Ruthenium porphyrin catalyzed nitrene insertion into C-H bonds of aromatic heterocycles, aldehydes and alkanes

Abstract

Transition metal catalyzed selective nitrene insertion into C-H bonds, which allows direct incorporation of nitrogen functionality into hydrocarbons, represents an appealing methodology for C-N bond formation, a type of bond formation of great importance in organic synthesis due to the prevalence of amino groups in biologically active natural products and pharmaceuticals. Organic azides are atom-economic and an environment-benign nitrene source. This dissertation reports the use of organic azides as a nitrene source to develop a series of protocols for C-H bond functionalization by metal-catalyzed nitrene insertion, including the diimination of indoles, the phosphoramidation of aldehydes and the amination of hydrocarbons catalyzed by ruthenium porphyrins.

Carbonylruthenium(II) porphyrin complex Ru(TTP)(CO) (TTP = meso-tetrakis(p-tolyl)porphyrinato dianion) is an effective catalyst for nitrene transfer to sp2 C-H bonds of indoles using aryl azides (ArN3) as a nitrene source. This “Ru(TTP)(CO) + ArN3” protocol selectively results in the diimination of indoles without the corresponding monoimination products being detected. In the presence of a catalyst Ru(TTP)(CO), the reactions of N-methylindole with ArN3 (Ar = 4-nitrophenyl; 3,5-bis(trifluoromethyl)phenyl), and reactions of a variety of N-substituted indoles with 4-nitrophenylazide, afford 2,3-diiminoindoles in good to excellent yields (up to 90%). This unique type of 2,3-diimination products was characterized by NMR spectroscopy, mass spectrometry and single crystal X-ray crystallography. The catalytic diimination product from N-methylindole and ArN3 (Ar = 3,5-bis(trifluoromethyl)phenyl) can also be obtained through stoichiometric reaction of N-methylindole with the corresponding bis(arylimido)ruthenium(VI) porphyrin, suggesting the possible involvement of RuVI(TTP)(NAr)2 intermediates in the Ru(TTP)(CO)-catalyzed diimination reactions.

Dichlororuthenium(IV) porphyrin complex Ru(TTP)Cl2 efficiently catalyzes the phosphoramidation of aldehydes with phosphoryl azides (RO)2P(O)N3 via a nitrene insertion into sp2 C-H bonds of aldehydes. This represents the first study on the catalytic activity of a ruthenium(IV) porphyrin towards nitrene insertion into C-H bonds. The “Ru(TTP)Cl2 + (RO)2P(O)N3” protocol exhibits high chemoselectivity and functional group tolerability. Good to excellent product yields (up to 99%) have been obtained for the Ru(TTP)Cl2-catalyzed phosphoramidation of a wide variety of aldehydes with commercially available (PhO)2P(O)N3 (DPPA) and phosphoramidation of p-tolualdehyde with various (RO)2P(O)N3 (R = Me, Et, CCl3CH2, 4-nitrophenyl). The reaction can be scaled up by adding phosphoryl azide dropwise. The use of commercially available DPPA in this protocol offers a convenient and practical method for the synthesis of N-acylphosphoramidates. “Ru(TDCPP)Cl2 + (CCl3CH2O)2P(O)N3” (TDCPP = meso-tetrakis(2,6-dichlorophenyl)porphyrinato dianion) serves as an effective protocol for intermolecular nitrene insertion into sp3 C-H bonds of hydrocarbons. Using this protocol, a variety of hydrocarbons including cycloalkanes (such as cyclohexane) and ethylbenzenes undergo sp3 C-H amination in moderate to high yields (up to 86%). Compared with ruthenium(II) porphyrins such as Ru(TDCPP)(CO) and dirhodium carboxylates such as Rh2(OAc)4, Ru(TDCPP)Cl2 displays a markedly higher catalytic activity towards the nitrene sp3 C-H insertion with (CCl3CH2O)2P(O)N3. In addition, intramolecular nitrene insertion into sp3 C-H bond can also take place in good yields with Ru(TDCPP)Cl2 as the catalyst.