Divergent Strain‐Release Amino‐Functionalization of [1.1.1]Propellane with Electrophilic Nitrogen‐Radicals

Abstract

Herein we report the development of a photocatalytic strategy for the divergent preparation of functionalized bicyclo[1.1.1]pentylamines. This approach exploits, for the first time, the ability of nitrogen‐radicals to undergo strain‐release reaction with [1.1.1]propellane. This reactivity is facilitated by the electrophilic nature of these open‐shell intermediates and the presence of strong polar effects in the transition‐state for C−N bond formation/ring‐opening. With the aid of a simple reductive quenching photoredox cycle, we have successfully harnessed this novel radical strain‐release amination as part of a multicomponent cascade compatible with several external trapping agents. Overall, this radical strategy enables the rapid construction of novel amino‐functionalized building blocks with potential application in medicinal chemistry programs as p‐substituted aniline bioisosteres.

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

“…However, the inverted geometry of the bridgehead carbon atom in 1 uniquely circumvents the need for planarization in the transition state, 39 which might suggest that the activation barrier has a greater contribution from a change in electronic structure than from geometric distortion. 23,26,27,33 To investigate the origin of this barrier to addition, a Distortion/ Interaction Analysis (DIA) was performed on a model hydride addition to 1. [37][38][39] This approach separates the overall energy of the addition was found to be positive, and to dominate over DE(dist) (70% contribution of DE(int) up to the TS) (Fig.…”

“…26 The reaction of 1 with amide anions was computed using NH Our attention next turned to the reactivity of 1 with radicals, chemistry that is of much utility in the synthesis of highlyfunctionalized BCPs. [15][16][17][18][19][20][21]23,24 Such reactions proceed through addition of a radical to the C1-C3 bond to give a bridgehead BCP radical that subsequently reacts either via atom transfer, or addition to a radical trap (such as an azodicarboxylate, a further molecule of 1, or an organometallic species). Alkoxycarbonyl, alkyl and aryl radical additions have been studied using DFT (B3LYP, M06-2X, uB97X-D, B2PLYP) 66,67,73,74 by the Uchiyama group 17 and ourselves, 18,20 where the focus has lain on the fate of the bicyclo[1.1.1]pentyl radical.…”

“…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).…”

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).…”

Recent Advances in Photocatalytic C–N Bond Coupling Reactions

“…57 Recently, Leonori, Sheikh and co-workers presented a divergent strain-release amination of [1.1.1]propellane for the synthesis of functionalized bicyclo[1.1.1]pentylamines (Scheme 54). 58…”