Deprotonative Metalation of Five-Membered Aromatic Heterocycles Using Mixed Lithium−Zinc Species

Abstract

Deprotonation of benzoxazole, benzothiazole, benzo[b]thiophene, benzo[b]furan, N-Boc-protected indole and pyrrole, and N-phenylpyrazole using an in situ mixture of ZnCl(2).TMEDA (0.5 equiv) and lithium 2,2,6,6-tetramethylpiperidide (1.5 equiv) in THF at room temperature is described. The reaction was evidenced by trapping with iodine, regioselectively giving the expected functionalized derivatives in 52-73% yields. A mixture of mono- and disubstituted derivatives was obtained starting from thiazole. Cross-coupling reactions of 2-metalated benzo[b]thiophene and benzo[b]furan with heteroaromatic chlorides proved possible under palladium catalysis. A reaction pathway where the lithium amide and zinc diamide present in solution behave synergically was proposed for the deprotonation reaction, taking account of NMR and DFT studies carried out on the basic mixture.

Contrasting Synergistic Heterobimetallic (Na–Mg) and Homometallic (Na or Mg) Bases in Metallation Reactions of Dialkylphenylphosphines and Dialkylanilines: Lateral versus Ring Selectivities

“…Molecular structure of [(TMEDA)Na(TMP)(CH 2 PCH 3 Ph)Mg(TMP)] 2 with thermalellipsoids at 40 %p robability.H ydrogen atomsh ave been omitted for clarity.Selected bond lengths( )a nd angles (8): Mg(1)ÀN(1), 2.069(5); Mg(1)ÀN(2), 2.001(5); Mg(1)ÀC(1), 2.182(6);Na(1)ÀN(1), 2.463(5); Na(1)ÀN(3), 2.528(6); Na(1)ÀN(4), 2.495(5);Na(1)ÀP(1), 2.919(2);P (1)ÀC(1), 1.777(6); P(1)ÀC(2), 1.823 (8);N(1)-Na(1)-P(1), 95.24 (12); Na(1)-N(1)-Mg(1), 103.5(2);N (1)-Mg(1)-C(1), 108.8(2); Mg(1)-C(1)-P(1), 118.4(3); C(1)-P(1)-Na(1), 88.40 (19). (16); Mg(1)ÀN(2), 1.9989 (17);N a(1)ÀC(3), 3.036(2);Na(1)ÀC(4), 2.648(2);N a(1)ÀN(3), 2.4779(18);Na(1)ÀN(4), 2.5401(18); Na(1)ÀN(5),2 .5291 (18);N(2)-Mg(1)-C(3), 120.48 (8); N(2)-Mg(1)-N(3), 134.32 (7); N(3)-Mg(1)-C(3), 105.16 (7); Na(1)-N(3)-Mg(1), 89.35 (6). (3); Na(1)ÀN(2), 2.457(3); Na(1)ÀN(4), 2.569(3); Na(1)ÀC(2), 3.038(4);Na(1)ÀC(3), 2.684(4); N(1)-Mg(1)-N(3), 133.51 (13);N(1)-Mg(1)-C(3), 119.21 (14);C(3)-Mg(1)-N(3), 107.11 (13);N a(1)-N(3)Mg(1), 87.25 (11).…”

“…[14,15] These metallating agents usually consist of a mixeda lkyl or amido lithiums peciesw ith either ad ivalent metals alt or ad ialkyl/amido metallic species. Of particular relevance to this work are the bimetallicb ases formed by the cocomplexation of an alkali metal amide (most commonly NaTMP) and ad ialkyl subordinate metal partner, typically zinc, [12,[16][17][18] magnesium [14,15,19,20] aluminium [21,22] or manganese. [23][24][25] Early examples of the effectiveness of these bases include the magnesiation (CÀHt oC ÀMg) of benzene [26] and the selective meta-magnesiation of toluene, [27] both achieved utilising the sodium magnesiate base [(TMEDA)Na(nBu)-(TMP)Mg(TMP)].…”

From Quinoxaline, Pyrido[2,3-b]pyrazine and Pyrido[3,4-b]pyrazine to Pyrazino-Fused Carbazoles and Carbolines

“…Previous studies have suggested that it is a 1:1 LiTMP-Zn(TMP) 2 combination. While LiTMP deprotonates the substrate, Zn(TMP) 2 intercepts the generated aryllithium [18,19,22]. A recent computer study on anisole showed that the reactive species is solvated LiTMP.…”

“…The use of in situ metal traps avoids the use of cryogenic conditions to achieve these reactions [16,17]. We have developed mixed lithium-zinc combinations based on TMP (TMP = 2,2,6,6-tetramethylpiperidino) capable of deprotonating sensitive substrates at temperatures close to rt [18,19,20,21]. In order to obtain original scaffolds such as pyrazino-fused carbazoles and carbolines, we decided to combine this deprotometalation under in situ trapping conditions with palladium- and copper-catalyzed coupling reactions.…”

Azine and Diazine Functionalization Using 2,2,6,6-Tetramethylpiperidino-Based Lithium–Metal Combinations: Application to the Synthesis of 5,9-Disubstituted Pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidines

“…The pyrimidine 2 being prone to nucleophilic attacks, 6 we first tried to use the base prepared in situ by mixing ZnCl 2 ·TMEDA and LiTMP in a 1:3 ratio, 7 and supposed to be a 1:1 LiTMP·2LiCl(±TMEDA)-Zn(TMP) 2 mixture. 8 It proved not appropriate, with the iodide 4a isolated in a low 18% yield when the deprotonation step was performed at 0 °C and only degradation noticed at higher temperatures.…”