Aza-Rubottom Oxidation: Synthetic Access to Primary α-Aminoketones

Abstract

An aza analogue of the Rubottom oxidation is reported. This facile transformation takes place at ambient temperature and directly converts silyl enol ethers to the corresponding primary α-aminoketones. The use of hexafluoro­isopropanol (HFIP) as the solvent is essential for the success of this reaction. Overall this process is well-suited for the aza-functionalization and derivatization of complex organic molecules.

Design and Scalable Synthesis of N‐Alkylhydroxylamine Reagents for the Direct Iron‐Catalyzed Installation of Medicinally Relevant Amines**

“…Sterically congested alkyl groups such as cyclohexyl (5), isopropyl (7)o ra damantyl (8)i nc lose proximity to the alkene were all tolerated. In products bearing an acidic CÀHb ond at the b-position relative to the chloride,n oe limination of HCl was observed (9). Alkenyl halides,s uch as chlorides (13)a nd fluorides (14)c ould undergo methylaminochlorination.…”

“…Methods which provide direct access to unprotected primary and secondary alkylamines from simple alkenes are highly attractive for the step-economical and protectinggroup-free synthesis of bioactive molecules. [8] Compared to the synthesis of unprotected primary amines from unsaturated compounds,inwhich significant advancement has been achieved over the recent years, [9] thed irect synthesis of unprotected secondary amines from simple hydrocarbon feedstocks remains underdeveloped. [5g,10-12] Broadly applicable,i ntermolecular catalytic methods for the direct synthesis of unprotected secondary amines from alkenes are limited to isolated examples of hydroamination [5g,10] and aziridination.…”

Nucleophilic Arylation of Halopurines Facilitated by Brønsted Acid in Fluoroalcohol

“…The success of the metal-free coupling reaction relies on the use of HFIP as the solvent. Although the precise role of HFIP [44,45,46] remains unclear, we presume that HFIP can increase the acidity of TfOH (Brønsted acid activation by H-bond donor) to enhance the reactivity of halopurine electrophiles through the purine nitrogen atoms [47,48,49,50]. Importantly, HFIP offers a means of improving the leaving group ability of the chloride atom in the purine substrates through hydrogen bonding as well as solvation [51].…”

Recent advances in the synthesis of α-amino ketones

“…65 Electrophilic nitrogen was also used by Kürti in an azaderivative of the Rubottom oxidation (Scheme 19). 66 Treatment of tetrasubstituted silyl enol ethers (85) with protected hydroxylamine 86 in HFIP generated amino ketones featuring a quaternary centre (87) in up to 82% yield. Even though most of the reported examples involved the synthesis of aromatic α,α-dimethyl substituted ketones, the methodology was also found to be compatible with unsaturated substituents (88) and alicyclic ketones (89).…”