Hypoiodite-Catalyzed Oxidative Umpolung of Indoles for Enantioselective Dearomatization.

Here we report the oxidative umpolung of 2,3-disubstituted indoles toward enantioselective dearomative aza-spirocyclization to give the corresponding spiroindolenines using chiral quaternary ammonium hypoiodite catalysis. Mechanistic studies revealed the umpolung reactivity of C3 of indoles by iodination of the indole nitrogen atom. Moreover, the introduction of pyrazole as an electron-withdrawing auxiliary group at C2 suppressed a competitive dissociative racemic pathway, and enantioselective spirocyclization proceeded to give not only spiropyrrolidines but also four-membered spiroazetidines that are otherwise difficult to access.

Indole-derived alkaloids are the largest group of nitrogen-containing secondary metabolites.[1] Because of their wide range of biological and pharmacological activities, a tremendous amount of research has been devoted to the development of efficient methods for the synthesis of indole alkaloids in synthetic organic chemistry, especially for drug discovery.[1c,2] From this perspective, dearomatization of structurally planar indoles into enantioenriched three-dimensional indoline or indolenine structures has emerged as a powerful tool for the asymmetric synthesis of indole-derived alkaloids.[3] Because of the inherent nucleophilicity of indoles, especially at C3 due to enamine-like reactivity, dearomatization reactions often proceed by addition of electrophiles at C3 (Scheme a, left).[3c,3d,4]

Scheme 1

Oxidative Umpolung of Indoles for Dearomative Coupling Reactions

Conventionally, the incorporation of strong electron-withdrawing substituents[5b,6] or leaving groups[7] on the indole nucleus is often required for inversion of the polarity (umpolung)[8] of nucleophilic indoles to give electrophilic indoles. Recently, several asymmetric transformations of indole derivatives based on the C3 umpolung reactivity of 2-indolylmethanols have been achieved using chiral Brønsted acid catalysis.[7b−7e] On the other hand, methods for direct umpolung without preactivation would open a new avenue for the dearomative functionalization of indoles (Scheme a, right).[5a] However, only a few examples of oxidative umpolung of indoles have been reported.[9−11] Recently, new methods, namely electro-[10] and photochemical[11] oxidation of indoles, have been developed. Enantioselective dearomative coupling of indoles has also been achieved in combination with chiral phosphate or phosphoric acid catalysts under photooxidation conditions. However, these methods have relied on the use of transition metal chromophores as photocatalyst as well as preoxidized nucleophiles such as nitroxyl radicals or hydroxylamine derivatives.[11a,11b]

We recently reported the quaternary ammonium hypoiodite-catalyzed[12] oxidative C2-cyclization/peroxidation of homotryptamine derivatives (Scheme b).[13] We envisioned that the introduction of a substituent at C2 of homotryptamines might sterically suppress cyclization or 1,2-migration[14] at C2, allowing spirocyclization to proceed at C3 to form five-membered rings. Dearomative spirocyclization of homotryptamine derivatives to form aza-spiroindolenines has been reported.[15] However, preinstallation of an O-based leaving group on an electrophilic nitrogen tether[15a−15c] or stoichiometric amounts of an organoiodine(III) as an oxidant[15d] were required. In addition, enantioselective dearomative aza-spirocyclization remains elusive. Here we report the oxidative umpolung of 2,3-disubstituted indoles toward enantioselective dearomatizative spirocyclization of not only homotryptamines but also tryptamines to afford the corresponding spiroindolenines using quaternary ammonium hypoiodite catalysis[12a,16] (Scheme c). Mechanistic studies revealed the umpolung reactivity of indole by iodination at N1.

We began our investigation by examining the oxidative spirocyclization of C2-methyl substituted homotryptamine derivative 1a using tert-butyl hydroperoxide (TBHP) as an oxidant in the presence of 10 mol % n-tetrabutylammonium iodide (Bu4NI) (Scheme a). Although the desired spiroindolenine 2a was obtained in 31% yield, intermolecular coupling with TBHP also proceeded to give peroxyindolenine 3 as a byproduct. To suppress this side reaction, we used cumene hydroperoxide (CHP) as a more sterically hindered oxidant instead of TBHP, and to our delight, a cleaner reaction was observed to give 2a in 67% yield.[17]

Scheme 2

Investigation of Reaction Conditions and Chiral Catalysts

Next, we investigated enantioselective spirocyclization using bis(binaphthyl)-based chiral quaternary ammonium iodide 4a, (Scheme b).[12a,16,18] After optimization of the reaction conditions (Table S1),[19]2a was obtained in 70% yield with 46% ee in a methyl tert-butyl ether (MTBE)/toluene mixed solvent. Toluene and MTBE were found to be effective as solvents to enhance the reactivity and enantioselectivity, respectively.

Since investigation of the substituents at the 3- and 3′-positions of bis(binaphthyl)ammonium cation 4 failed to improve the enantioselectivity, we explored the use of mono(binaphthyl)-based catalysts 4(18) (Table S3). The use of morpholine-derived mono(binaphthyl)ammonium iodides improved the enantioselectivity, and the best result (81% ee) was obtained with cis-2,6-dimethylmorpholine-derived 4b (Scheme b). To further improve the chemoselectivity, we used Na2SO4 as a desiccant to give 2a in 87% yield with 81% ee (Table S4). The absolute stereochemistry of 2a was assigned to be R by X-ray analysis of an enantiomerically pure sample that was obtained after a single recrystallization.

We examined the enantioselective dearomative aza-spirocyclization of several N-(4-nosyl)homotryptamines 1 under the optimized conditions (Scheme ). 2-Methylindole derivatives 1a–f bearing electron-donating or -withdrawing substituents at C5 gave the corresponding spiroindolenines 2a–f in high yields with good to moderate enantioselectivities (59–81% ee). The optical purity of 2a–f could be improved to 88–99% ee after a single recrystallization. Good to excellent enantioselectivities (75–98% ee) were achieved for the reaction of 2-alkyl (larger than methyl)- or 2-phenyl-substituted indoles bearing electron-withdrawing substituents (1g–o, 1q–t) or no substituent (1p) on the indole nucleus. Interestingly, while the reaction of rac-1u using Bu4NI gave high diastereoselectivity (12:1), the use of chiral catalyst 4b afforded a 2:1 mixture of 2u and 2u′ with higher enantioselectivity for the minor diastereomer 2u′.

Scheme 3

Enantioselective Oxidative Aza-spirocyclization to Give Spiropyrrolidines 2 Under the Optimized Conditions

Reaction conditions: 4b (10 mol %), CHP (2 equiv), Na2SO4, MTBE/toluene, 25 °C, 10–24 h.

After a single recrystallization.

Reaction conditions: Bu4NI (10 mol %), CHP (2 equiv), toluene, 25 °C, 10 h.

Control experiments revealed that the ammonium hypoiodite species might be the catalytically active species for the oxidative dearomative spirocyclization of 1 and that a free radical pathway might be unlikely (Table S7).

To gain further insight into the reaction mechanism, we performed kinetic studies using the oxidative dearomatization of 1v, a p-(trifluoromethyl)benzenesulfonyl-protected analogue of 1a, as a model reaction (Figures S1–S4).[20] The reaction rate was found to have a zeroth-order dependence on the concentration of substrate 1v and a first-order dependence on the concentrations of both CHP and 4b. However, a difference in the initial reaction rates was observed depending on the substituent of 1, suggesting that oxidation of a catalyst–substrate complex might be the rate-determining step.[21] To further evaluate the mechanism, we performed a Hammett analysis with a series of N-4-(trifluoromethyl)benzenesulfonyl homotryptamines 1v–y and N-sulfonyl 5-bromohomotryptamines 1z–ab to probe the electronic effects of the para substituents on the indole and sulfonamide nitrogens, respectively, on the reaction rate (Scheme a and Figures S5–S8). As a result, a linear correlation with a negative slope (ρ = −0.98) was observed from the corresponding plot of the σpara constants versus log(kR/kH) for indole substituents (R5). On the other hand, a poor correlation was observed from the corresponding plot of the σmeta constants, suggesting the accumulation of positive charge on the indole nitrogen rather than C3 in the rate-determining transition state.[22,23] Although a linear correlation was also obtained for sulfonamide substituents (R), the reaction constant was much smaller (ρ = −0.15), suggesting that accumulation of positive charge on the sulfonamide nitrogen might be unlikely.

Scheme 4

Mechanistic Studies

Next, to evaluate the roles of the N–H groups of the indole and sulfonamide units for the oxidation reactions, N-methylindole 5 and N-methylsulfonamide 6 were prepared and examined under the standard conditions (Scheme b). While most of the starting material was recovered from the reaction of 5, the dearomatization of 6 proceeded smoothly to give peroxide adduct 7 in good yield. Consistent with the results of the Hammett analysis, these results indicated that umpolung of the indole moiety through the generation of an N–I indole intermediate might be crucial for the oxidative dearomatization reaction. On the other hand, the smooth reaction of 1d using N-iodosuccinimide as a stoichiometric I+ reagent under neutral conditions gave C3-iodine adduct 8 (Scheme c). C3 iodination was not observed under our catalytic conditions (Figure S9), and exposure of 8 to our conditions gave a complex mixture of several unidentified products; 2d was not observed, suggesting that spirocyclization via iodination of indole C3 might be unlikely.

On the basis of these experimental results and previous works,[13a,16] a proposed catalytic reaction mechanism is depicted in Scheme d. Ammonium hypoiodite could be generated in situ as an active species from the oxidation of ammonium iodide with an oxidant. N-Iodo intermediate 9 might be produced by a reversible reaction of hypoiodite with the indole N–H directly or by iodination of the sulfonamide N–H followed by intramolecular iodo transfer.[24] To enhance the electrophilicity[21] of indole, N-iodine(III) intermediate 10 might be generated by rate-determining oxidation of 9. The accumulation of positive charge on the indole nitrogen in the rate-determining transition state with the generation of a highly electron-deficient iodine(III) species is also in agreement with the results of the Hammett analysis. Finally, reductive elimination of ammonium hypoiodite might proceed via intramolecular capture of highly electrophilic intermediate 10 by the chiral ammonium sulfonamide as the enantiodetermining step to give aza-spiroindolenine 2.

Given the high nucleofugality of hypervalent iodines,[25] we considered that zwitterionic intermediate 11 might be generated by the competitive dissociation of ammonium hypoiodite prior to spirocyclization,[26] which would render asymmetric induction difficult (Scheme d). A dissociative racemic pathway might preferentially proceed for the oxidation of electron-rich indoles (e. g., 1e and 1f) as a result of stabilization of cationic intermediate 11 by electron-donating substituents to give moderate enantioselectivity (Scheme ). In addition, plotting log(e.r.)[27] of products 2a–f against the corresponding σpara constants gave a linear correlation with a positive slope (Scheme d, inset), which might also support the existence of a dissociative pathway during umpolung of indole.

We envisioned that the introduction of an electron-deficient substituent at C2 might suppress the dissociative pathway by destabilization of cationic intermediate 11. In addition, an electron-deficient group at C2 would further reduce the LUMO energy at C3, which might enhance the rate of the spirocyclization step and further improve the chemoselectivity. Moreover, if an electron-deficient auxiliary could be used as a leaving group, the synthetic utility of the products would be enhanced. With these assumptions in mind, we focused on pyrazole as an electron-deficient auxiliary because it can be easily introduced[28] and removed via nucleophilic acyl substitution.[29] To our delight, spiroindolenines 2ac–ae were obtained after smooth reaction of the corresponding 2-pyrazol-1-ylhomotryptamine derivatives 1ac–ae (Scheme a). Most importantly, in sharp contrast to those for 2-methylindole analogues 2a, 2d, and 2f, good enantioselectivities (81–86% ee) were achieved regardless of the electron-donating or -withdrawing substituents at C5. A gram-scale oxidation of 1ac was also achieved with the use of 5 mol % 4b to give 2ac in enantiomerically pure form after recrystallization. In addition, an additive robustness screen analysis[30] revealed that a wide range of functional groups were tolerated under our mild conditions, including carbonyls, amines, alkyne, and heteroarenes (Table S5).

Scheme 5

Harnessing an Electrophilic Indole by Introducing a Pyrazolyl Auxiliary

4b (5 mol %).

After a single recrystallization.

In sharp contrast to previous methods,[31] with the introduction of a pyrazole auxiliary at C2, site-selective spirocyclization of 2-pyrazol-1-yltryptamine 12 at C3 proceeded to give the difficult-to-access four-membered spiroazetidine 13 with good enantioselectivity (Scheme b).[32]

Finally, we demonstrated the synthetic utility of enantioenriched spiroindolenines 2 (Scheme ). First, the 4-nosyl group of 2a could be easily removed under standard deprotection conditions to give free amine 14 (Scheme a).[19] Deprotonation of 2a triggered by N-tosylation gave 2-methyleneindoline 15 in good yield (Scheme b, left). Similarly, N-methylation of 2a followed by condensation with salicylaldehyde afforded spiropyran 16, a structure that is commonly found in photochromic compounds[33] (Scheme b, right). On the other hand, the pyrazole auxiliary of 2ac could be easily removed by Lewis acid-catalyzed hydrolysis to give oxindole 17 quantitatively (Scheme c).[34] Formal nucleophilic substitution of pyrazole 2ac with a carbon nucleophile was accomplished by triflation of 17 followed by a Sonogashira coupling reaction to give 2-alkynylspiroindoline 18. In addition, ethanolysis[13a] of pyrazole 2ac proceeded smoothly to give imino ester 19 in good yield (Scheme d, left). Moreover, we found that scandium-catalyzed nucleophilic substitution of pyrazole 2ac by trimethylsilyl azide followed by intramolecular click cyclization gave tetrazoloindole 20 as a unique structure, which was confirmed by X-ray analysis (Scheme d, right). No loss of enantioselectivity was observed in any of these transformations.

Scheme 6

Transformations

In summary, we have developed an oxidative umpolung strategy for the chiral ammonium hypoiodite-catalyzed enantioselective dearomative aza-spirocyclization of homotryptamine derivatives to give the corresponding aza-spiroindolenines with good to excellent enantioselectivity. Mechanistic studies revealed the unusual umpolung reactivity at C3 of indoles by N1 iodination. Moreover, by the introduction of pyrazole as an electron-deficient auxiliary at C2, site-selective spirocyclization of a tryptamine derivative was also achieved to give the difficult-to-access spiroazetidine in an enantioselective manner. Furthermore, to demonstrate the synthetic utility of our dearomative spirocyclization, 2-alkyl- and 2-pyrazole-substituted spiroindolenines were readily converted to various useful and unique structures. These results demonstrate the high potential of hypoiodite catalysis for oxidative umpolung of indoles toward the synthesis of polycyclic indole-derived alkaloids.