard bases such as TMPMgCl·LiCl and (TMP) 2 Mn·2 MgCl 2 ·4 LiCl. [10] However, under the kinetically controlled reaction conditions described herein, the strong TMPLi base is able to abstract the ring hydrogen at position 6, leading after Negishi cross-coupling or copper-mediated acylation to the trisubstituted arenes (2d,e) in 70-73 %y ield (entries 3a nd 4). Such kinetic metalations resulting in unique metalation regioselectivities are not limited to benzoate derivatives.2 ,4-Dichlorobenzonitrile (1d)i sa lso in situ zincated at position 6, affording the cyano-substituted biphenyl (2f)i n8 3% yield after Negishi cross-coupling (entry 5).…”

“…Table 1were performed on a1.7 mmol scale.However,these metalations can be scaled up by simply extending the reaction time.Thus,the preparation of the trisubstituted nitrile (2g)on a1 0mmol scale in 87 %y ield is possible without further optimization, demonstrating the striking advantages of continuously processed reactions.F urthermore,t he ortho-lithiation of haloarenes such as 1f and 1g,w hich are notoriously prone to decompose via benzyne formation, [11] undergo flow metalation with TMPLi in the presence of MgCl 2 (0.5 equiv) under standard conditions (0 8 8C, 40 s). Subsequent reactions with ethyl cyanoformate (1.5 equiv) or p-chlorobenzaldehyde (1.5 equiv) lead to the o-functionalized haloarenes (2i-k)i n 69-84 %y ield (entries [8][9][10].…”

Lewis‐Säure‐dirigierte regioselektive Metallierungen an Pyridazin

“…Auch die regioselektive Funktionalisierung des Pyridazin-Grundgerüstes (1)ist wenig erforscht. [2] Pyridazine sind besonders wichtige N-Heterocyclen, da sie in einer Reihe von Pharmazeutika und Agrochemikalien aufzufinden sind. [3] Ebenfalls sind sie Bioisostere von Pyridinen und daher wichtig fürd ie Wirkstoffforschung.…”

“…[4] Sie gehçren zu den sogenannten "Heterocyclen der Zukunft". [5] Über die Metallierung von Pyridazin (1)u nter Verwendung von TMPLi (TMP = 2,2,6, in Anwesenheit von ZnCl 2 ·TMEDA( TMEDA = Te tramethylethylendiamin) wurde bereits von Mongin berichtet. Jedoch war die ortho-Selektivitätd er Reaktion lediglich 83 %.…”