Functionalization of 4-bromobenzo[c][2,7]naphthyridine via regioselective direct ring metalation. A novel approach to analogues of pyridoacridine alkaloids

Abstract

Readily available 4-bromobenzo[c][2,7]naphthyridine undergoes regioselective direct ring metalation at C-5 with TMPMgCl∙LiCl at −40 °C. Quenching with various electrophiles gives a broad range of 5-substituted products, which are building blocks for the synthesis of heterocyclic natural products and analogues thereof. In combination with a Parham-type cyclization a novel approach to pyrido[4,3,2-mn]acridones has been worked out.

Recent Advances in Heterocyclic Nanographenes and Other Polycyclic Heteroaromatic Compounds

“…The same group later reported a related strategy, which relied on the biaryl 199.5 obtained from 4-bromobenzo[ c ][2,7]naphthyridine via Negishi cross-coupling. 380 199.5 was converted into the respective organomagnesium product by bromine–magnesium exchange with i -PrMgCl·LiCl, followed by intramolecular addition to the ester group which produced the expected pyridoacridone 199.6 , isomeric to 199.4 , in 28% yield.…”

“… Reagents and conditions: (a) 379 corresponding boronic acid, KF, Pd 2 (dba) 3 , ( t -Bu) 3 P, THF, 80 °C, 30 min; (b) TMPMgCl·LiCl, THF, 2 h at 0 °C, then 16 h, rt; (c) 380 i -PrMgCl·LiCl, THF, 0 °C, 2 h. …”

Divergent Syntheses of Pyridoacridine Alkaloids viaPalladium‐Catalyzed Reductive Cyclization with Nitro‐Biarenes

“…Both two types of pyridoacridine alkaloids have received enormous attentions due to the unique biological properties and many efforts have been devoted to construct these pyridoacridine frameworks, involving condensation of amino‐ketone substrates, [ 4 ] cyclization of anionic nucleophilic addition, [ 5 ] electrocyclic ring closure, [ 6 ] Cadogan reaction [ 7 ] and biomimetic cascade reaction. [ 8 ] However, these methods suffered from the drawbacks such as use of harsh conditions, prolonged reaction times and especially the narrow substrate scopes and they could not be applied in different ring systems.…”

A Predictive Model Towards Site‐Selective Metalations of Functionalized Heterocycles, Arenes, Olefins, and Alkanes using TMPZnCl⋅LiCl

“…[4] Recently, deprotometalations of arenes and heteroarenes using metal amide bases have allowed the regioselective introduction of abroad range of functional groups to aplethora of important substrates. [4] Both highly reactive lithium amides,s uch as LDA [5] or TMPLi [6] (TMP = 2,2,6,6-tetramethylpiperidinyl), or more selective reagents such as TMPMgCl•LiCl [7] or TMPZnCl•LiCl [8] have been used successfully.T his gave access to functionalized arenes or heteroarenes,i ncluding pharmaceutically relevant scaffolds such as pyrimidines, pyrazines or pyridazines. [8c,9] However,w hen novel scaffolds were investigated towards directed metalation reactions,t he regioselectivity was difficult to anticipate and had to be determined by experimental methods.…”

“…[8c,9] However,w hen novel scaffolds were investigated towards directed metalation reactions,t he regioselectivity was difficult to anticipate and had to be determined by experimental methods. [7,8] This tedious and inefficient approach hampers ar apid and straightforward systematic functionalization of new heterocycles of the future.…”