Dispersion-Controlled Regioselective Acid-Catalyzed Intramolecular Hydroindolation of cis-Methindolylstyrenes To Access Tetrahydrobenzo[cd]indoles

Readily prepared cis-β-(α′,α′-dimethyl)-4′-methindolylstyrenes undergo acid-catalyzed intramolecular hydroindolation to afford tetrahydrobenzo[cd]indoles. Our experimental and computational investigations suggest that dispersive interactions between the indole and styrene preorganize substrates such that 6-membered ring formation is preferred, apparently via concerted protonation and C−C bond formation. When dispersion is attenuated (by a substituent or heteroatom), regioselectivity erodes and competing oligomerization predominates for cis substrates. Similarly, all trans-configured substrates that we evaluated failed to cyclize efficiently. S conformational biasing arising from steric constraints, such as those imposed by geminal dialkyl groups (i.e., the Thorpe−Ingold effect), are often used to circumvent energetic barriers to bond formation in order to prepare new and useful molecules. We recently developed an intramolecular acid-catalyzed hydroarylation of β-(α′,α′dialkyl)benzylstyrenes (A, Scheme 1A), showing that a gemdialkyl group can be used to synthesize indanes efficiently (B). We became interested in applying this design concept to more complex and medicinally relevant substrates, namely 4-bromoindole-derived β-(α′,α′-dimethyl)-4′-methindolylstyrenes like C (Scheme 1B), which are rapidly prepared by sequential enolate cross-coupling, Wittig, and benzyl protection reactions. Cyclization could occur at either C3 to afford tetrahydrobenzo[cd]indole D or at C5 to afford tetrahydrocyclopenta[e]indole E. Herein, we report that a variety of 3-aryl-5,5-dimethyl-1,3,4,5-tetrahydrobenzo[cd]indoles (D) are efficiently prepared in good yield by treating the cis-configured isomer of C with Brønsted acid catalysts (Scheme 1B, top pathway). In contrast, trans-configured substrates predominantly oligomerize (Scheme 1B, bottom pathway). Our experimental and computational data suggest that angle compression can induce a ground-state stabilization of cis-substrates through dispersive interactions, presumably between arene π systems, enabling a concerted protonation and electrophilic attack to afford G, which rearomatizes to H (Scheme 1C). A concerted mechanism avoids generating a long-lived carbocation intermediate that would be more likely to participate in competing intermolecular decomposition pathways, which may explain the disparate cyclizing ability of trans-configured starting materials and nondispersible cisconfigured substrates (see below). Products like H contain quaternary geminal dimethyl and diarylmethine motifs, which are well-represented in natural products and medicines, and contain the 5,5-dimethyl-1,3,4,5tetrahydrobenzo[cd]indole framework (in blue) common to the important ambiguine and hapalindole natural product families and closely related to lysergic acid. Despite significant synthetic attention devoted to 5,5-dimethyl-1,3,4,5tetrahydrobenzo[cd]indoles, a general method for their synthesis has not been reported. Target-oriented cyclization strategies have included stoichiometric Lewis acid mediated alkene hydroindolations using 7-methoxy-substituted 3-alkenylindoles or additions to carbonyls and intramolecular Heck reactions of 4-bromoindoles. Our optimization revealed that cis-configured indole analogues could be cyclized with good regioselectivity (85:15) favoring tetrahydrobenzo[cd]indole by using arenecontaining Brønsted acid catalysts in non-Lewis basic polarizable aprotic solvents. Good yield was obtained after heating for 24 h at 130 °C in the presence of 25 mol % of anhydrous benzenesulfonic acid in toluene. Under the optimized conditions, our evaluation of different N protecting groups revealed their influence on the yield and regioselectivity of the reaction (Table 1). The best result was obtained using cisconfigured benzyl-protected substrate 1a, which afforded 73% isolated yield of major product 2a on 0.2 mmol scale (entry 1) Received: January 4, 2019 Published: February 26, 2019 Letter pubs.acs.org/OrgLett Cite This: Org. Lett. 2019, 21, 1574−1577 © 2019 American Chemical Society 1574 DOI: 10.1021/acs.orglett.9b00043 Org. Lett. 2019, 21, 1574−1577 D ow nl oa de d vi a U N IV O F C A L IF O R N IA M E R C E D o n Ju ly 1 5, 2 01 9 at 2 2: 15 :3 8 (U T C ). Se e ht tp s: //p ub s. ac s. or g/ sh ar in gg ui de lin es f or o pt io ns o n ho w to le gi tim at el y sh ar e pu bl is he d ar tic le s.

Substrate conformational biasing arising from steric constraints, such as those imposed by geminal dialkyl groups (i.e., Thorpe-Ingold effects), 1 are often used to circumvent energetic barriers to bond formation in order to prepare new and useful molecules. We recently developed an intramolecular acid-catalyzed hydroarylation of β-(α',α'dialkyl)benzylstyrenes (A, Scheme 1A), showing that a gem-dialkyl group can be used to synthesize indanes efficiently (B). 2, 3 We became interested in applying this design concept to more complex and medicinally relevant substrates, namely 4-bromoindole-derived β-(α',α'dimethyl)-4'-methindolylstyrenes like C (Scheme 1B), which are rapidly prepared by sequential enolate crosscoupling, Wittig, and benzyl protection reactions. 4 Cyclization could occur at either C3 to afford tetrahydrobenzo[cd]indole D, or at C5 to afford tetrahydrocyclopenta[e]indole E. Herein, we report that a variety of 3-aryl-5,5-dimethyl-1,3,4,5-tetrahydrobenzo[cd]indoles (D) are efficiently prepared in good yield by treating the cisconfigured isomer of C with Brønsted acid catalysts (Scheme 1B, top pathway). In contrast, trans-configured substrates predominantly oligomerize (Scheme 1B, bottom pathway). Our experimental and computational data suggest that angle compression can induce a ground state Scheme 1. Geminal Dimethyl-Enabled Catalytic Intramolecular Alkene Hydroarylation Reactions stabilization of cis-substrates through dispersive interactions, presumably between arene π systems, 5 enabling concerted protonation and electrophilic attack to afford G, which rearomatizes to H (Scheme 1C). 6 A concerted mechanism avoids generating a long-lived carbocation intermediate that would be more likely to participate in competing intermolecular decomposition pathwayswhich may explain the disparate cyclizing ability of transconfigured starting materials, and non-dispersable cisconfigured substrates (see below).
Products like H contain quaternary geminal dimethyl and diarylmethine motifs, which are well-represented in natural products and medicines, 7  indole framework (in blue) common to the important ambiguine and hapalindole natural product families, and closely related to lysergic acid. 8 Despite significant synthetic attention devoted to 5,5-dimethyl-1,3,4,5-tetrahydrobenzo[cd]indoles, a general method for their synthesis has not been reported. Target-oriented cyclization strategies have included stoichiometric Lewis acid-mediated alkene hydroarylations using 7-methoxy substituted 3-alkenylindoles 9 or additions to carbonyls, 10 and intramolecular Heck reactions of 4-bromoindoles. 11 Our optimization revealed that cis-configured indole analogues could be cyclized with good regioselectivity (85:15) favoring tetrahydrobenzo[cd]indole by using arene-containing Brønsted acid catalysts in non-Lewis basic polarizable aprotic solvents. 4 Good yield was obtained after heating for 24 hours at 130 °C in the presence of 25 mol % of anhydrous benzenesulfonic acid in toluene. Under the optimized conditions, our evaluation of different N protecting groups revealed their influence on the yield and regioselectivity of the reaction ( Table 1). The best result was obtained using cis-configured benzylprotected substrate 1a, which afforded 73% isolated yield of major product 2a on 0.2 mmol scale (entry 1), and similar yield at 1.0 mmol scale (entry 2). Another readilydeprotected indole, N-ethylsulfonyl analogue 1b, afforded 2b in slightly reduced yield and selectivity (entry 3). 12 Yields and regioselectivities for N-alkylindolyl substrates were similar to those of 1a, and include methyl (1c) ethyl (1d) and iso-propyl (1e) groups (entries 4-6). When an electron-withdrawing tosyl protecting group was used, selectivity diminished (1f, entry 7). Acetyl protection prevented substrate conversion (entry 8). Lastly, free N-H indole 1h simply decomposed (entry 9). Fortunately, the benzyl group in 2a is readily deprotected in 91% yield. 13

Table 1. Evaluation of Indole N-Protecting Groups
Reactions were conducted on 0.2 mmol scale unless otherwise noted. a Regioisomeric ratio determined by 1 H NMR analysis of the crude reaction.
b Reaction was conducted on 1.0 mmol scale. c Structure of 2e confirmed by X-ray crystallography. d Combined yield of inseparable regioisomers. e Structure of 1h confirmed by X-ray crystallography.
We next evaluated the influence of functional groups on the cyclization of N-benzylindolyl substrates (Table 2). Owing to the generally good regioselectivity of the reaction (ranging from 80:20 to >95:5), we were typically able to obtain the fused tricyclic isomer in good or excellent yield. Para-substituents on the styrene moiety, including Me, F, Cl, and Br (1i-1l), afforded fused tricycles in high yield, as did electron-donating groups positioned meta, like methoxy (1m) and methyl (1n). In contrast, stoichiometric amounts of benzenesulfonic acid are required to Table 2

. Scope of the Cyclization
Reactions employed pure cis-alkenyl starting materials unless otherwise noted and were conducted on 0.2 mmol scale. The substrates were fully consumed in all cases. Unless otherwise noted, yields refer to the isolated indicated major product, and regioselectivities (2:3, indicated in parentheses) were determined by 1  obtain acceptable yields when halogens are positioned meta to the alkene (1o-1q); for example, meta-bromo substrate 1q cyclized in 68% yield from a 65:35 mixture of inseparable cis and trans isomers. Beyond substituted benzenes, we found that the 2-naphthyl analogue 1r gave 76% yield of 2r from an inseparable 78:22 mixture of cis and trans starting stereoisomers, respectively. In our final variation of the alkene aromatic substituent, a 2thiophene analogue also afforded the fused tricycle 2s in good yield. Shifting our focus to functional group tolerance on the indole ring, a 2-methyl substituent was welltolerated, as were 6-chloro and 7-fluoro variants (2t-2v, respectively). The latter afforded the best yield and regioselectivity that we observed in this study. Surprisingly, adding electron-donating substituents to the 7 position impacted the regioselectivity significantly, with 7-methyl substrate 1w affording a 55% yield of an inseparable regioisomeric mixture of 2w and 3w. Even more surprisingly, formation of the 6-membered ring was completely prohibited by the presence of a 7-methoxy substituent-only 3x was isolated.
Based on the disparate outcomes observed for substrates 1v-1x, it appears that regioselectivity is highly dependent on the electronic nature of the indole ring, perhaps as a result of the Thorpe-Ingold effect driving overlap with the styrene π system. To probe this hypothesis, we computed the relative gas phase enthalpies (ΔΔH) of the two rotamers (cis-1 and cis-1') that would lead to the respective products 2 or 3 using B3PW91/6-311G(d) with the GD3 empirical dispersion correction (Table 3). 14 By comparing substrates varying only at the C7 substituent, we assume minimal entropic influence on the equilibrium between the two rotamers. Fluorinated rotamer cis-1v is 6.66 kcal/mol more stable than cis-1v', corresponding to an equilibrium constant favoring cis-1v by a factor of over 4000 at 130 °C. Cis-1v exhibits parallel facial alignment of the π systems within 3.0 Å; styrenyl phenyl C-H bonds are within 3.0 Å of the pyrrole center and N-Bn phenyl ring center as well. 15 The computed Keq at 130 °C and the experimental log(2/3) diminish linearly (R 2 = 0.93) across R = F, H, and Me. The computed rotamer enthalpies do not differ significantly without GD3 correction. 4 Keq and log(2/3)

Table 3. Correlated Calculated Ground State Enthalpies of Substrate Rotamers with Regioselectivity
Gas phase calculations of ΔΔH using B3PW91/6-311G(d) with the GD3 empirical dispersion correction.
for methoxy-bearing substrate 1x do not correlate, which may be due to steric encumbrance by the conjugated ether, or non-innocence of the methoxy group.
In contrast to cis alkenes (odd-numbered entries, Table 4), trans alkenes (even-numbered entries) afford uniformly low yields and reduced regioselectivities, presumably due to the absence of dispersive stabilization (see the Supporting Information for trans enthalpies). Further, while non-indolic cis-β-benzylstyrene cis-A isomerizes to trans-A in just 1 hour at 80 °C (Scheme 2A), indole analogue cis-1c is unreactive after 24 hours (Scheme 2B). In light of our computations, these configurational reactivity differences suggest that dispersive stabilization allows protonation and electrophilic attack to occur in concert since cis alkenes resist isomerization to trans alkenes under the despite the cation-promoting conditions. Additionally, trans-A cleanly cyclizes to indane B by increasing the reaction temperature to 130 °C (Scheme 2A).
We also found that benzothiophene analogue cis-4 cyclizes with regioselectivity similar to indoles under

Table 4. Influence of cis and trans Alkene Configuration on the Cyclization of Methindolylstyrenes
Reactions were conducted on 0.2 mmol scale, and substrates were consumed in full in all cases. The major decomposition pathway for trans substrates is oligomerization. a Yield and regioselectivity were determined by 1 H NMR analysis of the crude reaction mixture. b 80 mol % of catalyst was used. identical conditions, albeit a bit more sluggishly; our DFT calculations (with GD3 correction) show that ΔΔH = 4.70 kcal/mol for the two cis conformers of 4. 4 In contrast, trans-4 cyclized with slightly improved yield and regioselectivity compared to trans indoles (eq 1). In contrast, we did not observe formation of the corresponding fused tricycle when using benzofuran analogues (eq 2). Rather, cis-7 isomerized to trans-7 at just 80 °C, with some formation of regioisomer 8 observed. This disparate behavior compared to indoles and benzothiophenes is likely due to a combination of diminished nucleophilicity at C3 and diminished dispersibility, as our DFT calculations show ΔΔH = 3.16 kcal/mol for the two cis rotamers of 7. 4

Scheme 2. Disparate Reactivity Profiles of cis-β-Benzylstyrene and cis-β-4'-Methindolylstyrene
In conclusion, we have developed a catalytic hydroarylation to construct medicinally significant 5,5dimethyl-1,3,4,5-tetrahydrobenzo[cd]indoles from cismethindolylstyrenes bearing a benzylic gem-dimethyl group, putatively via concerted protonation and C-C bond formation. Empirical trends (substrate isomerizability, regioselectivity outcomes, electronic sensitivity, and temperature profile) and calculated ground state enthalpies of substrate conformers suggest that the marked disparity in behavior of certain substrates is best rationalized by energetic stabilization arising from dispersive interactions between the two aromatic π systems, which are driven into proximity by the gem dimethyl.