Zn‐, Mg‐, and Li‐TMP Bases for the Successive Regioselective Metalations of the 1,5‐Naphthyridine Scaffold (TMP=2,2,6,6‐Tetramethylpiperidyl)

Abstract

A set of successive regioselective metalations and functionalizations of the 1,5-naphthyridine scaffold are described. A combination of Zn-, Mg-, and Li-TMP (TMP=2,2,6,6-tetramethylpiperidyl) bases and the presence or absence of a Lewis acid (BF ⋅OEt ) allows the introduction of up to three substituents to the 1,5-naphthyridine core. Also, a novel "halogen dance" reaction was discovered upon metalation of an 8-iodo-2,4-trifunctionalized 1,5-naphthyridine allowing a fourth regioselective functionalization. Additionally, reactions leading to key 1,5-naphthyridines for the preparation of OLED materials and a potential antibacterial agent were performed.

Copper‐ and Cobalt‐Catalyzed Syntheses of Thiophene‐Based Tertiary Amines

“…91–93 °C; 1 H NMR (300 MHz, CDCl 3 ) δ 7.70 (dd, 1H, J = 8.5 and 4.2 Hz, H7), 8.28 (d, 1H, J = 4.5 Hz), 8.37 (dd, 1H, J = 8.4 and 1.6 Hz, H8), 8.53 (d, 1H, J = 4.5 Hz), 9.06 (dd, 1H, J = 4.2 and 1.6 Hz, H6); 13 C NMR (75 MHz, CDCl 3 ) δ 116.4 (C, C‐I), 125.5 (CH), 135.4 (CH), 138.4 (CH), 143.9 (C), 144.0 (C), 150.8 (CH), 152.2 (CH). These data are similar to those described previously . Using procedure 3 led to both 3‐I (34 % yield) and 4,8‐diiodo‐1,5‐naphthyridine 3′‐I .…”

“…The 1,5‐naphthyridine heterocycle is present in numerous compounds endowed with biological properties as well as in OLED materials . Besides direct introduction of an amino group by a Chichibabin reaction, its functionalization at C4 can be achieved by deprotometalation.…”

“…The latter was performed by using a lithium amide provided that a directing group is present at C3 . However, from bare 1,5‐naphthyridine, a regioselective reaction at C4 was found possible after precomplexation of the substrate with (TMP) 2 Mg · 2LiCl, and takes place in THF within 5 min at –78 °C . In order to prepare amines (Table ), we first evaluated the “deprotolithiation‐transmetalation to zinc‐copper catalyzed amination” sequence, successful from benzothiophene, by using N ‐(benzoyloxy)diallylamine as electrophile.…”

“…4‐Iodo‐1,5‐naphthyridine (3‐I) . To a stirred mixture of 1,5‐naphthyridine (0.26 g, 2.0 mmol) in THF (4 mL) at room temperature was added dropwise a solution of TMPZnCl · LiCl (1.04 M THF solution; 2.4 mmol). After 2 h at room temperature, a solution of iodine (0.76 g, 3.0 mmol) in THF (3 mL) was added.…”

Trans‐Metal‐Trapping: Concealed Crossover Complexes En Route to Transmetallation?

“…Knochel has led the way in this area reporting several multicomponent bases . Scheme shows a typical application of his most utilised base, the turbo‐Grignard reagent (TMP)MgCl⋅LiCl, whereby it selectively doubly deprotonates the heterocycle 1,5‐naphthyridine to form a di‐Grignard compound in situ, which following trapping with 1,2‐dibromotetrachloroethane generates a dibromo derivative that is a precursor to OLED materials …”