Preparation and Reactions of Indoleninyl Halides: Scaffolds for the Synthesis of Spirocyclic Indole Derivatives.

The dearomatization of 2-haloindole precursors allows access to indoleninyl halides, a hitherto underexploited functional handle with broad synthetic utility. Indoleninyl iodides have been shown to react via three distinct modes: hydrolysis, nucleophilic substitution, and cross-coupling. This allows a broad array of functionalized spirocyclic indole derivatives to be generated from a common starting material. They are also useful precursors to functionalized quinolines following migratory rearrangement and subsequent derivatization reactions.

S tructural motifs that pair high stability with versatile reactivity are of great value in organic synthesis. Moreover, such motifs are particularly useful if they are easy to prepare and can be incorporated into biologically significant frameworks, rendering them important in pharmaceutical and agrochemical research programs. Herein we detail the synthesis and subsequent reactions of indoleninyl halides 2, a vastly underexploited functional handle for the synthesis of a broad array of spirocyclic indole derivatives. Simple dearomative methods 1 for their generation (1 → 2) and a series of procedures for their subsequent reaction (via three distinct reaction modes, 1 → 3, 4, or 5) are outlined ( Figure 1). In view of their ease of formation, high stability, and diverse reactivity, indoleninyl halides are expected to be of broad utility in synthesis.
Indoleninyl halides are surprisingly rare in the chemical literature, with very little reported about their stability and reactivity. 2 Initially, we postulated that indoleninyl halides 2 would behave similarly to acid chlorides and react readily with nucleophiles. This notion is supported by literature precedent; indoleninyl chlorides and bromides have each been proposed as short-lived 3 or putative intermediates 4 in previous synthetic protocols and were found to hydrolyze readily in situ, generating oxindoles. 5 It was this precedent that prompted us to initiate the research program described herein, in which it was planned to react readily available 2-haloindole precursors of the form 6 with π-acidic catalysts in the expectation of promoting dearomatizing spirocyclization 6,7 and in situ hydrolysis to generate spirocyclic oxindoles (e.g., 6 → 7 → 8; Scheme 1). However, when ynone 6a (R = Ph) was reacted with 10 mol % Cu(OTf) 2 in DCM at rt, the only product isolated after workup and column chromatography was spirocyclic indolenine 7a in quantitative yield. None of the expected oxindole 8 was isolated, and spirocycle 7a proved to be surprisingly stable; it appears to be insensitive to air and moisture and can be stored in a freezer for several months with no evidence of decomposition.
While this Cu(II)-mediated spirocyclization worked well, a brief examination of other catalysts revealed that AgNO 3 ·SiO 2 was an even more convenient catalyst system for this transformation, enabling spirocycle 7a to be isolated in quantitative yield at just 1 mol % catalyst loading. 8 Indoleninyl iodides 7b−d, as well as indoleninyl bromide 7e and chloride 7f, were also prepared in quantitative yield using the same procedure and were found to have comparable stability.
With a simple method to generate spirocyclic indoleninyl halides established, it was next decided to examine their reactivity. Indoleninyl iodide 7a, an easy-to-handle solid product that could be readily prepared on a gram scale, was chosen as the main test substrate. Its reactivity with a range of nucleophilic reagents was investigated, with three distinct reaction modes [hydrolysis (8), nucleophilic substitution (9− 13), and transition-metal-catalyzed cross-coupling (14−21)] all being demonstrated. These results are summarized in Scheme 2.
To begin, indoleninyl iodide 7a was hydrolyzed using aqueous HCl in THF, affording spirocyclic oxindole 8 in quantitative yield (Scheme 2A). Next, a selection of nucleophilic substitution reactions were performed with sulfur and nitrogen nucleophiles, leading to the formation of indolenine derivatives 9−13 in high yields (Scheme 2B). With spirocycle 7a acting as a vinyl halide surrogate, crosscoupling reactions were performed (Scheme 2C). Suzuki reactions using arylboronic acids afforded phenyl and 2naphthyl derivatives 14 and 15 in good yields. Likewise, Sonogashira cross-couplings yielded alkyne derivatives 16 and 17, and Stille coupling reactions allowed furan (18), pyridine (19), thiophene (20), and olefin groups (21) to be added at the indolenine 2-position, all in good yields. Finally, alcohol derivative 22 was prepared in quantitative yield with 85:15 dr following a chemo-and diastereoselective Luche reduction of the enone moiety of 7a, leaving the indoleninyl halide moiety intact (Scheme 2D). In terms of the reduction step, hydride attack presumably occurs predominantly via the most accessible face of the molecule, i.e., anti to the indole unit.
Having successfully demonstrated the synthesis and utility of indoleninyl halides derived from ynone precursors, it was then decided to examine whether the same functional handle could be installed and used in a much broader range of indole systems. This was done by applying established indole dearomatization procedures to previously untested 2-halogenated starting materials, beginning with an enantioselective iridium-catalyzed allylic dearomatization procedure 10a developed by You and co-workers. 10 Thus, 2-iodoindole precursor 23 was prepared and reacted with bis(1,5-cyclooctadiene)diiridium(I) dichloride and commercially available chiral phosphoramidite ligand 27. 10a Pleasingly, indoleninyl iodide 24 was produced in near-quantitative yield with >9:1 dr and 86:14 er based on NMR and chiral HPLC data respectively, with its absolute stereochemistry assigned on the basis of comparison to literature precedent. 10a Its subsequent derivatization was also achieved successfully, with both cross-coupling and nucleophilic substitution reactions being performed to produce spirocycles 25 and 26 in good yields (Scheme 3).
In another application, indoleninyl iodide 30 was prepared from imine 29 and indole 28. These were treated with the peptide coupling agent T3P and iPr 2 NEt at rt, using the direct imine acylation (DIA) method developed by our group, 11 furnishing spirocycle 30 with 83:17 dr. The relative stereochemistry of 30 was assigned on the basis of analogy to related compounds. 11a This scaffold was again amenable to additional functionalization either by nucleophilic substitution with benzyl mercaptan or by hydrolysis, forming products 31 and 32, respectively (Scheme 4).
In addition, cyclopropyl substrate 34 was prepared in high yield by a Mitsunobu-type reaction of indole-tethered alcohol 33. Functionalization by nucleophilic displacement (35) and cross-coupling (36) again demonstrated the synthetic utility of the indoleninyl iodide substructure (Scheme 5).
Finally, it was found that indoleninyl halide 7a rearranges to form quinoline 37 under basic conditions. A related rearrangement reaction was reported by our group in a 2016 study, in which non-halogenated spirocyclic indolenines were shown to rearrange to form quinoline derivatives upon treatment with either strong base or Lewis acid. 6c It was found that treating spirocyclic indolenine 7a with LHMDS in THF at 0°C promoted its conversion into 2-iodoquinoline 37 in 78% yield via a similar process (Scheme 6; for mechanistic speculation, see our earlier publication 6c ). Of course, 2-iodoquinolines are valuable, versatile building blocks in their own right, and to demonstrate this, derivatization reactions similar to those performed on indoleninyl iodide 7a were also explored. These results are summarized in Scheme 6.
In summary, we have demonstrated that indoleninyl iodides are readily accessible via the dearomatization of 2-iodoindole derivatives and that they can be used to synthesize a range of diverse spirocyclic indole derivatives. In view of their ability to react via three distinct reaction modes (hydrolysis, nucleophilic substitution, and cross-coupling), we expect indoleninyl iodides to quickly become established as valuable intermediates and reagents. Their utility as precursors to easily functionalized 2iodoquinolines has also been demonstrated, further expanding their synthetic utility. Finally, while this work has focused largely on indoleninyl iodides, we have also demonstrated that indoleninyl bromide and chloride analogues can also be prepared using similar methods, and in future work the reactivity of these systems will also be examined.

Notes
The authors declare no competing financial interest.