Dearomatizing Spiroannulation Reagents: Direct Access to Spirocycles from Indoles and Dihalides

Abstract

Unfunctionalized indoles can be directly converted into 3,3'-spirocyclic indolenines and indolines upon reaction with electrophilic dihalides in the presence of t-BuOK/BEt. This double C-C bond forming reaction, which simultaneously generates a quaternary spirocyclic center, typically proceeds in high yield and has good functional group tolerance. In contrast to existing dearomatizing spirocyclization approaches, there is no need to prepare a prefunctionalized aromatic precursor, enabling faster access to valuable spirocyclic products from simple, commercially available aromatics in one step.

Three-component spiropyran synthesis via tandem alkylation-condensation

“…Herein, we document the development of alkylation-condensation as a 3component cascade sequence, complementary to related spirocycle syntheses employing indole dearomatisation cascades. 25,26 This has resulted in an operationally simple protocol which enables general, high-yielding synthesis of functionalised spiropyrans from accessible substrates, employing mild, catalyst-free conditions, environmentally benign solvents and short reaction times, and, for the majority of substrates, obviating the requirement for either microwave irradiation or silica gel chromatography. To demonstrate that this process is amenable to scale-up, we have applied this methodology on gram scale with no reduction in yield.…”

Dialkylation of Indoles with Trichloroacetimidates to Access 3,3-Disubstituted Indolenines

“…Evaporated the solvent, purified using silica gel chromatography (5% EA/95% DCM). This compound has been previously prepared [7]. Yellow oil (21 mg, 46%); TLC Rf = 0.43 (10% EA/90% DCM); 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.29 (dt, J = 7.6, 0.8 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 5.92 (s, 2H), 2.68 (s, 4H), 2.27 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.9, 153.7, 146.4, 129.8, 127.6, 125.5.…”

“…This includes complex alkaloids such as echiboline 3 [3], aspidophylline A 4 [4], and perophoramidine 5 [5] (Figure 1). 3,3-Dialkyl indolenines have also been utilized as platforms in medicinal chemistry studies [6,7], as a means to move towards more three-dimensional structures with a greater proportion of sp 3 hybridized carbons, which is desirable in order to create molecules which interact with more complex pharmaceutical target receptors [8,9,10,11]. Structurally related spiropiperidine-indanes have also been referred to as “privileged scaffolds” [12,13,14] for the design of medicinally relevant small molecules, including the ghrelin receptor agonists MK-0677 6 [15] and 7 [16], the Akt inhibitor 8 [17] and the P2Y 1 antagonist 9 [18].…”

Synergistic Sc(III)/Au(I)-Catalyzed Dearomative Spiroannulation of 2-(Ethynyl)aryl Cyclopropanes with 2-Aryl Indoles

“…7 In 2018, Unsworth and co-workers disclosed an elegant example of direct spiroannulation of indoles with dihalides in the presence of tBuOK/BEt 3 (Scheme 1B). 8 Despite these advances, novel and efficient strategies for stereoselective assembly of spiroindolenine skeleton is still highly desirable.…”