Consecutive Four-Component Coupling-Addition Aza-Anellation Pictet–Spengler Synthesis of Tetrahydro-β-Carbolines: An Optimized Michael Addition and Computational Study on the Aza-Anellation Step

Abstract

Starting from acid chlorides, alkynes, tryptamines, and acryloyl chloride, 21 densely substituted tetrahydro-β-carbolines were prepared in a four-component, one-pot reaction. In this study, the aza-Michael addition step to generate intermediate enaminones was optimized in the presence of ytterbium triflate. Moreover, apart from acryloyl chloride, all reactants could be deployed in almost equimolar ratios, which increases the atom economy of the sequence. For mechanistic rationalization, the concluding aza-anellation was investigated by DFT calculations on potential intermediates and corresponding activation energies, revealing that the aza-anellation proceeds via ene reaction rather than via electrocyclization.

1. Introduction

Increased ecological demands have challenged the chemical industry and have led to a growing interest in conducting chemical reactions as atom economically as possible, i.e., in an environmentally benign manner and with equimolar stoichiometry. Simultaneously, the consumption of chemicals should be reduced while maintaining synthetic efficiency in comparison with established methods [1,2,3,4]. One methodological approach for reaching this ambitious goal is provided by multicomponent reactions (MCR), where all reactants are combined in a single vessel either at the beginning of the reaction or successively over time to obtain the desired compounds [5,6]. The intermediates of such one-pot processes are not isolated, but react in situ with the next functionality in a subsequent reaction step, thereby eliminating the consumption of chemicals required for their purification. A major advantage of this approach is the possibility to very quickly create large compound libraries, for example by employing heterocycle synthesis via transition metal catalysis in a diversity-oriented fashion [7], which is of particular interest in the life sciences for obtaining hits of biologically active compounds and for studying modes of action.

A particularly active class of biologically active compounds are tetrahydro-β-carbolines (THBC), which represent a structural motif in many naturally occurring indole-based alkaloids [8]. Due to the influence on serotonin uptake in the membrane of nerve endings, they show analgesic, body temperature lowering, and appetite suppressing properties [9]. As PDE-5 inhibitors, they can be used to treat erectile dysfunction and finally exhibit both antiviral and antitumor effects [10,11,12]. We have previously provided a consecutive four-component synthesis of THBCs via a coupling-addition aza-anellation Pictet–Spengler (CAAPS) sequence [13,14]. Herein, we report, after an optimization of the Michael addition step by catalysis with ytterbium triflate, a more efficient, selective generation of a substance library of 21 THBC 5 in a very short time by strictly using almost equimolar amounts of the starting materials.

An open question of the CAAPS sequence is the mechanistic rationalization of the concluding aza-anellation Pictet–Spengler sequel, which is scrutinized by DFT calculations on potential intermediates and transition states starting from the enaminone intermediate herein.

2. Materials and Methods

2.1. General Considerations and Instrumentation

All reactions were performed in Schlenk or multineck flasks under nitrogen atmosphere and using the septum and syringe technique unless otherwise indicated. Dried solvents were taken from the MB-SPS 800 solvent drying system (M. Braun). Triethylamine was freshly distilled according to standard procedure under nitrogen atmosphere with potassium hydroxide and then with calcium hydride. The reaction temperature was adjusted using silicone oil baths preheated to the indicated temperatures or cooling baths (ice/water at 0 °C or dry ice/isopropanol at –78 °C). Column chromatography was performed on silica gel M60 (mesh 230–400, Macherey-Nagel, Düren, Germany). The column chromatographic separations were carried out using the flash technique (overpressure of approx. 2 bar compressed air). For the thin layer chromatography, silica-coated aluminum foils (60 F254 Merck) were used. The evaluation was performed under UV light (λ = 254 and 356 nm) and staining with iodine.

All commercially available chemicals were obtained from ABCR, ACROS, Alfa Aesar, Fluorochem, Macherey-Nagel, Merck, Roth, Sigma Aldrich, and VWR and were used without further purification. ¹H, ¹³C, and DEPT-135 NMR spectra were recorded at 293 K on Bruker Avance III 600 (600 MHz), Bruker Avance DRX 500 (500 MHz), and Bruker Avance III 300 (300 MHz) instruments unless otherwise noted. Poorly soluble compounds were measured at elevated temperature to increase solubility. CDCl₃ and DMSO-d₆ served as solvents. As an internal standard, the residual proton signal of the corresponding solvents was locked when recording the ¹H NMR spectra and the ¹³C NMR spectra (CDCl₃, δ_H 7.26, δ_C 77.16; DMSO-d₆, δ_H 2.50, δ_C 39.52). Spin multiplicities were abbreviated as follows: s—singlet; d—doublet, dd—doublet of doublet; ddd—doublet of doublet of doublet; dt—doublet of a triplet; t—triplet; m—multiplet. The quaternary carbon nuclei (C_quat) and the carbon nuclei of methine (CH), methylene (CH₂), and methyl (CH₃) groups were assigned based on DEPT-135 spectra. Melting points (uncorrected) were measured on the Büchi B545 instrument according to the protocol of Kofler [15]. EI mass spectra were measured on the TSQ 7000 triple quadrupole mass spectrometer (Finnigan MAT, Waltham, MA, USA). Indicated were all peaks with an intensity > 10% of the base peak, the mole peak, and any characteristic fragment peaks with an intensity < 10%. ESI mass spectra were measured on the Finnigan LCQ Deca ion-trap API mass spectrometer (Thermo Quest); HR-ESI mass spectra and HPLC chromatograms were measured on the UHR-QTOF maXis 4G mass spectrometer (Bruker Daltonics). IR spectra were measured on the IRAffinity-1 instrument (Shimadzu) (single reflection ATR unit with diamond ATR crystal, wavenumber range: 4000–600 cm⁻¹). The intensities of the absorption bands were given as s (strong), m (medium), and w (weak). Elemental analyses were measured on the Perkin Elmer Series II Analyzer 2400 at the Institute of Pharmaceutical Chemistry, Heinrich Heine University. Rotational angle measurements were performed on the Perkin Elmer 341 polarimeter.

2.2. General Procedure (GP) for the Synthesis of THBC 5

In a sintered dry screw-cap Schlenk tube with magnetic stir bar under nitrogen atmosphere PdCl₂(PPh₃)₂ (42 mg, 0.06 mmol), CuI (22 mg, 0.12 mmol), and acid chloride 1 (if a solid) were suspended in degassed dichloromethane (10 mL) and then stirred at rt for 5 min (for experimental details, see

Table 1. Experimental data on the CAAPS synthesis of THBCs 5.

Entry	Acid Chloride 1 (mg) (mmol)	Alkyne 2 (mg) (mmol)	Acryloyl Chloride (4) (mg) (mmol)	Yield THBC 5 (mg) (%)	Eluent a
1	293 (2.00) of 1a	214 (2.60) of 2a	905 (10.00)	250 (31%) of 5a	diethyl ether
2	281 (2.00) of 1b	197 (2.40) of 2a	905 (10.00)	213 (27%) of 5b	HE 1:1
3	309 (2.00) of 1c	197 (2.40) of 2a	905 (10.00)	150 (18%) of 5c	HE 1:1
4	341 (2.00) of 1d	197 (2.40) of 2a	905 (10.00)	163 (19%) of 5d	diethyl ether
5	352 (2.00) of 1e	197 (2.40) of 2a	905 (10.00)	260 (30%) of 5e	diethyl ether
6	439 (2.00) of 1f	197 (2.40) of 2a	905 (10.00)	385 (40%) of 5f	HE 1:1
7	319 (2.00) of 1g	197 (2.40) of 2a	905 (10.00)	472 (56%) of 5g	HE 6:4
8	371 (2.00) of 1h	197 (2.40) of 2a	905 (10.00)	334 (37%) of 5h	HE 1:1
9	293 (2.00) of 1a	197 (2.40) of 2b	905 (10.00)	210 (25%) of 5i	diethyl ether
10	341 (2.00) of 1d	197 (2.40) of 2c	724 (8.00)	360 (48%) of 5j	HE 1:2
11	352 (2.00) of 1e	197 (2.40) of 2b	905 (10.00)	313 (34%) of 5k	HE 1:1
12	352 (2.00) of 1e	197 (2.40) of 2d	905 (10.00)	160 (19%) of 5l	HE 1:2
13	293 (2.00) of 1a	590 (2.00) of 2e	724 (8.00)	390 (32%) of 5m	HE 1:1
14	352 (2.00) of 1e	590 (2.00) of 2e	724 (8.00)	624 (48%) of 5n	HE 1:1
15	317 (2.00) of 1g	590 (2.00) of 2e	724 (8.00)	332 (26%) of 5o	HE 1:1
16	439 (2.00) of 1f	590 (2.00) of 2e	724 (8.00)	687 (50%) of 5p	HE 1:1
17	281 (2.00) of 1b	590 (2.00) of 2e	724 (8.00)	418 (34%) of 5q	HE 1:1
18	341 (2.00) of 1d	590 (2.00) of 2e	724 (8.00)	423 (33%) of 5r	HE 1:1
19	309 (2.00) of 1c	590 (2.00) of 2e	724 (8.00)	458 (36%) of 5s	HE 1:1
20 b	176 (1.00) of 1e	99 (1.20) of 2a	362 (4.00)	198 (20%) of 5t	HE 1:1
21 c	439 (2.00) of 1f	197 (2.40) of 2a	724 (8.00)	195 (18%) of 5u	HE 1:1

^a HE—n-hexane/ethyl acetate. ^b 0.03 mol of PdCl₂(PPh₃)₂, 0.06 mol of CuI, and 0.01 mmol of Yb(OTf)₃ were employed. A mixture of (S)-tryptophan methyl ester (3b) (255 mg, 1.00 mmol) and NEt₃ (0.14 mL, 1.00 mmol) in CH₃CN (5 mL) was used instead of tryptamine. ^c A mixture of (S)-tryptophan methyl ester (3b) (509 mg, 2.00 mmol) and NEt₃ (0.28 mL, 2.00 mmol) in CH₃CN (10 mL) was used instead of tryptamine.

). Acid chloride 1 (if a liquid), alkyne 2, and NEt₃ (0.28 mL, 2.00 mmol) were then added sequentially; stirring was performed at rt for 1.5 h. Upon completion of the reaction (TLC control), Yb(OTf)₃ (12 mg, 0.02 mmol) was added, followed by tryptamine (3a) (320 mg, 2.00 mmol) dissolved in CH₃CN (10 mL). After heating to 80 °C (oil bath) for 16 h, the reaction mixture was allowed to cool to rt, then acryloyl chloride (4) was added dropwise and the mixture was heated to 70 °C (oil bath) for 2 h. After cooling to room temp the reaction mixture was diluted with MeOH (5 mL) and the crude product was adsorbed on Celite© under reduced pressure and subsequently purified by chromatography on silica gel to give the analytically pure compound 5.

2.3. rac-12b-Butyl-1-(thiophene-2-carbonyl)-2,3,6,7,12,12b-hexahydroindolo-[2,3-a]quinolizin-(1H)-4-one (5a)

According to the GP, compound 5a (250 mg, 31%) was isolated as a colorless solid, Mp 245–248 °C (Lit.: 250–251 °C) [13], R_f = 0.25 (diethyl ether). ¹H NMR (600 MHz, CDCl₃): δ 0.84 (t, ³J_HH = 7.1 Hz, 3H), 1.08 (tdd, ²J_HH = ³J_HH = 12.2 Hz, ³J_HH = 9.0 Hz, ³J_HH = 5.4 Hz, 1H), 1.25–1.37 (m, 3H), 2.12–2.24 (m, 2H), 2.41 (ddt, ²J_HH = 17.3 Hz, ³J_HH = 13.8 Hz, ³J_HH = 8.3 Hz, 1H), 2.73–2.83 (m, 4H), 2.88 (ddd, ²J_HH = 15.2 Hz, ³J_HH = 3.8 Hz, ³J_HH = 1.6 Hz, 1H), 2.98 (dt, ²J_HH = 12.4 Hz, ³J_HH = 3.7 Hz, 1H), 3.74 (dd, ³J_HH = 13.6 Hz, ³J_HH = 5.1 Hz, 1H), 5.23 (ddd, ²J_HH = 13.0 Hz, ³J_HH = 5.0 Hz, ³J_HH = 1.6 Hz, 1H), 6.92 (dd, ³J_HH = 4.9 Hz, ³J_HH = 3.8 Hz, 1H), 7.04–7.11 (m, 2H), 7.14–7.18 (m, 1H), 7.39 (dd, ³J_HH = 3.9 Hz, ⁴J_HH = 1.1 Hz, 1H), 7.48 (dd, ³J_HH = 7.3 Hz, ⁴J_HH = 1.5 Hz, 1H), 7.55 (dd, ³J_HH = 4.9 Hz, ⁴J_HH = 0.9 Hz, 1H), 7.94 (s, 1H). ¹³C NMR (151 MHz, CDCl₃): δ 14.12 (CH₃), 21.11 (CH₂), 21.94 (CH₂), 23.47 (CH₂), 27.35 (CH₂), 29.76 (CH₂), 36.10 (CH₂), 40.18 (CH₂), 55.13 (CH), 62.09 (C_quat), 111.20 (CH), 111.26 (C_quat),118.33 (CH), 119.69 (CH), 122.31 (CH), 126.14 (C_quat), 128.64 (CH), 132.68 (CH), 134.05 (C_quat), 135.41 (CH), 135.95 (C_quat), 144.09 (C_quat), 169.75 (C_quat), 195.69 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3296 (w), 3271 (w), 3202 (w), 3177 (w), 3100 (w), 3057 (w), 3034 (w), 2953 (w), 2928 (w), 2893 (w), 2849 (w), 1655 (w), 1614 (s), 1584 (w), 1518 (w), 1489 (w),1433 (m), 1406 (m), 1352 (w), 1317 (w), 1304 (w), 1290 (w), 1263 (w), 1236 (m), 1219 (w), 1200 (w), 1190 (w), 1146 (w), 1126 (w), 1084 (w), 1059 (w), 1036 (w), 1005 (w), 845 (w), 804 (w), 745 (m), 727 (m), 696 (w), 644 (w). ESI MS: 407 ([M]⁺). HR-ESI MS calcd. for C₂₄H₂₇N₂O₂S: 407.1788; found: 407.1784. HPLC (254 nm): t_R = 4.9 min, 99%.

2.4. rac-1-Benzoyl-12b-butyl-2,3,6,7,12,12b-hexahydroindolo[2,3-a]quinolizin-4(1H)-on (5b)

According to the GP, compound 5b (213 mg, 27%) was isolated as a colorless solid, Mp 241–244 °C, R_f = 0.4 (n-hexane/ethyl acetate 1:1). ¹H NMR (600 MHz, CDCl₃): δ 0.85 (t, ³J_HH = 7.1 Hz, 3H), 1.08–1.14 (m, 1H), 1.27–1.40 (m, 3H), 2.05–2.11 (m, 1H), 2.19–2.34 (m, 2H), 2.75–2.91 (m, 5H), 3.01 (dt, ²J_HH = 12.3 Hz, ³J_HH = 3.8 Hz, 1H), 3.95 (dd, ³J_HH = 13.6 Hz, ³J_HH = 4.7 Hz, 1H), 5.25 (dd, ²J_HH = 13.3 Hz, ³J_HH = 4.4 Hz, 1H), 7.04–7.11 (m, 2H), 7.11–7.16 (m, 1H), 7.29–7.36 (m, 2H), 7.44–7.51 (m, 2H), 7.67 (d, ³J_HH = 7.7 Hz, 2H), 7.97 (s, 1H). ¹³C NMR (151 MHz, CDCl₃): δ 14.08 (CH₃), 21.24 (CH₂), 21.79 (CH₂), 23.51 (CH₂), 27.52 (CH₂), 29.89 (CH₂), 36.32 (CH₂), 40.25 (CH₂), 53.55 (CH), 62.41 (C_quat), 111.27 (CH), 118.39 (CH), 119.80 (CH), 122.43 (CH), 126.26 (C_quat), 128.17 (2 CH), 128.61 (C_quat), 128.94 (2 CH), 133.81 (CH), 134.39 (C_quat), 136.07 (C_quat), 136.94 (C_quat), 169.94 (C_quat), 203.71 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3252 (w), 3246 (w), 3217 (w), 3192 (w), 3159 (w), 3140 (w), 3105 (w), 3084 (w), 3057 (w), 3032 (w), 2953 (w), 2930 (w), 2891 (w), 2870 (w), 2845 (w), 1676 (m), 1614 (s), 1595 (w), 1578 (w), 1489 (w), 1466 (w), 1449 (m), 1433 (m), 1402 (m), 1352 (w), 1302 (w), 1288 (w), 1263 (w), 1223 (m), 1182 (w), 1152 (w), 1123 (w), 1059 (w), 1038 (w), 1026 (w), 1002 (w), 968 (w), 926 (w), 870 (w), 822 (w), 760 (w), 743 (s), 708 (s), 685 (m), 644 (w), 631 (w). ESI MS: 401 ([M]⁺). HR-ESI MS calcd. for C₂₆H₂₈N₂O₂: 401.2224; found: 401.2229. HPLC (254 nm): t_R = 5.1 min, 99%.

2.5. rac-12b-Butyl-1-(4-methylbenzoyl)-2,3,6,7,12,12b-hexahydroindolo-[2,3-a]quinolizin-4(1H)-one (5c)

According to the GP, compound 5c (150 mg, 18%) was isolated as a colorless solid, Mp 214–216 °C, R_f = 0.36 (n-hexane/ethyl acetate 1:1). ¹H NMR (600 MHz, CDCl₃): δ 0.86 (t, ³J_HH = 7.1 Hz, 3H), 1.09–1.16 (m, 1H), 1.29–1.40 (m, 3H), 1.96–2.02 (m, 1H), 2.22 (dddd, ²J_HH = 17.9 Hz, ³J_HH = 13.7 Hz, ³J_HH = 10.8 Hz, ³J_HH = 5.8 Hz, 2H), 2.35 (s, 3H), 2.68 (ddd, ²J_HH = 18.3 Hz, ³J_HH = 9.9 Hz, ³J_HH = 7.7 Hz, 1H), 2.73–2.92 (m, 4H), 3.01 (td, ²J_HH = ³J_HH = 12.4 Hz, ³J_HH = 3.8 Hz, 1H), 3.75 (dd, ³J_HH = 13.6 Hz, ³J_HH = 4.7 Hz, 1H), 5.23 (ddd, ²J_HH = 12.8 Hz, ³J_HH = 5.0, ³J_HH = 1.5 Hz, 1H), 6.83 (d, ³J_HH = 7.8 Hz, 1H), 6.98 (t, ³J_HH = 7.6 Hz, 1H), 7.09–7.15 (m, 2H), 7.17–7.23 (m, 2H), 7.23–7.29 (m, 2H, superimposed by CDCl₃), 7.51–7.57 (m, 1H), 8.06 (s, 1H).¹³C NMR (151 MHz, CDCl₃): δ 14.17 (CH₃), 20.53 (CH₃), 21.01 (CH₂), 21.18 (CH₂), 23.56 (CH₂), 27.56 (CH₂), 29.88 (CH₂), 36.36 (CH₂), 40.01 (CH₂), 56.88 (CH), 62.07 (C_quat), 111.21 (C_quat), 111.43 (CH), 118.45 (CH), 119.79 (CH), 122.44 (CH), 126.00 (CH), 126.22 (C_quat), 127.43 (CH), 131.63 (CH), 131.84 (CH), 134.62 (C_quat), 136.01(C_quat), 137.48(C_quat), 138.75(C_quat), 169.61(C_quat), 208.46(C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3231 (w), 3177 (w), 3069 (w), 2951 (w), 2928 (w), 2887 (w), 2870 (w), 2839 (w), 2818 (w), 2359 (w), 2342 (w), 2313 (w), 1967 (w), 1948 (w), 1701 (w), 1672 (m), 1672 (m), 1612 (s), 1599 (m), 1587 (w), 1570 (w), 1522 (w), 1487 (w), 1452 (w), 1429 (m), 1404 (m), 1366 (w), 1354 (w), 1317 (w), 1302 (w), 1281 (w), 1261 (w), 1236 (w), 1217 (w), 1198 (w), 1186 (w), 1165 (w), 1155 (w), 1136 (w), 1121 (w), 1078 (w), 1057 (w), 1036 (w), 1026 (w), 1009 (w), 964 (w), 895 (w), 826 (w), 777 (w), 743 (s), 725 (s), 692 (w), 669 (w), 648 (w). ESI MS: 415 ([M]⁺). HR-ESI MS calcd. for C₂₆H₂₈N₂O₂: 415.2380; found: 415.2385. HPLC (254 nm): t_R = 5.4 min, 99%.

2.6. rac-12b-Butyl-1-(4-methoxybenzoyl)-2,3,6,7,12,12b-hexahydroindolo-[2,3a]quinolizin-4(1H)-one (5d)

According to the GP, compound 5d (163 mg, 19%) was isolated as a colorless solid, Mp 207–208 °C (Lit.: 201–202 °C) [13], R_f = 0.24 (diethyl ether). ¹H NMR (600 MHz, CDCl₃): δ 0.84 (t, ³J_HH = 7.1 Hz, 3H), 1.09 (dddd, ²J_HH = 12.5 Hz, ³J_HH = 10.9 Hz, ³J_HH = 9.3 Hz, ³J_HH = 5.5 Hz, 1H), 1.26–1.39 (m, 3H), 2.03–2.11 (m, 1H), 2.22 (ddd, ²J_HH = 14.4 Hz, ³J_HH = 12.2 Hz, ³J_HH = 4.3 Hz, 1H), 2.30 (ddd, ²J_HH = 13.8 Hz, ³J_HH = 11.3 Hz, ³J_HH = 6.8 Hz, 1H), 2.73–2.90 (m, 5H), 3.00 (td, ²J_HH = ³J_HH = 12.4 Hz, ³J_HH = 3.8 Hz, 1H), 3.78 (s, 3H), 3.89 (dd, ³J_HH = 13.6 Hz, ³J_HH = 4.9 Hz, 1H), 5.25 (ddd, ²J_HH = 13.0 Hz, ³J_HH = 5.1 Hz, ³J_HH = 1.7 Hz, 1H), 6.73–6.82 (m, 2H), 7.03–7.12 (m, 2H), 7.13–7.17 (m, 1H), 7.45–7.52 (m, 1H), 7.63–7.73 (m, 2H), 8.01 (s, 1H). ¹³C NMR (151 MHz, CDCl₃): δ 14.15 (CH₃), 21.13 (CH₂), 21.92 (CH₂), 23.53 (CH₂), 27.50 (CH₂), 29.92 (CH₂), 36.37 (CH₂), 40.08 (CH₂), 52.99 (CH), 55.65 (CH₃), 62.23 (C_quat), 111.01 (C_quat), 111.27 (CH), 114.09 (2CH), 118.30 (CH), 119.61 (CH), 122.23 (CH), 126.14 (C_quat), 129.61 (C_quat),, 130.64 (2CH), 134.51 (C_quat), 135.92 (C_quat), 164.13 (C_quat), 169.85 (C_quat), 201.95 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3366 (w), 3341 (w), 3319 (w), 3028 (w), 3015 (w), 2955 (w), 2928 (w), 2899 (w), 2866 (w), 2839 (w), 2357 (w), 1653 (w), 1634 (s), 1599 (m), 1576 (m), 1558 (w), 1514 (w), 1456 (w), 1423 (m), 1402 (m), 1377 (w), 1354 (w), 1339 (w), 1304 (m), 1281 (w), 1254 (m), 1231 (m), 1184 (m), 1152 (w), 1115 (w), 1084 (w), 1065 (w), 1040 (m), 1020 (m), 999 (w), 966 (w), 945 (w), 918 (w), 872 (w), 835 (m), 824 (w), 762 (m), 748 (s), 733 (m), 714 (m), 692 (m), 638 (w). ESI MS: 431 ([M]⁺). Anal. calcd. for C₂₇H₃₀N₂O₃ (430.55): C 75.32, H 7.02, N 6.51; found: C 75.02, H 6.88, N 6.42.

2.7. rac-12b-Butyl-1-(6-chloronicotinoyl)-2,3,6,7,12,12b-hexahydroindolo-[2,3a]quinolizin-4(1H)-one (5e)

According to the GP, compound 5e (260 mg, 30%) was isolated as a colorless solid, Mp 237–242 °C, R_f = 0.17 (diethyl ether). ¹H NMR (600 MHz, CDCl₃): δ 0.85 (t, ³J_HH = 7.04 Hz, 3H), 1.05–1.14 (m, 1H), 1.26–1.39 (m, 3H), 1.98–2.09 (m, 1H), 2.22 (dt, ²J_HH = 13.7 Hz, ³J_HH = 6.4 Hz, 1H), 2.35 (tt, ²J_HH = ³J_HH = 14.5 Hz, ³J_HH = 8.2 Hz, 1H), 2.63–2.71 (m, 1H), 2.72–2.87 (m, 3H), 2.88–2.94 (m, 1H), 2.96–3.04 (m, 1H), 3.83 (dd, ³J_HH = 13.7 Hz, ³J_HH = 5.0 Hz, 1H), 5.24 (dd, ²J_HH = 13.1 Hz, ³J_HH = 4.7 Hz, 1H), 7.05–7.15 (m, 3H), 7.22 (d, ³J_HH = 8.2 Hz, 1H), 7.50 (d, ³J_HH = 7.1 Hz, 1H), 7.69–7.82 (m, 2H), 8.62 (s, 1H). ¹³C NMR (151 MHz, CDCl₃): δ 14.13 (CH₃), 21.25 (2CH₂), 23.45 (CH₂), 27.20 (CH₂), 29.51 (CH₂), 35.84 (CH₂), 40.28 (CH₂), 54.20 (CH), 62.02 (C_quat), 111.19 (CH), 111.99 (C_quat), 118.59 (CH), 120.16 (CH), 122.79 (CH), 124.52 (CH), 126.21 (C_quat), 131.04 (C_quat), 133.60 (C_quat), 135.89 (C_quat), 137.75 (CH), 149.69 (CH), 156.26 (C_quat), 169.48 (C_quat), 201.35 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3227 (w), 3219 (w), 3167 (w), 3154 (w), 3107 (w), 3059 (w), 2953 (w), 2930 (w), 2847 (w), 1684 (m), 1620 (s), 1578 (m), 1555 (w), 1452 (m), 1433 (m), 1406 (m), 1366 (m), 1352 (m), 1319 (w), 1288 (m), 1263 (m), 1227 (m), 1196 (w), 1148 (w), 1136 (w), 1103 (m), 1034 (w), 1007 (w), 968 (w), 870 (w), 822 (w), 743 (s), 712 (w), 702 (w), 662 (w). ESI MS: 438 ([M(³⁷Cl)⁺], 436 ([M(³⁵Cl)]⁺). HR-ESI MS calcd. for C₂₅H₂₇ClN₃O₂: 436.1786; found: 436.1786. HPLC (254 nm): t_R = 4.8 min, 99%.

2.8. rac-1-(4-Bromobenzoyl)-12b-butyl-2,3,6,7,12,12b-hexahydroindolo-[2,3-a]quinolizin-4(1H)one (5f)

According to the GP, compound 5f (385 mg, 40%) was isolated as a colorless solid, Mp 228–232 °C, R_f = 0.35 (n-hexane/ethyl acetate 1:1). ¹H NMR (600 MHz, CDCl₃): δ 0.85 (t, ³J_HH = 7.1 Hz, 3H), 1.10 (dddd, ²J_HH = 15.7 Hz, ³J_HH = 12.4 Hz, ³J_HH = 8.7 Hz, ³J_HH = 5.4 Hz, 1H), 1.27–1.39 (m, 3H), 2.03 (ddt, ²J_HH = 13.7 Hz, ³J_HH = 9.1 Hz, ³J_HH = 4.6 Hz, 1H), 2.18–2.26 (m, 1H), 2.29 (ddd, ²J_HH = 12.6 Hz, ³J_HH = 9.0, ³J_HH = 5.5 Hz, 1H), 2.72–2.82 (m, 4H), 2.89 (ddd, ²J_HH = 15.2 Hz, ³J_HH = 3.8 Hz, ³J_HH = 1.6 Hz, 1H), 3.00 (td, ²J_HH = ³J_HH = 12.4 Hz, ³J_HH = 3.7 Hz, 1H), 3.87 (dd, ³J_HH = 13.6 Hz, ³J_HH = 5.0 Hz, 1H), 5.24 (ddd, ²J_HH = 13.0 Hz, ³J_HH = 5.1 Hz, ³J_HH = 1.6 Hz, 1H), 7.06–7.15 (m, 3H), 7.44 (d, ³J_HH = 8.7 Hz, 2H), 7.46–7.53 (m, 3H), 7.86 (s, 1H). ¹³C NMR (151 MHz, CDCl₃): δ 14.14 (CH₃), 21.18 (CH₂), 21.59 (CH₂), 23.50 (CH₂), 27.37 (CH₂), 29.68 (CH₂), 36.13 (CH₂), 40.18 (CH₂), 53.54 (CH), 62.17 (C_quat), 111.25 (CH), 111.44 (C_quat), 118.40 (CH), 119.87 (CH), 122.51 (CH), 126.15 (C_quat), 129.20 (C_quat), 129.56 (2CH), 132.21 (2CH), 134.17 (C_quat), 135.55 (C_quat), 135.92 (C_quat), 169.75 (C_quat), 202.74 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3225 (w), 3156 (w), 3146 (w), 3105 (w), 3057 (w), 2951 (w), 2927 (w), 2893 (w), 2868 (w), 2361 (w), 1680 (m), 1616 (s), 1585 (m), 1566 (w), 1485 (w), 1449 (w), 1431 (m), 1406 (m), 1352 (w), 1319 (w), 1300 (w), 1283 (m), 1263 (m), 1221 (m), 1179 (w), 1153 (w), 1146 (w), 1121 (w), 1072 (m), 1036 (w), 1009 (m), 966 (w), 926 (w), 912 (w), 870 (w), 837 (w), 820 (w), 760 (w), 741 (s), 683 (w). ESI MS: 481 ([M(⁸¹Br)]⁺), 479 ([M(⁷⁹Br)]⁺). HR-ESI MS calcd. for C₂₆H₂₈BrN₂O₂: 479.1329; found: 479.1325. HPLC (254 nm): t_R = 5.6 min, 99%.

2.9. rac-12b-Butyl-1-(2-fluorobenzoyl)-2,3,6,7,12,12b-hexahydroindolo[2,3-a]-quinolizin-4(1H)one (5g)

According to the GP, compound 5g (472 mg, 56%) was isolated as a colorless solid, Mp 233–236 °C, R_f = 0.21 (n-hexane/ethyl acetate 3:2). ¹H NMR (600 MHz, CDCl₃): δ 0.85 (t, ³J_HH = 7.1 Hz, 3H), 1.12 (tdd, ²J_HH = ³J_HH = 12.0 Hz, ³J_HH = 8.7 Hz, ³J_HH = 5.3 Hz, 1H), 1.27–1.39 (m, 3H), 2.13–2.20 (m, 1H), 2.23 (ddt, ²J_HH = 16.7 Hz, ³J_HH = 12.2 Hz, ³J_HH = 2.1 Hz, 2H), 2.72–2.87 (m, 5H), 3.00 (td, ²J_HH = ³J_HH = 12.4 Hz, ³J_HH = 3.8 Hz, 1H), 3.86 (dd, ³J_HH = 13.1 Hz, ³J_HH = 4.8 Hz, 1H), 5.23 (ddd, ²J_HH = 12.9 Hz, ³J_HH = 5.0 Hz, ³J_HH = 1.6 Hz, 1H), 7.02 (ddd, ³J_HF = 11.5 Hz, ³J_HH = 8.3 Hz, ⁴J_HH = 1.0 Hz, 1H), 7.06–7.11 (m, 1H), 7.13 (tdd, ³J_HH = 7.0 Hz, ⁵J_HF = 2.9 Hz, ⁴J_HH = 1.2 Hz, 2H), 7.24 (d, ³J_HH = 8.0 Hz, 1H), 7.44 (dddd, ³J_HH = 8.6 Hz, ³J_HH = 7.0 Hz, ⁴J_HF = 4.9 Hz, ⁴J_HH = 1.8 Hz, 1H), 7.49 (d, ³J_HH = 7.8 Hz, 1H), 7.62 (td, ³J_HH = 7.7 Hz, ⁴J_HH = 1.9 Hz, 1H), 8.11 (s, 1H). ¹³C NMR (151 MHz, CDCl₃): δ 14.13 (CH₃), 21.08 (CH₂), 21.14 (CH₂), 23.53 (CH₂), 27.56 (CH₂), 30.14 (CH₂), 36.75 (CH₂), 40.06 (CH₂), 57.41(d, ⁴J_CF = 6.18 Hz, CH), 62.21 (C_quat), 111.25 (CH), 111.29 (C_quat), 117.13(d, ²J_CF = 23.61 Hz, CH), 118.39 (CH), 119.70 (CH), 122.33 (CH), 124.76(d, ⁴J_CF = 3.27 Hz, CH), 125.93(d, ²J_CF = 11.39 Hz, C_quat), 126.19 (C_quat), 130.52(d, ³J_CF = 1.57 Hz, CH), 134.39 (C_quat), 135.27(d, ³J_CF = 9.27 Hz, CH), 135.98 (C_quat), 161.08(d, ¹J_CF = 255.70 Hz, C_quat), 169.77 (C_quat), 202.04(d, ³J_CF = 4.05 Hz, C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3250 (w), 3196 (w), 3181 (w), 3109 (w), 3059 (w), 3040 (w), 2955 (w), 2932 (w), 2891 (w), 2872 (w), 2859 (w), 2847 (w), 1682 (w), 1611 (s), 1574 (w), 1557 (w), 1528 (w), 1479 (w), 1450 (m), 1433 (m), 1404 (m), 1362 (w), 1352 (m), 1317 (w), 1269 (m), 1261 (m), 1234 (m), 1213 (m), 1190 (w), 1152 (w), 1123 (w), 1101 (w), 1076 (w), 1061 (w), 1036 (w), 1007 (w), 968 (w), 926 (w), 912 (w), 897 (w), 872 (w), 827 (w), 808 (w), 779 (w), 743 (s), 733 (s), 696 (m), 665 (m), 640 (m), 621 (w). ESI MS: 419 ([M]⁺). HR-ESI MS calcd. for C₂₆H₂₈FN₂O₂: 419.2129; found: 419.2134. HPLC (254 nm): t_R = 5.1 min, 99%.

2.10. rac-12b-Butyl-1-(4-nitrobenzoyl)-2,3,6,7,12,12b-hexahydroindolo[2,3-a]-quinolizin-4(1H)-one (5h)

According to the GP, compound 5h (334 mg, 37%) was isolated as a colorless solid, Mp 222–224 °C, R_f = 0.30 (n-hexane/ethyl acetate 1:1). ¹H NMR (600 MHz, CDCl₃): δ 0.86 (t, ³J_HH = 7.1 Hz, 3H), 1.11 (dtt, ²J_HH = 12.9 Hz, ³J_HH = 9.7 Hz, ³J_HH = 5.3 Hz, 1H), 1.28–1.41 (m, 3H), 1.98–2.06 (m, 1H), 2.23 (ddd, ²J_HH = 14.2 Hz, ³J_HH = 13.3 Hz, ³J_HH = 4.1 Hz, 1H), 2.30–2.40 (m, 1H), 2.67 (td, ²J_HH = ³J_HH = 13.4 Hz, ³J_HH = 3.8 Hz, 1H), 2.82 (ddt, ²J_HH = 17.2 Hz, ³J_HH = 10.5 Hz, ³J_HH = 6.0 Hz, 3H), 2.91 (dd, ²J_HH = 15.3 Hz, ³J_HH = 3.7 Hz, 1H), 3.00 (td, ²J_HH = ³J_HH = 12.5 Hz, ³J_HH = 3.7 Hz, 1H), 3.93 (dd, ³J_HH = 13.5 Hz, ³J_HH = 4.9 Hz, 1H), 5.26 (dd, ²J_HH = 13.0 Hz, ³J_HH = 4.6 Hz, 1H), 7.03–7.12 (m, 3H), 7.46–7.54 (m, 1H), 7.70 (d, ³J_HH = 8.5 Hz, 2H), 7.74 (s, 1H), 8.09 (d, ³J_HH = 8.4 Hz, 2H). ¹³C NMR (151 MHz, CDCl₃): δ 14.13 (CH₃), 21.25 (2CH₂), 23.46 (CH₂), 27.19 (CH₂), 29.52 (CH₂), 35.71 (CH₂), 40.30 (CH), 54.28 (CH), 62.12 (C_quat), 111.16 (CH), 112.00 (C_quat), 118.53 (CH), 120.18 (CH), 122.78 (CH), 123.96 (2CH), 126.22 (C_quat), 128.97 (2CH), 133.68 (C_quat), 135.88 (C_quat), 141.44 (C_quat), 150.43 (C_quat), 169.49 (C_quat), 202.23 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3273 (w), 3221 (w), 3113 (w), 3053 (w), 2978 (w), 2947 (w), 2909 (w), 2868 (w), 2845 (w), 2156 (w), 1971 (w), 1690 (m), 1616 (s), 1582 (w), 1526 (s), 1495 (w), 1452 (m), 1431 (w), 1406 (m), 1383 (w), 1344 (s), 1319 (w), 1302 (w), 1277 (w), 1254 (w), 1233 (m), 1204 (w), 1173 (m), 1150 (w), 1101 (w), 1043 (w), 1032 (w), 1007 (w), 984 (m), 962 (w), 943 (w), 930 (w), 860 (m), 853 (m), 824 (w), 745 (s), 723 (m), 716 (m), 706 (w), 677 (w), 652 (w). ESI MS: 446 ([M]⁺). HR-ESI MS calcd. for C₂₆H₂₈N₃O₄: 446.2074; found: 446.2075. HPLC (254 nm): t_R = 5.1 min, 99%.

2.11. rac-12b-Phenyl-1-(thiophene-2-carbonyl)-2,3,6,7,12,12b-hexahydro-indolo-[2,3-a]quino-lizin-4(1H)-one (5i)

According to the GP, compound 5i (210 mg, 55%) was isolated as a colorless solid, Mp 302–303 °C (Lit.: 315–316 °C) [13], R_f = 0.24 (diethyl ether). ¹H NMR (600 MHz, DMSO-d₆): δ 1.85 (tt, ²J_HH = ³J_HH = 13.7 Hz, ³J_HH = 5.3 Hz, 1H), 1.92–2.01 (m, 1H), 2.27 (dd, ²J_HH = 17.7 Hz, ³J_HH = 5.7 Hz, 1H), 2.43 (dd, ²J_HH = 15.2 Hz, ³J_HH = 4.5 Hz, 1H), 2.79 (ddd, ²J_HH = 17.7 Hz, ³J_HH = 13.0 Hz, ³J_HH = 6.8 Hz, 1H), 2.92 (ddd, ²J_HH = 15.2 Hz, ³J_HH = 12.0 Hz, ³J_HH = 5.9 Hz, 1H), 3.00 (td, ²J_HH = ³J_HH = 12.4 Hz, ³J_HH = 4.7 Hz, 1H), 4.67 (dd, ²J_HH = 12.9 Hz, ³J_HH = 5.8 Hz, 1H), 4.77–4.86 (m, 1H), 7.02 (td, ³J_HH = 7.4 Hz, ⁴J_HH = 2.3 Hz, 2H), 7.09–7.21 (m, 4H), 7.27 (d, ³J_HH = 7.8 Hz, 2H), 7.40 (d, ³J_HH = 7.8 Hz, 1H), 7.52 (d, ³J_HH = 8.1 Hz, 1H), 7.89 (d, ³J_HH = 4.9 Hz, 1H), 8.07 (d, ³J_HH = 3.8 Hz, 1H), 11.76 (s, 1H).¹³C NMR (151 MHz, DMSO-d₆): δ 19.79 (CH₂), 21.77 (CH₂), 28.88 (CH₂), 39.00 (CH₂), 47.17 (CH), 66.70 (C_quat), 109.47 (C_quat), 111.39 (CH), 118.08 (CH), 118.98 (CH), 121.79 (CH), 126.62 (C_quat), 126.91 (2 CH), 126.95 (CH), 127.80 (2CH), 128.30 (CH), 134.01 (CH), 135.81 (C_quat), 136.05 (CH), 136.16 (C_quat), 141.31 (C_quat), 144.71 (C_quat), 171.69 (C_quat), 192.09 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3267 (w), 1738 (w), 1651 (m), 1607 (s), 1585 (w), 1574 (w), 1516 (w), 1495 (w), 1454 (w), 1416 (m), 1393 (m), 1377 (w), 1342 (m), 1298 (w), 1283 (w), 1263 (w), 1250 (m), 1231 (m), 1217 (w), 1186 (w), 1153 (w), 1140 (w), 1080 (w), 1065 (w), 1094 (w), 961 (w), 947 (w), 914 (w), 880 (w), 854 (w), 826 (w), 814 (w), 729 (s), 702 (s), 681 (w), 658 (w), 627 (w). MS (ESI): 427 (M⁺). ESI MS: 427 ([M]⁺). HR-ESI MS calcd. for C₂₆H₂₃N₂O₂S: 427.1475; found: 427.1479. HPLC (254 nm): t_R = 4.8 min, 99%.

2.12. rac-1-(4-Methoxybenzoyl)-2,3,6,7,12,12b-hexahydroindolo[2,3-a]quinolizin-4(1H)-one (5j)

According to the GP, compound 5j (360 mg, 48%) was isolated as a colorless solid, Mp 160 °C, R_f = 0.20 (n-hexane/ethyl acetate 1:2). ¹H NMR (600 MHz, CDCl₃): δ 1.94–2.02 (m, 1H), 2.17–2.23 (m, 1H), 2.64 (ddd, ²J_HH = 17.9 Hz, ³J_HH = 11.9 Hz, ³J_HH = 6.0 Hz, 1H), 2.71 (ddd, ²J_HH = 17.6 Hz, ³J_HH = 5.8 Hz, ³J_HH = 2.5 Hz, 1H), 2.76–2.82 (m, 1H), 2.84–2.93 (m, 2H), 3.73 (ddd, ²J_HH = 12.8 Hz, ³J_HH = 10.1 Hz, ³J_HH = 3.1 Hz, 1H), 3.90 (s, 3H), 5.17–5.24 (m, 1H), 5.46–5.51 (m, 1H), 6.99 (d, ³J_HH = 8.5 Hz, 2H), 7.06–7.12 (m, 2H), 7.17 (d, ³J_HH = 7.9 Hz, 1H), 7.48 (d, ³J_HH = 7.6 Hz, 1H), 7.71 (s, 1H), 7.99 (d, ³J_HH = 8.5 Hz, 2H). ¹³C NMR (151 MHz, CDCl₃): δ 21.37 (CH₂), 25.97 (CH₂), 32.10 (CH₂), 40.96 (CH₂), 48.92 (CH), 55.42 (CH), 55.81 (CH₃), 111.17 (C_quat), 111.36 (CH), 114.51 (2CH), 118.36 (CH), 119.94 (CH), 122.41 (CH), 126.61 (C_quat), 128.04 (C_quat), 131.20 (2CH), 132.81 (C_quat), 136.26 (C_quat), 164.71 (C_quat), 168.54 (C_quat), 201.08 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3900 (m), 3647 (m), 3005 (w), 2924 (w), 2845 (w), 2438 (w), 2365 (w), 1622 (s), 1616 (m), 1597 (s), 1570 (m), 1506 (m), 1437 (m), 1420 (m), 1373 (w), 1350 (w), 1317 (m), 1304 (m), 1292 (w), 1260 (s), 1234 (m), 1215 (m), 1169 (s), 1155 (m), 1117 (w), 1099 (w), 1053 (w), 1028 (m), 1009 (m), 980 (w), 841 (m), 741 (s), 685 (w), 673 (w), 606 (s). EI MS (70 eV, m/z (%)): 374 (43), 318 ([C₂₀H₁₈N₂O₂]²⁺, 41), 317 (83), 240 (17), 239 ([C₁₅H₁₅N₂O]⁺, 100), 170 ([C₁₁H₁₀N₂]²⁺, 26), 169 (56), 168 (12), 167 (12), 142 (10), 135 ([C₈H₇O₂]⁺, 50), 115 (14), 107 ([C₇H₇O]⁺, 12), 92 (11), 77 (18), 49 (12). HR-ESI MS calcd. for C₂₃H₂₃N₂O₃: 375.1703; found: 375.1705. HPLC (254 nm): t_R = 4.3 min, 97%.

2.13. rac-1-(6-Chloronicotinoyl)-12b-phenyl-2,3,6,7,12,12b-hexahydroindolo-[2,3-a]quinolizin-4(1H)-one (5k)

According to the GP, compound 5k (313 mg, 34%) was isolated as a colorless solid, Mp 233 °C (dec.), R_f = 0.27 (n-hexane/ethyl acetate 1:1). ¹H NMR (600 MHz, DMSO-d₆): δ 1.77–1.86 (m, 1H), 2.05 (dd, ²J_HH = 14.2 Hz, ³J_HH = 6.6 Hz, 1H), 2.29 (dd, ²J_HH = 17.8 Hz, ³J_HH = 5.9 Hz, 1H), 2.44 (dd, ²J_HH = 15.2 Hz, ³J_HH = 4.3 Hz, 1H), 2.82 (ddd, ²J_HH = 18.7 Hz, ³J_HH = 12.8 Hz, ³J_HH = 6.9 Hz, 1H), 2.92 (ddd, ²J_HH = 13.6 Hz, ³J_HH = 12.1 Hz, ³J_HH = 5.6 Hz, 1H), 2.99 (td, ²J_HH = ³J_HH = 12.4 Hz, ³J_HH = 4.4 Hz, 1H), 4.68 (dd, ²J_HH = 12.8 Hz, ³J_HH = 5.6 Hz, 1H), 4.88–4.95 (m, 1H), 6.98–7.04 (m, 2H), 7.13 (t, ³J_HH = 7.8 Hz, 2H), 7.17 (t, ³J_HH = 7.6 Hz, 1H), 7.24 (d, ³J_HH = 7.9 Hz, 2H), 7.40 (d, ³J_HH = 7.8 Hz, 1H), 7.51 (d, ³J_HH = 8.2 Hz, 1H), 7.55 (d, ³J_HH = 8.4 Hz, 1H), 8.09 (dd, ³J_HH = 8.5 Hz, ⁴J_HH = 2.4 Hz, 1H), 8.85 (d, ⁴J_HH = 2.4 Hz, 1H), 11.76 (s, 1H). ¹³C NMR (151 MHz, DMSO-d₆): δ 19.84 (CH₂), 21.06 (CH₂), 28.78 (CH₂), 39.00 (CH₂), 46.35 (CH), 66.65 (C_quat), 109.63 (C_quat), 111.44 (CH), 118.15 (CH), 119.06 (CH), 121.89 (CH), 124.11 (CH), 126.58 (C_quat), 126.88 (2CH), 127.15 (CH_.), 128.10 (2CH), 131.58 (C_quat), 135.84 (2C_quat), 138.90 (CH), 141.06 (C_quat), 150.01 (CH), 153.94 (C_quat), 171.71 (C_quat), 198.28 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3271 (w), 1686 (m), 1630 (m), 1605 (s), 1574 (w), 1555 (w), 1491 (w), 1449 (m), 1423 (w), 1398 (w), 1387 (w), 1364 (w), 1341 (w), 1325 (w), 1290 (w), 1277 (w), 1263 (w), 1221 (w), 1200 (w), 1182 (w), 1138 (w), 1101 (m), 1080 (w), 1047 (w), 986 (w), 947 (w), 901 (w), 835 (w), 779 (w), 758 (s), 743 (m), 704 (s), 685 (m), 656 (w), 625 (m), 607 (s). ESI MS: 458 ([M(³⁷Cl)]⁺), 456 ([M(³⁵Cl)]⁺). HR-ESI MS calcd. for C₂₇H₂₃ClN₃O₂: 456.1473; found: 427.1475. HPLC (254 nm): t_R = 4.8 min, 99%.

2.14. rac-1-(6-Chloronicotinoyl)-12b-cyclopropyl-2,3,6,7,12,12b-hexahydroindolo[2,3-a]quino-lizin-4(1H)-one (5l)

According to the GP, compound 5l (160 mg, 19%) was isolated as a colorless solid, Mp 234–236 °C, R_f = 0.21 (n-hexane/ethyl acetate 1:2). ¹H NMR (600 MHz, CDCl₃): δ 1.85–1.92 (m, 1H), 2.05–2.11 (m, 1H), 2.30–2.39 (m, 2H), 2.77–2.85 (m, 3H), 2.88–2.98 (m, 3H), 3.47–3.56 (m, 2H), 3.85 (dd, ²J_HH = 13.5 Hz, ³J_HH = 5.1 Hz, 1H), 5.26 (dd, ²J_HH = 12.5 Hz, ³J_HH = 4.7 Hz, 1H), 7.07–7.15 (m, 3H), 7.25 (d, ³J_HH = 8.8 Hz, 1H), 7.50 (d, ³J_HH = 7.5 Hz, 1H), 7.81 (dd, ³J_HH = 8.4 Hz, ⁴J_HH = 2.5 Hz, 1H), 7.86 (s, 1H), 8.64 (d, ⁴J_HH = 2.5 Hz, 1H). ¹³C NMR (151 MHz, CDCl₃): δ 21.17 (CH₂), 21.27 (CH₂), 28.12 (CH₂), 29.52 (CH₂), 33.49 (CH₂), 40.25 (CH₂), 45.07 (CH₂), 54.14 (CH), 61.57 (C_quat), 111.33 (CH), 112.35 (C_quat), 118.64 (2CH), 120.29 (CH), 123.03 (CH), 124.61 (CH), 126.10 (C_quat), 130.86 (C_quat), 132.76 (C_quat), 136.03 (C_quat), 137.83 (CH), 149.73 (CH), 156.42 (C_quat), 169.45 (C_quat), 201.17 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3582 (w), 3271 (w), 3248 (w), 3171 (w), 3113 (w), 3084 (w), 3055 (w), 2965 (w), 2922 (w), 2891 (w), 2843 (w), 2360 (w), 2008 (w), 1686 (m), 1618 (s), 1578 (m), 1555 (w), 1497 (w), 1433 (m), 1412 (m), 1369 (m) 1350 (w), 1314 (m), 1296 (m), 1283 (m), 1260 (m), 1234 (m), 1223 (m), 1200 (w), 1173 (w), 1157 (w), 1148 (w), 1103 (m), 1078 (w), 1063 (w), 1030 (w), 1003 (w), 964 (w), 920 (w), 907 (w), 891 (w), 878 (w), 845 (w), 833 (w), 818 (w), 772 (w), 745 (s), 731 (m), 708 (m), 679 (w), 656 (w). ESI MS: 422 ([M(³⁷Cl)]⁺), 420 ([M(³⁵Cl)]⁺). HR-ESI MS calcd. for C₂₄H₂₂ClN₃O₂: 420.1473; found: 420.1480. HPLC (254 nm): t_R = 4.5 min, 97%.

2.15. rac-1-(Thiophene-2-carbonyl)-12b-(1-tosyl-1H-indol-3-yl)-2,3,6,7,12,12b-hexahydroindolo-[2,3-a]quinolizin-4(1H)-one (5m)

According to the GP, compound 5m (390 mg, 32%) was isolated as a colorless solid, Mp 314–316 °C, R_f = 0.24 (n-hexane/ethyl acetate 1:1). ¹H NMR (600 MHz, CDCl₃): δ 2.14–2.22 (m, 1H), 2.34 (s, 3H), 2.55–2.71 (m, 3H), 2.91 (td, ²J_HH = ³J_HH = 12.5 Hz, ³J_HH = 4.2 Hz, 1H), 2.99 (d, ²J_HH = 17.5 Hz, 1H), 3.07 (ddd, ²J_HH = 16.0 Hz, ³J_HH = 12.1 Hz, ³J_HH = 5.4 Hz, 1H), 4.08 (d, ²J_HH = 11.0 Hz, 1H), 4.94 (dd, ²J_HH = 13.0 Hz, ³J_HH = 5.3 Hz, 1H), 6.87 (t, ³J_HH = 4.1 Hz, 1H), 7.12–7.18 (m, 3H), 7.18–7.28 (m, 4H, superimposed by CDCl₃), 7.32–7.36 (m, 1H), 7.39 (d, ³J_HH = 8.1 Hz, 1H), 7.48–7.56 (m, 4H), 7.66 (d, ³J_HH = 8.0 Hz, 2H), 7.81 (d, ³J_HH = 8.3 Hz, 1H), 9.18 (s, 1H). ¹³C NMR (151 MHz, CDCl₃): δ 20.87 (CH₂), 21.77 (CH₃), 23.45 (CH₂), 32.36 (CH₂), 38.81 (CH₂), 55.55 (CH), 62.90 (C_quat), 110.30 (C_quat), 111.93 (CH), 113.78 (CH), 118.83 (CH), 120.17 (CH), 120.88 (CH), 122.54 (C_quat), 122.93 (CH), 124.03 (CH), 124.90 (CH), 126.55 (C_quat), 127.16 (2CH), 127.64 (CH), 128.34 (CH), 128.94 (C_quat), 130.00 (2CH), 132.46 (CH), 134.94 (C_quat), 134.96 (C_quat), 135.31 (CH), 135.92 (C_quat), 136.03 (C_quat), 143.48 (C_quat), 145.15 (C_quat), 169.45 (C_quat), 193.93 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3152 (s), 3134 50 (s), 3103 (s), 3063 (s), 2959 (s), 2932 (s), 2916 (s), 2841 (s), 2720 (s), 1672 (m), 1609 (m), 1601 (m), 1445 (m), 1420 (m), 1406 (m), 1391 (m), 1369 (m), 1342 (m), 1329 (s), 1294 (s), 1277 (m), 1263 (s), 1240 (m), 1233 (m), 1217 (s), 1175 (w), 1159 (m), 1140 (m), 1123 (m), 1088 (m), 1040 (m), 1015 (s), 988 (m), 978 (m), 957 (s), 903 (s), 876 (s), 853 (m), 822 (m), 810 (m), 745 (w), 721 (w), 696 (w), 669 (m), 654 (w), 604 (m). EI MS (70 eV, m/z (%)): 619 ([M]⁺, 26), 465 ([C₂₈H₂₂N₃O₂S]⁺, 17), 464 ([C₂₈H₂₂N₃O₂S]⁺, 52), 439 (15), 438 (28), 327 (21), 326 (87), 323 (13), 298 (24), 285 (16), 284 (42), 283 (31), 282 (26), 281 (11), 269 (22), 257 (24), 256 (61), 255 (29), 155 ([C₇H₇O₂S]⁺, 11), 143 (10), 111 ([C₅H₃OS]⁺, 100), 91 ([C₇H₇]⁺, 53), 65 (10). HR-ESI MS calcd. for C₃₅H₂₉N₃O₄S₂: 620.1672; found: 620.1675. HPLC (254 nm): t_R = 5.8 min, 99%.

2.16. rac-1-(6-Chloronicotinoyl)-12b-(1-tosyl-1H-indol-3-yl)-2,3,6,7,12,12b-hexahydroindolo-[2,3-a]quinolizin-4(1H)-one (5n)

According to the GP, compound 5n (624 mg, 48%) was isolated as a colorless solid, Mp 294–296 °C, R_f = 0.18 (n-hexane/ethyl acetate 1:1). ¹H NMR (600 MHz, DMSO-d₆): δ 1.83 (tt, ²J_HH = ³J_HH = 13.9 Hz, ³J_HH = 5.5 Hz, 1H), 2.01 (dd, ²J_HH = 15.1 Hz, ³J_HH = 6.7 Hz, 1H), 2.27 (s, 3H), 2.30–2.37 (m, 1H), 2.44–2.49 (m, 1H), 2.70 (ddd, ²J_HH = 18.6 Hz, ³J_HH = 12.8 Hz, ³J_HH = 6.6 Hz, 1H), 2.81–2.95 (m, 2H), 4.68–4.74 (m, 1H), 4.98–5.03 (m, 1H), 7.05–7.12 (m, 3H), 7.21–7.30 (m, 3H), 7.45 (d, ³J_HH = 7.8 Hz, 1H), 7.50 (d, ³J_HH = 10.3 Hz, 2H), 7.55 (d, ³J_HH = 8.0 Hz, 2H), 7.59 (d, ³J_HH = 8.1 Hz, 1H), 7.62–7.68 (m, 2H), 7.98 (dd, ³J_HH = 8.4 Hz, ⁴J_HH = 2.6 Hz, 1H), 8.82 (d, ⁴J = 2.5 Hz, 1H), 11.76 (s, 1H). ¹³C NMR (151 MHz, DMSO-d₆): δ 19.77 (CH₂), 20.99 (CH₃), 21.30 (CH₂), 28.64 (CH₂), 40.06 (CH₂), 47.49 (CH), 63.04 (C_quat), 109.25 (C_quat), 111.61 (CH), 112.54 (CH), 118.29 (CH), 119.19 (CH), 122.07 (CH), 122.45 (CH), 123.50 (CH), 124.13 (CH), 124.87 (CH), 125.10 (CH), 125.11 (C_quat), 126.32 (2CH), 126.60 (C_quat), 127.80 (C_quat), 129.92 (2CH), 130.85 (C_quat), 133.54 (_Cquat), 133.55 (C_quat), 135.67 (C_quat), 136.31 (C_quat), 138.74 (CH), 145.30 (C_quat), 149.86 (CH), 154.24 (C_quat), 170.72 (C_quat), 197.1 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3838 (s), 3233 (s), 3194 (s), 3157 (s), 2911 (s), 2847 (s), 1688 (m), 1605 (m), 1582 (m), 1557 (s), 1449 (m), 1420 (s), 1404 (m), 1368 (m), 1348 (m), 1331 (s), 1310 (s), 1298 (s), 1279 (m), 1263 (s), 1231 (m), 1192 (m), 1175 (w), 1142 (m), 1125 (m), 1107 (m), 1086 (m), 1072 (s), 1059 (s), 1028 (s), 988 (m), 959 (s), 893 (s), 874 (s), 827 (s), 804 (m), 777 (m), 750 (w), 702 (m), 677 (m), 656 (m), 633 (m). EI MS (70 eV, m/z (%)): 650 ([M (³⁷Cl)]⁺, 4), 648 ([M (³⁵Cl)]⁺, 11), 495 ([C₂₉H₂₂³⁷ClN₄O₂]⁺, 16), 494 (15), 493 ([C₂₉H₂₂³⁵ClN₄O₂]⁺, 40), 439 (12), 438 (33), 327 (23), 326 (100), 298 (22), 285 (13), 284 (35), 283 (26), 282 (21), 269 (19), 257 (20), 256 (50), 255 (24), 144 (13), 143 (59), 142 ([C₆H₃³⁷ClNO]⁺, 11), 140 ([C₆H₃³⁵ClNO]⁺, 25), 130 (37), 91 ([C₇H₇]⁺, 28). Anal. calcd. for C₃₆H₂₉ClN₄O₄S (649.16): C 66.61, H 4.50, N 8.63, S 4.94; found: C 66.34, H 4.55, N 8.47, S 5.19.

2.17. rac-1-(2-Fluorobenzoyl)-12b-(1-tosyl-1H-indol-3-yl)-2,3,6,7,12,12b-hexahydroindolo-[2,3-a]quinolizin-4(1H)-one (5o)

According to the GP, compound 5o (332 mg, 26%) was isolated as a colorless solid, Mp 268–270 °C, R_f = 0.26 (n-hexane/ethyl acetate 1:1). ¹H NMR (600 MHz, CDCl₃,): δ 2.02–2.09 (m, 1H), 2.24–2.33 (m, 4H), 2.60 (dd, ²J_HH = 15.5 Hz, ³J_HH = 4.2 Hz, 1H), 2.70 (ddd, ²J_HH = 18.1 Hz, ³J_HH = 10.0 Hz, ³J_HH = 6.4 Hz, 1H), 2.78 (td, ²J_HH = ³J_HH = 12.6 Hz, ³J_HH = 4.3 Hz, 1H), 2.98–3.08 (m, 2H), 4.09–4.13 (m, 1H), 4.89 (dd, ²J_HH = 13.0 Hz, ³J_HH = 5.4 Hz, 1H), 6.90 (td, ³J_HH = 7.5 Hz, ⁴J_HH = 1.9 Hz, 1H), 6.94–6.99 (m, 1H), 7.06 (dd, ³J_HF = 11.1 Hz, ³J_HH = 8.3 Hz, 1H), 7.12–7.22 (m, 4H), 7.25–7.30 (m, 3H, superimposed by CDCl₃), 7.38–7.48 (m, 3H), 7.53 (d, ³J_HH = 7.8 Hz, 1H), 7.59 (s, 1H), 7.69 (d, ³J_HH = 8.3 Hz, 2H), 7.89 (d, ³J_HH = 8.3 Hz, 1H), 8.99 (s, 1H). ¹³C NMR (151 MHz, CDCl₃): δ 20.90 (CH₂), 21.73 (CH₃), 22.46 (CH₂), 32.26 (CH₂), 38.85 (CH₂), 56.17(d, ⁴J_CF = 5.93 Hz, CH), 63.39 (C_quat), 110.77 (C_quat), 111.89 (CH), 113.80 (CH), 116.57(d, ²J_CF = 23.1 Hz, CH), 118.85 (CH), 120.19 (CH), 121.09 (CH), 122.60 (C_quat), 122.99 (CH), 124.06 (CH), 124.81(d, ⁴J_CF = 3.17 Hz, CH), 124.85 (CH), 126.45(d, ²J_CF = 13.7 Hz, C_quat), 126.73 (C_quat), 127.16 (2CH), 128.29 (CH), 128.99 (C_quat), 129.69(d, ³J_CF = 2.24 Hz, CH), 129.95 (2CH), 134.51(d, ³J_CF = 9.10 Hz, CH), 134.86 (C_quat), 134.92 (C_quat), 135.70 (C_quat), 135.74 (C_quat), 145.15 (C_quat), 160.00(d, ¹J_CF = 251 Hz, C_quat), 169.37 (C_quat), 200.83(d, ³J_CF = 3.56 Hz, C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3981 (w), 3854 (w), 3802 (w), 3736 (w), 3723 (w), 3588 (w), 3524 (w), 3424 (w), 3404 (w), 3271 (w), 3175 (w), 3159 (w), 3136 (w), 3105 (w), 3084 (w), 3067 (w), 3040 (w), 3019 (w), 2974 (w), 2953 (w), 2934 (w), 2913 (w), 2886 (w), 2841 (w), 2810 (w), 2752 (w), 2714 (w), 2695 (w), 2621 (w), 2488 (w), 2359 (w), 2342 (w), 1690 (w), 1609 (s), 1576 (w), 1452 (m), 1410 (m), 1396 (w), 1368 (m), 1350 (m), 1333 (w), 1294 (w), 1277 (m), 1261 (w), 1223 (w), 1213 (w), 1175 (s), 1142 (m), 1123 (m) 1086 (m), 1042 (w), 986 (m), 961 (w), 876 (w), 841 (w), 808 (w), 787 (w), 746 (s), 702 (m), 669 (s), 656 (s), 629 (m). EI MS (70 eV, m/z (%)): 631 ([M]⁺, 21), 476 ([C₃₀H₂₃FN₃O₂]⁺, 57), 438 ([C₂₆H₂₀N₃O₂S]⁺, 31), 326 ([C₂₁H₁₆N₃O]²⁺, 98), 298 ([C₁₉H₁₂N₃O]³⁺, 23), 284 ([C₁₉H₁₄N₃]⁺, 51), 256 ([C₁₇H₁₀N₃]⁴⁺, 68), 123 ([C₇H₄FO]⁺, 100), 91 ([C₇H₇]⁺, 51). Anal. calcd. for C₃₇H₃₀FN₃O₄S (631.72): C 70.35, H 4.79, N 6.65, S 5.08; found: C 70.24, H 4.87, N 6.38, S 4.97.

2.18. rac-1-(4-Bromobenzoyl)-12b-(1-tosyl-1H-indol-3-yl)-2,3,6,7,12,12b-hexahydroindolo-[2,3-a]quinolizin-4(1H)-one (5p)

According to the GP, compound 5p (687 mg, 50%) was isolated as a colorless solid, Mp 290–292 °C, R_f = 0.21 (n-hexane/ethyl acetate 1:1). ¹H NMR (600 MHz, CDCl₃): δ 1.95–2.03 (m, 1H), 2.28–2.43 (m, 4H), 2.65 (d, ²J_HH = 15.2 Hz, 2H), 2.83–2.97 (m, 2H), 3.01–3.10 (m, 1H), 4.07–4.16 (m, 1H), 4.90–4.98 (m, 1H), 7.07–7.12 (m, 2H), 7.13–7.18 (m, 1H), 7.20–7.27 (m, 5H, superimposed by CDCl₃), 7.28–7.32 (m, 1H), 7.33–7.41 (m, 3H), 7.44–7.48 (m, 1H), 7.50–7.54 (m, 1H), 7.56 (s, 1H), 7.65 (d, ³J_HH = 7.4 Hz, 2H), 7.85–7.92 (m, 1H), 9.11 (s, 1H).¹³C NMR (151 MHz, CDCl₃): δ 20.90 (CH₂), 21.79 (CH₃), 23.22 (CH₂), 32.06 (CH₂), 38.98 (CH₂), 53.55 (CH), 63.10 (C_quat), 110.51 (C_quat), 111.86 (CH), 113.87 (CH), 118.88 (CH), 120.22 (CH), 120.98 (CH), 122.68 (C_quat), 123.01 (CH), 124.18 (CH), 125.04 (CH), 126.60 (C_quat), 127.05 (2CH), 127.85 (CH), 128.49 (C_quat), 128.90 (C_quat), 129.33 (2CH), 129.90 (2CH), 131.98 (2CH), 134.79 (C_quat), 134.87 (C_quat), 135.83 (C_quat), 135.89 (C_quat), 135.93 (C_quat), 145.26 (C_quat), 169.51 (C_quat), 201.69 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3244 (w), 3082 (w), 2913 (w), 1676 (w), 1618 (s), 1582 (w), 1489 (w), 1447 (m), 1420 (w), 1398 (m), 1377 (m), 1366 (w), 1342 (w), 1298 (w), 1279 (w), 1265 (w), 1233 (m), 1209 (w), 1175 (s), 1144 (m), 1125 (m), 1092 (m), 1072 (w), 1053 (w), 1009 (w), 988 (m), 955 (w), 890 (w), 878 (w), 810 (m), 746 (s), 719 (w), 691 (w), 675 (s), 656 (m). EI MS (70 eV, m/z (%)): 693 ([⁸¹Br-M]⁺, 3), 692 ([M]⁺, 3), 691 ([⁷⁹Br-M]⁺, 6), 538 ([C₃₀H₂₃⁸¹BrN₃O₂]⁺, 21), 536 ([C₃₀H₂₃⁷⁹BrN₃O₂]⁺, 22), 439 ([C₂₆H₂₁N₃O₂S]⁺, 13), 438 ([C₂₆H₂₀N₃O₂S]⁺, 30), 327 (25), 326 ([C₂₁H₁₆N₃O]²⁺, 100), 298 ([C₁₉H₁₂N₃O]⁴⁺, 21), 285 (20), 284 ([C₁₉H₁₄N₃]⁺, 55), 283 (33), 282 (34), 257 (24), 256 ([C₁₇H₁₀N₃]⁴⁺, 58), 255 (27), 185 ([C₇H₄⁸¹BrO]⁺, 38), 183 (35, [C₇H₄⁷⁹BrO]⁺, 35), 155 ([C₇H₇O₂S]⁺, 22), 143 (15), 92 (16), 91 ([C₇H₇]⁺, 51), 65 (22). Anal. calcd. for C₃₇H₃₀BrN₃O₄S (692.63): C 64.16, H 4.37, N 6.07, S 4.63; found: C 64.22, H 4.46, N 5.90, S 4.47.

2.19. rac-1-Benzoyl-12b-(1-tosyl-1H-indol-3-yl)-2,3,6,7,12,12b-hexahydro-indolo[2,3-a]quino-lizin-4(1H)-one (5q)

According to the GP, compound 5q (418 mg, 34%) was isolated as a colorless solid, Mp 294–297 °C, R_f = 0.22 (n-hexane/ethyl acetate 1:1). ¹H NMR (600 MHz, CDCl₃): δ 2.01–2.09 (m, 1H), 2.31 (s, 3H), 2.33–2.42 (m, 1H), 2.61–2.75 (m, 2H), 2.85 (td, ²J_HH = 12.5 Hz, ³J_HH = 4.2 Hz, 1H), 2.95 (ddd, ²J_HH = 17.8 Hz, ³J_HH = 5.6 Hz, ³J_HH = 3.8 Hz, 1H), 3.05 (ddd, ²J_HH = 15.4 Hz, ³J_HH = 12.1 Hz, ³J_HH = 5.5 Hz, 1H), 4.23 (dd, ²J_HH = 11.6 Hz, ³J_HH = 3.2 Hz, 1H), 4.96 (dd, ²J_HH = 12.9 Hz, ³J_HH = 5.3 Hz, 1H), 7.10 (d, ³J_HH = 8.1 Hz, 2H), 7.15 (t, ³J_HH = 7.4 Hz, 1H), 7.19–7.24 (m, 2H), 7.25–7.36 (m, 4H), 7.43 (d, ³J_HH = 8.1 Hz, 1H), 7.47–7.55 (m, 4H), 7.60 (s, 1H), 7.67 (d, ³J_HH = 8.2 Hz, 2H), 7.89 (d, ³J_HH = 8.3 Hz, 1H), 8.98 (s, 1H).¹³C NMR (151 MHz, CDCl₃): δ 20.99 (CH₂), 21.74 (CH₃), 23.25 (CH₂), 32.35 (CH₂), 38.69 (CH₂), 53.47 (CH), 63.16 (C_quat), 110.44 (C_quat), 111.85 (CH), 113.92 (CH), 118.83 (CH), 120.20 (CH), 120.85 (CH), 122.56 (C_quat), 122.96 (CH), 124.10 (CH), 124.83 (CH), 126.52 (C_quat), 127.10 (2CH), 127.92 (2CH), 128.24 (CH), 128.89 (2CH), 129.20 (C_quat), 129.91 (2CH), 133.43 (CH), 134.90 (C_quat), 134.94 (C_quat), 135.81 (C_quat), 135.87 (C_quat), 137.19 (C_quat), 145.09 (C_quat), 169.22 (C_quat), 202.45 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3136 (w), 3132 (w), 3107 (w), 3086 (w), 3067 (w), 3030 (w), 2959 (w), 2934 (w), 2843 (w), 1734 (w), 1686 (w), 1609 (m), 1582 (w), 1545 (w), 1493 (w), 1447 (m), 1408 (m), 1389 (w), 1369 (m), 1350 (w), 1331 (w), 1294 (w), 1275 (w), 1261 (w), 1227 (w), 1211 (w), 1175 (s), 1159 (m), 1140 (m), 1123 (m), 1070 (w), 1047 (w), 986 (m), 959 (w), 903 (w), 876 (w), 829 (w), 810 (w), 797 (w), 746 (s), 712 (m), 692 (w), 671 (m), 656 (s), 627 (w). EI MS (70 eV, m/z (%)): 613 ([M]⁺, 16), 459 (18), 458 ([C₃₀H₂₄N₃O₂]⁺, 54), 438 ([C₂₆H₂₀N₃O₂S]⁺, 26), 327 (23), 326 ([C₂₁H₁₆N₃O]²⁺, 100), 298 (22), 285 (18), 284 ([C₁₉H₁₄N₃]⁺, 46), 283 (31), 282 (26), 269 (18), 257 (25), 256 ([C₁₇H₁₀N₃]⁴⁺, 66), 255 (29), 105 ([C₇H₅O]⁺, 76), 91 ([C₇H₇]⁺, 32), 77 (31). HR-ESI MS calcd. for C₃₇H₃₂N₃O₄S: 614.2108; Found: 614.2108. HPLC (254 nm): t_R = 5.8 min, 99%. Anal. calcd. for C₃₇H₃₁N₃O₄S (613.73): C 72.41, H 5.09, N 6.85, S 5.22; found: C 71.56, H 5.04, N 6.52, S 4.97.

2.20. rac-1-(4-Methoxybenzoyl)-12b-(1-tosyl-1H-indol-3-yl)-2,3,6,7,12,12b-hexahydroindolo-[2,3-a]quinolizin-4(1H)-one (5r)

According to the GP, compound 5r (423 mg, 33%) was isolated as a colorless solid, Mp 273–274 °C, R_f = 0.16 (n-hexane/ethyl acetate 1:1). ¹H NMR (600 MHz, CDCl₃): δ 2.01–2.07 (m, 1H), 2.32 (s, 3H), 2.36–2.46 (m, 1H), 2.63–2.69 (m, 1H), 2.74 (ddd, ²J_HH = 18.0 Hz, ³J_HH = 10.8 Hz, ³J_HH = 6.8 Hz, 1H), 2.84 (td, ²J_HH = ³J_HH = 12.5 Hz, ³J_HH = 4.2 Hz, 1H), 2.97 (ddd, ²J_HH = 18.3 Hz, ³J_HH = 5.7 Hz, ³J_HH = 3.4 Hz, 1H), 3.03 (ddd, ²J_HH = 15.4 Hz, ³J_HH = 12.1 Hz, ³J_HH = 5.5 Hz, 1H), 3.82 (s, 3H), 4.17 (dd, ²J_HH = 11.8 Hz, ³J_HH = 3.1 Hz, 1H), 4.92–4.98 (m, 1H), 6.78–6.81 (m, 2H), 7.12–7.16 (m, 3H), 7.18–7.23 (m, 2H), 7.24–7.28 (m, 2H, superimposed by CDCl₃), 7.30–7.33 (m, 1H), 7.39 (d, ³J_HH = 8.1 Hz, 1H), 7.52 (d, ³J_HH = 7.8 Hz, 1H), 7.59 (s, 1H), 7.59–7.63 (m, 2H), 7.66–7.70 (m, 2H), 7.86–7.89 (m, 1H), 8.81 (s, 1H).¹³C NMR (151 MHz, CDCl₃): δ 21.02 (CH₂), 21.72 (CH₃), 23.31 (CH₂), 32.32 (CH₂), 38.74 (CH₂), 52.90 (CH), 55.70 (CH₃), 63.30 (C_quat), 110.29 (C_quat), 111.85 (CH), 113.88 (CH), 114.10 (2CH), 118.80 (CH), 120.17 (CH), 120.82 (CH), 122.62 (C_quat), 122.92 (CH), 124.06 (CH), 124.75 (CH), 126.48 (C_quat), 127.13 (2CH), 128.20 (CH), 129.30 (C_quat), 129.59 (C_quat), 129.91 (2CH), 130.62 (2CH), 134.92 (C_quat), 134.95 (C_quat), 135.81 (C_quat), 135.88 (C_quat), 145.08 (C_quat), 163.99 (C_quat), 169.51 (C_quat), 200.04 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3298 (w), 3258 (w), 3063 (w), 2947 (w), 2851 (w), 1668 (w), 1618 (m), 1599 (m), 1574 (w), 1508 (w), 1445 (w), 1422 (w), 1395 (m), 1375 (m), 1323 (w), 1300 (w), 1279 (w), 1233 (m), 1209 (w), 1175 (s), 1144 (m), 1124 (m), 1090 (w), 1082 (w), 1051 (w), 1032 (w), 1013 (w), 988 (m), 835 (w), 810 (w), 760 (m), 750 (m), 737 (s), 706 (w), 675 (s), 656 (w), 621 (w). EI MS (70 eV, m/z (%)): 643 ([M]⁺, 14), 488 ([C₃₁H₂₆N₃O₃]⁺, 39), 439 ([C₂₆H₂₁N₃O₂S]⁺, 17), 438 ([C₂₆H₂₀N₃O₂S]⁺, 21), 326 ([C₂₁H₁₆N₃O]²⁺, 62), 284 ([C₁₉H₁₄N₃]⁺, 36), 283 (19), 282 (16), 269 (15), 257 (19), 256 ([C₁₇H₁₀N₃]⁴⁺, 51), 255 (20), 135 (100), 91 ([C₇H₇]⁺, 20). Anal. Calcd. For C₃₈H₃₃N₃O₅S (643.76): C 70.90, H 5.17, N 6.53, S 4.98; found: C 70.86, H 5.12, N 6.39, S 4.82.

2.21. rac-1-(4-Methylbenzoyl)-12b-(1-tosyl-1H-indol-3-yl)-2,3,6,7,12,12b-hexahydroindolo-[2,3-a]quinolizin-4(1H)-one (5s)

According to the GP, compound 5s (458 mg, 36%) was isolated as a colorless solid, Mp 293–296 °C, R_f = 0.29 (n-hexane/ethyl acetate 1:1). ¹H NMR (600 MHz, CDCl₃): δ 2.01–2.07 (m, 1H), 2.32 (s, 3H), 2.36–2.44 (m, 4H), 2.66 (dd, ²J_HH = 15.5 Hz, ³J_HH = 4.0 Hz, 1H), 2.72 (ddd, ²J_HH = 18.1 Hz, ³J_HH = 11.2 Hz, ³J_HH = 6.8 Hz, 1H), 2.82 (td, ²J_HH = ³J_HH = 12.5 Hz, ³J_HH = 4.2 Hz, 1H), 2.93 (ddd, ²J_HH = 18.2 Hz, ³J_HH = 5.7 Hz, ³J_HH = 3.1 Hz, 1H), 3.03 (ddd, ²J_HH = 15.6 Hz, ³J_HH = 12.0 Hz, ³J_HH = 5.4 Hz, 1H), 4.15 (dd, ²J_HH = 12.1 Hz, ³J_HH = 3.0 Hz, 1H), 4.93–4.97 (m, 1H), 7.11–7.16 (m, 5H), 7.17–7.24 (m, 2H), 7.25–7.29 (m, 2H, superimposed by CDCl₃), 7.32 (dd, ³J_HH = 8.1 Hz, ⁴J_HH = 1.1 Hz, 1H), 7.38 (d, ³J_HH = 8.1 Hz, 1H), 7.47 (d, ³J_HH = 8.0 Hz, 2H), 7.52 (d, ³J_HH = 7.8 Hz, 1H), 7.59 (d, ⁴J_HH = 1.1 Hz, 1H), 7.67–7.71 (m, 2H), 7.89 (d, ³J_HH = 8.3 Hz, 1H), 8.77 (s, 1H). ¹³C NMR (151 MHz, CDCl₃): δ 21.02 (CH₂), 21.75 (CH₃), 21.77 (CH₃), 23.32 (CH₂), 32.46 (CH₂), 38.58 (CH₂), 53.35 (CH), 63.16 (C_quat), 110.37 (C_quat), 111.85 (CH), 113.93 (CH), 118.82 (CH), 120.18 (CH), 120.79 (CH), 122.55 (C_quat), 122.93 (CH), 124.07 (CH), 124.76 (CH), 126.49 (C_quat), 127.14 (2CH), 128.19 (2CH), 128.34 (CH), 129.31 (C_quat), 129.62 (2CH), 129.90 (2CH), 134.48 (C_quat), 134.96 (C_quat), 134.98 (C_quat), 135.79 (C_quat), 135.91 (C_quat), 144.66 (C_quat), 145.05 (C_quat), 169.15 (C_quat), 201.80 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3323 (w), 3285 (w), 3238 (w), 1668 (w), 1618 (s), 1580 (w), 1491 (w), 1447 (m), 1420 (w), 1396 (w), 1377 (m), 1344 (w), 1323 (w), 1300 (w), 1279 (w), 1263 (w), 1236 (w), 1209 (w), 1186 (m), 1175 (m), 1144 (m), 1125 (m), 1086 (w), 1053 (w), 1022 (w), 988 (m), 957 (w), 837 (w), 810 (w), 748 (s), 704 (w), 675 (s), 656 (w). EI MS (70 eV, m/z (%)): 627 ([M]⁺, 14), 473 (15), 472 ([C₃₁H₂₆N₃O₂]⁺, 47), 438 ([C₂₆H₂₀N₃O₂S]⁺, 25), 327 (22), 326 ([C₂₁H₁₆N₃O]²⁺, 88), 323 (16), 298 ([C₁₉H₁₂N₃O]⁴⁺, 20), 285 (20), 284 ([C₁₉H₁₄N₃]⁺, 55), 283 (31), 282 (25), 269 (19), 257 (28), 256 ([C₁₇H₁₀N₃]⁴⁺, 75), 255 (30), 119 ([C₈H₇O]⁺, 100), 91 ([C₇H₇]⁺, 72). Anal. Calcd. For C₃₈H₃₃N₃O₄S (627.76): C 72.71, H 5.30, N 6.69, S 5.11; found: C 72.91, H 5.34, N 6.55, S 5.03.

2.22. Methyl (6S)-12b-Butyl-1-(6-chloronicotinoyl)-4-oxo-1,2,3,4,6,7,12,12b-octahydroindolo-[2,3-a]quinolizin-6-carboxylate (5t)

According to the GP, compound 5t (198 mg, 20%) was isolated as a colorless solid, Mp 220–230 °C, R_f = 0.33 (n-hexane/ethyl acetate 5:7). [α]_D²⁵: +92° (c = 1 mg/mL, CH₂Cl₂), ¹H NMR (500 MHz, CDCl₃) δ 0.79 (t, ³J_HH = 7.0 Hz, 3H), 1.19–1.25 (m, 4H), 2.57–2.65 (m, 1H), 2.81–2.89 (m, 2H), 3.13 (dd, ²J_HH = 16.0 Hz, ³J_HH = 6.9 Hz, 1H), 3.47 (dd, ²J_HH = 16.0 Hz, ³J_HH = 2.7 Hz, 1H), 3.69 (s, 3H), 5.05–5.11 (m, 1H), 5.58 (dd, ²J_HH = 6.9 Hz, ³J_HH = 2.6 Hz, 1H), 7.08–7.19 (m, 3H), 7.42 (d, ³J_HH = 8.4 Hz, 1H), 7.48 (d, ³J_HH = 7.7 Hz, 1H), 7.95 (s, 1H), 8.17 (dd, ³J_HH = 8.4 Hz, ⁴J_HH = 2.5 Hz, 1H), 8.99 (d, ⁴J_HH = 2.5 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 14.08 (CH₃), 22.62 (CH₂), 22.67 (CH₂), 22.84 (CH₂), 25.68 (CH₂), 30.08 (CH₂), 37.40 (CH₂), 51.45 (CH), 52.80 (CH₃), 55.10 (CH), 63.05 (C_quat), 108.39 (C_quat), 111.51 (CH), 118.54 (CH), 120.18 (CH), 122.92 (CH), 124.83 (CH), 125.48 (C_quat), 131.34 (C_quat), 133.81 (C_quat), 136.43 (C_quat), 138.54 (CH), 150.61 (CH), 156.80 (C_quat), 172.93 (C_quat), 173.14 (C_quat), 204.15 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3377 (w), 3055 (w), 2955 (w), 2926 (w), 2860 (w), 2359 (w), 1726 (m), 1688 (m), 1630 (s), 1574 (w), 1555 (w), 1472 (w), 1445 (w), 1406 (m), 1381 (w), 1354 (w), 1337 (m), 1304 (m), 1288 (w), 1275 (w), 1261 (w), 1224 (m), 1206 (w), 1177 (w), 1148 (w), 1126 (m), 1099 (m), 1067 (w), 1013 (w), 974 (w), 962 (w), 943 (w), 912 (w), 839 (w), 787 (w), 766 (w), 743 (s), 712 (w), 677 (w), 633 (w). EI MS (70 eV, m/z (%)): 495 ([M(³⁷Cl)]⁺), 493 ([M(³⁵Cl)]⁺, 4), 438 ([C₂₃H₁₉³⁷ClN₃O₄]⁺, 16), (16), 437 (12), 436 ([C₂₃H₁₉³⁵ClN₃O₄]⁺, 49), 283 (10), 237 ([C₁₅H₁₃N₂O]³⁺, 15), 225 ([C₁₅H₁₇N₂]²⁺, 21), 195 (16), 183 (17), 182 (26), 181 ([C₁₂H₉N₂]⁵⁺, 10), 142, ([C₆H₃³⁷ClNO]⁺, 33), 140 ([C₆H₃²⁵ClNO]⁺, 100), 112 (14). Anal. calcd. for C₂₇H₂₈ClN₃O₄ (493.99): C 65.65, H 5.71, N 8.51; found: C 65.43, H 5.51, N 8.23.

2.23. Methyl (6S)-1-(4-Bromobenzoyl)-12b-butyl-4-oxo-1,2,3,4,6,7,12,12b-octahydroindolo-[2,3-a]quinolizin-6-carboxylate (5u)

According to the GP, compound 5u (195 mg, 18%) was isolated as a yellow solid, Mp 245–248 °C, R_f = 0.19 (n-hexane/ethyl acetate 7:3). [α]_D²⁵: +58° (c = 1 mg/mL, CH₂Cl₂), ¹H NMR (600 MHz, CDCl₃) δ 0.86 (t, ³J_HH = 7.3 Hz, 3H), 1.07–1.15 (m, 1H), 1.17–1.23 (m, 1H), 1.27 1.36 (m, 2H), 2.00–2.08 (m, 1H), 2.30–2.44 (m, 2H), 2.59 (ddd, ²J_HH = 14.7 Hz, ³J_HH = 12.7 Hz, ³J_HH = 4.2 Hz, 1H), 2.85 (ddd, ²J_HH = 18.5 Hz, ³J_HH = 10.3 Hz, ³J_HH = 5.8 Hz, 1H), 2.91–3.00 (m, 2H), 3.61 (s, 4H), 3.83 (dd, ²J_HH = 13.4 Hz, ³J_HH = 5.6 Hz, 1H), 6.08–6.18 (m, 1H), 7.04–7.10 (m, 3H), 7.34–7.46 (m, 4H), 7.50–7.58 (m, 1H), 7.74 (s, 1H). ¹³C NMR (151 MHz, CDCl₃) δ 14.24 (CH₃), 21.36 (CH₂), 21.39 (CH₂), 23.64 (CH₂), 26.72 (CH₂), 29.89 (CH₂), 35.62 (CH₂), 50.73 (CH), 52.36 (CH₃), 53.94 (CH), 62.73 (C_quat), 108.69 (C_quat), 111.09 (CH), 118.66 (CH), 119.97 (CH), 122.76 (CH), 126.04 (C_quat), 129.12 (C_quat), 129.33 (2CH), 132.09 (2CH), 132.58 (C_quat), 135.54 (C_quat), 136.10 (C_quat), 171.19 (C_quat), 171.39 (C_quat), 202.11 (C_quat). IR: $\tilde{\nu }$ [cm⁻¹] 3275 (w), 3057 (w), 2953 (w), 2928 (w), 2901 (w), 2870 (w), 2857 (w), 1736 (m), 1672 (m), 1630 (s), 1584 (m), 1566 (w), 1483 (w), 1454 (m), 1435 (m), 1387 (s), 1356 (m), 1327 (m), 1292 (m), 1279 (m), 1254 (m), 1202 (s), 1179 (m), 1167 (m), 1153 (m), 1109 (m), 1070 (m), 1028 (m), 1007 (s), 970 (m), 912 (w), 889 (w), 839 (m), 812 (m), 741 (s), 679 (m). EI MS (70 eV, m/z (%)): 538 ([M(⁸¹Br)]⁺, 3), 536 ([M(⁷⁹Br)]⁺, 3), 481 ([C₂₄H₂₀BrN₂O₄(⁸¹Br)]⁺, 33), 479 ([C₂₄H₂₀BrN₂O₄(⁷⁹Br)]⁺, 27), 283 ([C₁₆H₁₅N₂O₃]³⁺, 33), 242 (17), 225 ([C₁₅H₁₇N₂]²⁺, 33), 201 (13), 195 (13), 185 ([C₇H₄BrO(⁸¹Br)]⁺, 66), 184 (10), 183 ([C₇H₄BrO(⁷⁹Br)]⁺, 100), 182 (26), 155 (11), 130 (31). HR-ESI MS calcd. for C₂₈H₃₀BrN₂O₄: 537.1383. Found: 537.1375. HPLC (245 nm): t_R = 5.4 min, 99%. Anal. calcd. for C₂₈H₂₉BrN₂O₄ (537.45): C 62.57, H 5.44, N 5.21; found: C 61.68, H 5.67, N 4.93.

3. Results and Discussion

According to Karpov’s CAAPS synthesis of THBC, enaminones 7 prepared from acid chlorides 1, alkynes 2, and amines 3 via Sonogashira alkynylation and Michael addition are the second intermediates (Scheme 1) [13,14].

Previous calculations concerning the transition state of the addition of an amine to an acceptor-substituted alkyne strongly support a two-step mechanism, where methanol as a co-additive stabilizes the zwitterion intermediate [16]. However, since acryloyl chloride (4) is a reactive electrophile in the further course of the sequence, methanol as a nucleophilic cosolvent turns out to be incompatible. As an alternative to the polar solvent additive, an excess of amine 3 gives reasonable yields of enaminones 7, but a catalytic approach would be preferable to avoid the use of overstoichiometric reagents [13,17,18,19]. As described in the literature, bismuth, yttrium, scandium, and ytterbium salts with weakly coordinating counterions have already been successfully employed as catalysts for Michael and aldol additions [20,21,22]. Since ytterbium (III) triflate shows a high tolerance to various solvents, this Lewis acid catalyst was chosen for the Michael addition step in the sequence [23]. After a short optimization study with selected ynones 6a and one equivalent of tryptamine (3a) as a model reaction furnished the desired enaminone 7a in excellent yield using only 1 mol% ytterbium (III) triflate as a catalyst (Scheme 2). It is noteworthy that the uncatalyzed reactions only showed incomplete conversion after up to 48 h (see Table S1, Supplementary Information).

Lewis acid-catalyzed Michael additions proceeds smoothly in dichloromethane or acetonitrile as solvents, whereas a much lower conversion is observed in tetrahydrofuran (THF). This observation matches the finding that the catalytic activity of ytterbium triflate is reduced in aldol reactions of silyl enol ethers and formaldehyde [24].

The implementation of the optimized ytterbium triflate catalyzed Michael addition to give the central enaminone intermediate in the consecutive four-component CAAPS sequence furnished a library of 21 THBCs 5 in yields of 18–56% in a one-pot process (Figure 1). Since the CAAPS sequence comprises alkynylation, Michael addition, aza-anellation, and Pictet–Spengler cyclization (which amounts to five bond forming steps), an overall yield within a range between 18 and 56% adds up to 71–89% per bond forming step, which makes the one-pot process quite efficient.

The initial Sonogashira coupling of acid chlorides 1 with alkynes 2 proceeded efficiently in dichloromethane as a solvent within 1–2 h by using only a single equivalent of triethylamine as a base. Poor solubility of ytterbium (III) triflate and tryptamine (3a) in the Michael step (which led to suspensions and prolonged reaction times) was overcome by the addition of acetonitrile as a cosolvent (CH₂Cl₂/CH₃CN 1:1) and by placing the reaction vessel in an oil bath at 80 °C. Acetonitrile, as the sole solvent medium, was discarded due to incomplete conversions of some substrates in the initial Sonogashira step. The lower effective concentration in the Michael step required a longer reaction time of 16 h for full conversion. The terminal aza-anellation Pictet–Spengler step proceeded at 70 °C in the same reaction vessel to terminate the sequence and to give THBCs 5 after a single chromatographic purification.

The scope of acid chlorides 1 (R¹) allowed for electron-rich and electron-deficient aromatic and heteroaromatic substituents, the alkynes 2 can be aliphatic, aromatic, and heterocyclic substituents (R²) and, besides tryptamine (3a), L-tryptophan methyl ester (3c) was also well tolerated in the Michael addition.

The structures of the THBCs 5 were unambiguously assigned by NMR spectroscopy and mass spectrometry. The occurrence of a single set of signals in the ¹H and ¹³C NMR spectra confirms the highly selective formation of the syn-diastereomer. This can be rationalized by a highly diastereofacial formation of the contiguous stereocenters in the aza-anellation Pictet–Spengler step [13]. As expected, the products formed from enantiomerically pure L-tryptophan were obtained as a single diastereomer [25,26,27].

In the ¹H spectra (CDCl₃, 600 MHz), the relevant signals of the protons 1–7 of the quinolizinone core (Figure 2) appeared within the range δ 1.80–6.10 and were split into diastereotopic signals with a characteristic coupling pattern due to the neighboring stereocenters. The assignment of the corresponding protons was performed by HSQC and COSY experiments. The signals that most strongly shifted to low field at δ 4.90–6.10 could be assigned to the protons 7-H_α, which experienced the strongest de-shielding by the adjacent amide nitrogen atom.

They usually appeared as a doublet of doublets of doublets, with coupling constants of ²J_HH = 12.9–13.0 Hz, ³J_HH = 5.0–5.1 Hz, and ³J_HH = 1.5–1.7 Hz. In contrast, if the resolution of the 7-H_α signal was too low, only a doublet of doublets with coupling constants of ²J_HH = 12.5–13.0 Hz and ³J_HH = 4.6–5.4 Hz could be observed. Due to the geminal ester group, the 7-H_α resonance for methyl ester 5t only appeared as a doublet of doublets, with coupling constants of ³J_HH = 6.9 Hz and ³J_HH = 2.6 Hz. The signals of the C₄ protons could be readily identified from the HSQC spectra since they exhibited only one CH coupling and were usually found at δ 3.70–4.20. In the case of the indole-substituted hexahydroquinolizinones 5m-5s, they appeared as doublets of doublets, with coupling constants of ³J_HH = 11.0–12.1 Hz and ³J_HH = 3.0–3.2 Hz, whereas the C₄-H resonances of the remaining THBC 5 could be observed with coupling constants of ³J_HH = 13.1–13.6 Hz and ³J_HH = 4.7–5.1 Hz. Compounds 5j and 5t formed the exception, whose C₄ proton signals were observed deep field shifted at chemical shifts of δ 5.20 and 5.10, respectively. All other proton signals of the quinolizinone nucleus could not always be clearly identified for each spectrum and often overlapped with the signals of the butyl or methyl substituents. However, in the NMR spectrum of THBC 5r, the aliphatic proton signals were sufficiently separated to make an exemplary assignment. Compared with 7-H_α, the 7-H_β signal was clearly shifted to high field and appeared as a triplet of doublets at δ 2.84, with coupling constants of ²J_HH = ³J_HH = 12.5 Hz and ³J_HH = 4.2 Hz. Proton 2-H_α could be assigned to the resonance at δ 2.97 and presented itself as a doublet of doublets of doublets, with coupling constants of ²J_HH = 18.3 Hz, ³J_HH = 5.7 Hz, and ³J_HH = 3.4 Hz. The signal for 2-H_β appeared at a chemical shift of δ 2.74 and split into a doublet of doublets of doublets, with coupling constants of ²J_HH = 18.0 Hz, ³J_HH = 10.8 Hz, and ³J_HH = 6.8 Hz. Furthermore, the 6-H_α proton signal could be observed at δ 3.03 and appeared as a doublet of doublets of doublets, with coupling constants of ²J_HH = 15.4 Hz, ³J_HH = 12.1 Hz, and ³J_HH = 5.5 Hz. The signal for 6-H_β appeared as a multiplet at δ 2.63–2.69. Of all the diastereotopic protons of the quinolizine core, the 3-H proton signals were most shifted to high field and appeared as multiplets at δ 2.36–2.46 for 3-H_α and δ 2.01–2.07 for 3-H_β.

All the recorded ¹H NMR spectra support the strict diastereoselectivity of the presented MCR, forming a single diastereomer of compound 5. As reported previously, the concluding Pictet–Spengler step, which essentially represents an intramolecular electrophilic aromatic substitution at the pyrrole fragment of the indole core, determines the relative syn-relation between the substituents at carbon centers C₄ and C₅ in the pyridone part [13]. The previously observed syn-orientation of the substituent at C₃ demands a cyclic rather than an open transition state of the aza-anellation step, which suggests two alternative mechanistic scenarios via pericyclic elementary steps (Figure 3). On the one hand, nitrogen attack of the (Z)-configured enaminone 7 on the carbonyl function of acryloyl chloride (4) and condensation could result in an azonia hexatriene structure 8, which could undergo a disrotatory ring closure to the dihydropyridinium enol intermediate 9 (electrocyclization pathway), which could easily tautomerize to the acyliminium ion 11. The electrophilic iminium moiety in 11 could attack the indole with the face opposite to the adjacent carbonyl substituent, resulting in a syn-orientation of carbonyl substituent and R² [28].

Alternatively, the aza-anellation [27] could be initiated by ene reaction [29,30] with enaminone 7 as the ene component and acryloyl chloride (4) as an enophile (aza–ene pathway), which represents a rare example, as aza–enes are seldom employed in inter- and intramolecular ene reactions [31,32,33]. The (Z)-configured enaminone 7 and acryloyl chloride (4) give rise to an envelope conformation of the transition state, leading to the acid chloride 10, which cyclizes to the acyliminium ion 11 by the intramolecular attack of the imine nitrogen atom on the acid chloride moiety. Thereafter, the acyliminium ion 11 enters the intramolecular electrophilic ring closure with the indole, i.e., the Pictet–Spengler anellation, as already outlined above, to furnish syn-configured THBCs 5 [28].

Discrimination between both plausible alternatives for the aza-anellation Pictet–Spengler sequence can be made by calculation of the transition state energies of both pathways, namely via the envisioned initial pericyclic steps. As a computational model, diphenyl-substituted enaminone 7b and acryloyl chloride (4) were chosen as starting points and DFT calculations with Spartan ‘18 were performed, employing the standard B3LYP hybrid functional and the 6–31G* basis set using the conductor-like polarizable continuum model (C-PCM) [34] with a dipolar aprotic implicit dielectric medium with a dielectric constant of 37.22 (e.g., DMF) to mimic the mixture of dichloromethane and acetonitrile (Figure 4).

The electrocyclization pathway (in red) commences by condensation of acryloyl chloride (4) and enaminone 7b, giving an azonia hexatriene system 8. Energetically, the formation of intermediate 8 is endothermic by 27.47 kJ/mol. Disrotatory 6π-electro cyclization proceeds via transition state TS₈→₉, which lies 140.33 kJ/mol above the starting point, to give the hydroxy dihydropyridinium intermediate 9, which is formed exothermically and lies energetically close to the aza–ene product 10. The aza–ene pathway (in green) directly proceeds from acryloyl chloride (4) and the enaminone 7b to exothermically give the aza–ene product 10, which lies 18.83 kJ/mol lower in energy with respect to the starting point. With 82.39 kJ/mol, the computed transition state TS_(4+7b)→₁₀ of the aza–ene reaction lies almost 58 kJ/mol lower in energy than the transition state TS₈→₉ of the electrocyclization pathway. This clearly speaks for the aza–ene reaction as the operative mechanism based upon our computational kinetic reasoning. The remainder of the sequence after the exothermic formation of the acyliminium ion 11 represents the Pictet–Spengler anellation, which was also calculated, referencing the energies of the intermediates and transition states to the starting point of acryloyl chloride (4) and enaminone 7b. The intramolecular electrophilic attack of the acyliminium ion 11 on the tethered indole moiety gives slightly exothermically the spirocyclic intermediate 12 via a transition state TS₁₁→₁₂ that lies 68.48 kJ/mol above the acyliminium ion 11. The subsequent Wagner–Meerwein rearrangement proceeds slightly endothermically to carbenium ion 13 via a transition state TS₁₂→₁₃ that lies 31.55 kJ/mol above the spirocyclic intermediate 12. Finally, the carbenium ion 13 aromatizes to the indole structure 14, which lies 79.37 kJ/mol below the starting point and represents the global energy minimum in this calculated scenario.

Based on the respective activation barriers of the aza–ene reaction (+82.39 kJ/mol) and the electrocyclization (+112.86 kJ/mol), we propose that the aza–ene pathway is the operative mechanism as well as the rate-determining step of the overall sequence, as all subsequent steps possess lower activation barriers.

4. Conclusions

Ytterbium triflate not only efficiently catalyzes the Michael addition of tryptamines to ynones to form enaminones, but it can readily be implemented in the four-component CAAPS sequence for the synthesis of tetrahydro-β-carbolines. Thereby, acid chlorides, alkynes, tryptamines, and triethylamine could be employed in equistoichiometric amounts to generate the enaminone, which reacted in the terminal step of the sequence with acryloyl chloride to give the desired products. The scope shows that a quite dense and electronically variable substitution could be readily introduced to the central hexahydroquinolizinone core, employing acid chlorides and alkyne substrates as points of diversity.

Mechanistic insight into the aza-anellation Pictet–Spengler step was achieved by DFT calculations on two potential pericyclic pathways that can furnish the crucial acyliminium ion intermediate, which terminates the sequence via Pictet–Spengler anellation. The computed transition state for the aza–ene reaction lies 30.47 kJ/mol lower in energy than the transition state for electrocyclization and represents the rate determining step of the aza-anellation Pictet–Spengler sequence. We therefore propose that a rate determining aza–ene reaction is the operative mechanism of the concluding steps of the CAAPS sequence.

The substance library of THBC analogues might contain potentially biologically active derivatives. Therefore, medicinal chemistry screening for biological activity is currently underway.