Aminofluorene-Mediated Biomimetic Domino Amination–Oxygenation of Aldehydes to Amides

Abstract

A conceptually novel biomimetic strategy based on a domino amination-oxygenation reaction was developed for direct amidation of aldehydes under metal-free conditions employing molecular oxygen as the oxidant. 9-Aminofluorene derivatives acted as pyridoxamine-5'-phosphate equivalents for efficient, chemoselective, and operationally simple amine-transfer oxygenation reaction. Unprecedented RNH transfer involving secondary amine to produce secondary amides was achieved. In the presence of O, O-amide was formed with excellent (95%) isotopic purity.

Metal-Free Thermal Activation of Molecular Oxygen Enabled Direct α-CH2-Oxygenation of Free Amines

“…Therefore, the reaction proceeded through the imine/iminum ion 14 which could be formed from the condensation of amine 8 and 9H-fluoren-9-imine ( 2b ). Amine-assisted deprotonation of 14 forms the azomethine anion/ylide 15 which subsequently reacted with molecular oxygen to provide the peroxide intermediate 16 . , Related 1,2,4-dioxazolidine was known to be prepared from the reaction of α-hydroperoxy-amine with carbonyl compounds and from the reaction of carbonyl oxide with imine . Thermal disintegration of peroxide 16 provided the desired amide/lactam and 9-fluorenone. , Interestingly, imine 17b derived from benzaldehyde and benzylamine did not provide the desired amides under the standard conditions (Scheme b, eq 7).…”

“…To avoid this drawback, amidation reactions using catalytic amounts of coupling reagents have been developed . Additionally, conversions of alcohol and aldehyde, , oximes and nitrile, α-keto acids, and α-bromo nitroalkanes to amides were developed as alternative direct methods. However, relatively less examples were known for the direct oxidation of α-methylene group of free amines to corresponding amides because of the higher reactivity of the amine moiety.…”

“…A biomimetic domino amination-oxygenation strategy for direct conversion of aldehydes to amides has been developed recently by our group (eq ). An azomethine ylide related to 1a , , which was formed from aldehyde and fluorenyl amine, reacted with molecular oxygen/air to provide the corresponding amide. We anticipated the formation of an iminium ion 1b /zwitterion 1c from the reaction of an aliphatic amine with the suitable ketone or its derivatives (eq ).…”

Metal-Free Synthesis of N-(Pyridine-2-yl)amides from Ketones via Selective Oxidative Cleavage of C(O)–C(Alkyl) Bond in Water

“…In order to circumvent this problem, alternative strategies toward the synthesis of amides have been explored. In recent years, oxidative amidation of aromatic aldehyde or benzyl alcohol with N , N -disubstituted formamides, amines, aminofluorenes, and 2-aminopyridines has been studied. Methylarenes as acyl donors for oxidative amidation have also been reported …”

“…11 Made from aryl alkyl carbinol. White solid; 96.3 mg, 81% yield; mp 85−87 °C; 1 H NMR (300 MHz, Chloroform-d): δ 9.02 (s, 1H), 8.40 (d, J = 8 4. Hz, 1H), 8.18 (d, J = 4.9 Hz, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.74 (t, J = 7.7 Hz, 1H), 7.54 (t, J = 6.5 Hz, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.04 (t, J = 6.2 Hz, 1H).4-Methyl-N-(pyridin-2-yl)benzamide (4) 17.…”