Cyclization for Synthesis of [3,4

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Cascade [1,5]-Hydride Transfer/Cyclization for Synthesis of [3,4]-Fused Oxindoles Shuai Zhu, Chunqi Chen, Kang Duan, Yun-Ming Sun, Shuai-Shuai Li, Qing Liu, and Jian Xiao J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00489 • Publication Date (Web): 28 May 2019 Downloaded from http://pubs.acs.org on May 28, 2019

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The Journal of Organic Chemistry

Cascade [1,5]-Hydride Transfer/Cyclization for Synthesis of [3,4]-Fused Oxindoles Shuai Zhu,† Chunqi Chen,† Kang Duan,† Yun-Ming Sun, Shuai-Shuai Li,*,† Qing Liu,§ Jian Xiao*,†,‡ † College ‡

of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China

College of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China.

§College

of Chemical and Environmental Engineering, Shandong University of Science and Technology, Qingdao 266590, China.

Corresponding author: Shuai-Shuai Li; Jian Xiao E-mail address: [email protected]; [email protected]

Graphic Abstract

Abstract: The scandium-catalyzed redox-neutral cascade [1,5]-hydride transfer/cyclization between C4-amine-substituted isatins and 1,3-dicarbonyl compounds have been developed. This protocol enabled the synthesis of tricyclic

[3,4]-fused oxindoles in good to high yields and

excellent diastereoselectivities, featuring high atom- and step economy as well as wide functional group tolerance. INTRODUCTION The cascade [1,5]-hydride transfer/cyclization has recently emerged as a powerful tool for the efficient construction of architecturally complex moleclues via an intramolecular redox process.1 In recent decades, organic chemists have developed several hydride acceptors including electron-poor alkene,2 alkyne,3 aldehyde,4 imine5 and others6 to snatch the hydrides adjacent to heteroatoms, with production of the active carbocation intermediates. Then the in situ generated carbocation intermediates were captured immediately via intramolecular or intermolecular nucleophilic attack to release the heterocyclic compounds. Although significant progress has been made in this field,

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there are still some limitations that must be pointed out. One of these limitations is the tedious preparation of substrates beforehand anchored with hydride donors and acceptors, which tremendously limits the application of these strategies in the assembly of molecular complexity as well as the synthesis of biologically important target molecules. Notably, there are sporadic examples for the involvement of isatin-dervived substrates, despite their importance in organic synthesis.2h,5e In recent years, the cascade [1,5]-hydride transfer/cyclization via in situ generated hydride acceptors with two independent substrates to initiate intramoleculer hydride transfer have made great progress.7-9 For instance, Seidel group reported the diphenyl phosphate catalyzed redoxneutral annulation between indoles and o-aminobenzaldehydes via cascade condensation/[1,5]hydride transfer/cyclization, furnishing polycyclic azepinoindoles in good yields (Scheme 1, A).8 Very recently, our group developed a HFIP-promoted dearomative cyclization from phenols and oaminobenzaldehydes via cascade dearomatization/rearomatization/dearomatization sequence to construct highly functionalized tetrahydroquinolines (Scheme 1, B).9 The above success with in situ generated hydride acceptors encourage us to exploit new type of reactions for the construction of complex pharmaceutical intermediates from readily available starting materials. Polycyclic molecules containing oxindole moieties are embedded in a number of natural products and biologically active compounds.10 In the past few years, great advances have been achieved in the synthesis of diversely functionalized spirooxindoles.11 However, the approches for direct access to [3,4]-fused oxindoles from simple precursors remain underdeveloped and only sporadic examples were reported, despite their prevalence in a number of natural products.12 As a continuation of our interest in one-step assembly of molecular complexity via hydride transfer,7c,9,14 herein, we would like to report the scandium-catalyzed redox-neutral cascade cyclizations between C4-aminesubstituted isatins and 1,3-dicarbonyl compounds, providing a variety of tricylic [3,4]-fused oxindoles in good yields and excellent diastereoselectivities(Scheme 1, C). Scheme 1. Cascade [1,5]-hydride Transfer/Cyclization for Construction of Biologically Important Skeletons


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RESULTS AND DISCUSSION

In our initial study, 1-benzyl-4-(pyrrolidin-1-yl)indoline-2,3-dione 1a and 1H-indene-1,3(2H)dione 2a were selected as model substrates with 10 mol % of Sc(OTf)3 as a catalyst to examine the reaction (Table 1). Satisfyingly, this reaction proceeded very well, affording the desired 6/5/6 [3,4]fused oxindole 3a in 91% yield (Table 1, entry 1). The structure of 3a has been unambiguously confirmed by X-ray crystallographic analysis (See Supporting Information). More intriguingly, this reaction exhibited excellent stereocontrol (>20:1 dr). Encouraged by this result, a variety of triflate salts were further evaluated (Table 1, entries 2-5). Good yields could also be obtained when Zn(OTf)2 and Cu(OTf)2 were used. Besides, InBr3 and ZnBr2 showed good catalytic activity as well to give product 3a in 90% and 87% yields, respectively (Table 1, entries 6 and 7). In terms of the yield, Sc(OTf)3 was chosen as the most suitable catalyst to perform the further screening. Subsequently, different types of molecular sieves were added in this reaction to test the reaction efficiency. To our delight, 5 Å molecular sieves turned out to be the most effective additive, furnishing 3a in 99% yield with excellent diastereoselectivity (Table 1, entries 8-10). Not surprisingly, the solvent screening showed that the reactivity was strongly affected by the solvents and the employment of chloralkane such as dichloromethane and trichloromethane was crucial for yielding the excellent results (Table 1, entries 11-14). However, further decrease of the catalyst loading gave rise to diminishing yield of 3a, albeit without influence on the diastereoselectivity



(Table 1, entry 15). Finally, the control experiment displayed that this reaction did not proceed at all in the absence of Sc(OTf)3 catalyst (Table 1, entry 16). Table 1. Optimization of the Reaction Conditionsa

entry catalyst additive solvent yield (%)b drc 1 Sc(OTf)3 -DCE 91 >20:1 2 Mg(OTf)2 -DCE 55 >20:1 3 Zn(OTf)2 -DCE 90 >20:1 4 Cu(OTf)2 -DCE 87 >20:1 5 AgOTf -DCE 60 >20:1 6 InBr3 -DCE 90 >20:1 7 ZnBr2 -DCE 87 >20:1 8 Sc(OTf)3 3 Å MS DCE 89 >20:1 9 Sc(OTf)3 4 Å MS DCE 93 >20:1 10 Sc(OTf)3 5 Å MS DCE 99 >20:1 11 Sc(OTf)3 5 Å MS DCM 99 >20:1 12 Sc(OTf)3 5 Å MS CHCl3 99 >20:1 13 Sc(OTf)3 5 Å MS toluene 76 >20:1 14 Sc(OTf)3 5 Å MS hexane 63 >20:1 15d Sc(OTf)3 5 Å MS DCE 93 >20:1 16 -5 Å MS DCE --aReaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst (10 mol %), additive (50 mg) in 1.0 mL of distilled solvent at 60 C for 12 h. bIsolated yield after column chromatography. cDetermined by 1H NMR spectroscopy. dCatalyst

Sc(OTf)3 (5 mol %).

With the optimal reaction conditions in hand, we turned our attention to evaluate the scope of this reaction (Table 2). Initially, a wide range of electronically and sterically diverse isatins 1 were reacted with 1H-indene-1,3(2H)-dione 2a. Satisfyingly, in most cases, these reactions displayed good yields and excellent diastereoselectivities (>20:1 dr). For instance, both the electron-rich and electron-deficient substituents installed on the N-benzyl groups were fully amenable, leading to the corresponding products 3a-e in excellent yields (91-99%). In addition, a couple of N-protected isatin derivatives were allowed to react with 2a, such as N-allyl, -phenyl, -methyl and even cyclopropyl isatins, furnishing the desired products 3f-k in satisfying yields. However, the detrimental effects were observed when the carbamate group was used as a protecting group, affording the corresponding product 3l in moderate yield. Pleasingly, the N-H free substrate still yielded the product 3m in acceptable yield. It was noteworthy that these reactions exhibited good compatibility of functional moieties such as cyclopropyl and allyl groups, which not only improved the availability of the [3,4]-fused oxindole products, but also favored the late stage functionalization.


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Table 2. Substrate Scope of C4-amine-Substituted Isatins and 1,3-Dicarbonyl Compoundsa

aReaction

conditions: 1 (0.1 mmol), 2 (0.15 mmol), Sc(OTf)3 (0.01 mmol), 5 Å MS (50 mg) in 1.0 mL of distilled

DCE at 60 C for 12 h; isolated yield after column chromatography; dr >20:1, dr was determined by 1H NMR spectroscopy. bHf(OTf)4 (0.02 mmol) as a catalyst.

As expected, either electron-rich or electron-deficient substituents on phenyl ring of isatins were fully compatible for this reaction (3n-o). In addition to the pyrrolidine ring, a wide range of cyclic amines were also good reaction partners, such as octahydroisoindole (3p), piperidine (3q-r),



morpholine (3s-t), thiomorpholine (3u), as well as the seven-membered azepane (3v). Intriguingly, the substrate incorporating unsymmetrical acyclic N-benzyl-N-methylamine was also successful in this reaction, which was inapplicable in most hydride transfer reactions, affording the regioselective benzylic C-H functionalized product 3w in 73% yield with excellent diastereoselectivity (>20:1 dr). Unfortunately, other cyclic or acyclic 1,3-dicarbonyl compounds, such as 1,3-cyclohexanedione and acetylacetone, were ineffective in this transformation, which might be due to the relatively weaker nucleophilicity than 1H-indene-1,3(2H)-dione. Nevertheless, 1,3-dimethylbarbituric acid could survive in this cascade cyclization with 20 mol % Hf(OTf)4 as a catalyst, delivering the desired product 3x in 87% yield with excellent diastereoselectivity. Inspired by the success of facile construction of [3,4]-fused oxindoles, the asymmetric reaction of 1-benzyl-4-(pyrrolidin-1-yl)indoline-2,3-dione 1a with 1H-indene-1,3(2H)-dione 2a was further investigated (Scheme 2). A large number of chiral catalysts, including different chiral phosphoric acids and various bis(oxazoline) ligands, were systematically screened with Sc(OTf)3 as a catalyst to achieve stereocontrol (see Supporting Information). The results showed that the combination of SPINOL-derived chiral phosphoric acid with Sc(OTf)3 presented the best result, affording 3a in 50% yield and 35% ee. Scheme 2. Investigation of Asymmetric Synthesis

On the basis of the above experimental results, a plausible reaction mechanism was proposed (Scheme 3). Under the catalysis of Sc(OTf)3, 1-benzyl-4-(pyrrolidin-1-yl)indoline-2,3-dione 1a and 1H-indene-1,3(2H)-dione 2a undergo Knoevenagel condensation to generate the electron deficient alkene I, which induces the hydride transfer from α-position of amine for production of zwitterionic iminium intermediate II. Subsequently, the intramolecular cyclization occurs to furnish the desired product 3a. Scheme 3. Proposed Mechanism


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CONCLUSION In conclusion, we have developed a scandium-catalyzed redox-neutral cascade [1,5]-hydride transfer/cyclization between C4-amine-substituted isatins and 1,3-dicarbonyl compounds. A variety of tricyclic 6/5/6 [3,4]-fused oxindoles are produced in good to high yields with excellent diastereoselectivities. In addition, the isatin scaffold was successfully introduced as a new skeleton in the hydride transfer reactions. This methodology opens a new avenue for the construction of [3,4]-fused oxindole alkaloids featuring redox- and step-economy, ready availability of reactants, wide substrate scope as well as good functional group compatibility. Further investigations to develop new applications of this methodology are underway in our laboratory. Experimental Section Unless otherwise noted, all reagents were commercial available (from Adamas-beta) and used as received. All the solvents used in the reaction were distilled prior to use. Molecular sieves were activated at 550 °C for 6 h before use. The C-4 hydride donor substituted isatins were prepared according to literature.14a Thin layer chromatography (TLC) was used to monitor the reaction on Merck 60 F254 precoated silica gel plate (0.2 mm thickness). TLC spots were visualized by UVlight irradiation on Spectroline Model ENF-24061/F 254 nm. The products were purified by flash column chromatography (200-300 mesh silica gel) eluted with the gradient of petroleum ether and ethyl acetate. Proton nuclear magnetic resonance spectra (1H NMR) were recorded on a Bruker 500 MHz NMR spectrometer (CDCl3 or DMSO-d6 solvent). The chemical shifts were reported in parts per million (ppm), downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 7.26, singlet) or dimethyl sulfoxide-d6 (δ 2.54, singlet). Multiplicities were given as: s (singlet); d (doublet); t (triplet); q (quartet); dd (doublets of doublet) or m (multiplets). The number of protons for a given resonance is indicated by nH. Coupling constants were reported as a J value in Hz. Carbon nuclear magnetic resonance spectra (13C NMR) were referenced to the appropriate residual solvent peak. High resolution mass spectral analysis (HRMS) was performed on Waters XEVO G2 Q-TOF.



General Procedure for the Synthesis of [3,4]-Fused Oxindoles An oven-dried reaction tube was charged with C4-amine-substituted isatins 1 (0.1 mmol), 1,3dicarbonyl compounds 2 (0.15 mmol), Sc(OTf)3 (10 mol %), 5 Å MS (50 mg) and distilled DCE (1 mL). The reaction mixture was stirred vigorously at 60 °C and monitored by TLC. After the consumption of 1, the reaction mixture was directly purified by flash column chromatography (column chromatography eluent, petroleum ether/ethyl acetate = 20/1) to afford products 3. General Procedure for the Large-scale Synthesis of [3,4]-Fused Oxindole 3a An oven-dried round-bottom flask was charged with C4-amine-substituted isatins 1a (2 mmol), 1Hindene-1,3(2H)-dione 2a (3 mmol), Sc(OTf)3 (10 mol %), 5 Å MS (1000 mg) and distilled DCE (20 mL). The reaction mixture was stirred vigorously at 60 °C and monitored by TLC. After the consumption of 1a, the reaction mixture was directly purified by flash column chromatography (column chromatography eluent, petroleum ether/ethyl acetate = 20/1) to afford [3,4]-fused oxindole 3a (520 mg, 60% yield). General Procedure for Asymmetric Synthesis of [3,4]-Fused Oxindole 3a An oven-dried reaction tube was charged with Sc(OTf)3 (0.01 mmol, 10 mol %), ligand (x mol %), 5 Å MS (50 mg) and distilled DCE (1 mL). The mixture was stirred at room temperature for 30 min. Then C4-amine-substituted isatin 1a (0.1 mmol) and 1,3-dicarbonyl compounds 2a (0.15 mmol) were added to the tube. The reaction mixture was stirred vigorously at 60 °C and monitored by TLC. After the consumption of 1a, the reaction mixture was directly purified by flash column chromatography (column chromatography eluent, petroleum ether/ethyl acetate = 20/1) to afford product 3a. Ee was determined by chiral HPLC (CHIRALPAK AS-H (4.6 mm ø×250 mmL); hexane/2-propanol 70/30; flow rate 0.6 ml/min; temp 25 °C; detection UV 240~260 nm).


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4-benzyl-4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline-6,2'-indene]1',3',5-trione (3a). Yellow solid, 43.0 mg, 99% yield; 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.4 Hz, 1H), 7.83 (d, J = 7.0 Hz, 1H), 7.78 (d, J = 11.9 Hz, 2H), 7.30 – 7.24 (m, 2H), 7.24 – 7.18 (m, 1H), 7.15 (t, J = 7.8 Hz, 3H), 6.35 (d, J = 8.2 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 4.86 (d, J = 15.7 Hz, 1H), 4.51 (d, J = 15.7 Hz, 1H), 4.16 (s, 1H), 4.14 – 4.06 (m, 1H), 3.64 (t, J = 7.8 Hz, 1H), 3.11 (dd, J = 16.7, 8.5 Hz, 1H), 1.98 (s, 2H), 1.91 – 1.80 (m, 1H), 1.28 – 1.14 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.6, 197.7, 175.2, 143.6, 143.1, 142.9, 142.4, 136.1, 135.8, 130.1, 128.6, 127.4, 127.1, 123.1, 122.8, 106.3, 105.0, 98.3, 64.3, 49.5, 47.9, 47.3, 43.8, 27.1, 24.8 ppm. HRMS (ESI): calcd. for C28H23N2O3 [M+H]+: 435.1703, found: 435.1702. 4-(2-chlorobenzyl)-4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline-6,2'indene]-1',3',5-trione (3b). Yellow solid, 46.4 mg, 99% yield; 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.4 Hz, 1H), 7.84 (d, J = 3.2 Hz, 1H), 7.77 (s, 2H), 7.33 (d, J = 7.0 Hz, 1H), 7.20 – 7.10 (m, 3H), 6.93 (d, J = 6.7 Hz, 1H), 6.37 (d, J = 8.1 Hz, 1H), 6.12 (d, J = 7.5 Hz, 1H), 4.89 (d, J = 16.8 Hz, 1H), 4.74 (d, J = 16.8 Hz, 1H), 4.20 (s, 1H), 4.16 – 4.07 (m, 1H), 3.65 (t, J = 7.9 Hz, 1H), 3.13 (dd, J = 16.8, 8.3 Hz, 1H), 2.02 (d, J = 21.6 Hz, 2H), 1.93 – 1.82 (m, 1H), 1.29 – 1.13 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.4, 197.8, 175.3, 143.3, 143.0, 142.9, 142.3, 135.7, 135.7, 133.1, 132.7, 130.1, 129.4, 128.5, 127.8, 126.9, 123.1, 122.7, 106.1, 105.0, 98.2, 64.3, 49.4, 47.8, 47.3, 41.4, 27.1, 24.7 ppm. HRMS (ESI): calcd. for C28H22ClN2O3 [M+H]+: 469.1313, found: 469.1318. 4-(4-bromobenzyl)-4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline-6,2'indene]-1',3',5-trione (3c). Yellow solid, 47.1 mg, 91% yield; 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.6 Hz, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.81 – 7.73 (m, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.16 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 8.2 Hz, 2H), 6.36 (d, J = 8.3 Hz, 1H), 6.10 (d, J = 7.7 Hz, 1H), 4.75 (d, J = 15.9 Hz, 1H), 4.52 (d, J = 15.9 Hz, 1H), 4.15 (s, 1H), 4.09 (dd, J = 10.3, 5.9 Hz, 1H), 3.64 (t, J = 7.8 Hz, 1H), 3.11 (td, J = 9.5, 7.0 Hz, 1H), 2.09 – 1.93 (m, 2H), 1.86 (dt, J = 11.7, 5.7 Hz, 1H), 1.19 (ddd, J = 22.6, 11.6, 7.4 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.4, 197.6, 175.1, 143.2, 143.0, 142.9, 142.3, 135.7, 135.0, 131.6, 130.0, 128.7, 123.1, 122.7, 121.2, 106.1, 105.0, 98.0, 64.3, 49.4, 47.7, 47.3, 43.1, 27.1, 24.7 ppm. HRMS (ESI): calcd. for C28H22BrN2O3 [M+H]+: 513.0808, found: 513.0806. 4-(4-methylbenzyl)-4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline-6,2'indene]-1',3',5-trione (3d). Yellow solid, 43.5 mg, 97% yield; 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.4 Hz, 1H), 7.83 (s, 1H), 7.76 (s, 2H), 7.14 (t, J = 7.8 Hz, 1H), 7.06 (s, 4H), 6.34 (d, J = 8.1 Hz,



1H), 6.15 (d, J = 7.6 Hz, 1H), 4.82 (d, J = 15.6 Hz, 1H), 4.46 (d, J = 15.6 Hz, 1H), 4.14 (s, 1H), 4.11 – 4.05 (m, 1H), 3.63 (t, J = 7.7 Hz, 1H), 3.10 (dd, J = 16.5, 8.3 Hz, 1H), 2.28 (s, 3H), 1.97 (s, 2H), 1.90 – 1.80 (m, 1H), 1.20 (dd, J = 19.9, 10.4 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.5, 197.5, 175.1, 143.5, 143.0, 142.8, 142.3, 136.9, 135.7, 133.0, 129.9, 129.2, 127.0, 123.0, 122.6, 106.2, 104.8, 98.3, 64.2, 49.4, 47.8, 47.2, 43.4, 27.0, 24.7, 21.0 ppm. HRMS (ESI): calcd. for C29H25N2O3 [M+H]+: 449.1860, found: 449.1861. 4-(naphthalen-2-ylmethyl)-4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'de]quinoline-6,2'-indene]-1',3',5-trione (3e). Yellow solid, 40.2 mg, 83% yield; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.6 Hz, 1H), 7.83 (t, J = 6.9 Hz, 1H), 7.80 – 7.71 (m, 5H), 7.55 (s, 1H), 7.43 (p, J = 6.9 Hz, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 6.17 (d, J = 7.7 Hz, 1H), 4.99 (d, J = 15.8 Hz, 1H), 4.71 (d, J = 15.8 Hz, 1H), 4.20 (s, 1H), 4.12 (dd, J = 10.1, 6.0 Hz, 1H), 3.64 (t, J = 8.0 Hz, 1H), 3.12 (dd, J = 16.9, 8.7 Hz, 1H), 2.07 – 1.94 (m, 2H), 1.87 (dt, J = 11.8, 5.8 Hz, 1H), 1.28 – 1.17 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.5, 197.7, 175.2, 143.5, 143.0, 142.9, 142.3, 135.7, 133.3, 133.2, 132.6, 130.0, 128.4, 127.7, 127.5, 126.0, 125.7, 125.6, 125.0, 123.1, 122.7, 106.2, 104.9, 98.3, 64.3, 49.5, 47.9, 47.3, 43.8, 27.1, 24.7 ppm. HRMS (ESI): calcd. for C32H25N2O3 [M+H]+: 485.1860, found: 485.1861. 4-allyl-4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline-6,2'-indene]1',3',5-trione (3f). Yellow solid, 34.6 mg, 90% yield; 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 7.6 Hz, 1H), 7.84 (t, J = 7.1 Hz, 1H), 7.80 – 7.71 (m, 2H), 7.22 (t, J = 8.0 Hz, 1H), 6.36 (d, J = 8.2 Hz, 1H), 6.24 (d, J = 7.7 Hz, 1H), 5.73 (ddd, J = 22.1, 10.2, 5.1 Hz, 1H), 5.09 (dd, J = 22.6, 13.8 Hz, 2H), 4.34 – 4.16 (m, 1H), 4.13 – 4.06 (m, 2H), 4.00 (dd, J = 16.5, 5.3 Hz, 1H), 3.65 (t, J = 7.9 Hz, 1H), 3.11 (td, J = 9.6, 6.8 Hz, 1H), 2.07 – 1.93 (m, 2H), 1.90 – 1.79 (m, 1H), 1.19 (ddd, J = 22.5, 11.7, 7.3 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.5, 197.5, 174.8, 143.5, 143.0, 142.8, 142.3, 135.6, 131.4, 129.9, 123.0, 122.7, 116.9, 106.2, 104.8, 98.1, 64.3, 49.3, 47.7, 47.3, 42.3, 27.0, 24.7 ppm. HRMS (ESI): calcd. for C24H21N2O3 [M+H]+: 385.1547, found: 385.1549. 4-phenyl-4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline-6,2'-indene]1',3',5-trione (3g). Yellow solid, 39.9 mg, 95% yield; 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.6 Hz, 1H), 7.84 (ddd, J = 9.7, 6.4, 3.9 Hz, 1H), 7.80 – 7.77 (m, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.32 (d, J = 7.4 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.40 (d, J = 8.2 Hz, 1H), 6.27 (d, J = 7.8 Hz, 1H), 4.27 (s, 1H), 4.13 (dd, J = 10.3, 5.9 Hz, 1H), 3.68 (dd, J = 12.0, 4.5 Hz, 1H), 3.15 (td, J = 9.7, 6.8


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Page 11 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Hz, 1H), 2.09 – 1.97 (m, 2H), 1.88 (ddd, J = 16.8, 8.4, 3.7 Hz, 1H), 1.23 (ddd, J = 22.4, 11.8, 7.3 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.5, 197.6, 174.2, 144.1, 143.1, 143.0, 142.4, 135.7, 135.7, 134.8, 130.0, 129.1, 127.4, 125.7, 123.1, 122.8, 106.3, 105.2, 98.7, 64.3, 49.3, 48.1, 47.4, 27.1, 24.8 ppm. HRMS (ESI): calcd. for C27H21N2O3 [M+H]+: 421.1547, found: 421.1545. 4-methyl-4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline-6,2'-indene]1',3',5-trione (3h). Yellow solid, 30.8 mg, 86% yield; 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.4 Hz, 1H), 7.84 (t, J = 7.2 Hz, 1H), 7.80 – 7.71 (m, 2H), 7.25 (d, J = 8.7 Hz, 1H), 6.38 (d, J = 8.2 Hz, 1H), 6.26 (d, J = 7.6 Hz, 1H), 4.12 – 4.02 (m, 2H), 3.64 (t, J = 8.0 Hz, 1H), 3.17 – 3.07 (m, 1H), 3.05 (d, J = 22.7 Hz, 3H), 2.09 – 1.93 (m, 2H), 1.91 – 1.79 (m, 1H), 1.25 – 1.11 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.6, 197.5, 175.1, 144.3, 142.9, 142.7, 142.3, 135.6, 130.1, 123.0, 122.8, 106.2, 104.9, 97.2, 64.3, 49.3, 47.8, 47.2, 27.0, 26.3, 24.7 ppm. HRMS (ESI): calcd. for C22H19N2O3 [M+H]+: 359.1390, found: 359.1391. 4-ethyl-4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline-6,2'-indene]1',3',5-trione (3i). Yellow solid, 31.3 mg, 84% yield; 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.6 Hz, 1H), 7.84 (t, J = 7.2 Hz, 1H), 7.80 – 7.71 (m, 2H), 7.30 – 7.20 (m, 1H), 6.36 (d, J = 8.2 Hz, 1H), 6.27 (d, J = 7.7 Hz, 1H), 4.12 – 4.04 (m, 2H), 3.66 (dt, J = 16.0, 7.9 Hz, 2H), 3.40 (dd, J = 14.1, 7.1 Hz, 1H), 3.11 (td, J = 9.6, 6.8 Hz, 1H), 2.09 – 1.92 (m, 2H), 1.90 – 1.79 (m, 1H), 1.23 – 1.11 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.6, 197.5, 174.8, 143.5, 143.0, 142.9, 142.3, 135.6, 130.0, 123.0, 122.7, 106.4, 104.7, 97.4, 64.3, 49.4, 47.9, 47.3, 34.8, 27.0, 24.7, 12.9 ppm. HRMS (ESI): calcd. for C23H21N2O3 [M+H]+: 373.1547, found: 373.1544. 4-(cyclopropylmethyl)-4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline6,2'-indene]-1',3',5-trione (3j). Yellow solid, 31.1 mg, 78% yield; 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 7.6 Hz, 1H), 7.84 (t, J = 7.3 Hz, 1H), 7.79 – 7.70 (m, 2H), 7.25 (dd, J = 10.8, 5.0 Hz, 1H), 6.37 (d, J = 8.2 Hz, 1H), 6.32 (d, J = 7.7 Hz, 1H), 4.10 (dd, J = 11.4, 4.7 Hz, 2H), 3.65 (t, J = 8.0 Hz, 1H), 3.45 (dd, J = 14.5, 7.4 Hz, 1H), 3.29 (dd, J = 14.5, 6.3 Hz, 1H), 3.12 (td, J = 9.6, 6.8 Hz, 1H), 2.09 – 1.93 (m, 2H), 1.90 – 1.80 (m, 1H), 1.26 – 1.14 (m, 1H), 1.12 – 1.02 (m, 1H), 0.49 – 0.38 (m, 2H), 0.33 – 0.15 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.6, 197.4, 175.1, 144.0, 142.9, 142.9, 142.3, 135.7, 135.6, 130.0, 123.0, 122.6, 106.3, 104.7, 97.6, 64.2, 49.3, 48.0, 47.3, 44.2, 27.0, 24.7, 9.9, 3.6, 3.5 ppm. HRMS (ESI): calcd. for C25H23N2O3 [M+H]+: 399.1703, found: 399.1705.



4-cyclopropyl-4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline-6,2'indene]-1',3',5-trione (3k). Yellow solid, 28.4 mg, 74% yield; 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 7.6 Hz, 1H), 7.89 – 7.79 (m, 1H), 7.76 (q, J = 7.7 Hz, 2H), 7.26 – 7.23 (m, 1H), 6.46 (d, J = 7.7 Hz, 1H), 6.37 (d, J = 8.2 Hz, 1H), 4.06 (dd, J = 10.3, 6.0 Hz, 1H), 4.01 (s, 1H), 3.64 (t, J = 7.8 Hz, 1H), 3.11 (td, J = 9.5, 6.9 Hz, 1H), 2.53 – 2.40 (m, 1H), 2.05 – 1.93 (m, 2H), 1.92 – 1.81 (m, 1H), 1.20 (ddd, J = 22.5, 11.7, 7.4 Hz, 1H), 0.98 – 0.83 (m, 3H), 0.76 – 0.64 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.7, 197.7, 176.4, 144.7, 143.1, 142.7, 142.4, 135.6, 130.0, 123.0, 122.8, 106.0, 104.8, 98.5, 64.1, 49.2, 48.1, 47.3, 27.0, 24.7, 22.0, 5.9, 5.6 ppm. HRMS (ESI): calcd. for C24H21N2O3 [M+H]+: 385.1547, found: 385.1545. ethyl1',3',5-trioxo-1',3',5,5a,6a,7,8,9-octahydro-4H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline6,2'-indene]-4-carboxylate (3l). Yellow solid, 20.0 mg, 48% yield; 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 7.5 Hz, 1H), 7.85 (t, J = 7.0 Hz, 1H), 7.78 (q, J = 7.4 Hz, 2H), 7.29 (t, J = 8.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.45 (d, J = 8.2 Hz, 1H), 4.45 – 4.30 (m, 2H), 4.27 (s, 1H), 4.04 (dd, J = 10.2, 5.9 Hz, 1H), 3.65 (t, J = 6.9 Hz, 1H), 3.14 (dd, J = 16.8, 8.9 Hz, 1H), 2.00 (t, J = 16.2 Hz, 2H), 1.90 – 1.76 (m, 1H), 1.35 (t, J = 7.1 Hz, 3H), 1.20 (dt, J = 22.2, 11.2 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 200.8, 197.4, 172.8, 150.5, 143.1, 142.3, 142.2, 139.4, 135.8, 135.7, 130.2, 123.1, 122.9, 106.3, 105.4, 103.8, 64.0, 63.0, 48.9, 48.1, 47.2, 27.1, 24.6, 14.1 ppm. HRMS (ESI): calcd. for C24H21N2O5 [M+H]+: 417.1445, found: 417.1446. 4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline-6,2'-indene]-1',3',5-trione (3m). Yellow solid, 21.7 mg, 63% yield; 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.5 Hz, 1H), 7.85 (t, J = 7.0 Hz, 1H), 7.78 (q, J = 7.4 Hz, 2H), 7.19 (t, J = 7.8 Hz, 1H), 7.12 (s, 1H), 6.34 (d, J = 8.1 Hz, 1H), 6.24 (d, J = 7.5 Hz, 1H), 4.17 – 4.01 (m, 2H), 3.64 (t, J = 7.9 Hz, 1H), 3.12 (dd, J = 17.0, 8.4 Hz, 1H), 2.01 (d, J = 29.0 Hz, 2H), 1.88 – 1.78 (m, 1H), 1.25 – 1.11 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.5, 197.6, 176.8, 143.1, 142.3, 141.1, 135.7, 130.1, 123.2, 122.8, 107.3, 104.6, 98.6, 64.4, 49.2, 47.8, 47.2, 27.1, 24.8 ppm. HRMS (ESI): calcd. for C21H17N2O3 [M+H]+: 345.1234, found: 345.1235. 4-benzyl-1-methyl-4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline-6,2'indene]-1',3',5-trione (3n). Yellow solid, 35.4 mg, 79% yield; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.5 Hz, 1H), 7.82 (ddt, J = 21.6, 14.5, 7.4 Hz, 3H), 7.26 (dd, J = 10.2, 4.4 Hz, 2H), 7.21 (d, J = 7.1 Hz, 1H), 7.16 (d, J = 7.4 Hz, 2H), 6.92 (d, J = 7.7 Hz, 1H), 6.11 (d, J = 7.7 Hz, 1H), 4.88 (dd, J = 15.8, 7.1


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Hz, 1H), 4.51 (d, J = 15.8 Hz, 1H), 4.19 (d, J = 9.1 Hz, 1H), 4.12 – 4.04 (m, 1H), 3.96 (dd, J = 13.8, 8.1 Hz, 1H), 3.28 (dd, J = 15.4, 7.6 Hz, 1H), 2.40 (s, 3H), 2.06 – 1.94 (m, 1H), 1.89 – 1.78 (m, 1H), 1.74 – 1.58 (m, 1H), 1.40 (tt, J = 21.2, 10.6 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.9, 198.8, 174.9, 143.3, 142.8, 142.7, 140.9, 136.0, 135.6, 135.5, 131.7, 128.5, 127.3, 127.0, 123.0, 122.7, 116.7, 108.7, 99.4, 66.4, 51.5, 49.0, 48.4, 43.6, 27.0, 24.4, 20.6 ppm. HRMS (ESI): calcd. for C29H25N2O3 [M+H]+: 449.1860, found: 449.1862. 4-benzyl-3-chloro-4,5a,6a,7,8,9-hexahydro-5H-spiro[dipyrrolo[1,2-a:4',3',2'-de]quinoline-6,2'indene]-1',3',5-trione (3o). Yellow solid, 35.6 mg, 76% yield; 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.5 Hz, 1H), 7.88 – 7.82 (m, 1H), 7.78 (s, 2H), 7.25 (dd, J = 7.7, 5.5 Hz, 2H), 7.21 – 7.15 (m, 1H), 7.10 (d, J = 4.6 Hz, 3H), 6.31 (d, J = 8.6 Hz, 1H), 5.16 – 5.05 (m, 2H), 4.14 (s, 1H), 4.11 – 4.04 (m, 1H), 3.63 (t, J = 7.1 Hz, 1H), 3.12 (q, J = 8.4 Hz, 1H), 2.01 (s, 2H), 1.89 – 1.77 (m, 1H), 1.25 – 1.16 (m, 1H); C{1H} NMR (125 MHz, DMSO) δ 196.2, 192.8, 170.2, 138.2, 137.6, 136.5, 133.8, 132.6, 131.2, 131.1,

13

127.1, 123.7, 122.2, 121.7, 118.5, 118.0, 103.4, 101.4, 98.7, 59.4, 44.4, 42.9, 42.7, 39.6, 22.3, 20.0 ppm. HRMS (ESI): calcd. for C28H22ClN2O3 [M+H]+: 469.1313, found: 469.1315. 4'-benzyl-4',5a',6a',6b',7',8',9',10',10a',11'-decahydro-5'H-spiro[indene-2,6'-isoindolo[2,1a]pyrrolo[4,3,2-de]quinoline]-1,3,5'-trione (3p). Yellow solid, 47.8 mg, 98% yield; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.4 Hz, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.77 (s, 2H), 7.25 (d, J = 6.0 Hz, 2H), 7.21 (d, J = 6.4 Hz, 1H), 7.13 (t, J = 11.3 Hz, 3H), 6.33 (d, J = 8.2 Hz, 1H), 6.13 (d, J = 7.5 Hz, 1H), 4.84 (d, J = 15.7 Hz, 1H), 4.50 (d, J = 15.8 Hz, 1H), 4.24 – 4.14 (m, 2H), 3.30 (d, J = 8.9 Hz, 1H), 3.26 – 3.17 (m, 1H), 2.07 (d, J = 5.5 Hz, 1H), 1.81 (s, 1H), 1.70 (d, J = 11.4 Hz, 2H), 1.53 – 1.46 (m, 1H), 1.41 (d, J = 14.0 Hz, 2H), 1.28 – 1.16 (m, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.8, 197.7, 175.1, 143.6, 143.4, 142.9, 142.8, 136.0, 135.8, 135.5, 130.0, 128.5, 128.5, 127.3, 127.0, 126.9, 122.8, 122.8, 106.1, 104.9, 98.1, 64.2, 53.5, 48.9, 48.3, 43.6, 39.1, 38.0, 27.7, 25.7, 24.7, 20.5 ppm. HRMS (ESI): calcd. for C32H29N2O3 [M+H]+: 489.2173, found: 489.2174. 4'-benzyl-4',5a',6a',7',9',10'-hexahydro-5'H,8'H-spiro[indene-2,6'-pyrido[1,2-a]pyrrolo[4,3,2de]quinoline]-1,3,5'-trione (3q). Yellow solid, 42.1 mg, 94% yield; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.9 Hz, 1H), 7.90 – 7.76 (m, 3H), 7.25 (d, J = 5.5 Hz, 2H), 7.21 (d, J = 6.4 Hz, 1H), 7.15 (d, J = 7.0 Hz, 2H), 7.10 (t, J = 7.9 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 4.86 (d, J = 15.8 Hz, 1H), 4.51 (d, J = 15.7 Hz, 1H), 4.17 (s, 1H), 4.10 (d, J = 12.2 Hz, 1H), 3.53 (d, J = 11.7 Hz, 1H), 2.95 (t, J = 12.4 Hz, 1H), 1.72 (d, J = 12.0 Hz, 2H), 1.53 (dd, J = 25.1, 12.8 Hz, 1H), 1.45 (d, J = 12.5



Hz, 1H), 1.35 (dd, J = 25.5, 12.9 Hz, 1H), 1.02 (q, J = 12.2 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.0, 197.4, 174.9, 143.4, 143.2, 143.0, 142.5, 136.0, 135.9, 135.8, 129.5, 128.6, 127.4, 127.1, 123.2, 123.1, 107.6, 107.3, 99.4, 61.4, 54.5, 47.8, 46.1, 43.7, 28.0, 25.1, 24.3 ppm. HRMS (ESI): calcd. for C29H25N2O3 [M+H]+: 449.1860, found: 449.1861. 4'-benzyl-8'-methyl-4',5a',6a',7',9',10'-hexahydro-5'H,8'H-spiro[indene-2,6'-pyrido[1,2a]pyrrolo[4,3,2-de]quinoline]-1,3,5'-trione (3r). Yellow solid, 42.5 mg, 92% yield; 1H NMR (500 MHz, CDCl3) δ 8.09 (t, J = 7.0 Hz, 1H), 7.90 – 7.80 (m, 3H), 7.26 (dd, J = 8.0, 6.4 Hz, 2H), 7.21 (dd, J = 8.6, 5.9 Hz, 1H), 7.15 (d, J = 7.1 Hz, 2H), 7.10 (t, J = 8.0 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 4.86 (d, J = 15.8 Hz, 1H), 4.50 (d, J = 15.8 Hz, 1H), 4.17 (d, J = 11.7 Hz, 1H), 4.14 – 4.07 (m, 1H), 3.55 (dd, J = 11.8, 2.2 Hz, 1H), 2.97 (td, J = 12.6, 2.7 Hz, 1H), 1.72 (d, J = 12.9 Hz, 1H), 1.56 – 1.48 (m, 1H), 1.44 – 1.37 (m, 1H), 1.27 – 1.17 (m, 1H), 0.79 (d, J = 6.5 Hz, 3H), 0.70 (q, J = 11.9 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.0, 197.3, 174.8, 143.3, 143.2, 142.9, 142.5, 136.0, 135.9, 135.8, 129.5, 128.6, 127.4, 127.1, 123.2, 123.1, 107.6, 107.3, 99.3, 60.8, 54.3, 47.3, 46.3, 43.7, 36.0, 33.4, 31.2, 21.7 ppm. HRMS (ESI): calcd. for C30H27N2O3 [M+H]+: 463.2016, found: 463.2018. 4'-benzyl-4',5a',6a',7',9',10'-hexahydro-5'H-spiro[indene-2,6'-[1,4]oxazino[4,3-a]pyrrolo[4,3,2de]quinoline]-1,3,5'-trione (3s). Yellow solid, 38.3 mg, 85% yield; 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 7.2 Hz, 1H), 7.90 – 7.79 (m, 3H), 7.30 – 7.24 (m, 2H), 7.24 – 7.19 (m, 1H), 7.13 (dd, J = 16.7, 7.7 Hz, 3H), 6.56 (d, J = 8.4 Hz, 1H), 6.19 (d, J = 7.5 Hz, 1H), 4.86 (d, J = 15.8 Hz, 1H), 4.53 (d, J = 15.8 Hz, 1H), 4.21 (s, 1H), 3.91 (d, J = 11.2 Hz, 1H), 3.82 (t, J = 11.9 Hz, 2H), 3.55 (dd, J = 19.4, 10.9 Hz, 2H), 3.26 (t, J = 12.1 Hz, 1H), 3.02 (t, J = 10.8 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 199.6, 196.4, 174.6, 143.5, 142.7, 142.0, 141.8, 136.3, 136.2, 135.7, 129.7, 128.7, 127.5, 127.1, 123.4, 123.2, 107.3, 106.2, 100.0, 67.2, 66.6, 59.6, 51.5, 46.0, 43.8 ppm. HRMS (ESI): calcd. for C28H23N2O4 [M+H]+: 451.1652, found: 451.1651. 4'-benzyl-7',9'-dimethyl-4',5a',6a',7',9',10'-hexahydro-5'H-spiro[indene-2,6'-[1,4]oxazino[4,3a]pyrrolo[4,3,2-de]quinoline]-1,3,5'-trione (3t). Yellow solid, 34.9 mg, 73% yield, dr = 6:1; 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 7.6 Hz, 1H), 7.89 (ddd, J = 8.0, 5.1, 2.1 Hz, 1H), 7.83 – 7.79 (m, 2H), 7.22 (ddd, J = 8.5, 6.6, 3.6 Hz, 3H), 7.12 – 7.05 (m, 3H), 6.55 (d, J = 8.5 Hz, 1H), 6.12 (d, J = 7.6 Hz, 1H), 4.74 (d, J = 15.7 Hz, 1H), 4.51 (d, J = 15.7 Hz, 1H), 4.00 (s, 1H), 3.94 (dd, J = 12.9, 2.5 Hz, 1H), 3.72 – 3.63 (m, 2H), 3.41 – 3.34 (m, 1H), 2.97 (dd, J = 12.9, 10.6 Hz, 1H), 1.21 (d, J = 6.2 Hz, 3H), 0.87 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 199.5, 196.0, 173.6, 142.8, 142.3, 141.8, 141.5,


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136.3, 135.7, 135.7, 129.8, 128.5, 127.4, 127.0, 127.0, 123.3, 123.2, 106.4, 106.3, 98.8, 73.3, 71.4, 63.8, 53.2, 52.3, 46.9, 43.7, 20.5, 18.4 ppm. HRMS (ESI): calcd. for C30H27N2O4 [M+H]+: 479.1965, found: 479.1962. 4'-benzyl-4',5a',6a',7',9',10'-hexahydro-5'H-spiro[indene-2,6'-pyrrolo[4,3,2-de][1,4]thiazino[4,3a]quinoline]-1,3,5'-trione (3u). Yellow solid, 35.4 mg, 76% yield, dr = 3.3:1; 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 7.5 Hz, 1H), 7.91 – 7.84 (m, 3H), 7.27 (dd, J = 10.9, 5.4 Hz, 3H), 7.23 – 7.21 (m, 1H), 7.14 (d, J = 6.1 Hz, 2H), 6.60 (d, J = 8.5 Hz, 1H), 6.18 (d, J = 7.6 Hz, 1H), 4.84 (d, J = 15.8 Hz, 1H), 4.52 (d, J = 15.7 Hz, 1H), 4.38 (dd, J = 10.5, 2.9 Hz, 1H), 4.14 (s, 1H), 3.87 (dd, J = 10.9, 1.5 Hz, 1H), 3.47 – 3.38 (m, 1H), 2.91 – 2.82 (m, 1H), 2.53 (d, J = 11.9 Hz, 1H), 2.40 (dd, J = 12.8, 11.1 Hz, 1H), 2.16 (d, J = 13.0 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 199.8, 196.5, 174.3, 143.4, 143.0, 142.9, 142.3, 136.2, 136.1, 135.6, 128.6, 127.0, 123.7, 123.4, 123.2, 108.2, 100.1, 62.6, 55.4, 51.2, 45.7, 43.7, 29.0, 27.5 ppm. HRMS (ESI): calcd. for C28H23N2O3S [M+H]+: 467.1424, found: 467.1425. 4-benzyl-4,5a,6a,7,8,9,10,11-octahydro-5H-spiro[azepino[1,2-a]pyrrolo[4,3,2-de]quinoline-6,2'indene]-1',3',5-trione (3v). Yellow solid, 32.8 mg, 71% yield, dr = 1:1; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.6 Hz, 1H), 7.82 – 7.76 (m, 3H), 7.28 (s, 1H), 7.26 (s, 1H), 7.23 – 7.21 (m, 2H), 7.16 (s, 1H), 7.11 (s, 1H), 6.47 (d, J = 8.4 Hz, 1H), 6.11 (d, J = 7.7 Hz, 1H), 4.84 (d, J = 15.8 Hz, 1H), 4.50 (d, J = 15.7 Hz, 1H), 4.18 (s, 1H), 3.96 – 3.88 (m, 1H), 3.49 (ddd, J = 14.8, 7.8, 2.9 Hz, 2H), 2.07 – 1.97 (m, 1H), 1.89 – 1.80 (m, 1H), 1.78 – 1.68 (m, 2H), 1.63 – 1.44 (m, 3H), 1.33 (dd, J = 15.1, 9.3 Hz, 1H); C{1H} NMR (125 MHz, CDCl3) δ 201.9, 197.8, 175.1, 144.2, 143.4, 141.6, 141.4, 136.0, 135.8, 135.7,

13

129.6, 128.6, 127.3, 127.1, 123.6, 123.1, 105.8, 103.0, 98.2, 64.1, 52.2, 48.0, 43.7, 42.0, 29.4, 27.1, 25.9, 25.3 ppm. HRMS (ESI): calcd. for C30H27N2O3 [M+H]+: 463.2016, found: 463.2015. 1'-benzyl-5'-methyl-4'-phenyl-1',2a',4',5'-tetrahydro-2'H-spiro[indene-2,3'-pyrrolo[4,3,2de]quinoline]-1,2',3-trione (3w). Yellow solid, 35.3 mg, 73% yield; 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 7.1 Hz, 1H), 7.62 – 7.51 (m, 3H), 7.27 (t, J = 7.6 Hz, 2H), 7.22 (d, J = 6.6 Hz, 1H), 7.17 (t, J = 8.0 Hz, 3H), 7.11 – 6.93 (m, 5H), 6.61 (d, J = 8.2 Hz, 1H), 6.20 (d, J = 7.5 Hz, 1H), 4.86 (d, J = 15.7 Hz, 1H), 4.79 (s, 1H), 4.59 (d, J = 15.7 Hz, 1H), 4.33 (s, 1H), 2.81 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 200.0, 197.1, 174.9, 144.0, 143.1, 143.1, 141.7, 135.9, 135.3, 135.2, 135.0, 129.6, 128.5, 128.4, 127.3, 127.0, 122.8, 122.5, 107.3, 106.9, 99.2, 68.2, 55.9, 45.6, 43.8, 35.6 ppm. HRMS (ESI): calcd. for C32H25N2O3 [M+H]+: 485.1860, found: 485.1861.



4-benzyl-1',3'-dimethyl-4,5a,6a,7,8,9-hexahydro-2'H,5H-spiro[dipyrrolo[1,2-a:4',3',2'de]quinoline-6,5'-pyrimidine]-2',4',5,6'(1'H,3'H)-tetraone (3x). Yellow solid, 38.6 mg, 87% yield; 1H NMR (500 MHz, CDCl3) δ 7.29 – 7.25 (m, 2H), 7.23 (d, J = 7.1 Hz, 1H), 7.19 (d, J = 7.2 Hz, 2H), 7.15 (t, J = 7.9 Hz, 1H), 6.33 (d, J = 8.2 Hz, 1H), 6.18 (d, J = 7.7 Hz, 1H), 4.87 (d, J = 15.7 Hz, 1H), 4.67 (d, J = 15.7 Hz, 1H), 4.34 (s, 1H), 4.23 (dd, J = 9.4, 5.9 Hz, 1H), 3.66 (t, J = 8.1 Hz, 1H), 3.46 (s, 3H), 3.18 – 3.11 (m, 1H), 3.10 (s, 3H), 2.08 (dddd, J = 18.5, 14.5, 7.8, 4.5 Hz, 3H), 1.45 – 1.33 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.4, 170.3, 164.7, 150.8, 143.3, 142.5, 136.0, 130.0, 128.7, 127.5, 127.1, 106.5, 105.1, 98.5, 67.0, 50.3, 47.6, 46.2, 43.9, 29.4, 28.3, 27.0, 24.4 ppm. HRMS (ESI): calcd. for C25H25N4O4 [M+H]+: 445.1870, found: 445.1873.

ACKNOWLEDGMENTS We are grateful for the financial support from the NSFC (21702117, 21878167). The Natural Science Foundation of Shandong Province for Distinguished Young Scholars (JQ201604) and General Project (ZR2017BB005) are also gratefully acknowledged. We thank Dr. Fengying Dong and Central Laboratory of Qingdao Agricultural University for NMR determination. Supporting Information X-ray crystallography data, CIF file of compound 3a (CIF) and NMR spectra of the products. This material is available free of charge via the Internet at http: //pubs.acs.org. ORCID Shuai-Shuai Li: 0000-0001-7279-2885 Jian Xiao: 0000-0003-4272-6865 Notes The authors declare no competing financial interest.

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Li, S.-S.; Lv, X.; Ren, D.; Shao, C.-L.; Liu, Q.; Xiao, J. Redox-Triggered Cascade Dearomative Cyclizations Enabled by Hexafluoroisopropanol. Chem. Sci. 2018, 9, 8253.

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Cyclization for Synthesis of [3,4

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