Chemoselective Synthesis of Aryl Ketones from Amides and Grignard Reagents via C(O)–N Bond Cleavage under Catalyst-Free Conditions

Abstract

Conversion of a wide range of N-Boc amides to aryl ketones was achieved with Grignard reagents via chemoselective C(O)−N bond cleavage. The reactions proceeded under catalyst-free conditions with different aryl, alkyl, and alkynyl Grignard reagents. α-Ketoamide was successfully converted to aryl diketones, while α,β-unsaturated amide underwent 1,4-addition followed by C(O)−N bond cleavage to provide diaryl propiophenones. N-Boc amides displayed higher reactivity than Weinreb amides with Grignard reagents. A broad substrate scope, excellent yields, and quick conversion are important features of this methodology.

A Fast and General Route to Ketones from Amides and Organolithium Compounds under Aerobic Conditions: Synthetic and Mechanistic Aspects

“…[10] Stable twisted amides have also been successfully employed by Szostak and co‐workers as effective acylating reagents to promote the chemoselective 1,2‐addition reaction of highly polarized s ‐block organometallic reagents by exploiting pyramidalization as a reactive controlling feature (Figure 1 b). [9c, 11] Reaction of Grignard reagents with N ‐Boc protected amides under kinetic control [8b] and the transformation of amides using gem ‐diborylalkanes as pro‐nucleophiles are other viable alternatives in using modified amides [9b] . A second approach includes the chemical activation of the amide functional group via highly electrophilic intermediates (Figure 1 c), [6a, 12] whereas a third synthetic route makes use of transition metal‐catalyzed C‐N activation reactions of activated amides delivering a metal acylating agent (Figure 1 d).…”

An Easy Route to Aziridine Ketones and Carbinols

“…In a recent alternative approach to the expected Weinreb amides, bis-Boc activation was used [ 16 ]. With N-Boc aziridine 2a , it formed the desired Boc-protected Weinreb amide 3b in a moderate (31%) yield (entry 6).…”

“…Tertiary amides represent useful alternatives to Weinreb amides in carbonyl compound synthesis. Recently, the reaction of activated mono-Boc and bis-Boc amides with Grignard reagents led to high yields in the corresponding aromatic ketones [ 16 ]. Some examples of successful utilization of non-activated tertiary dimethylamides in aldehyde and ketone synthesis are also found in the literature [ 17 , 18 , 19 ].…”

Synthesis of N‐Cbz Amides and Their Applications in the Transamidation Reactions at Room Temperature

“…In the last few years, our group has been focused on amide activation reactions. In this context, we have demonstrated tert-butyl nitrite mediated transamidation of secondary amides, [8] transformation of N-Boc-amides into aryl ketones with Grignard reagents, [9] diversification of α-ketoamides via transamidation reactions [10] and controlled reduction of N-Boc and N-Ts amides into aldehydes with DIBAL-H. [11] In transamidation reactions, undoubtedly, Boc-activated amides are more reactive due to high steric distortion. The N-Boc amides are typically prepared from corresponding amides and Boc-anhydride in the presence of a base.…”