Synthesis of (Arylamido)pyrrolidinone Libraries through Ritter‐Type Cascade Reactions of Dihydroxylactams

Abstract

The Ritter‐type reaction of arylnitriles and N‐acyliminium ions generated in situ from dihydroxy‐γ‐lactams gave tetrahydropyrrolo[2,3‐d]oxazol‐5‐ones in excellent yields. A subsequent acidic hydrolysis in EtOH/H2O/TFA (trifluoroacetic acid) yielded new (arylamido)pyrrolidinones with excellent cis diastereoselectivity. A combined one‐step Ritter–hydrolysis procedure proved to be of equal efficiency. This versatile method, which was successfully used for the construction of a screening library containing 706 molecules within the European Lead Factory consortium, provides a simple way to access new compounds incorporating an arylamido and a pyrrolidinone moiety, both of which are widely found in marketed drugs and in biologically active molecules.

Reactivity and Synthetic Applications of Multicomponent Petasis Reactions

“…141 Nielsen and coworkers reported an efficient reductive cyclization approach for the synthesis of N-substituted β,γdihydroxy-γ-lactams 115, which were used as precursors to generate cyclic N-acyliminium ions in the presence of boron trifluoride-diethyl ether. 142,143 Cyclic N-acyliminium ions derived from β,γ-dihydroxy-γ-lactams 115 reacted with electron-deficient boronic acids in this two-component PR to give substituted γ-lactams 116 with high cis-diastereoselectivity, albeit in low yield, probably through the chelationcontrolled addition via the hydroxyl moiety similar to that of canonical PRs. In contrast, the use of electron-rich boronic acids resulted in γ-lactams 117 with no or poor diastereoselectivity owing to a possible pathway of the direct addition of boronic acids to cyclic N-acyliminium ions (Scheme 36).…”

Scaffold Diversity from N-Acyliminium Ions

“…121 Dimerization of NAIs derived from other 4,5-dihydroxy-γ-lactams has also been observed in Rittertype cascade reactions for the synthesis of arylamidopyrrolidinone libraries (Scheme 35). 123 The series of N,O-acetal TMS ethers 127 were conveniently prepared as NAI precursors from the corresponding amides in the synthesis of 5,6-dihydrophenanthridines 128−130. 124 Electron-rich aromatic rings (of high nucleophilicity) led to the formation of cyclized compounds in high yields, whereas less reactive rings, such as the unsubstituted benzene ring and a 3chloro derivative, failed to give the desired dihydrophenanthridines 128s and 128t (Scheme 36).…”

Diastereoselective Ritter-like Reaction on Cyclic Trifluoromethylated N,O-Acetals Derived from l-Tartaric Acid

“…We now report a practical way to prepare some original, highly functionalized derivatives of 2-trifluoromethylpyrrolidinones using a strategy based on the creation of the tetrasubstituted carbon bearing the fluorinated substituent. For this purpose, we have studied the addition of various nitriles on cyclic α-trifluoromethyl N -acyliminium ions derived from l -tartaric acid, which were generated in situ under an acidic treatment of the corresponding α-trifluoromethyl N , O -acetals. During this work, we have highlighted the influence of the protecting groups of the tartaric acid scaffold alcohols both on the nature of the reaction product and on the diastereoselectivity of the reaction.…”