Stereoselective Synthesis of β‐Sulfinylamino Isocyanides and 2‐Imidazolines

Abstract

An efficient asymmetric synthesis of β‐sulfinylamino isocyanides is reported on the basis of the highly diastereoselective addition of 9‐isocyanofluorene to optically pure N‐tert‐butanesulfinimines. The resulting optically pure isocyanides readily cyclized to give optically pure 2‐imidazolines upon removal of the sulfinyl group. Furthermore, the β‐sulfinylamino isocyanides were used as chiral inputs in Ugi and Passerini multicomponent reactions to generate new types of (pseudo)peptide scaffolds.

Recent Advances in the Synthesis of Imidazolines (2009–2020)

“…Orru and co-workers developed an asymmetric synthesis of β-sulfinylamino isocyanides (143), which further cyclized to 2-imidazolines (144) (Scheme 42). [54] The β-sulfinylamino isocyanides were synthesized from the reaction of 9-isocyanofluorene (142) with optically pure N-tert-butanesulfinimines (141) in the presence of a Lewis acid and diisopropylethylamine (DIPEA). For the initial optimization, several Lewis acids, including 4 , Sc(OTf) 3 , TMSOTf were screened in combination with DIPEA.…”

Chiral N‐tert‐Butylsulfinyl Imines: New Discoveries

“…In the presence of this base, compounds 273 were isolated with good yields and excellent diastereoselectivities (Scheme 117). [156] However, in the absence of the base, compounds 274 were the reaction products [157] . DFT calculations support the mechanism depicted in Scheme 117, involving intermediates I–V .…”

Fluorene-Based Multicomponent Reactions

“…[27][28][29][30][31][32] Structural diversity and complexity in such libraries are critical to the elucidation of structure-activity relationships that drive the development of new products and technologies. Orru and co-workers, 33 in their pioneering work, took advantage of the -acidic nature of 9-isocyano-1H-fluorene (1; pK a = 12.3 in DMSO), which becomes aromatic after deprotonation, [34][35][36] and were able to synthesize the druglike spiro-2-imidazolines 2 through a threecomponent reaction, now known as the Orru reaction (Orru-3CR; Scheme 1). 33,[37][38][39] Due to the acidic nature of the isocyanide, in which the isocyano functionality competes with -Η acidity, the Mannich-type intermediate 3 is prob-ably formed.…”