Reactions of 2‐Aryl‐1,3‐Dithianes and [1.1.1]Propellane

Abstract

Bicyclo[1.1.1]pentanes (BCPs) have sparked the interest of medicinal chemists due to their recent discovery as bioisosteres of aromatic rings.T os tudy the biological activity of this relatively new class of bioisosteres,r eliable methods to incorporate BCPs into target molecules are in high demand, as reflected by af lurry of methods for BCP synthesis in recent years.I nt his work, we disclose ag eneral method for the synthesis of BCP-containing dithianes which,u pon deprotection, provide access to BCP analogues of medicinally abundant diarylketones.Abroad scope of 2-aryl-1,3-dithianes,including several heterocyclic derivatives,react with [1.1.1]propellane to afford2 6n ew derivatives in good to excellent yields.F urther transformation of the dithiane portion into av ariety of functional groups demonstrates the robustness of the products. Acomputational study indicates that the reaction of 2-aryl-1,3dithianes and [1.1.1]propellane proceeds via at wo-electron pathway.Scheme 1. Previous synthesis of BCP ketones, examples of bioactive diaryl ketones, general reactivity of dithianes, and synthesis of BCP dithianes.

Rationalizing the diverse reactivity of [1.1.1]propellane through σ–π-delocalization

“…[25][26][27][28][29] Given the apparent strain relief associated with this chemistry, it is perhaps surprising that extended reaction times ($16 h) and elevated temperatures (>50 C) are oen required for successful addition. Walsh et al have studied the related addition of dithiane anions, 29 complementing their synthetic work with DFT calculations at the M06-2X level of theory, 73 which revealed carbanion addition to be highly endergonic. These examples led us to question the role of strain relief in the reaction of anions with 1, and in particular how a thermodynamically disfavored process could occur in a system thought to be primed to react.…”

“…BCPs are also useful motifs for organic materials, including rodlike one-dimensional polymers, 11 supramolecular spacer units, 12 liquid crystals 13 and FRET sensors. 14 Such applications have stimulated the development of a number of methods to access BCPs in a single step from 1 via radical [15][16][17][18][19][20][21][22][23][24] and anionic [25][26][27][28][29] intermediates (Fig. 1b).…”

“…36 To date, a handful of experimental studies have employed density functional theory (DFT) to investigate the pathways of addition of radicals and anions to [1.1.1]propellane, offering useful insight to support reaction development. 17,18,20,28,29 However, no in-depth theoretical analysis has tackled the origin of the omniphilic reactivity of 1. Here we combine ab initio approaches with electron density difference analysis and Distortion/Interaction Analysis (DIA) [37][38][39] to develop a unied model for the reactivity of [1.1.1]propellane.…”

Highly Regioselective Addition of Allylic Zinc Halides and Various Zinc Enolates to [1.1.1]Propellane

“…[9] Av ariety of methods to convert [1.1.1]propellane into functionalized BCPs have been developed, including the "strain release" amination by Baran [10] and Gleason, [11] as well as the radical additions by Wiberg, [3] Uchiyama, [12] Anderson, [13] Bräse [14] and Leonori. [15] Thea ddition of organometallic compounds to [1.1.1]propellane has been achieved using 2-azaallyllithiums, [16] sodium 2-aryl-1,3-dithiyl anions [17] as well as aryl, alkyl and alkenyl Grignard reagents [5,18] (Scheme 2).…”

Hoch regioselektive Addition von allylischen Zinkhalogeniden und verschiedenen Zinkenolaten an [1.1.1]Propellan

“…[9] Eine Vielzahl von Methoden zur Umwandlung von [1.1.1]Propellan in funktionalisierte BCPs wurden entwickelt, einschließlich der "strain release" Aminierung von Baran [10] und Gleason, [11] sowie der Radikaladditionen von Wiberg, [3] Uchiyama, [12] Anderson, [13] Bräse [14] und Leonori. [15] Die Addition von Organometallverbindungen an [1.1.1]Propellan wurde mit 2-Azaallyllithiumverbindungen, [16] Natrium-2-aryl-1,3-dithiyl-Aionen [17] sowie Aryl-, Alkyl-und Alkenyl-Grignardreagenzien [5,18] erreicht (Schema 2).…”