Review. Regioselective Functionalization of Pyridines using a Directed Metalation or a Halogen/Metal Exchange

Manolikakes, Sophia M.; Barl, Nadja M.; Sämann, Christoph; Knöchel, Paul

doi:10.5560/znb.2013-3061

Cited by 28 publications

(15 citation statements)

References 38 publications

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“…Based on these DFT results, a modular ligand synthesis starting from 3‐hydroxypyridine was devised, which allows a late‐stage functionalization with the chiral auxiliary (Scheme ). After dibromination of 3‐hydroxypyridine and MOM protection of the hydroxy group, the phosphine moiety was selectively introduced at the 2‐position through a directed bromo–lithium exchange followed by reaction with chlorodiphenylphosphine . Substitution of the remaining bromide with KO t Bu allowed subsequent simultaneous removal of both protecting groups with formic acid.…”

Section: Methodsmentioning

confidence: 99%

Inducing Axial Chirality in a Supramolecular Catalyst

2018

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A new type of ligand, which is able to form axially chiral, supramolecular complexes was designed using DFT calculations. Two chiral monomers, each featuring a covalently bound chiral auxiliary, form a bidentate phosphine ligand with a twisted, hydrogen-bonded backbone upon coordination to a transition metal center which results in two diastereomeric, tropos complexes. The ratio of the diastereomers in solution is very temperature- and solvent-dependent. Rhodium and platinum complexes were analyzed through a combination of NMR studies, ESI-MS measurements, as well as UV-VIS and circular dichroism spectroscopy. The chiral self-organized ligands were evaluated in the rhodium-catalyzed asymmetric hydrogenation of α-dehydrogenated amino acids and resulted in good conversion and high enantioselectivity. This research opens the way for new ligand designs based on stereocontrol of supramolecular assemblies through stereodirecting chiral centers.

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Section: Methodsmentioning

confidence: 99%

Inducing Axial Chirality in a Supramolecular Catalyst

2018

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“…In spite of extensive efforts, however, the regioselective functionalization of pyridine still remains a significant challenge due to their low reactivity and presence of Lewis‐basic sp 2 nitrogen. Ongoing investigations have identified transition metal‐catalyzed C−H functionalization as a leading strategy for this endeavor [19–23] . However, a persistent challenge in the development of transition metal‐catalyzed C−H functionalization methods for pyridine and other heteroarenes is regioselectivity, where a single C−H bond is cleaved in the presence of several other C−H bonds with similar properties [24] .…”

Section: Introductionmentioning

confidence: 99%

Hydrogen‐Bonding as a Factor to Determine the Regioselectivity for Pd‐mediated C−H Activation of Pyridine

Haines

Musaev

2020

ChemCatChem

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Direct and regioselective functionalization of pyridine is a topic of high scientific and technological importance. In spite of extensive efforts, the regioselective functionalization of pyridine still remains a significant challenge due to their low reactivity and presence of Lewis‐basic sp2 nitrogen. Here, we studied the effect of hydrogen bonding interactions on the regiochemical outcome of Pd‐mediated C−H activation of pyridine by utilizing DFT calculations. We demonstrated that hydrogen bonding can act as a second independent factor to override the inherent regioselectivity of pyridine. This novel approach complements previously reported strategies, such as: (a) coordination of pyridine to transition metal center via its N‐center, (b) installation of directing group (DG) and then coordination of pyridine to the transition metal center via this DG (i. e. chelation assistant strategy), (c) protection of its nitrogen lone pair with N‐oxide or N‐imino groups or with Lewis acids, (d) the inherent positional reactivity of C−H bonds based on the electronic or steric properties of the substituents, and (e) by the identity of the oxidant used. We have also demonstrated that the oxidation state of the Pd catalyst has impact on the regiochemical outcome of the C−H activation step in pyridine. The implications of our study for regioselective C−H functionalization catalyst design of heteroarenes are twofold: It demonstrates (1) hydrogen bonding as a viable design principle, and (2) Pd(IV) as a catalyst for C−H functionalization.

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“…Taking into account our preliminary results described in a previous communication, [42] as well as the literature data, [42][43][44] we have envisaged that the required chemo-and regioselectivity could be achieved via directed ortho metalation (DOM) of 2-or 3bromopyridines (Scheme 3). [45][46][47][48] The bromine atom might serve as the directed metalation group, which could be easily removed under reductive conditions. Other modifications necessary for the preparation of the title compounds included pyridine ring hydrogenation and deoxygenation; all the aforementioned transformations could be achieved under reductive reaction conditions.…”

Section: Introductionmentioning

confidence: 99%

“…[45][46][47] First of all, we have tested reaction of 20 with LDA ( Table 2, Entries 1-3); LDA/TMEDA (Entries 4 and 5), and LiTMP (Entries 6-8); D 2 O was used as an electrophile to quench the corresponding organolithium intermediate 21. [45][46][47] First of all, we have tested reaction of 20 with LDA ( Table 2, Entries 1-3); LDA/TMEDA (Entries 4 and 5), and LiTMP (Entries 6-8); D 2 O was used as an electrophile to quench the corresponding organolithium intermediate 21.…”

Section: Introductionmentioning

confidence: 99%

Scalable and Straightforward Synthesis of All Isomeric (Cyclo)alkylpiperidines

et al. 2019

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An efficient approach towards introducing (cyclo)alkyl substituents at C‐2, C‐3 or C‐4 positions of the piperidine ring was described. The method relied on the straightforward two‐step reaction sequence based on the formal sp3–sp3 retrosynthetic disconnection. The procedure commenced with selective directed ortho metalation of 2‐ and 3‐bromopyridine, followed by reaction with aldehydes or ketones. The optimized methods were developed for all three isomers of hydroxyalkyl‐substituted pyridines, which were synthesized in 28–84 % overall yield (20 examples). Catalytic hydrogenation of these adducts could be performed selectively with or without retention of the hydroxyl group in their molecules, so that either (cyclo)alkylpiperidines (14 examples) or the corresponding saturated amino alcohols (16 examples) were obtained (28–96 % and 82–96 % yield, respectively). After minor modifications, the developed method was also implemented in a flow reactor and a 5 L autoclave, which allowed for the preparation of up to 0.5 kg of the representative (cyclo)alkylpiperidines.

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Review. Regioselective Functionalization of Pyridines using a Directed Metalation or a Halogen/Metal Exchange

Cited by 28 publications

References 38 publications

Inducing Axial Chirality in a Supramolecular Catalyst

Inducing Axial Chirality in a Supramolecular Catalyst

Hydrogen‐Bonding as a Factor to Determine the Regioselectivity for Pd‐mediated C−H Activation of Pyridine

Scalable and Straightforward Synthesis of All Isomeric (Cyclo)alkylpiperidines

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