Intermolecular Amination of Unactivated C(sp³)−H Bonds with Cyclic Alkylamines: Formation of C(sp³)−N Bonds through Copper/Oxygen‐Mediated C(sp³)−H/N−H Activation

Abstract

The first example of intermolecular amination of unactivated C(sp )-H bonds by cyclic alkylamines mediated by Cu(OAc) /O is reported. This method avoids the use of benzoyloxyamines as the aminating reagent, which are normally prepared from alkylamines in extra steps. A variety of unnatural β -amino acid analogues are synthesized by this simple and efficient procedure. This approach offers a solution to the previous unmet challenge of C(sp )-H/N-H activation for the formation of C(sp )-N bonds.

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

“… 506 Intermolecular processes were also disclosed, using simples alkylamines ( Scheme 83D and E ). 507 , 508 Both systems are Cu-mediated, but in the first case the scope was limited to secondary cyclic alkylamines. However, a broad variety of substituent was tolerated on the amide partner (aryl or bulky aliphatic groups).…”

Copper‐Catalyzed Oxidative Dehydrogenative C(sp3)−H Bond Amination of (Cyclo)Alkanes using NH‐Heterocycles as Amine Sources

“…When FeCl 3 (5 mol %) in the presence of phenanthroline (L1;1 0mol %) was used as the catalytic system, 1 waso btained in low yield with predominant formation of other C2-, C3-, and C7-alkylated products ( [Cu I Br(Me 2 S)] displayed the highest catalytic activity for this reaction and 1 wasisolated in 67 %y ield (Table 1, entry 10). Next, we evaluated withouts uccesst he influence of other N,N-bidentate ligands (Table1,e ntries1 [1][2][3][4][5][6][7][8][9][10][11][12][13][14], such as 4,7-diphenyl-1,10-phenanthroline (L2), 2,2'-bipyridine (L3), 4,4'-di-tert-butyl-Scheme1.N-Alkylation of amines and NH-heterocycles:a)Synthesis of Nalkyl heterocyclesb yS N 2r eaction. [6] b) Copper-catalyzed oxidative dehydrogenativeamination of electron-deficienta mine derivatives (Warren).…”

“…137.0, 128.2, 126.6, 126.5, 124.1, 120.9, 110.3, 102.3, 102.2, 55.6, 33.5, 25.8, 25.5 3, 138.0, 128.0, 125.5, 124.0, 122.5, 121.3, 109.0, 102.8, 55.4, 51.8, 33.5, 25.9, 25.6 165.6, 136.2, 131.0, 126.7, 122.4 121.8, 121.8, 110.0, 106.9, 55.6, 50.9, 33.4, 25.8, 25.5 87 (m, 2H), ChemSusChem 2017, 10,3075 -3082 www.chemsuschem.org 1.81-1.70 (m, 1H), 1.70-1.57 (m, 2H), 1.52-1.37 (m, 2H), 1.33-1.19 ppm (m, 1H); 13 CNMR (101 MHz, CDCl 3 ): d = 118. 4,107.4,58.7,34.7,25.8,25.5 ppm;M S( EI): m/z (%): 149 ([M] + ,6 7), 106 (19), 94 (23), 67 (100), 55 (23).…”

“…[3] The N-cyclopentylindazole III was used as a selective inhibitor of EZH2. [4] The N- (tert-butoxymethyl)indole IV has shown inhibition properties on vascular endothelial growth factors, which are important signaling proteins involved in both vasculogenesis and angiogenesis ( Figure 1). [5] Despite this wide applicability, ecofriendly routes for the synthesis of N-alkyl heterocycles are limited.…”

Base Metal Catalysis in Directed C(sp3)−H Functionalisation

“…Qin developed the first copper mediated C(sp 3 )-H amination, using unactivated secondary amines, and O2 as an oxidant (Scheme 22a). [64] Other amide directing groups could not promote the reaction, and omission of oxygen led to only trace amounts of product. On all amide substrates the amination was mono selective when using morpholine as the coupling partner, and displayed excellent selectivity for β-CH3 groups over β-methylene, γ-sp 2 and β-or γ-benzylic positions.…”