Functionalization of Pyridine and Quinoline Scaffolds by Using Organometallic Li‐, Mg‐ and Zn‐Reagents

Abstract

This Review discusses the various methods for functionalizing pyridine and quinoline scaffolds, including direct selective metalation (DoM), halogen/metal exchange reactions, Li, Mg, and Zn insertion, and trans‐metalation approaches, which are then followed by cross‐coupling reactions of the Kumada or Negishi types. Selective deprotonation of aryl or pyridyl/quinolinyl derivatives can be performed using n‐BuLi, LDA, and TMP‐based different organolithium, ‐magnesium, and ‐zinc reagents. The functionalized pyridine and quinoline‐based heterocyclic compounds were prepared by selectively deprotonating with presenting a directing functional group substituted pyridine/quinoline analogues in the presence of TMP‐bases (TMP−Li, Mg, Zn reagents). Different aryl or alkyl Li, Mg, and Zn reagents with electron‐donating and electron‐withdrawing substituents undergo transition metal‐catalyzed C(sp2)−C(sp2) and C(sp2)−C(sp3) types of cross‐coupling reactions with pyridine/quinoline halides under mild conditions with the sustainable process producing complex N‐heterocycles. Using moderate and sustainable reaction conditions, sensitive functional group tolerance, and inexpensive and low toxic chemicals, highly functionalization of pyridine and quinoline‐based bioactive therapeutic scaffolds and natural products was accomplished. Therefore, in this article, we provide a succinct overview of the numerous synthetic strategies and practical methods used by various authors between 2010 and 2023 to functionalize pyridine and quinoline analogues using diverse Li, Mg, and Zn organometallic reagents.

Direct C–H Hydroxylation of N-Heteroarenes and Benzenes via Base-Catalyzed Halogen Transfer

“…The compatibility of deprotonation and halogenation within this method allows for the use of alkoxide bases to achieve arene C–H functionalization, as compared to traditional metalation that relies on substantially stronger bases ( e.g ., LiTMP) and whose selectivity has been the subject of much research. − Here, alkoxide-promoted hydroxylation occurs with high regioselectivity on arenes with multiple acidic sites ( e.g ., 15 , 18 , 39 , 43 , 47 , 59 , 63 , 70 ) or potentially competitive directing groups ( e.g ., 14 , 17 , 48 , 67 ) and tolerance of base-sensitive functional groups ( e.g ., nitriles, carboxylic acids, halogens, and azoles). An additional striking contrast was observed while investigating pyridazine ( 72 ), a challenging benchmark for metalation chemistry where selectivity control has only recently been achieved by Knochel using “ate” bases in conjunction with Lewis acids (Figure , top). , In our studies, we found that the C–H hydroxylation site-selectivity switches by a simple change of reaction conditions: 3-hydroxylation occurs in PhMe, while 4-hydroxylation occurs in DMF with 18-crown-6 additive (Figure , bottom) .…”

“…A reliable and well-developed approach for electron-deficient arene C–H functionalization is through multistep deprotonative procedures . These protocols employ strongly basic reagents for arene metalation prior to treatment with an electrophile, where site-selectivity is governed by C–H acidity and/or coordinating effects. , While organoalkali and alkaline intermediates readily undergo electrophilic halogenation, direct access to hydroxylated products is challenging due to a lack of effective electrophilic oxygen sources.…”

Synthesis of (3‐Thienyl)‐Substituted 2,2’‐Bipyridines and Their Application as Activators of Platinum Electrode Catalytic Activity Towards Cholesterol Electrooxidation

“…An alternative approach for introducing (het)arylethynyl fragments into heterocyclic compounds is the reaction of nucleophilic substitution of hydrogen (S N H ) in azines [39] by the action of various acetylenides. [40] So, in a number of works, the possibilities of functionalization of azynes scaffolds by using organometallic Li-, Mg-and Zn-reagents, [41] including introducing ethynyl residues into various positions of the 1,2,4-triazine ring by S N H approach in the deoxygenative version [42,43] or according to the "addition-oxidation" scheme [44][45][46] were described, and in the latter case the reaction involved the formation of the corresponding styryl-substituted 1,2,4triazines. [47,48] In this work, we used the reaction of S N H at the C6 position of the 1,2,4-triazine ring [55] of the previously described compound 12 [49] with the in situ obtained lithium salt of 3ethynylthiophene at À 78 °C.…”

Synthesis of anti-depressant molecules via metal-catalyzed reactions: a review

“…30,31 Metal-catalyzed transformations have been employed in the synthesis of antidepressants at several sites along the pathway, leading to the development of C-C, and C-N bonds and the functionalization of aromatic rings. 32 In particular, SSRIs, including sertraline and uoxetine, which are extensively used to treat depression, have been synthesized via couplings catalyzed by palladium. 16,33 Moreover, the synthesis of other kinds of antidepressants, MO inhibitors, and tricyclic antidepressants has also been accomplished via metal-catalyzed reactions.…”