Regioselectivity of the SEAr-based cyclizations and SEAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

Indole-3,4- and 4,5-fused carbo- and heterocycles are ubiquitous in bioactive natural products and pharmaceuticals, and hence, a variety of synthetic approaches toward such compounds have been developed. Among these, cyclization and annulation of 3,5-unsubstituted, 4-substituted indoles involving an electrophilic aromatic substitution (SEAr) as the ring closure are particularly attractive, because they avoid the use of 3,4- or 4,5-difunctionalized indoles as starting materials. However, since 3,5-unsubstituted, 4-substituted indoles have two potential ring-closure sites (indole C3 and C5 positions), such reactions in principle can furnish either or both of the indole 3,4- and 4,5-fused ring systems. This Commentary will briefly highlight the issue by summarizing recent relevant literature reports.


Introduction
Over the decades, countless cyclization and annulation reactions of substituted arenes/heteroarenes involving an electrophilic aromatic substitution (S E Ar) reaction as the ring-closure step have been routinely employed for the construction of diverse arene-and heteroarene-fused rings (Scheme 1A) [1][2][3]. In most of these approaches, the new C Ar -C bond is formed ortho to the tether/directing functionality on an aromatic or a heteroaromatic ring, as the geometrical constraints do not normally allow meta or para-selective cyclization/annulation. In certain such cyclization and annulation reactions, however, formation of the C Ar -C bond at the ortho position is not guaranteed. As an example, cyclization and annulation of 3,5-unsubstituted, 4-substituted indoles involving an S E Ar reaction as the ring-closure step can generate indole 3,4-fused cabo-and heterocycles or/and their indole 4,5-fused counterparts (Scheme 1B). This is primarily due to the fact that such substrates have two proximal nucleophilic sites: the indole C5 as the ortho position and intrinsically highly nucleophilic indole C3 as the peri position, with the latter being often more nucleophilic than the former. Noteworthy is that the kinetic preference for ring-closure onto the C5 position may be a more dominating factor than the higher nucleophilicity of the C3 position (or vice versa).
Due to this regiochemical uncertainty, it is no surprise that the scope of cyclization and annulation of 3,5-unsubstituted, 4-substituted indoles has not been studied to the same extent as the scope of the cyclization and annulation of N-, 2-, or 3-substituted indoles [4]. However, several synthetically attractive cyclization and annulation of 3,5-unsubstituted, 4-substituted indoles have been reported in the recent past. Herein, we summarize these literature reports, with a special attention on the regiochemistry. Noteworthy is that although three reviews on the synthesis of 3,4-fused indoles have been published in the last decade [5][6][7], this is the first time the regioselectivity of the S E Ar-based/terminated cyclization and annulation reactions of 3,5-unsubstituted, 4-substituted indolesis is sytematized as a dedicated topic.

Discussion
The Tsuji-Trost reaction serves as a powerful tool in constructing carbon-carbon and carbon-heteroatom bonds in organic synthesis [8][9][10]. In the course of their diversity-oriented synthesis of indole-based peri-annulated compounds, You and co-workers in 2013 reported the intramolecular Tsuji-Trost reaction of indolyl allyl carbonates 1 under the catalysis of [Pd(C 3 H 5 )Cl] 2 and ligand L1 (Scheme 2) [11]. The reaction, that could also be considered as Friedel-Crafts type, intramolecular allylic alkylation, delivered ninemembered ring bearing 3,4-fused indoles 2 in moderate to good yields. In the asymmetric version of the reaction catalyzed by [Ir(cod)Cl] 2 (4 mol %) and ligand L2, the ring closure also took place regioselectively at the indole C3 position, albeit the products 3 were embedded with a seven-membered ring instead of a nine-membered one. The absolute configuration of products 3 was proposed to be S, based on the general rule of stereochemistry in the Ir-catalyzed allylic substitution reactions. In 2016, Billingsley and co-workers disclosed the total synthesis of (−)-indolactam V (6), a nanomolar agonist of protein kinase C (Scheme 3) [12]. The authors applied an intramolecular S E Ar reaction of 4-substituted indole derivative to construct a 3,4-fused tricyclic indole in a late stage of their total synthesis. Specifically, Michael-type addition of compound 4 took place regio-and diastereoselectively at the indole C3 position, furnishing tricyclic compound 5 (77%) which was then elaborated into the target natural product 6 in two steps.
Results of the acid-catalyzed intramolecular hydroindolation of cis-β-(α′,α′-dimethyl)-4′-methindolylstyrenes 17 were reported by Stokes and co-workers in 2019 (Scheme 6) [16].  be purified from the regioisomeric mixtures. Notably, no reaction took place with a N-acetyl-protected substrate, and a free N−H indole substrate decomposed. Furthermore, introduction of an electron-donating OMe group at the indole 7 position reversed the regioselectivity in favor of the 4,5-fused indole system. Based on their experimental and computational investigations, the researchers hypothesized that Thorpe-Ingold effect could induce dispersive interactions between the indole and styrene moieties, triggering the preferential formation of the 3,4-fused indoles 18 via a concerted protonation and C-C bond formation. Weakened dispersive interactions caused by a sub-stituent or heteroatom resulted in low yields and reduced regioselectivities.
In 2020, Li and Van der Eycken and co-workers reported the synthesis of densely functionalized, polycyclic azepino [5,4,3cd]indoles 21 from the intramolecular cyclization of Ugi adducts 20 in moderate to good yields and excellent chemo-, regio-, and diastereoselectivity (Scheme 7) [17]. Mechanistically, the reaction involves a tandem gold(I)-catalyzed dearomatization/ipso-cyclization/Michael addition sequence to substrates 20. Noteworthy is that substrates bearing an Recently, An and Xiao and co-workers disclosed high-yielding syntheses of a wide range of indole-3,4-fused nine-membered rings 27 via triflic acid (TfOH)-catalyzed reaction of indolederived phenylenediamine 25 with aldehydes 26 (Scheme 9) [19]. Mechanistically, the initially formed iminium ion I undergoes isomerization to iminium ion II through a 1,3-hydride shift process. Iminium ion III could then be generated via 1,6hydride shift in both I and II. Finally, an intramolecular Mannich-type cyclization then furnishes products 27. The cascade protocol enjoys several advantageous synthetic features, including high step-and atom-economy, transition-metalfree and room temperature conditions. In all cases shown above, the new C Ar -C bond is exclusively formed at the indole C3 position. However, cyclization of 4-substituted indoles that takes place regioselectively at the indole C5 positions has also been reported, albeit on rare occasions. One of the first such reports was disclosed by Dumas and Fillion in their studies on the intramolecular Friedel−Crafts (FC) acylation of 4-substituted indoles [20]. Specifically, N-Ns/ Ts-indolyl Meldrum's acid derivatives 28a-f delivered 4,5fused indoles 29a-f under BF 3 ·OEt 2 or Yb(OTf) 3 catalysis (Scheme 10A). It should be noted that the authors could not extend this methodology to related substrates with free indolyl NH as such reactions resulted into a complex mixture (not shown here), possibly due to the decomposition of the substrates. Nevertheless, the same regioselectivity was observed when the FC-acylation of N-protected 3-(4-indolyl)propanoic acids 28g-j was performed by converting them into the corresponding acid chloride, followed by treatment with AlCl 3 in refluxing 1,2-dichloroethane (DCE) (Scheme 10B). The reactions furnished indole 4,5-fused indanones 29g-j as the only detectable cyclized products. The authors noted that the kinetic preference for cyclization onto the C5 position is more dominating than the higher nucleophilicity of the C3 position, making the C Ar -C bond formation completely regioselective at the C5 position. Subsequently in 2017, Li and co-workers also applied the intramolecular Friedel-Crafts acylation strategy to get cyclopenta[e]indol-6-one 29k and cyclohepta[e]indol-6-one 29l from compounds 28k and 28l, respectively (Scheme 10C) [21].
In 2009, the Hansen group disclosed that treatment of 2-diazo-4-(4-indolyl)-3-oxobutanoate 30 with a catalytic amount of Rh 2 (OAc) 4 resulted in the formation of the 4,5-fused tricyclic indole derivative 31 in 82% yield (Scheme 11) [22]. Being a kinetically very active catalyst, Rh 2 (OAc) 4 favored the formation of the five-membered ring. On the other hand, employment of Pd(OAc) 2 -catalysis switched the regioselectivity of this C-H insertion reaction. More specifically, under Pd(OAc) 2 catalysis diazo compound 30 delivered 3,4-fused tricyclic indole derivative 32 which underwent spontaneous rearrangement to thermodynamically more stable naphthalene derivative 33 upon standing for a few hours. To the best of our knowledge, this is the only report of catalyst-controlled C3 versus C5 regioselec- In the course of their studies on chemospecific cyclization of α-carbonyl sulfoxonium ylides on aryls and heteroaryls, the Aïssa group in 2019 demonstrated hexafluoroisopropanol (HFIP)-promoted regioselective cyclization of β-carbonyl sulfoxonium ylides 34a,b in the presence of K 2 CO 3 to access cyclopenta[e]indol-6-ones 35a,b in moderate yields (Scheme 12) [23]. The authors proposed that under the experimental conditions β-carbonyl sulfoxonium ylides 34a,b were isomerized to IV which then produced oxy-allyl cation V. Elec-trocyclization of V followed by loss of proton from the intermediate VI afforded the corresponding cyclopenta[e]indol-6-ones 35a,b.

Conclusion
As illustrated by these studies, S E Ar-based intramolecular cyclization and annulation reactions of 3,5-unsubstituted, 4-substituted indoles have recently been successfully applied in the construction of indole 3,4-and 4,5-fused carbo-and heterocycles. Notably, most of these reactions are highly to completely regioselective, despite having two potential ring-closure sites in the substrates. From these reports, some trends in the prediction of site of ring-closure can be derived. In general, absence of an electron-donating group in the indole benzene ring promotes C3 regioselective cyclization, provided the size of the newly formed ring is greater than six. Under the opposite scenario, C5 regioselective cyclization is observed. Moreover, the use of the electron-withdrawing protecting group on the indole N atom could favor the formation of 4,5-fused indoles by decreasing the nucleophilicity at the indole C3 position. However, detailed studies of the effect of the electronic nature of the indole NH protecting group on the regioselectivity are yet to be reported for S E Ar-based intramolecular cyclization and annulation reactions of 3,5-unsubstituted, 4-substituted indoles. Such studies in this area will certainly aid in elucidating the regioselectivity more precisely.