|Author:||Ng, Ka Ho|
|Title:||Transition metal catalyzed carbon-hydrogen bond functionalizations for aromatic carbon-nitrogen bond formation : development of palladium-catalyzed intermolecular amidation of anilides and benzoic acids and rhodium-catalyzed direct aryl C-H amination using N-chloroamines|
|Subject:||Transition metal catalysts.|
Hong Kong Polytechnic University -- Dissertations
|Pages:||xxxv, 430 pages : illustrations ; 30 cm|
|Abstract:||Site-selective aromatic C-N bond formation is an attractive approach of fundamental importance in organic synthesis, since arylamines are common motifs in pharmaceutical products and advanced functional materials. Currently, palladium-catalyzed cross coupling of aryl halides with amines (Buchwald-Hartwig amination) remains a widely employed method for arylamines synthesis. However, the reliance of prefunctionalized arenes and the need for strongly basic medium constitute the major drawback of this method. It is envisioned that direct amination of aryl C-H bonds should improve atom-economy and synthetic efficiency for arylamine synthesis. Transition metal-mediated nitrenoid insertion to aliphatic C-H bonds has been extensively investigated over the past decades. Reactive metal-nitrene/imido complexes are known to react with sp³ C-H bonds with a reactivity order of tertiary C-H > secondary C-H >> primary C-H bonds. This reactivity order is reminiscent of the hydrogen atom abstraction mechanism for the C-H bond cleavage. Due to the higher bond dissociation energy of aromatic C-H bonds, nitrenoid insertion to arene C-H bonds is largely unsuccessful. In this work, palladium(II)-catalyzed aromatic amidation of pivalanilides with ethyl N-nosyloxycarbamate (1.2 equiv) and [Pd(OTs)₂(MeCN)₂] (OTs = p-toluenesulfonate) (10 mol%) in 1,4-dioxane at 80 °C to afford ortho-amidated pivalanilides in up to 87% yields. Excellent functional group tolerance was achieved, for instance, substrates bearing halogens and -OMe as substituents were smoothly transformed to the desired amides under mild conditions. Notably, benzyl and vinyl moiety, which are known to react with nitrenes, were well tolerated. This Pd-catalyzed approach has been extended successfully to the direct ortho-C-H amidation of benzoic acids to give anthranilic acids. Reaction of lithium benzoates with Pd(OAc)₂ (10 mol%) and ethyl N-(2,4,6-trimethylbenzenesulfonyloxy)carbamates gave anthranilic acids in up to 73% yields. Strong dependence on the counter ion of the benzoates was observed; when Li+ is the counter ion (versus Na⁺, K ⁺ and NnBu₄⁺), the reaction gave the best results.|
A kinetic study on the [Pd(OTs)₂(MeCN)₂]-catalyzed amidation of 2,4-dimethylpivalanilide (1a) with ethyl N-nosyloxycarbamate (2aNs) was performed; an experimental rate law: rate = k[1a][2aNs][Pd]² was observed. Also, a significant primary kinetic isotope effect (kH/kD = 2.8) was observed, implying that the turnover-limiting step involves substantial C-H bond cleavage. The palladacyclic complex [Pd(C~O)(μ-OTs)]₂ (C~O = 2,4-dimethylpivalanilide) (1aPd) was prepared and structurally characterized, and a stoichiometric reaction of 1aPd with 2aNs (1.2 equiv) in 1,4-dioxane afforded amide 3aa in 45% yield. A plot of log krel versus the Hammett substituent σpara constants for the amidation of pivalanilides revealed a linear free energy relationship with a ρ value of -0.53. The small negative ρ value implies that the Pd(II)-mediated C-H bond cleavage should not proceed through an cationic arene intermediate (arenium intermediate). Apart from C-H amidation reactions, we also achieved the aromatic C-H amination with N-chloroamines under Rh(III) catalysis. With [Cp*RhCl₂]₂ (Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl) (2.5 mol%) as catalyst, treating acetophenone O-methyloximes with secondary N-chloroamines, AgSbF6 (1.5 equiv) and CsOAc (0.3 equiv) in THF at 40 °C afforded the N-arylamines in up to 85% yield. Both electron-donating and electron-withdrawing substituents were well tolerated. A one-pot C-H amination protocol was also developed; this involves in situ generation of the N-chloroamines by reacting N-H amines with N-chlorosuccinimide. The Rh-catalyzed C-N bond coupling reaction was also extended to primary N-chloroamines (ClNHR) as coupling partners. In the literature, primary N-chloroamines are poor substrates for electrophilic amination. In this work, when acetophenone O-methyloximes reacted with primary N-chloroamines in the presence of [Cp*RhCl₂]₂ (5 mol%), AgSbF6 (1.5 equiv) and CsOAc (1.3 equiv) in THF at 40 °C, the C-N coupled products were obtained in up to 92% yield. Regarding the reaction mechanism, an apparent primary kinetic isotope effect (kH/kD = 2.1) indicates C-H rhodation being turnover-limiting in the catalysis. Furthermore, the cyclorhodated complex [Cp*Rh(C~N)Cl] (C~N = 2-phenylpyridine) (11aRh) was prepared and spectroscopically characterized. The stoichiometric reaction of 11aRh with N-chloroamines afforded the amination products in 52 93% yields.
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