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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.


Preparation of iodo-substituted THQs via PA-directed C−H functionalization strategy. a) ArI (2 equiv), Pd(OAc)2 (10 mol %), (BnO)2PO2H (20 mol %), Ag2CO3 (1.5 equiv), t-AmylOH, 110 °C, 24h; b) Pd(OAc)2 (10 mol %), I2 (4 equiv), PhI(OAc)2 (4 equiv), KHCO3 (1 equiv), 130 °C, DMF, 24 h; c) NIS (1.1 equiv), HBF4.OEt2 (4), TFA/DCM (1:9), 2.5 mM, 0 °C, 4 h; d) CuI (10 mol %), CsOAc (2.5 equiv), DMSO, Ar, 90 °C, 20 h; e) NIS (1.1 equiv), TFA/DCM (1:9), 2.5 mM, rt, 16 h; f) Pd(OAc)2 (15 mol %), NIS (2.5 equiv), α,α,α-trifluorotoluene, Ar, 100 °C, 24 h.
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C2: Preparation of iodo-substituted THQs via PA-directed C−H functionalization strategy. a) ArI (2 equiv), Pd(OAc)2 (10 mol %), (BnO)2PO2H (20 mol %), Ag2CO3 (1.5 equiv), t-AmylOH, 110 °C, 24h; b) Pd(OAc)2 (10 mol %), I2 (4 equiv), PhI(OAc)2 (4 equiv), KHCO3 (1 equiv), 130 °C, DMF, 24 h; c) NIS (1.1 equiv), HBF4.OEt2 (4), TFA/DCM (1:9), 2.5 mM, 0 °C, 4 h; d) CuI (10 mol %), CsOAc (2.5 equiv), DMSO, Ar, 90 °C, 20 h; e) NIS (1.1 equiv), TFA/DCM (1:9), 2.5 mM, rt, 16 h; f) Pd(OAc)2 (15 mol %), NIS (2.5 equiv), α,α,α-trifluorotoluene, Ar, 100 °C, 24 h.

Mentions: Arenes bearing meta-substituents (e.g., 12) were selectively iodinated at the less hindered ortho position. Pd-catalyzed iodination of substrate 15 bearing a strongly electron-withdrawing NO2 group also proceeded smoothly to give 16; this substrate is unreactive to directed SEAr. The rigid arylnorbornane scaffold 18 is incompatible with directed SEAr, but was iodinated selectively at the ortho position under Pd-catalyzed conditions without the formation of regioisomeric side products. The strong para-directing effect exerted by aryl fluoride substituents overrides directed SEAr selectivity [38–39]. Thus, we observed only para-iodinated compound 23 when 21 was subjected to the directed SEAr protocol. In contrast, using our Pd-catalyzed iodination (conditions B), ortho-iodinated product 22 was obtained via Pd-catalyzed iodination as the only product in excellent yield. The iodinated intermediates could be readily cyclized under our previously reported Cu-catalyzed conditions to give PA-coupled THQ products with various substitution patterns in good yields (Scheme 2) [8].


Palladium-catalyzed picolinamide-directed iodination of remote ortho -C − H bonds of arenes: Synthesis of tetrahydroquinolines
Preparation of iodo-substituted THQs via PA-directed C−H functionalization strategy. a) ArI (2 equiv), Pd(OAc)2 (10 mol %), (BnO)2PO2H (20 mol %), Ag2CO3 (1.5 equiv), t-AmylOH, 110 °C, 24h; b) Pd(OAc)2 (10 mol %), I2 (4 equiv), PhI(OAc)2 (4 equiv), KHCO3 (1 equiv), 130 °C, DMF, 24 h; c) NIS (1.1 equiv), HBF4.OEt2 (4), TFA/DCM (1:9), 2.5 mM, 0 °C, 4 h; d) CuI (10 mol %), CsOAc (2.5 equiv), DMSO, Ar, 90 °C, 20 h; e) NIS (1.1 equiv), TFA/DCM (1:9), 2.5 mM, rt, 16 h; f) Pd(OAc)2 (15 mol %), NIS (2.5 equiv), α,α,α-trifluorotoluene, Ar, 100 °C, 24 h.
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C2: Preparation of iodo-substituted THQs via PA-directed C−H functionalization strategy. a) ArI (2 equiv), Pd(OAc)2 (10 mol %), (BnO)2PO2H (20 mol %), Ag2CO3 (1.5 equiv), t-AmylOH, 110 °C, 24h; b) Pd(OAc)2 (10 mol %), I2 (4 equiv), PhI(OAc)2 (4 equiv), KHCO3 (1 equiv), 130 °C, DMF, 24 h; c) NIS (1.1 equiv), HBF4.OEt2 (4), TFA/DCM (1:9), 2.5 mM, 0 °C, 4 h; d) CuI (10 mol %), CsOAc (2.5 equiv), DMSO, Ar, 90 °C, 20 h; e) NIS (1.1 equiv), TFA/DCM (1:9), 2.5 mM, rt, 16 h; f) Pd(OAc)2 (15 mol %), NIS (2.5 equiv), α,α,α-trifluorotoluene, Ar, 100 °C, 24 h.
Mentions: Arenes bearing meta-substituents (e.g., 12) were selectively iodinated at the less hindered ortho position. Pd-catalyzed iodination of substrate 15 bearing a strongly electron-withdrawing NO2 group also proceeded smoothly to give 16; this substrate is unreactive to directed SEAr. The rigid arylnorbornane scaffold 18 is incompatible with directed SEAr, but was iodinated selectively at the ortho position under Pd-catalyzed conditions without the formation of regioisomeric side products. The strong para-directing effect exerted by aryl fluoride substituents overrides directed SEAr selectivity [38–39]. Thus, we observed only para-iodinated compound 23 when 21 was subjected to the directed SEAr protocol. In contrast, using our Pd-catalyzed iodination (conditions B), ortho-iodinated product 22 was obtained via Pd-catalyzed iodination as the only product in excellent yield. The iodinated intermediates could be readily cyclized under our previously reported Cu-catalyzed conditions to give PA-coupled THQ products with various substitution patterns in good yields (Scheme 2) [8].

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.