Rhodium-Catalyzed Oxidative Annulation of 2- or 7-Arylindoles with Alkenes/Alkynes Using Molecular Oxygen as the Sole Oxidant Enabled by Quaternary Ammonium Salt

Developing an efficient catalytic system using molecular oxygen as the oxidant for rhodium-catalyzed cross-dehydrogenative coupling remains highly desirable. Herein, rhodium-catalyzed oxidative annulation of 2- or 7-phenyl-1H-indoles with alkenes or alkynes to assemble valuable 6H-isoindolo[2,1-a]indoles, pyrrolo[3,2,1-de]phenanthridines, or indolo[2,1-a]isoquinolines using the atmospheric pressure of air as the sole oxidant enabled by quaternary ammonium salt has been accomplished. Mechanistic studies provided evidence for the fast intramolecular aza-Michael reaction and aerobic reoxidation of Rh(I)/Rh(III), facilitated by the addition of quaternary ammonium salt.

To gain further insights into the impact of quaternary ammonium salts in the present transformation, we conducted several kinetic studies via 1 H NMR spectroscopy. The time study shown in Figure 1 revealed that the one-pot C-H olefination/aza-Michael reaction under air atmosphere afforded 50% yield of 4a after 30 min and was completed within 2 h by adding n-Bu 4 NOAc. It must be pointed out that the C-H olefinated product was not detected during monitoring period. Without n-Bu 4 NOAc, 4a was not obtained at all, and nor was the C-H olefinated product (3a) formed. Quaternary ammonium salts have always been considered to be an effective catalyst for Michael reactions [74][75][76][77][78][79]. As one can see from Figure 2, the intramolecular aza-Michael reaction of ortho-alkenylated-2phenyl-1H-indole could indeed be improved by the addition of n-Bu 4 NOAc. 1 equiv. of n-Bu 4 NOAc, and provided complete conversion and quantitative yield of 4a after just 3 min. In the absence of n-Bu 4 NOAc, no reaction occurred, and the ortho-alkenylated-2-phenyl-1H-indole was totally recovered. The further kinetic experiments were carried out using Cu(OAc) 2 instead of O 2 as the terminal oxidant. As seen in Figure 3, the C-H olefination of 2-phenylindole with with n-butyl acrylate completed within 2 h in the absence of n-Bu 4 NOAc, affording 90% yield of 3a. By adding n-Bu 4 NOAc, the C-H olefinated product (3a) was totally transformed into aza-Michael product 4a within 2 h (Figure 4). In order to illustrate the impact of n-Bu 4 NOAc in the C-H olefination step, styrene was chosen as the coupling partner because it is not a Michael acceptor, and the reaction can stop after C-H olefination. As shown in Figure 5, no significant differences were observed between experiments performed with or without n-Bu 4 NOAc. These observations suggest that quaternary ammonium salt plays at least two roles in the oxidative annuation of 2-phenyl-1H-indole with with alkenes: (a) It promotes the intramolecular aza-Michael reaction of the C-H olefinated product; and (b) It promotes aerobic reoxidation of Rh(I) to Rh(III). The second role was partly validated by the fact that the current catalytic system ([Cp*RhCl 2 ] 2 /n-Bu 4 NOAc/O 2 ) was also effective for the oxidative annulation of 2-phenylindoles with alkynes to assemble indolo[2,1-a]isoquinoline skeletons. One reason why quaternary ammonium salt can speed up aerobic reoxidation is probably due to the increased dissolved quantity of O 2 from adding quaternary ammonium salt [80][81][82]. Table 1. Optimization of the reaction conditions a . Scheme 1. Rhodium-catalyzed oxidative annulation of 2-or 7-phenyl-1H-indoles with alkenes or alkynes using molecular oxygen as the sole oxidant enabled by quaternary ammonium salt.

Results and Discussions
Our investigation on the aerobic rhodium-catalyzed CDC reaction began with the NH-indole-directed ortho-C-H alkenylation of 2-phenyl-1H-indole (1a) with n-butyl acrylate. The catalytic system consisting of [Cp*RhCl2]2 (2.5 mol%) and n-Bu4NOAc (1 equiv.) promoted the reaction at 140 °C under air atmosphere in xylenes to afford 6H-isoindolo[2,1-a]indole (4a) in 93% yield (Table 1, entry 2), derived from ortho-C-H olefination and the subsequent intramolecular aza-Michael addition. The addition of n-Bu4NOAc was indispensable as the reaction became very sluggish in its absence in various solvents such as xylenes, DMF, THF, EtOAc, and 1,4-dioxane (entry 1). A similar yield was obtained when Me4NOAc (1 equiv.) was added (entry 3), while other quaternary ammonium salts gave inferior results (entries [4][5][6][7][8][9][10][11]. Control experiments have shown that no reaction occurred in the absence of rhodium catalyst or molecular oxygen (entry 12). To gain further insights into the impact of quaternary ammonium salt transformation, we conducted several kinetic studies via 1 H NMR spectros study shown in Figure 1 revealed that the one-pot C-H olefination/aza-M under air atmosphere afforded 50% yield of 4a after 30 min and was com h by adding n-Bu4NOAc. It must be pointed out that the C-H olefinated p detected during monitoring period. Without n-Bu4NOAc, 4a was not obta nor was the C-H olefinated product (3a) formed. Quaternary ammonium ways been considered to be an effective catalyst for Michael reactions [74see from Figure 2, the intramolecular aza-Michael reaction of ortho-alkeny 1H-indole could indeed be improved by the addition of n-Bu4NOAc. Bu4NOAc, and provided complete conversion and quantitative yield of 4a In the absence of n-Bu4NOAc, no reaction occurred, and the ortho-alkeny 1H-indole was totally recovered. The further kinetic experiments were ca Cu(OAc)2 instead of O2 as the terminal oxidant. As seen in Figure 3, the C of 2-phenylindole with with n-butyl acrylate completed within 2 h in th Bu4NOAc, affording 90% yield of 3a. By adding n-Bu4NOAc, the C-H olef (3a) was totally transformed into aza-Michael product 4a within 2 h (Figur illustrate the impact of n-Bu4NOAc in the C-H olefination step, styrene wa coupling partner because it is not a Michael acceptor, and the reaction can olefination. As shown in Figure 5, no significant differences were observ periments performed with or without n-Bu4NOAc. These observations su ternary ammonium salt plays at least two roles in the oxidative annuatio 1H-indole with with alkenes: (a) It promotes the intramolecular aza-Mich the C-H olefinated product; and (b) It promotes aerobic reoxidation of Rh(I second role was partly validated by the fact that the current ca ([Cp*RhCl2]2/n-Bu4NOAc/O2) was also effective for the oxidative annulati indoles with alkynes to assemble indolo[2,1-a]isoquinoline skeletons. O quaternary ammonium salt can speed up aerobic reoxidation is probably creased dissolved quantity of O2 from adding quaternary ammonium salt            With the optimized conditions in hand, the generality of the rhodium-catalyzed aerobic C-H olefination/aza-Michael reaction was then explored (Scheme 2). The reaction of 2-phenyl-1H-indole, which contains two ortho-C-H bonds with n-butyl acrylate, provided the desired annulated product 4b in low yield (30%) with recovered starting material (65%). Therefore, blocking one of the ortho-C-H bonds with methyl or chloro is essential for full conversion. 2-phenyl-1H-indole derivatives with substituents at the benzene ring or indole ring were delivered the corresponding products in good to excellent yields, showing very limited effect on the reaction efficiency (4c-4f). As expected, other acrylates bearing methyl, ethyl, or tert-butyl all well reacted with 1a to afford the desired product 4g-4i in good yields. The C-H olefination/aza-Michael reaction of 7-phenyl-1H-indoles with ethyl acrylate afforded the corresponding pyrrolo[3,2,1-de]phenanthridine derivatives under the reaction conditions by changing n-Bu 4 NOAc with Me 4 NOAc. By contrast, only one ortho-C-H bond was cleaved, showing good chemoselectivity (4j-4q). 7-phenylindoles and acrylates bearing various substituents, such as chloro (4l), ketone (4m), CN (4n), NO 2 (4o), naphthyl (4p), and n-butyl (4q) coupled well with ethyl acrylate or ethyl acrylate, showing good functional group tolerance. The experiment results also showed no electronic effect on the reaction efficiency.
Based on the experimental results obtained above and precedent reports [31,32,34,44], a plausible mechanism for the aerobic rhodium-catalyzed oxidative annulation of 2phenylindole with alkene or alkyne is postulated in Scheme 4. Coordination of N atom of phenylindole to Rh(III) and the subsequent ortho-C-H activation produced the fivemembered rhodacycle B. B inserted into the alkene or alkyne affording the intermediate C1 or C2, and the subsequent β-H elimination/reductive elimination provided Rh(I) sandwich complex D1 or D2. Then D1 or D2 was oxidized by oxygen to regenerate the active Rh(III) species and released the corresponding product 3 or 5. The C-H olefinated product (3) can be transformed into aza-Michael product 4 efficiently, and the oxidation step by molecular oxygen will be sped up substantially by adding quaternary ammonium salts. Based on the experimental results obtained above and precedent reports [31,32,34,44], a plausible mechanism for the aerobic rhodium-catalyzed oxidative annulation of 2-phenylindole with alkene or alkyne is postulated in Scheme 4. Coordination of N atom of phenylindole to Rh(III) and the subsequent ortho-C-H activation produced the five-membered rhodacycle B. B inserted into the alkene or alkyne affording the intermediate C1 or C2, and the subsequent β-H elimination/reductive elimination provided Rh(I) sandwich complex D1 or D2. Then D1 or D2 was oxidized by oxygen to regenerate the active Rh(III) species and released the corresponding product 3 or 5. The C-H olefinated product (3) can be transformed into aza-Michael product 4 efficiently, and the oxidation step by molecular oxygen will be sped up substantially by adding quaternary ammonium salts.

General Information
Unless otherwise noted, the reagents (chemicals) were purchased from commercial sources and were used without further purification. 2-phenyl-1H-indole is commercially available. The other 2-arylindoles were synthesized from phenylhydrazine hydrochlorides via Fisher indole synthesis [44]. 7-phenyl-1H-indoles were synthesized from 7-bromo-1Hindoles and phenylboronic acid via Suzuki coupling [34,35]. Quaternary ammonium salts were purchased from commercial sources. Their purity was more than 99.0% and they were stored in a glovebox. 1 H NMR spectra were recorded at 400 MHz and 13 C NMR spectra at 100 MHz, respectively (Supplementary material). 1 H chemical shifts (δ) were referenced to TMS, and 13 C NMR chemical shifts (δ) were referenced to internal solvent resonance. ESI-HRMS spectra were recorded by using a Q-TOF mass spectrometer.

General Procedure for Rhodium-Catalyzed Oxidative Annulation of 2-or 7-Arylindoles with Alkenes/Alkynes
Under air atmosphere, 2-or 7-arylindoles (0.2 mmol), alkenes or alkynes (0.4 mmol), [Cp*RhCl 2 ] 2 (3.2 mg, 0.005 mmol, 2.5 mol%), n-Bu 4 NOAc or Me 4 NOAc (0.2 mmol, 1 equiv.), and xylenes (4 mL) were placed in a 25 mL tube. The mixture was heated in oil bath at 140 • C for 2 h or 80 • C for 20 h. After the reaction mixture cooled to room temperature, the crude reaction mixture was diluted with EtOAc to 5 mL, filtered through a celite pad, and then washed with 10 mL EtOAc. The combined mixture was washed with saturated aqueous Na 2 CO 3 and dried over anhydrous MgSO 4 . After filtration, the volatiles were removed under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting with petroleum ether/dichloromethane = 1/1 or petroleum ether/ethyl acetate = 100/1) to afford the corresponding product.  13 C NMR and HRMS data for the desired product were in agreement with the previously reported literature data [44].  13 C NMR and HRMS data for the desired product were in agreement with the previously reported literature data [44].    13 C NMR and HRMS data for the desired product were in agreement with the previously reported literature data [44].

Conclusions
In conclusion, we have reported on the rhodium-catalyzed oxidative annulation of 2-or 7-phenyl-1H-indoles with alkenes or alkynes to assemble valuable 6H-isoindolo[2,1a]indoles, pyrrolo[3,2,1-de]phenanthridines, or indolo[2,1-a]isoquinolines using molecular oxygen as the sole oxidant enable by quaternary ammonium salt. Salient features of present catalytic system comprise (a) the atmospheric pressure of air as the sole oxidant, (b) one catalytic system for three discrete reactions, and (c) mechanistic insights. Mechanistic studies provided support for fast intramolecular aza-Michael reaction and aerobic reoxidation of Rh(I) to Rh(III) by adding quaternary ammonium salt. Additional mechanistic/computational studies will be needed to fully elucidate the unique influence of quaternary ammonium salt on the catalytic cycle, and are in progress in our laboratory.
Supplementary Materials: The following are available online. Figure S1: Copies of the 1 H NMR, 13 C NMR charts for compounds.