Diversity‐Oriented Catalytic Asymmetric Dearomatization of Indoles with o‐Quinone Diimides

Abstract Herein, the first diversity‐oriented catalytic asymmetric dearomatization of indoles with o‐quinone diimides (o‐QDIs) is reported. The catalytic asymmetric dearomatization (CADA) of indoles is one of the research focuses in terms of the structural and biological importance of dearomatized indole derivatives. Although great achievements have been made in target‐oriented CADA reactions, diversity‐oriented CADA reactions are regarded as more challenging and remain elusive due to the lack of synthons featuring multiple reaction sites and the difficulty in precise control of chemo‐, regio‐, and enantio‐selectivity. In this work, o‐QDIs are employed as a versatile building block, enabling the chemo‐divergent dearomative arylation and [4 + 2] cycloaddition reactions of indoles. Under the catalysis of chiral phosphoric acid and mild conditions, various indolenines, furoindolines/pyrroloindolines, and six‐membered‐ring fused indolines are collectively prepared in good yields with excellent enantioselectivities. This diversity‐oriented synthesis protocol enriches the o‐quinone chemistry and offers new opportunities for CADA reactions.


Introduction
Dearomatized indole motifs bearing a C3-quaternary stereocenter occur prevalently in natural alkaloids and pharmaceutical molecules.3,3-Disubstituted indolenines, pyrroloindolines/furoindolines, and six-membered ring fused indolines are representative ones (Figure 1A).Structurally, the C3-quaternary DOI: 10.1002/advs.202305101stereocenters render rigid architectures, thus posing a daunting synthetic challenge.Biologically, they display a wide range of anti-cancer, anti-bacterial, and anti-fungal properties. [1]The combination of structural complexity and biological importance has inspired continuous interest from the chemical community in developing catalytic asymmetric approaches for these unique skeletons. [2]Among many strategies, the catalytic asymmetric dearomatization (CADA) reaction has emerged as the most powerful one preparing enantioenriched 3D molecules directly from planar indoles (Figure 1B). [3]To date, significant progresses have been made by You and others, which include the well-investigated tandem C3-functionalization/cyclization [4] and [3 + 2] cycloaddition reactions [5] , and the less studied arylation [6] and [4 + 2] cycloaddition reactions. [7]While impressive, these methods are usually target-oriented and provide the specified type of products.To our knowledge, the diversity-oriented CADA reaction of indoles that allows facile access to structurally diversified scaffolds from the same starting materials, however, still remains elusive. [8]The key to the success of such a protocol is the use of a synthon featuring multiple reaction sites and the precise control of chemo-, regio-, and enantio-selectivity.Therefore, developing diversity-oriented CADA reactions of indoles for rapid synthesis of indolenines and indolines is a highly desirable yet challenging subject.
Quinones, known for biological relevance, chemical versatility, and industrial importance, have attracted increasing attention in asymmetric synthesis. [9]p-Quinones and their imine derivatives are a typical class, which render substantial catalytic enantioselective arylations and annulations on the basis of 1,4-conjugate addition reaction on quinone sp 2 hybridized carbon. [10,11]Their 'ortho'-analogs o-quinones, in stark contrast, have been dismissed for a long time due to the structural characteristics of high electrophilicity and easy dimerization/aromatization. [12,13]n fact, o-quinones with multiple reaction sites show the potential to become a kind of versatile synthons.For example, the Nprotected o-quinone diimide (o-QDI) is a structurally stable variant and possesses imine, diene, ,-unsaturated system, and 1,4diazadiene etc. structural motifs. [14]In this regard, o-QDIs could serve as either arylation reagents via 1,4-conjugate addition or heterodienes via [4 + n] cycloaddition (Figure 1C).15c] Furthermore, the enantioselective arylation reaction of QDIs has never been reported.Our team has a long-term program to develop new reaction modes of traditional aza-dienes. [16]Herein, we envision that chemo-divergent dearomative arylation and [4 + 2] cycloaddition reactions of indoles 1 with o-QDIs 2 are feasible under the catalysis of chiral phosphoric acid (CPA) (Figure 1D).Namely, the dearomative C3arylation of indoles 1 via the 1,4-conjugate addition of o-QDIs 2 on quinone sp 2 hybridized carbon allows the enantioselective synthesis of indolenines 3; the dearomative arylation-cyclization cascade of tryptophols/tryptamines leads to the formation of furoindolines/pyrroloindolines 4; the chemo-selective dearomative [4 + 2] cycloaddition of indoles with o-QDIs on imine nitrogen delivers various six-membered ring fused indolines 5.This chemo-divergent protocol not only provides a diversity-oriented synthesis (DOS) of dearomatized indole derivatives but also enriches the quinone chemistry.
Considering that substituents could affect selectivity, further optimization was carried out by employing disubstituted indole 1b and o-QDI 2b (Figure 2).Notably, under the conditions in entry 1 (Table 1), the reaction between 2,3-dimethyl indole 1b and o-QDI 2a occurred in a chemo-specific manner, giving the only dearomative arylation product 3b in 92% yield with 97% enantioselectivity (Figure 2A).In this regard, the steric hindrance had a significant influence on the dearomative [4 + 2] cycloaddition.On the other hand, by using dibromo-substituted o-QDI 2b, the arylation reaction was avoided to give the reversed chemo-selectivity (Figure 2B).In the presence of CPA-5 in toluene (Table 1, entry 11), only the dearomative [4 + 2] cycloaddition reaction of 1a with 2b took place, affording product 5b in 95% yield with 94% ee.Consequently, chemo-divergent CADA reactions of indoles with o-QDIs were accomplished via the substrate-control strategy.

Substrate Scope
With the best conditions, we subsequently examined the substrate generality of CADA arylation of 2,3-disubstituted indoles CPA solvent 3a:5a 3a 5a with o-QDIs (Figure 3).Considering that the variation of the C3quarternary carbon center is of great value in organic synthesis, the tolerance of different substituents at indole C3-position was explored.We were pleased to find that substituents, such as ethyl (3c), n-butyl (3d), benzyl (3e) as well as i-propyl (3f) groups, were well compatible with the optimal conditions.It was also feasible to change the methyl group at indole C2-position to ethyl (3g) and phenyl (3h) groups.Notably, fused indolenines (3i−j) were readily prepared with equally excellent yields and ee values.Various indole partners containing substituents on the phenyl ring were then evaluated.The consistently good results (3k−s) implied that neither the electronic nature nor position of these substituents affected the reaction efficiency and enantioselectivity.Furthermore, the reaction was applicable to a wide range of substituted o-QDIs 2. Although substituents on cyclohexadiene ring reduced the enantioselectivity, this could be simply addressed by lowering the reaction temperature (3t−v).In addition, the N-protecting group of o-QDIs could be altered, delivering a variety of synthet-ically interesting dearomative arylation products (3w−f′) in excellent yields and enantioselectivities.Of particular note is the use of o-QDI with an easily removable Boc group.A low reaction temperature was employed to ensure a high ee value (3g′).The absolute configuration of compound 3g′ was unambiguously determined by X-ray crystallography, and other arylation products were assigned by analogy. [17]2a] In this context, we assumed the CADA arylation of tryptophols/tryptamines with o-QDIs followed by intramolecular cyclization was feasible (Figure 4).To demonstrate this concept, tryptophol was directly subjected to the reaction with o-QDI 2a under standard conditions.Pleasingly, furoindoline 4a was created with 97% yield and 96% ee.Then, various tryptophols bearing substituents on the phenyl ring were employed to explore the electronic effect (4b−h).The electron-donating and halogen  groups afforded the corresponding products in good yields with excellent ee values, while the strong electron-withdrawing -CN group gave no reaction result (4e).Additionally, the reaction cascade could be extended to tryptamine.A series of structurally important pyrroloindolines (4i−m) were prepared via the reaction of NTs tryptamine with o-QDIs 2. The observed excellent chemo-selectivity could be attributed to the -XH group, which acted as a directing group via hydrogen-bonding interaction.
Next, we turned our attention to the substrate scope of dearomative [4 + 2] cycloaddition reaction (Figure 5).The tolerance of the substituents at the indole ring was tested by reacting with o-QDI 2b under standard conditions.All patterns of substituents on the phenyl ring were well tolerated, and cycloaddition products (5c−k) were obtained in excellent yields with excellent enantioselectivities.However, the substituents at the C3-position had some influence on the enantio-control.As the steric hindrance increased, the ee value significantly decreased (5l−m).This once again indicated that the dearomative [4 + 2] cycloaddition reaction was sensitive to the steric effect.Besides, the optimized conditions were well compatible to other disubstituted o-QDIs (5n−p).When monosubstituted o-QDIs were employed, regioisomers (5q−r) appeared.Finally, the N-protecting groups of o-QDIs were varied (5s−b′), whose steric hindrance deteriorated the enantioselectivity as shown in the results of 5z and 5b′.The absolute configuration of compound 5g was unambiguously determined by X-ray crystallography, and other [4 + 2] cycloaddition products were assigned by analogy. [17]o explore the mechanism, control experiments were conducted (Figure 6).Under standard conditions, the reaction of 2,3-dimethyl indole 1b with disubstituted o-QDI 2c delivered indole C6-arylation product 6 rather than the dearomative C3-arylation or [4 + 2] cycloaddition product (Figure 6A). [18]his chemical event should involve an interesting 1,6-addition process, which will be investigated in detail in the future.The use of N-methylated indoles 1c and 1d as substrates gave rise to messy results and racemic [4 + 2] product 5c′ respectively (Figure 6B,C).These outcomes underlined the importance of indole NH for the reactivity and stereoselectivity.On the basis of these experimental results, plausible transition states were proposed for this divergent dearomatization reaction (Figure 6D).First of all, the CPA catalyst simultaneously activated indoles and o-QDIs via H-bonding interaction.Similar to quinone methides, [19] the driving force of aromatization and the profound electrophilicity of imine nitrogen make o-QDIs as good 1,4-diazadienes (N═C─C═N).Therefore, dearomative [4 + 2] cycloaddition occurred via transition state TS-1, facilitating the formation of a six-membered ring fused indoline 5a.Nevertheless, electronic effects can be overwhelmed by steric interactions.In this event, 1,4-addition reaction of o-QDI took place via TS-2, leading to the dearomative arylation product indolenine 3a.Dual H-bonding interaction, plausible - interaction, as well as steric hindrance might contribute to the observed excellent enantio-control.Finally, to demonstrate the synthetic utility of this diversityoriented dearomatization protocol, large-scale preparations of indolenine 3e′ and six-membered ring fused indoline 5b were carried out.As shown in Figure 7A, in the presence of 1 mol% CPA, the reactions readily occurred without erosion of enantioselectivity.Furthermore, the prepared indolenine 3e′ can be transformed into some interesting indole derivatives (Figure 7B).Reduction of the imine motif with NaBH 4 afforded indoline 7. TsOH-triggered Boc deprotection furnished compound 8 in a good yield.The vicinal NH 2 groups can undergo further cyclization reactions with CDI, CS 2 , and glyoxal to form other useful indolenines 9−11 bearing a heteroaromatic group at the C3position.Additionally, the facile synthesis of (+)-Naseseazines C analog was accomplished (Figure 7C).The synthetic route commenced with the CPA-catalyzed diastereoselective dearomatization of cyclo(L-Pro-L-Trp-) 12 with o-QDI 2d.In the presence of (R)-CPA-1, the pentacyclic product 13 was obtained in 85% yield with 12:1 dr.The following deprotection and cyclization delivered the corresponding compound 15, a 3′-aza analog of (+)-Naseseazines C. [20]

Conclusion
In conclusion, we have established the first diversity-oriented CADA of indoles with o-QDIs.Given the importance of dearomatized indole derivatives, CADA reaction of indoles is a hot topic in organic synthesis.As opposite to the well-developed target-oriented CADA reactions, diversity-oriented CADA reactions are more challenging and remain elusive due to the lack of synthons featuring multiple reaction sites and the difficulty in precise control of chemo-, regio-, and enantio-selectivity.In this work, o-QDIs were employed as a versatile building block, enabling the chemo-divergent dearomative arylation and [4 + 2] cycloaddition reactions of indoles.Under the catalysis of CPA, various indolenines, furoindolines/pyrroloindolines, and six-membered ring fused indolines were collectively prepared in a DOS manner.This chemo-divergent protocol not only enriches the CADA reaction of indoles but also offers new reaction modes for o-QDIs.Further investigations along this line are ongoing in our laboratory and will be reported in due course.

Experimental Section
Typical Procedure for Arylation Reaction: To a solution of 2,3disubstituted indoles 1 (0.1 mmol, 1 equiv.)and catalyst CPA-1 (5 mol%) in anhydrous CH 2 Cl 2 (1 mL), was added o-QDIs 2 (1 equiv.) in five portions.The reaction mixture was stirred for 10 min at room temperature.After completion (monitored by TLC), the solvent was removed under reduced pressure and the crude product was directly purified by flash chromatography on silica gel employing mixtures of petroleum and ethyl acetate (petroleum ether/ethyl acetate 4:1-2:1) as eluents to afford the desired product 3.
Typical Procedure for [4 + 2] Reaction: To a solution of 3-substituted indoles 1 (0.1 mmol, 1 equiv.)and catalyst CPA-5 (5 mol%) in anhydrous toluene (1 mL), was added 50 mg 5Å MS and o-QDIs 2 (1 equiv.) in five portions.The reaction mixture was stirred for 10 min at 0 °C.After completion (monitored by TLC), the solvent was removed under reduced pressure, and the crude product was directly purified by flash chromatography on silica gel employing mixtures of petroleum and ethyl acetate (petroleum ether/ethyl acetate 4:1) as eluents to afford the desired product 5.
[CCDC 2268394 for 3g′ and 2268391 for 5g contain the supplementary crystallographic data for this paper.These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif .]