[2+2] Cycloadditions Involving 2

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Stereoselective Sequential [4+2]/[2+2] Cycloadditions Involving 2-Alkenylindolenines: An Approach to Densely Functionalized Benzo[b]indolizidines Longchen Cui, Guodong Zhu, Siyuan Liu, Xiangyu Zhao, Jingping Qu, and Baomin Wang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00346 • Publication Date (Web): 11 Apr 2018 Downloaded from http://pubs.acs.org on April 11, 2018

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The Journal of Organic Chemistry

Stereoselective Sequential [4+2]/[2+2] Cycloadditions Involving 2-Alkenylindolenines: An Approach to Densely Functionalized Benzo[b]indolizidines Longchen Cui, Guodong Zhu, Siyuan Liu, Xiangyu Zhao, Jingping Qu, and Baomin Wang* State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024, P. R. China E-mail: [email protected]

ABSTRACT: A stereoselective sequential [4+2]/[2+2] cycloaddition process involving 2-alkenylindolenines has been developed. This unprecedented protocol allows rapid access to densely functionalized benzo[b]indolizidines containing a fully substituted piperidine ring with five contiguous stereogenic centers in good yields with excellent diastereoselectivities. This finding demonstrated the unique synthetic utility of 2-alkenylindolenine species in the construction of complex polycyclic N-heterocycles.

INTRODUCTION The development of synthetic protocols that lead to rapid and stereoselective creation of remarkable molecular complexity from simple starting materials remains an attractive goal in synthetic organic chemistry, since these endeavors can often help to enrich the arsenal of synthetic methodology and streamline the total synthesis of complex natural products. Within this context, the efficient construction of polycyclic N-heterocycles via short simple operations represents a preeminent target because of the prevalence of such structural motifs in natural alkaloid products. In this regard, the benzoindolizidine scaffolds figure prominently. Among various benzoindolizidine structures resulting from the position difference of the fused benzene ring, the benzo[b]indolizidine member is particularly noteworthy. Many architecturally complex bioactive natural alkaloids contain this nucleus, as represented by Strychnine, Mangochinine, Pleiocarpamine, Vincamine, and so on (Figure 1).1 Accordingly, considerable efforts have been devoted to the assembly of the benzo[b]indolizidine skeleton, which led to the production of a broad spectrum of synthetic methods with varying starting materials. With N-substituted indole species as the starting material, the Reissig group reported a general stereoselective procedure for the synthesis of benzannulated indolizidines and pyrrolizidines by samarium diiodide induced cyclizations. 2 Starting from 1- or 3-olefinic indole derivatives, Reisman and co-workers developed an elegant conjugate addition/asymmetric protonation/aza-Prins cascade reaction delivering enantioenriched benzoindolizidine products.3 In addition, Ye and co-workers documented an interesting formal aza-Diels−Alder reaction between 3H-indoles and α,β-unsaturated ketones toward the asymmetric construction of benzo[b]indolizidines.4 Alternatively, through appropriate substrate design and utilizing carbenoid chemistry, the Fillion group realized a non-carbonyl-stabilized rhodium carbenoid C-H insertion of N-aziridinyl imines leading to the formation of N-fused indolines including benzo[b]indolizidines.5 Moreover, an efficient electrocyclization/1,4-conjugate addition process toward benzo[b]indolizidine derivatives was developed by the Smith group starting from simple 1

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anilines and benzaldehydes.6

Figure 1. Examples of bioactive natural alkaloids containing the benzo[b]indolizidine core.

Despite the recent notable advances in the construction of the benzo[b]indolizidine derivatives, synthetic strategies toward the highly stereoselective assembly of densely functionalized entities, such as those with a fully substituted piperidine moiety, are very rare. Given this fact together with the structural challenge and the potential synthetic utility of such densely functionalized benzo[b]indolizidine frameworks, efficient and practical synthetic methods are in high demand. In continuation of our program directed toward the stereoselective construction and modification of pharmacophore heterocycles,7 very recently we explored the synthetic utility of 2-alkenylindolenine compounds as a suitable dipolarophile in the context of a stereoselective [3+2] cycloaddition with oxindole-based azomethine ylides.7e Inspired by this result, we reasoned whether the 2-alkenylindolenine synthon could function as both an azadiene and a dienophile to undergo dimerization via a [4+2] cycloaddition event. The electron-rich enamine double bond of the dimeric aza-Diels-Alder cycloadduct could be further elaborated, thus leading to the formation of densely functionalized benzo[b]indolizidine products featuring a fully substituted piperidine ring with five contiguous stereogenic centers. Herein, we wish to document our effort to develop such a synthetic process.

RESULTS AND DISCUSSION Our studies began with the aza-Diels-Alder dimerization of (E)-3,3-dimethyl-2-styryl-3H-indole 1a in the presence of the common Lewis acid BF3·Et2O (0.2 equiv) in CH3CN at 60 oC for 10 h. To our delight, new products were observed by monitoring the reaction process using TLC. However, the new products were not stable enough to chromatography purification on silica gel. Thus, in order to get stable products and to further increase the structural complexity, we planned to functionalize the enamine double bond with aryne species through a [2+2] cycloaddition reaction.8 Accordingly, upon completion of the [4+2] process, the reaction mixture was directly exposed to benzyne generated in situ by the addition of 2-(trimethylsilyl)phenyl triflate 2a (2 equiv), KF (3 equiv) and 18-crown-6 (3 equiv). Much to our delight, we successfully obtained the [4+2]/[2+2] cycloaddition product 3a in a 61% overall yield with a respectable 8:1 dr (Table 1, entry 1). Relative configurations of the major product 3a and the minor one 3’a were confirmed by X-ray crystallographic analysis.9 In order to further improve the yield and diastereoselectivity of the sequential process, investigations toward identification of the optimal reaction conditions were conducted. Initially, it was found that no reaction occurred in the absence of any acidic catalyst (Table 1, entry 2). Next, other Lewis acids were examined. While ZnCl2 did not promote the reaction (Table 1, entry 3), Mg(OTf)2 provided comparable product yield and diastereoselectivity to BF3·Et2O (Table 1, entry 4). Other metal triflates including Bi(OTf)3, Ni(OTf)2, Yb(OTf)3 and La(OTf)3 were then screened (Table 1, entries 5-8). All these triflate Lewis acids can catalyze the [4+2]/[2+2] reaction sequence with moderate to good overall yields and reasonable levels of diastereocontrol, but no marked improvement of the reaction outcome was observed compared to the use of BF3·Et2O. We then turned our attention to the investigation of Brønsted acids. While diphenylphosphate (DPP) performed very well in the [3+2] cycloaddition of azomethine ylides with 2-alkenylindolenines,7e however, in the current 2


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reaction low yield and poor diastereoselectivity was observed with DPP as the catalyst (Table 1, entry 9). In addition, p-toluenesulfonic acid (PTSA) and CF3COOH can only afford moderate yield and stereoselectivity (Table 1, entries 10 and 11). In contrast, triflic acid gave a much better result with a high 81% yield and good 6:1 dr (Table 1, entry 12). Subsequently, with triflic acid as the catalyst of choice, the solvent effect was briefly surveyed (Table 1, entries 13-17). Of various solvents screened, 2,2,2-trifluoroethanol gave the best result of 75% Table 1. Screening of the Optimal [4+2]/[2+2] Cycloaddition Reaction Conditionsa

entry

catalyst

solvent

yield (%)b

1

BF3·Et2O

CH3CN

61

8:1

2

--

CH3CN

--

--

3

ZnCl2

CH3CN

trace

--

4

Mg(OTf)2

CH3CN

62

8:1

5

Bi(OTf)3

CH3CN

79

7:1

6

Ni(OTf)2

CH3CN

77

7:1

7

Yb(OTf)3

CH3CN

53

6:1

8

La(OTf)3

CH3CN

73

8:1

9

DPP

CH3CN

46

1:1

10

PTSA

CH3CN

57

2:1

11

CF3COOH

CH3CN

51

3:1

12

CF3SO3H

CH3CN

81

6:1

13

CF3SO3H

Cl(CH2)2Cl

51

2:1

14

CF3SO3H

THF

39

1:2

15

CF3SO3H

Toluene

33

1:2

16

CF3SO3H

PhCF3

40

1:1

17

CF3SO3H

EtOH

57

2:1

18

drc

CF3SO3H

CF3CH2OH

75

>20:1

19

d

CF3SO3H

CF3CH2OH

69

10:1

20

e

CF3SO3H

CF3CH2OH

61

>20:1

f

CF3SO3H

CF3CH2OH

69

>20:1

22

g

CF3SO3H

CF3CH2OH

56

>20:1

23

h

CF3SO3H

CF3CH2OH

78

>20:1

21

a

Unless otherwise noted, the reaction was conducted with 1a (0.2 mmol), catalyst (20 mol %) in solvent (2.0 mL) for 10 h. 2a (0.4 mmol), KF (0.6 mmol) and 18-crown-6 (0.6 mmol) were then added in CH3CN (2.0 mL) for 1 h. 3



b

Isolated yield of major product 3a. cThe dr was detected by 1H NMR of the crude product. d[4+2] cycloaddition was run at 80 oC. e[4+2] cycloaddition was run at 40 oC for 24 h. fCsF as fluoride source without 18-crown-6. g TBAF·3H2O as fluoride source without 18-crown-6. h[2+2] cycloaddition was conducted in 1 mL CH3CN.

yield and excellent diastereoselectivity of greater than 20:1 dr (Table 1, entry 18). Interestingly, diastereoselectivity inversion was observed in THF and toluene despite low reactivity (Table 1, entries 14 and 15). Temperature dependence investigation indicated that increasing the temperature to 80 oC lowered both the yield and diastereoselelctivity and decreasing to 40 oC reduced the reactivity (Table 1, entries 19 and 20). Finally, other fluoride sources for the benzyne generation in the [2+2] step were evaluated. Although CsF and TBAF·3H2O also worked, the KF/18-crown-6 combination maintained the best choice with respect to the product yield (Table 1, entries 21 and 22). In addition, doubling the concentration of the benzyne had no influence on the reaction outcome (Table 1, entry 23). Scheme 1. Substrate Scope of the [4+2]/[2+2] Cycloaddition Reaction a,b,c

a

The reaction was conducted with 1 (0.4 mmol), CF3SO3H (20 mol %) in CF3CH2OH (4 mL) for 10 h. After 4


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removal of CF3CH2OH, CH3CN (2.0 mL), 2 (0.8 mmol), KF (1.2 mmol) and 18-crown-6 (1.2 mmol) were added in and the resulting mixture was stired for 1 h. bIsolated yield. cThe dr was detected by 1H NMR of the crude product. With the optimal reaction conditions being established as those in entry 23 of Table 1, the substrate scope with respect to the 2-alkenylindolenine component was evaluated (Scheme 1). Substitution on the benzene ring of the styrene moiety was investigated first. In general, a variety of substituents were tolerated, irrespective of their electronic character and substitution position. But compared to meta- and para-substitutions, the ortho-substitution afforded slightly reduced product yield probably due to the larger steric hindrance of the ortho-substituent (3b, 3c vs. 3d, 3e and 3f, 3g). Relatively bulky para-isopropyl group was well accommodated (3h). Electron-withdrawing p-fluoro and p-nitro groups, and o,p-dihalo substitution were also amenable to the optimal conditions, with the nitro modified substrate affording the best yield (3i, 3j, 3k). In addition, substrates featuring ring-fused aromatic and heteroaromatic rings performed well in the sequential cycloadditions, as represented by 2-naphthyl and 2-thienyl groups (3l, 3m). Next, modification of the indolenine phenyl ring was surveyed. Both 5-methyl and 5-fluoro substituents were tolerated (3n, 3o), but unfortunately, the presence of a 5-nitro substitution shut down the reaction (3p). Finally, the benzyne partner can also be varied, as exemplified by the result with methylenedioxybenzyne (3q).

Scheme 2. Gram-Scale Synthesis

To demonstrate the practical utility of the sequential cycloaddition process, a gram-scale reaction was conducted, and the cycloadduct 3a was obtained in maintained yield with excellent diastereoselectivity (Scheme 2). Furthermore, facile reduction of the remaining indolenine moiety of the [4+2]/[2+2] cycloaddition product to indoline was demonstrated to afford diindoline derivative 4a in 61% yield and 2:1 diastereomeric ratio, of which the two diastereomers can be separated by column chromatography (Scheme 3). Relative configuration of the major product 4a was determined by X-ray crystallographic analysis.9 Notably, a stable [4+2] cycloadduct 5 was isolated in good yield with excellent diastereoselectivity, which confirmed the occurrence of the aza-Diels-Alder dimerization process and predicted potential elaborations other than the [2+2] manipulation (Scheme 4).

Scheme 3. Reduction of 3a

5



Scheme 4. Isolation of the [4+2] Cycloadduct 5

Finally, we proposed the stereochemical model of the [4+2]/[2+2] cycloaddition process (Scheme 5). The strong hydrogen bonding interaction between the Brønsted acid catalyst with (E)-3,3-dimethyl-2-styryl-3H-indole lowers the energy of the LUMO of the dienophile. The [4+2] cycloaddition product was obtained by endo-cycloaddition. The [4+2] cycloadduct next underwent [2+2] cycloaddition with benzyne. Because of the steric effect of the allylic phenyl ring, the trans-configuration product was obtained.

Scheme 5. Stereochemical Model of the [4+2]/[2+2] Cycloaddition Reaction

CONCLUSION In summary, we have developed a highly stereoselective [4+2]/[2+2] cycloaddition sequence consisting of aza-Diels-Alder dimerization of 2-alkenylindolenines and subsequent [2+2] cycloaddition to aryne species. This unprecedented process provides a facile entry to the construction of the benzo[b]indolizidine scaffold of prominent structural complexity, thus leading to a broad array of densely functionalized benzo[b]indolizidine derivatives bearing five continuous stereogenic carbon centers in a highly diastereoselective manner. The development of an asymmetric version of this process and further exploration of the reactivity of 2-alkenylindolenine species are currently underway in our laboratory and the results will be reported in due course.

EXPERIMENTAL SECTION General Information. Reactions were monitored by thin layer chromatography (TLC) using silica gel plates. Flash chromatography was carried out utilizing silica gel 200-300 mesh. 1H NMR, 19F NMR spectra were recorded on a Bruker Avance II 400 MHz and Bruker Avance III 471 MHz, respectively, 13C NMR spectra were recorded on a Bruker Avance II 101 MHz. The solvent used for NMR spectroscopy was CDCl3 or CD3COCD3, using tetramethylsilane as the internal reference. Data for 1H NMR are recorded as follows: chemical shift (δ, ppm), 6


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multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, dd = double doublet, coupling constants in Hz, integration). Data for

13

C NMR and

19

F NMR are reported in terms of chemical shift (δ, ppm).

HRMS (ESI) was determined by an HRMS instrument (LTQ Orbitrap XL TM). The relative configurations of 3a, 3’a and 4a were assigned by the X-ray crystallographic analysis. General Procedure for the Synthesis of [4+2]/[2+2] Cycloadduct 3. A reaction tube was charged with 1 (0.4 mmol) and CF3CH2OH (4 mL), then CF3SO3H (0.08 mmol, 20 mol %) was added at 60 oC. After the [4+2] cycloaddition reaction was stirred for 10 h, the reaction mixture was cooled to room temperature. Upon removal of the solvent under reduced pressure, CH3CN (2 mL), KF (1.2 mmol, 3.0 equiv), 18-crown-6 (1.2 mmol, 3.0 equiv) and 2 (0.8 mmol, 2.0 equiv) were added to the tube at room temperature. After the [2+2] cycloaddition reaction was stirred for 1 h, the crude product was purified by column chromatography on silica gel to give the product 3. General Procedure for Gram-scale Reaction. A round-bottom flask was charged with 1a (4.4 mmol, 1.1 g) and CF3CH2OH (44 mL), then CF3SO3H (0.88 mmol, 20 mol %) was added at 60 oC. After the [4+2] cycloaddition reaction was stirred for 10 h, the reaction mixture was cooled to room temperature. Upon removal of the solvent under reduced pressure, to the residue were added CH3CN (22 mL), KF (13.2 mmol, 3.0 equiv), 18-crown-6 (13.2 mmol, 3.0 equiv) and 2a (8.8 mmol, 2.0 equiv) at room temperature. After the [2+2] cycloaddition reaction was stirred for 1 h, usual workup was conducted and the crude product was purified by column chromatography on silica gel to give the product 3a. 7-(3,3-Dimethyl-3H-indol-2-yl)-13,13-dimethyl-6,8-diphenyl-7,8,8a,13-tetrahydro-6H-benzo[3',4']cyclobuta[1',2': 2,3]pyrido[1,2-a]indole (3a) Rf = 0.15 (Petroleum ether/EtOAc = 50/1), yield: 78% (89 mg); > 20:1 dr; white solid, mp: 229.3 – 230.1 oC; 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.65 (m, 1H), 7.51 – 7.49 (m, 2H), 7.41 – 7.38 (m, 3H), 7.33 – 7.31 (m, 1H), 7.23 – 6.94 (m, 11H), 6.74 (t, J = 8.0 Hz, 1H), 6.70 (s, 1H), 6.68 (s, 1H), 6.28 (d, J = 8.0 Hz, 1H), 4.85 (d, J = 12.0 Hz, 1H), 4.56 (s, 1H), 3.44 (d, J = 4.0 Hz, 1H), 3.29 (dd, J = 12.0, 4.0 Hz, 1H), 1.48 (s, 3H), 1.41 (s, 3H), 1.09 (s, 3H), -0.03 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 185.5, 150.6, 150.2, 145.5, 143.1, 139.9, 136.5, 130.2, 129.6, 128.5, 128.0, 127.9, 127.8, 127.7, 127.4, 126.7, 126.6, 125.4, 125.1, 121.9, 121.3, 120.8, 120.4, 117.8, 106.9, 80.5, 61.6, 54.5, 54.1, 48.4, 45.9, 40.5, 31.6, 24.2, 22.2, 21.8; HRMS (ESI) m/z calcd for C42H39N2 [M+H]+ 571.3108, found 571.3102. 7-(3,3-Dimethyl-3H-indol-2-yl)-13,13-dimethyl-6,8-di-o-tolyl-7,8,8a,13-tetrahydro-6H-benzo[3',4']cyclobuta[1',2': 2,3]pyrido[1,2-a]indole (3b) Rf = 0.12 (Petroleum ether/EtOAc = 50/1), yield: 55% (66 mg); > 20:1 dr; white solid, mp: 247.4 – 247.8 oC; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 1H), 7.64 – 7.60 (m, 1H), 7.52 – 7.46 (m, 2H), 7.32 – 7.30 (m, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.15 (td, J = 8.0, 1.2 Hz, 1H), 7.10 – 6.97 (m, 8H), 6.89 – 6.81 (m, 2H), 6.75 – 6.71 (m, 2H), 6.14 (d, J = 8.0 Hz, 1H), 5.22 (d, J = 12.0 Hz, 1H), 4.42 (s, 1H), 3.62 (d, J = 2.8 Hz, 1H), 3.40 (dd, J = 12.0, 3.2 Hz, 1H), 2.28 (s, 3H), 1.73 (s, 3H), 1.40 (s, 3H), 1.35 (s, 3H), 0.99 (s, 3H), -0.11 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 185.1, 153.8, 151.2, 150.0, 145.7, 145.0, 141.3, 139.7, 137.0, 136.8, 135.6, 130.3, 130.0, 129.5, 129.4, 129.1, 128.0, 127.8, 127.3, 126.6, 126.4, 126.0, 125.9, 125.3, 125.0, 121.8, 121.4, 120.9, 120.4, 117.6, 106.4, 80.8, 57.5, 55.3, 54.5, 45.9, 43.9, 40.3, 31.6, 25.5, 22.4, 20.9, 20.7, 20.1; HRMS (ESI) m/z calcd for C44H43N2 [M+H]+ 599.3421, found 599.3414. 6,8-Bis(2-bromophenyl)-7-(3,3-dimethyl-3H-indol-2-yl)-13,13-dimethyl-7,8,8a,13-tetrahydro-6H-benzo[3',4']cyclo buta[1',2':2,3]pyrido[1,2-a]indole (3c) Rf = 0.1 (Petroleum ether/EtOAc = 50/1), yield: 46% (67 mg); > 20:1 dr; white solid, mp: 277.6 – 278.1 oC; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 1H), 7.58 – 7.49 (m, 3H), 7.43 – 7.38 (m, 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.20 – 6.94 (m, 11H), 6.87 (t, J = 8.0 Hz, 1H), 6.76 (t, J = 8.0 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 5.52 (d, J = 7



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12.0 Hz, 1H), 4.40 (s, 1H), 4.02 (d, J = 4.0 Hz, 1H), 3.36 (dd, J = 12.0, 4.0 Hz, 1H), 1.34 (s, 3H), 1.33 (s, 3H), 1.10 (s, 3H), -0.08 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 182.9, 150.7, 149.2, 145.4, 145.0, 142.2, 140.3, 136.6, 133.0, 132.5, 131.5, 130.5, 129.7, 128.5, 128.2, 128.2, 128.0, 127.5, 127.1, 125.1, 124.8, 123.5, 122.2, 121.5, 120.7, 120.6, 118.0, 107.3, 80.5, 60.2, 54.4, 54.3, 46.9, 45.9, 40.0, 30.8, 29.7, 25.7, 22.2, 21.2; HRMS (ESI) m/z calcd for C42H37Br2N2 [M+H]+ 727.1318, found 727.1327. 7-(3,3-Dimethyl-3H-indol-2-yl)-6,8-bis(3-methyphenyl)-13,13-dimethyl-7,8,8a,13-tetrahydro-6H-benzo[3',4']cyclo buta[1',2':2,3]pyrido[1,2-a]indole (3d) Rf = 0.13 (Petroleum ether/EtOAc = 50/1), yield: 75% (90 mg); > 20:1 dr; white solid, mp: 241.2 – 242.0 oC; 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.66 (m, 1H), 7.51 – 7.49 (m, 2H), 7.42 (d, J = 4.0 Hz, 1H), 7.32 – 7.30 (m, 1H), 7.26 – 7.03 (m, 7H), 7.00 – 6.87 (m, 4H), 6.77 – 6.73 (m, 2H), 6.53 (s, 1H), 6.38 (d, J = 8.0 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 4.73 (d, J = 12.0 Hz, 1H), 4.55 (s, 1H), 3.40 (d, J = 3.2 Hz, 1H), 3.26 (dd, J = 12.0, 2.9 Hz, 1H), 2.10 (s, 3H), 1.83 (s, 3H), 1.49 (s, 3H), 1.43 (s, 3H), 1.08 (s, 3H), -0.02 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 185.5, 153.4, 150.7, 150.5, 145.7, 144.9, 143.0, 139.6, 137.5, 137.1, 136.6, 130.4, 129.6, 129.3, 128.2, 128.0, 127.8, 127.6, 127.4, 127.3, 127.3, 126.9, 125.6, 125.5, 125.0, 122.0, 121.2, 120.7, 120.3, 117.8, 107.0, 80.7, 61.8, 54.5, 54.3, 48.0, 45.9, 40.4, 31.9, 23.7, 22.2, 21.9, 21.2, 21.1; HRMS (ESI) m/z calcd for C44H43N2 [M+H]+ 599.3421, found 599.3425. 6,8-Bis(3-chlorophenyl)-7-(3,3-dimethyl-3H-indol-2-yl)-13,13-dimethyl-7,8,8a,13-tetrahydro-6H-benzo[3',4']cyclo buta[1',2':2,3]pyrido[1,2-a]indole (3e) Rf = 0.1 (Petroleum ether/EtOAc = 50/1), yield: 71% (90 mg); > 20:1 dr; white solid; mp: 259.4 – 260.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 1H), 7.56 – 7.50 (m, 3H), 7.43 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.26 – 7.10 (m, 5H), 7.07 – 7.01 (m, 2H), 6.95 – 6.90 (m, 3H), 6.80 (t, J = 8.0 Hz, 1H), 6.65 (d, J = 4.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.25 (d, J = 8.0 Hz, 1H), 4.78 (d, J = 12.0 Hz, 1H), 4.52 (s, 1H), 3.40 (s, 1H), 3.24 (dd, J = 12.0, 4.0 Hz, 1H), 1.49 (s, 3H), 1.43 (s, 4H), 1.08 (s, 3H), 0.04 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 184.7, 153.02, 150.2, 149.8, 145.4, 145.0, 144.6, 141.6, 136.2, 133.9, 133.7, 130.2, 129.9, 129.0, 128.7, 128.5, 128.3, 128.2, 127.6, 127.0, 126.9, 126.8, 125.4, 125.4, 122.0, 121.6, 120.8, 120.5, 118.6, 106.7, 80.5, 61.3, 54.4, 53.8, 47.9, 45.9, 40.0, 31.7, 23.7, 22.1, 21.9; HRMS (ESI) m/z calcd for C42H37Cl2N2 [M+H]+ 639.2328, found 639.2327. 7-(3,3-Dimethyl-3H-indol-2-yl)-13,13-dimethyl-6,8-di-p-tolyl-7,8,8a,13-tetrahydro-6H-benzo[3',4']cyclobuta[1',2': 2,3]pyrido[1,2-a]indole (3f) Rf = 0.1 (Petroleum ether/EtOAc = 50/1), yield: 74% (88 mg); 19:1 dr; white solid; mp: 241.7 – 242.9 oC; 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.61 (m, 1H), 7.49 – 7.45 (m, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.30– 7.26 (m, 3H), 7.22 – 7.18 (m, 1H), 7.10 – 7.02 (m, 3H), 6.97 – 7.93 (m, 1H), 6.83 – 7.79 (m, 4H), 6.71 (t, J = 8.0 Hz, 1H), 6.56 (d, J = 8.0 Hz, 2H), 6.26 (d, J = 8.0 Hz, 1H), 4.80 (d, J = 12.0 Hz, 1H), 4.52 (s, 1H), 3.39 (s, 1H), 3.25 (dd, J = 12.0, 4.0 Hz, 1H), 2.23 (s, 3H), 2.09 (s, 3H), 1.46 (s, 3H), 1.39 (s, 3H), 1.08 (s, 3H), 0.00 (s, 3H);

13

C NMR (101 MHz,

CDCl3) δ 185.7, 153.4, 150.7, 150.3, 145.6, 144.9, 140.1, 136.9, 136.5, 136.0, 130.1, 129.5, 128.5, 128.4, 128.0, 127.8, 127.4, 125.4, 125.0, 121.9, 121.2, 120.8, 120.5, 117.6, 106.9, 80.6, 61.4, 54.5, 54.3, 48.0, 45.8, 40.5, 31.7, 24.2, 22.3, 22.0, 21.1, 20.9; HRMS (ESI) m/z calcd for C44H43N2 [M+H]+ 599.3412, found 599.3412. 6,8-Bis(4-chlorophenyl)-7-(3,3-dimethyl-3H-indol-2-yl)-13,13-dimethyl-7,8,8a,13-tetrahydro-6H-benzo[3',4']cyclo buta[1',2':2,3]pyrido[1,2-a]indole (3g) Rf = 0.18 (Petroleum ether/EtOAc = 50/1), yield: 69% (88 mg); > 20:1 dr; white solid; mp: 265.7 – 266.8 oC; 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.60 (m, 1H), 7.53 – 7.48 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 3H), 7.25 – 7.21 (m, 1H), 7.13 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 7.07 – 6.94 (m, 7H), 6.77 (t, J = 8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 6.22 (d, J = 8.0 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.50 (s, 1H), 3.41 (d, J = 4.0 Hz, 1H), 3.23 (dd, J = 12.0, 3.2 Hz, 1H), 1.46 (s, 3H), 1.40 (s, 3H), 1.08 (s, 3H), 0.04 (s, 3H). 8


13

C NMR (101 MHz, CDCl3) δ

Page 9 of 14 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


185.0, 153.0, 150.3, 149.9, 145.1, 144.7, 141.7, 138.1, 136.3, 132.6, 132.5, 131.5, 129.9, 128.2, 128.1, 128.1, 127.8, 127.6, 125.5, 125.2, 122.1, 121.5, 120.9, 120.5, 118.3, 106.9, 80.5, 61.1, 54.4, 53.9, 47.7, 45.9, 40.1, 31.6, 23.9, 22.2, 22.1; HRMS (ESI) m/z calcd for C42H37Cl2N2 [M+H]+ 639.2328, found 639.2327. 7-(3,3-Dimethyl-3H-indol-2-yl)-6,8-bis(4-isopropylphenyl)-13,13-dimethyl-7,8,8a,13-tetrahydro-6H-benzo[3',4']cy clobuta[1',2':2,3]pyrido[1,2-a]indole (3h) Rf = 0.12 (Petroleum ether/EtOAc = 50/1), yield: 61% (80 mg); > 20:1 dr; white solid; mp: 220.7 – 221.1oC; 1H NMR (400 MHz, CDCl3) δ 7.65 – 7.63 (m, 1H), 7.51 – 7.45 (m, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.31 – 7.28 (m, 3H), 7.24 – 7.20 (m, 1H), 7.12 – 6.96 (m, 4H), 6.89 – 6.85 (m, 4H), 6.73 (t, J = 8.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 2H), 6.31 (d, J = 8.0 Hz, 1H), 4.88 (d, J = 12.0 Hz, 1H), 4.53 (s, 1H), 3.39 (s, 1H), 3.26 (dd, J = 12.0, 4.0 Hz, 1H), 2.85 – 2.78 (m, 1H), 2.69 – 2.63 (m, 1H), 1.46 (s, 3H), 1.40 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 1.03 (s, 3H), -0.03 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 185.9, 153.4, 150.7, 150.2, 147.2, 146.7, 145.7, 145.0, 140.5, 137.4, 136.5, 130.1, 129.5, 128.3, 127.9, 127.8, 127.3, 125.8, 125.5, 125.0, 121.8, 121.2, 120.8, 120.4, 117.6, 107.0, 80.5, 61.3, 54.5, 54.4, 48.2, 45.8, 40.7, 33.6, 33.4, 31.6, 24.4, 24.0, 23.9, 22.2, 21.6; HRMS (ESI) m/z calcd for C48H51N2 [M+H]+ 655.4047, found 655.4034. 7-(3,3-Dimethyl-3H-indol-2-yl)-6,8-bis(4-fluorophenyl)-13,13-dimethyl-7,8,8a,13-tetrahydro-6H-benzo[3',4']cyclo buta[1',2':2,3]pyrido[1,2-a]indole (3i) Rf = 0.1 (Petroleum ether/EtOAc = 50/1), yield: 62% (75 mg); > 20:1 dr; white solid; mp: 230.1 – 230.8 oC; 1H NMR (400 MHz, CDCl3) δ 7.65 – 7.50 (m, 1H), 7.53 – 7.49 (m, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.38 – 7.31 (m, 3H), 7.30 (td, J = 8.0, 1.2 Hz, 2H), 7.12 (m, 2H), 7.06 (dd, J = 8.0, 1.6 Hz, 1H), 6.99 (td, J = 3.6, 1.2 Hz, 1H), 6.80 – 6.59 (m, 7H), 6.24 (d, J = 8.0 Hz, 1H), 4.80 (d, J = 12.0 Hz, 1H), 4.52 (s 1H), 3.42 (d, J = 4.0 Hz, 1H), 3.23 (dd, J = 12.0, 4.0 Hz, 1H), 1.47 (s, 3H), 1.41 (s, 3H), 1.08 (s, 3H), 0.03 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 185.2,

161.7 (d, JC-F = 246.4 Hz), 161.6 (d, JC-F = 245.4 Hz), 153.1, 150.3, 150.0, 145.3, 144.7, 138.9 (d, JC-F = 3.0 Hz), 136.4, 135.4 (d, JC-F = 3.0 Hz) 131.6, (d, JC-F = 7.1 Hz), 130.0, (d, JC-F = 7.1 Hz), 129.8, 128.1, 128.0, 127.5, 125.4, 125.2, 122.0, 121.4, 120.9, 120.4, 118.2, 114.8 (d, JC-F = 18.2 Hz), 114.6 (d, JC-F = 18.2 Hz), 106.8, 80.5, 61.0, 54.5, 54.1, 47.6, 45.9, 40.4, 31.6, 24.0, 22.1, 22.0;

19

F NMR (471 MHz, CDCl3) δ -116.19, -116.21; HRMS (ESI) m/z

+

calcd for C42H37F2N2 [M+H] 607.2919, found 607.2908. 7-(3,3-Dimethyl-3H-indol-2-yl)-13,13-dimethyl-6,8-bis(4-nitrophenyl)-7,8,8a,13-tetrahydro-6H-benzo[3',4']cyclob uta[1',2':2,3]pyrido[1,2-a]indole (3j) Rf = 0.2 (Petroleum ether/EtOAc = 20/1), yield: 85% (112 mg); > 20:1 dr; yellow solid; mp > 300 oC; 1H NMR (400 MHz, CDCl3) δ 7.96 – 7.94 (m, 2H), 7.86 – 7.82 (m, 2H), 7.71 – 7.67 (m, 1H), 7.60 – 7.57 (m, 4H), 7.40 – 7.35 (m, 2H), 7.26 (td, J = 7.6, 1.6 Hz, 2H), 7.20 (dd, J = 7.2, 1.2 Hz, 1H), 7.16 (td, J = 8.4, 1.2 Hz, 1H), 7.08 (dd, J = 7.6, 1.2 Hz, 1H), 7.04 (td, J = 8.0, 1.2 Hz, 1H), 6.81 – 6.77 (m, 2H), 6.18 (d, J = 7.8 Hz, 1H), 4.87 (d, J = 12.0 Hz, 1H), 4.56 (s, 1H), 3.57 (d, J = 2.8 Hz, 1H), 3.34 (dd, J = 12.0, 3.2 Hz, 1H), 1.50 (s, 3H), 1.44 (s, 3H), 1.12 (s, 3H), 0.01 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 183.9, 152.5, 150.6, 149.8, 149.5, 147.1, 146.8, 146.8, 144.4,

144.3, 136.2, 131.0, 130.3, 129.8, 128.9, 128.3, 127.9, 126.0, 125.2, 123.3, 122.8, 122.2, 121.8, 121.0, 120.6, 119.2, 106.7, 80.5, 61.5, 54.3, 53.3, 48.2, 46.1, 39.7, 31.6, 23.6, 22.1, 22.1; HRMS (ESI) m/z calcd for C42H37N4O4 [M+H]+ 661.2809, found 661.2799. 6,8-Bis(4-chloro-2-fluorophenyl)-7-(3,3-dimethyl-3H-indol-2-yl)-13,13-dimethyl-7,8,8a,13-tetrahydro-6H-benzo[3 ',4']cyclobuta[1',2':2,3]pyrido[1,2-a]indole (3k) Rf = 0.1 (Petroleum ether/EtOAc = 40/1), yield: 67% (90 mg); > 20:1 dr; white solid; mp: 263.6 – 264.2 oC; 1H NMR (400 MHz, CDCl3) δ 7.60 – 7.57 (m, 1H), 7.54 – 7.52 (m, 2H), 7.44 (t, J = 8.0 Hz, 1H), 7.38 – 7.34 (m, 2H), 7.22 – 7.18 (m, 1H), 7.13 – 7.03 (m, 4H), 6.94 (dd, J = 8.0, 4.0 Hz, 1H), 6.82 – 6.76 (m, 3H), 6.69 – 6.61 (m, 2H), 6.43 (d, J = 8.0 Hz, 1H), 5.11 (d, J = 12.0 Hz, 1H), 4.35 (s, 1H), 3.82 (d, J = 4.0 Hz, 1H), 3.43 (dd, J = 12.0, 4.0 Hz, 1H), 1.40 (s, 3H), 1.36 (s, 3H), 1.11 (s, 3H), 0.16 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 184.7, 160.9 (d, JC-F 9



Page 10 of 14

= 219.2 Hz), 159.7 (d, JC-F = 252.5 Hz), 153.6, 150.0, 149.9, 144.8, 144.7, 136.1, 133.5 (d, JC-F = 9.0 Hz), 133.4 (d, JC-F = 9.0 Hz), 132.0 (d, JC-F = 4.0 Hz), 130.6 (d, JC-F = 4.0 Hz), 130.0, 128.5, 128.4, 128.2, 127.4, 125.9 (d, JC-F = 14.0 Hz), 125.8 (d, JC-F = 3.0 Hz), 125.3, 124.5 (d, JC-F = 4.0 Hz), 124.4 (d, JC-F = 3.0 Hz), 122.0, 121.5, 120.8, 120.4, 118.7, 116.2 (d, JC-F = 27.3 Hz), 115.4 (d, JC-F = 27.3 Hz), 106.8, 80.7, 55.5, 54.3, 53.4, 46.0, 40.0, 38.27, 31.5, 23.3, 23.0, 21.3; 19F NMR (471 MHz, CDCl3) δ -111.40, -111.65; HRMS (ESI) m/z calcd for C42H35Cl2F2N2 [M+H]+ 675.2140, found 675.2133. 7-(3,3-Dimethyl-3H-indol-2-yl)-13,13-dimethyl-6,8-di(naphthalen-2-yl)-7,8,8a,13-tetrahydro-6H-benzo[3',4']cyclo buta[1',2':2,3]pyrido[1,2-a]indole (3l) Rf = 0.2 (Petroleum ether/EtOAc = 50/1), yield: 62% (83 mg); > 20:1 dr; white solid; mp: 150.8 – 151.4 oC; 1H NMR (400 MHz, CDCl3) δ 7.95 – 7.90 (m, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.70 – 7.59 (m, 7H), 7.49 – 7.45 (m, 3H), 7.39 – 7.33 (m, 5H), 7.29 – 7.26 (m, 1H), 7.17 – 7.13 (m, 1H), 7.10 – 7.05 (m, 2H), 6.98 (m, 2H), 6.82 – 6.79 (m, 1H), 6.44 (dd, J = 8.0, 4.0 Hz, 1H), 5.16 (d, J = 12.0 Hz, 1H), 4.78 (d, J = 4 Hz, 1H), 3.75 (d, J = 4.0 Hz, 1H), 3.57 (dt, J = 12.0, 4.0 Hz, 1H), 1.66 (s, 3H), 1.61 (s, 3H), 1.25 (s, 3H), 0.00 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ

185.5, 153.3, 150.9, 150.5, 145.7, 144.8, 140.5, 137.5, 136.7, 133.6, 133.0, 132.4, 132.4, 130.2, 129.8, 128.5, 128.3, 128.1, 127.9, 127.7, 127.5, 127.4, 127.4, 127.3, 126.7, 126.0, 125.6, 125.5, 125.3, 125.1, 122.2, 121.4, 120.8, 120.4, 118.2, 107.2, 81.0, 62.1, 54.6, 54.5, 48.2, 46.1, 40.3, 31.9, 23.6, 22.3, 22.3; HRMS (ESI) m/z calcd for C50H43N2 [M+H]+ 671.3421, found 671.3403. 7-(3,3-Dimethyl-3H-indol-2-yl)-13,13-dimethyl-6,8-di(thiophen-2-yl)-7,8,8a,13-tetrahydro-6H-benzo[3',4']cyclobu ta[1',2':2,3]pyrido[1,2-a]indole (3m) Rf = 0.15 (Petroleum ether/EtOAc = 50/1), yield: 74% (86 mg); > 20:1 dr; white solid; mp: 210.9 – 211.4 oC; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.45 (m, 2H), 7.30 – 7.24 (m, 2H), 7.19 – 7.09 (m, 3H), 7.02 (d, J = 4.0 Hz, 1H), 6.99 (d, J = 4.0 Hz, 1H), 6.94 (d, J = 4.0 Hz, 1H), 6.77 – 7.73 (m, 3H), 6.61 (t, J = 4.0 Hz, 1H), 6.39 – 6.35 (m, 2H), 5.49 (d, J = 8.0 Hz, 1H), 4.56 (s, 1H), 3.80 (d, J = 4.0 Hz, 1H), 3.30 (dd, J = 12.0, 2.8 Hz, 1H), 1.46 (s, 3H), 1.40 (s, 3H), 1.15 (s, 3H), 0.31 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 185.5, 153.2, 149.8, 149.3, 148.2, 145.2, 144.6, 142.2, 136.7, 129.6, 127.9, 127.5, 126.7, 126.6, 126.5, 126.3, 125.3, 125.2, 124.1, 123.8, 121.7, 121.2, 120.9, 120.7, 117.9, 106.9, 80.0, 56.7, 54.8, 54.5, 45.7, 43.3, 40.9, 31.1, 24.2, 22.7, 21.8; HRMS (ESI) m/z calcd for C38H35N2S2 [M+H]+ 583.2236, found 583.2225. 2,13,13-Trimethyl-6,8-diphenyl-7-(3,3,5-trimethyl-3H-indol-2-yl)-7,8,8a,13-tetrahydro-6H-benzo[3',4']cyclobuta[ 1',2':2,3]pyrido[1,2-a]indole (3n) Rf = 0.17 (Petroleum ether/EtOAc = 50/1), yield: 59% (70 mg); > 20:1 dr; white solid; mp: 240.2 – 240.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.62 (m, 1H), 7.51 – 7.46 (m, 2H), 7.38 – 7.36 (m, 2H), 7.33 – 7.26 (m, 2H), 7.15 (t, J = 8.0 Hz, 1H), 7.03 – 6.99 (m, 5H), 6.94 (d, J = 4.0 Hz, 1H), 6.92 (s, 1H), 6.85 (s, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 2H), 6.14 (d, J = 8.0 Hz, 1H), 4.82 (d, J = 12.0 Hz, 1H), 4.54 (s, 1H), 3.41 (d, J = 4.0 Hz, 1H), 3.23 (dd, J = 12.0, 3.2 Hz, 1H), 2.31 (s, 3H), 2.29 (s, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 1.06 (s, 3H), -0.05 (s, 3H).

13

C NMR (101 MHz, CDCl3) δ 184.4, 151.2, 150.9, 147.9, 145.5, 145.0, 143.3, 140.1, 136.5, 134.8, 130.2,

129.4, 128.5, 128.1, 127.9, 127.8, 127.7, 127.6, 126.6, 126.6, 126.5, 125.3, 122.1, 121.9, 121.6, 120.0, 106.6, 80.6, 61.5, 54.2, 54.1, 48.6, 45.8, 40.4, 31.5, 24.4, 22.3, 21.8, 21.4, 20.9; HRMS (ESI) m/z calcd for C44H43N2 [M+H]+ 599.3421, found 599.3424. 2-Fluoro-7-(5-fluoro-3,3-dimethyl-3H-indol-2-yl)-13,13-dimethyl-6,8-diphenyl-7,8,8a,13-tetrahydro-6H-benzo[3', 4']cyclobuta[1',2':2,3]pyrido[1,2-a]indole (3o) Rf = 0.12 (Petroleum ether/EtOAc = 50/1), yield: 62% (75 mg); > 20:1 dr; white solid; mp: 238.5 – 239.1 oC; 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.64 (m, 1H), 7.52 – 7.50 (m, 2H), 7.37 – 7.28 (m, 4H), 7.19 – 7.15 (m, 1H), 7.06 – 6.98 (m, 5H), 6.91 – 6.84 (m, 2H), 6.73 (dd, J = 8.0, 2.4 Hz, 1H), 6.69 – 6.64 (m, 3H), 6.14 (dd, J = 8.0, 4.0 Hz, 1H), 4.74 (d, J = 12.0 Hz, 1H), 4.55 (s, 1H), 3.41 (d, J = 3.2 Hz, 1H), 3.22 (dd, J = 12.0, 3.2 Hz, 1H), 1.46 (s, 10


Page 11 of 14 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


3H), 1.41 (s, 3H), 1.07 (s, 3H), -0.05 (s, 3H).

13

C NMR (101 MHz, CDCl3) δ 185.0, 161.2 (d, JC-F = 245.4 Hz),

156.8 (d, JC-F = 235.3 Hz), 150.2, 149.1 (d, JC-F = 2.0 Hz), 146.8 (d, JC-F = 8.0 Hz), 146.4, 145.3, 143.0, 139.8, 138.1, 138.0, 130.1, 129.8, 128.4, 128.0, 127.9, 127.7, 126.8, 125.3, 121.9, 120.1 (d, JC-F = 8.0 Hz), 113.9 (d, JC-F = 24.2 Hz), 113.5 (d, JC-F = 24.2 Hz), 109.1 (d, JC-F = 24.2 Hz), 108.5 (d, JC-F = 24.2 Hz), 106.6 (d, JC-F = 8.0 Hz), 80.9, 61.9, 55.0, 54.9, 54.0, 48.4, 46.0, 40.4, 31.4, 23.8, 22.0, 21.7;

19

F NMR (471 MHz, CDCl3) δ -117.46,

+

-127.72; HRMS (ESI) m/z calcd for C42H37F2N2 [M+H] 607.2919, found 607.2905. 7-(3,3-Dimethyl-3H-indol-2-yl)-14,14-dimethyl-6,8-diphenyl-7,8,8a,14-tetrahydro-6H-[1,3]dioxolo[4''',5''':4'',5'']b enzo[1'',2'':3',4']cyclobuta[1',2':2,3]pyrido[1,2-a]indole (3q) Rf = 0.18 (Petroleum ether/EtOAc = 40/1), yield: 61% (75 mg); > 20:1 dr; white solid; mp: 112.9 – 113.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.37 (m, 3H), 7.22 (td, J = 7.6, 1.6 Hz, 1H), 7.16 – 6.94 (m, 10H), 6.82 (s, 1H), 6.73 (td, J = 7.2, 0.8 Hz, 1H), 6.68 – 6.65 (m, 2H), 6.26 (d, J = 8.0 Hz, 1H), 6.08 (d, J = 1.2 Hz, 1H), 6.04 (d, J = 1.2 Hz, 1H), 4.85 (d, J = 8.0 Hz, 1H), 4.37 (s, 1H), 3.42 – 3.37 (m, 2H), 1.45 (s, 3H), 1.39 (s, 3H), 1.16 (s, 3H), 0.08 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 185.4, 153.3, 150.1, 149.0, 147.4, 144.8, 143.2, 142.2, 139.8, 137.8, 136.3, 130.2, 128.4, 127.9, 127.9, 127.6, 127.3, 126.6, 125.1, 121.2, 120.8, 120.4, 117.7, 107.0, 106.8, 103.3, 100.6, 78.9, 61.6, 54.4, 52.4, 48.4, 45.8, 40.3, 31.5, 24.2, 22.3, 22.0; HRMS (ESI) m/z calcd for C43H39N2O2 [M+H]+ 615.3006, found 615.2999. Procedure for the Synthesis of [4+2]/[2+2] Cycloadducts 3'a. A reaction tube was charged with 1 (0.2 mmol) and toluene (2 mL), then CF3SO3H (0.04 mmol, 20 mol %) was added at 60 oC. After the [4+2] cycloaddition reaction was stirred for 10 h. Cooled to the room temperature, removing the solvent. Without isolating [4+2] cycloaddition products, add CH 3CN (2 mL), KF (0.6 mmol, 3.0 equiv), 18-crown-6 (0.6 mmol, 3.0 equiv) and 2 (0.4 mmol, 2.0 equiv) to the tube at room temperature. After the [2+2] cycloaddition reaction was stirred for 1 h, the crude product was purified by column chromatography on silica gel to give the product 3'a. 7-(3,3-Dimethyl-3H-indol-2-yl)-13,13-dimethyl-6,8-diphenyl-7,8,8a,13-tetrahydro-6H-benzo[3',4']cyclobuta[1',2': 2,3]pyrido[1,2-a]indole (3'a) Rf = 0.18 (Petroleum ether/EtOAc = 50/1), yield = 59% (33 mg); White solid; mp: 198.0 – 199.3 oC; 1H NMR (400 MHz, Acetone-d6) δ 7.42 (d, J = 8.0 Hz, 1H), 7.36 – 7.33 (m, 4H), 7.29 – 7.10 (m, 9H), 7.07 – 7.01 (m, 3H), 6.94 (dd, J = 8.0, 4.0 Hz, 1H), 6.64 – 6.62 (m, 3H), 5.29 – 5.26 (m, 1H), 4.95 (d, J = 8.0 Hz, 1H), 4.04 (d, J = 8.0 Hz, 1H), 3.80 – 3.66 (m, 2H), 1.62 (s, 3H), 1.02 (s, 3H), 0.12 (s, 3H), 0.03 (s, 3H); 13C NMR (101 MHz, Acetone-d6) δ 189.7, 153.3, 149.1, 147.4, 146.8, 145.5, 145.3, 140.0, 140.0, 129.8, 129.5, 129.0, 128.5, 128.1, 127.7, 127.0, 126.9, 126.7, 126.0, 125.0, 123.1, 121.3, 120.7, 119.8, 118.0, 111.0, 81.8, 63.0, 55.0, 54.5, 51.5, 48.7, 44.4, 23.6, 21.0, 20.8, 20.4; HRMS (ESI) m/z calcd for C42H39N2 [M+H]+ 571.3108, found 571.3107. General Procedure for the Transformation of 3a. A reaction tube was charged with 3a (0.2 mmol) and anhydrous THF (4 mL) in argon atmosphere, then BH3·Me2S (1 mmol, 5.0 equiv) was added at 60 oC. After stirred for 12 h. the reaction mixture was cooled to room temperature and quenched with MeOH. Then the mixture was added 10 mL H2O and extracted with CH2Cl2 (2×10 mL). The combined organic phase was dried with anhydrous sodium sulfate. After filtration and removal of the solvent, the crude product was purified by column chromatography on silica gel to give the product 4a and 4'a. (6S,7R,8R,8aR,12bS)-7-((S)-3,3-dimethylindolin-2-yl)-13,13-dimethyl-6,8-diphenyl-7,8,8a,13-tetrahydro-6H-benzo [3',4']cyclobuta[1',2':2,3]pyrido[1,2-a]indole (4a) (major product) Rf = 0.12 (Petroleum ether/EtOAc = 100/1), yield: 61% (82 mg); 2:1 dr; white solid; mp: 91.2 – 91.9 oC; 1H NMR (400 MHz, CDCl3) δ 7.39 (t, J = 8.0 Hz, 1H), 7.33 – 7.22 (m, 6H), 7.18 – 7.10 (m, 5H), 7.05 – 6.97 (m, 5H), 6.86 (t, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.65 (t, J = 8.0 Hz, 1H), 6.56 (t, J = 8.0 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 4.75 (d, J = 8.0 Hz, 1H), 4.36 (d, J = 2.4 Hz, 1H), 3.90 – 3.68 (m, 1H), 3.43 (t, J = 11



3.2 Hz, 1H), 3.12 (d, J = 3.6 Hz, 1H), 2.81 – 2.77 (m, 1H), 1.24 (s, 3H), 1.13 (s, 3H), 1.05 (s, 3H), 0.28 (s, 3H); 13

C NMR (101 MHz, CDCl3) δ 149.4, 149.0, 148.6, 145.8, 143.4, 141.6, 138.5, 137.0, 129.7, 129.2, 128.5, 127.7,

127.6, 127.4, 126.9, 126.5, 125.7, 121.6, 121.5, 118.3, 116.9, 109.1, 105.5, 79.2, 71.3, 60.3, 53.0, 50.1, 45.0, 44.7, 37.6, 29.7, 27.9, 26.1, 23.0; HRMS (ESI) m/z calcd for C42H41N2 [M+H]+ 573.3264, found 573.3261. (6S,7R,8R,8aR,12bS)-7-((R)-3,3-dimethylindolin-2-yl)-13,13-dimethyl-6,8-diphenyl-7,8,8a,13-tetrahydro-6H-benz o[3',4']cyclobuta[1',2':2,3]pyrido[1,2-a]indole (4'a) (minor product)

Rf = 0.11 (Petroleum ether/EtOAc = 100/1), yield: 25% (28 mg) white foam; mp: 71.2 – 72.3 oC; 1H NMR (400 MHz, CDCl3) δ 7.38 (t, J = 8.0 Hz, 1H), 7.31 – 7.26 (m, 3H), 7.18 – 7.11 (m, 6H), 7.07 – 7.01 (m, 4H), 6.98 (d, J = 8.0 Hz, 1H), 6.85 (td, J = 7.6, 1.2 Hz, 1H), 6.74 (dd, J = 7.6, 1.2 Hz, 1H), 6.65 (t, J = 8 Hz, 1H), 6.56 (t, J = 8.0 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 4.75 (d, J = 8.0 Hz, 1H), 4.36 (d, J = 2.0 Hz, 1H), 3.75 (d, J = 5.2 Hz, 1H), 3.43 (dd, J = 4.0, 2.4 Hz, 1H), 3.13 (s, 1H), 2.79 (m, 1H), 1.24 (s, 3H), 1.13 (s, 3H), 1.05 (s, 3H), 0.29 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 149.4, 149.0, 148.6, 145.8, 143.5, 141.6, 138.5, 137.0, 129.7,

129.2, 128.6, 127.8, 127.6, 127.4, 126.9, 126.6, 126.5, 125.7, 121.6, 121.5, 118.3, 116.9, 109.1, 105.5, 79.2, 77.2, 71.3, 60.3, 53.0, 50.2, 45.0, 44.7, 37.6, 29.7, 28.0, 26.2, 23.0; HRMS (ESI) m/z calcd for C42H41N2 [M+H]+ 573.3264, found 573.3272. Synthesis of [4+2] Cycloadduct 5. A reaction tube was charged with 3a (0.4 mmol) and CF3CH2OH (4 mL), then CF3SO3H (0.08 mmol, 20 mol %) was added at 60 oC. After stirred for 10 h, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel to give the product 5. 6,8-Bis(2-bromophenyl)-7-(3,3-dimethyl-3H-indol-2-yl)-10,10-dimethyl-6,7,8,10-tetrahydropyrido[1,2-a]indole (5) Rf = 0.2 (Petroleum ether/EtOAc = 50/1), yield: 69% (90 mg); > 20:1 dr; slight yellow solid; mp: 195.7 -196.9 oC; 1

H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 4.0 Hz, 1H), 7.34 (dd, J = 8.0, 4.0 Hz, 2H),

7.27 (t, J = 8.0 Hz, 1H), 7.24 – 7.20 (m, 1H), 7.15 (t, J = 8.0 Hz, 3H), 7.04 (dt, J = 12.0, 8.0 Hz, 2H), 6.94 (q, J = 8.0 Hz, 2H), 6.88 – 6.85 (m, 1H), 6.71 (t, J = 8.0 Hz, 1H), 6.25 (d, J = 8.0 Hz, 1H), 5.24 (s, 1H), 4.69 (s, 1H), 4.37 (d, J = 4.0 Hz, 1H), 3.64 (d, J = 4.0 Hz, 1H), 1.77 (s, 3H), 1.56 (s, 3H), 1.46 (s, 3H), 0.16 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 185.8, 154.2, 154.2, 145.1, 144.9, 142.0, 140.3, 138.1, 133.1, 132.2, 131.5, 129.3, 128.7, 128.1, 127.4, 127.3, 127.0, 125.7, 125.0, 121.8, 121.7, 120.7, 120.6, 118.4, 104.8, 89.2, 57.2, 55.4, 44.0, 38.3, 36.9, 30.0, 29.0, 25.4, 19.2; HRMS (ESI) m/z calcd for C36H33Br2N2 [M+H]+ 651.1005, found 651.1002. ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (No. 21542007) and the Fundamental Research Funds for the Central Universities (DUT18LAB16) for support of this work. Supporting Information. 1H and 13 C NMR spectra of all products and X-ray crystallographic data for compounds 3a, 3’a and 4a.

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Baldridge, K. K.; Suziki, K. Poly-Oxygenated Tricyclobutabenzenes via Repeated [2+2] Cycloaddition of Benzyne and Ketene Silyl Acetal. J. Am. Chem. Soc. 2006, 128, 3534 - 3535. (f) Bhojgude, S. S.; Thangaraj, M.; Suresh, E.; Biju, A. T. Tandem [4+2]/[2+2] Cycloaddition Reactions Involving Indene or Benzofurans and Arynes. Org. Lett. 2014, 16, 3576 - 3579. (g) Shin, J.; Lee, J.; Ko, D.; De, N.; Yoo, E. J. Synthesis of Fused Polycyclic 1,4-Benzodiazepines via Metal-Free Cascade [5+2]/[2+2] Cycloadditions. Org. Lett. 2017, 16, 2901 - 2904. (h) Kiran, I. N.; Reddy, R. S.; Lagishetti, C.; Xu, H.; Wang, Z.; He Y. Selective Aza Diels-Alder and Domino [4+2]/[2+2] Cycloaddition Reactions of Arynes with N-Sulfonyl Ketimines. J. Org. Chem. 2017, 82, 1823 - 1832. (9) CCDC 1813751 (3a), 1813747 (3’a), 1833193 (4a). See the Supporting Information for details.

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[2+2] Cycloadditions Involving 2

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