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Palladium-catalyzed picolinamide-directed iodination of remote ortho -C − H bonds of arenes: Synthesis of tetrahydroquinolines

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ABSTRACT

A new palladium-catalyzed picolinamide (PA)-directed ortho-iodination reaction of ε-C(sp2)−H bonds of γ-arylpropylamine substrates is reported. This reaction proceeds selectively with a variety of γ-arylpropylamines bearing strongly electron-donating or withdrawing substituents, complementing our previously reported PA-directed electrophilic aromatic substitution approach to this transformation. As demonstrated herein, a three step sequence of Pd-catalyzed γ-C(sp3)−H arylation, Pd-catalyzed ε-C(sp2)−H iodination, and Cu-catalyzed C−N cyclization enables a streamlined synthesis of tetrahydroquinolines bearing diverse substitution patterns.

No MeSH data available.


New synthetic strategy for THQs via PA-directed C−H functionalization.
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C1: New synthetic strategy for THQs via PA-directed C−H functionalization.

Mentions: Tetrahydroquinoline (THQ) is an important N-heterocyclic scaffold found in many natural products and pharmaceutical agents [1–2]. Efficient and generally applicable methods for the synthesis of THQs with complex substitution patterns are still in great demand [3–7]. Recently, we reported a synthetic strategy for THQs based on picolinamide (PA)-directed sequential C−H functionalization reactions starting from readily accessible aryl iodide and alkylamine precursors (Scheme 1) [8]. Alkylpicolinamides were first subjected to Pd-catalyzed γ-C(sp3)−H arylation with aryl iodides to form γ-arylpropylpicolinamides [9–20]. These γ-arylpropylpicolinamides were then selectively iodinated at the remote ε-C(sp2)−H position via a rarely precedented PA-directed electrophilic aromatic substitution (SEAr) reaction (Scheme 1, reaction 2) [21–22]. Copper-catalyzed intramolecular C−N cyclization of these ortho-iodinated intermediates provided PA-coupled THQ products in good yields.


Palladium-catalyzed picolinamide-directed iodination of remote ortho -C − H bonds of arenes: Synthesis of tetrahydroquinolines
New synthetic strategy for THQs via PA-directed C−H functionalization.
© Copyright Policy - Beilstein
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4979757&req=5

C1: New synthetic strategy for THQs via PA-directed C−H functionalization.
Mentions: Tetrahydroquinoline (THQ) is an important N-heterocyclic scaffold found in many natural products and pharmaceutical agents [1–2]. Efficient and generally applicable methods for the synthesis of THQs with complex substitution patterns are still in great demand [3–7]. Recently, we reported a synthetic strategy for THQs based on picolinamide (PA)-directed sequential C−H functionalization reactions starting from readily accessible aryl iodide and alkylamine precursors (Scheme 1) [8]. Alkylpicolinamides were first subjected to Pd-catalyzed γ-C(sp3)−H arylation with aryl iodides to form γ-arylpropylpicolinamides [9–20]. These γ-arylpropylpicolinamides were then selectively iodinated at the remote ε-C(sp2)−H position via a rarely precedented PA-directed electrophilic aromatic substitution (SEAr) reaction (Scheme 1, reaction 2) [21–22]. Copper-catalyzed intramolecular C−N cyclization of these ortho-iodinated intermediates provided PA-coupled THQ products in good yields.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

A new palladium-catalyzed picolinamide (PA)-directed ortho-iodination reaction of ε-C(sp2)−H bonds of γ-arylpropylamine substrates is reported. This reaction proceeds selectively with a variety of γ-arylpropylamines bearing strongly electron-donating or withdrawing substituents, complementing our previously reported PA-directed electrophilic aromatic substitution approach to this transformation. As demonstrated herein, a three step sequence of Pd-catalyzed γ-C(sp3)−H arylation, Pd-catalyzed ε-C(sp2)−H iodination, and Cu-catalyzed C−N cyclization enables a streamlined synthesis of tetrahydroquinolines bearing diverse substitution patterns.

No MeSH data available.