CHEMOSELECTIVE ACTIVATION OF AMIDE CARBONYLS TOWARDS NUCLEOPHILIC REAGENTS

Amides represent an important class of compounds in chemistry, chemical biology and pharmaceutical industry. Their broad utility in many fields is closely tied to the structure of the amide moiety which endows these compounds with unique features. The low reactivity of amide carbonyls towards nucleophiles is a major obstacle to their further functionalization. Selective activation of amides and lactams enables access to novel reactivity pathways and opens up intriguing perspectives in synthesis.

To date, we have demonstrated that upon treatment with Cp₂Zr(H)Cl (Schwartz’s reagent), five- and six-membered lactams, including sugar- and hydroxy acid-derived lactams,^1,2,3 can be easily converted into imines under mild conditions. In addition, as was also shown, in situ generated cyclic imines can be directly subjected to further reactions with nucleophilic reagents such as allyltributylstannane,² Grignard reagents,² enolates² or Danishefsky’s diene¹ to afford α-functionalized pyrrolidines, piperidines and polyhydroxylated pyrrolidine peptidomimetic1c scaffolds in a one-pot manner. The key advantage of the presented approach is the simplicity and convenience of generation of sugar-derived imines from readily available starting materials: sugar-derived lactams. The use of sugar-derived lactams as cyclic imine precursors is crucial to the efficiency of the described synthetic method. Thesecompounds are more readily prepared, handled, and stored than the alternative precursors of cyclic imines such as nitrones, N-chloroamines or azido aldehydes.

Very recently, by selectively activating the amide carbonyl in isatin-derived oxindoles, we obtained a number of the 2,3-disubstituted indoles in a regiospecific and functional group-tolerant manner.⁴ The methodology is normally characterized by excellent yields. The reaction proceeds by chemoselective partial reduction of the amide moiety to an iminium salt and a subsequent nucleophilic addition followed by dehydration, which furnishes the target indole. A number of nucleophiles, including C- and S-nucleophiles, have been examined. The obtained compounds were studied towards acetylcholinesterase inhibitory activity and concurrently considered using a molecular docking approach.

Our current work focuses on a synthesis of previously inaccessible imines from readily available amides. Recently, we have developed an alternative method to classic condensation between amine and aldehyde for fluorinated imines.⁵ The methodology based on the reduction of fluoroacetamides by Schwartz’s reagent and further one-pot addition to imines generated in situ was carried out. Our protocol makes it possible to avoid expensive and difficult to acquire aldehydes and as a source of fluorinated moieties proposes amides that are easily obtained from fluoroacetic acids, esters or anhydrides.

[1] P. Szcześniak, S. Stecko, E. Maziarz, O. Staszewska-Krajewska, B. Furman J. Org. Chem. 2014, 79, 10487-10503
[2] P. Szcześniak, S. Stecko, O. Staszewska-Krajewska, B. Furman Tetrahedron 2014, 70, 1880-1888
[3] P. Szcześniak, S. Stecko, E. Maziarz, B. Furman J. Org. Chem. 2015, 80, 3621-3633
[4] A. Ulikowski, B. Furman Org. Lett. 2016, 18, 149-153
[5] P. J. Czerwiński, B. Furman Chem. Commun. 2019, 55, 9436-9439