Efficient Access to All‐Carbon Quaternary and Tertiary α‐Functionalized Homoallyl‐type Aldehydes from Ketones

Abstract

β,γ-Unsaturated aldehydes with all-carbon quaternary or tertiary α-centers were rapidly assembled from ketones through a unique synthetic operation consisting of 1) C homologation, 2) Lewis acid mediated epoxide-aldehyde isomerization, and 3) electrophilic trapping. The synthetic equivalence of a vinyl oxirane and a β,γ-unsaturated aldehyde is the key concept of this previously undisclosed tactic. Mechanistic studies and labeling experiments suggest that an aldehyde enolate is a crucial intermediate. The homologating carbenoid formation plays a critical role in determining the chemoselectivity.

A practical guide for using lithium halocarbenoids in homologation reactions

“…The α,β-unsaturated cyclic ketone 7 was then chosen as electrophile, due to our previous interest in its challenging reactivity [40]. Surprisingly, it showed a very good stability profile even at temperature close to 0 °C and practically the same reactivity of benzaldehyde with chloromethyllithium (Table 3, entries 5–9).…”

“…In recent years, our group launched a research program [23] focused on the use of carbenoid-type reagents for the homologation of different carbon (Weinreb amides [24–32], ketones [33, 34], isocyanates [35–38]) or heteroatom electrophiles [39] for preparing in a single step α-halo or rearranged (thereof) derivatives [40]. We observed a paramount importance of the conditions employed for generating the carbenoid and, herein, we disclose full details on how to prepare and use these highly reactive species under Barbier type conditions [41, 42].…”

Telescoped, Divergent, Chemoselective C1 and C1‐C1 Homologation of Imine Surrogates: Access to Quaternary Chloro‐ and Halomethyl‐Trifluoromethyl Aziridines

“…Thep rotocol is highly versatile,c hemoselective,a nd of general applicability,a sd ocumented by the structural diversity of the synthesized compounds.T he following points underline the potential of the methodology: 1) neither the substituents electronic behavior nor their position across the aromatic ring influence the outcome;2)no concomitant halogen-lithium exchange occurs in systems featuring bromine,chlorine,and fluorine (2, 5-7). Thesuperb chemocontrol is clearly evidenced in reactions carried out with substrates presenting functionalities that are notoriously highly sensitive to organolithium reagents such as nitrile (8-9), ester (10-11), or even aW einreb amide (12). Taken together these examples showcase the formidable electrophilicity of TFAICs,e nabling the selective homologation exactly at the targeted carbon center.…”

“…Recently,o ur group documented that homologation processes mediated by lithium carbenoids (LiCH 2 X) [11] might forge complex molecular architectures in an extremely convenient and effective way by simply selecting the reaction conditions, [12] thus making the strategy to ag iven target flexible and modular. [13] By introducing the unprecedented concept of C1-C1 double homologation, eventually realized with two distinct homologating agents,w ithin au nique chemical event, we present herein astraightforward protocol enabling the construction of unknown a-halo-a-trifluoromethylaziridines and a-halomethyl-a-trifluoromethyl aziridines.…”

“…Thesuperb chemocontrol is clearly evidenced in reactions carried out with substrates presenting functionalities that are notoriously highly sensitive to organolithium reagents such as nitrile (8-9), ester (10-11), or even aW einreb amide (12). Thep rotocol is highly versatile,c hemoselective,a nd of general applicability,a sd ocumented by the structural diversity of the synthesized compounds.T he following points underline the potential of the methodology: 1) neither the substituents electronic behavior nor their position across the aromatic ring influence the outcome;2)no concomitant halogen-lithium exchange occurs in systems featuring bromine,chlorine,and fluorine (2, 5-7).…”