Abstract
A protocol has been developed to access indole-annulated eight- and nine-membered lactams through protonation-induced ring-opening of spiroindolines, which are dearomative Heck products of tetrahydro-β-carbolines or hexahydroazepino[3,4-b]indoles. Brønsted acids and nucleophiles were explored and compared in the transformation. A combination of deuterated hydrochloride and deuterated methanol enables deuterative ring-opening of spiroindolines to afford medium-sized lactam diastereoisomers with a deuterium content ratio around 1:1.
Introduction
Indole-annulated medium-sized nitrogen-containing heterocyclic rings are core structures embedded in bioactive natural alkaloids, including balasubramide,1 deoxyisoaustamide,2 okaramine,3 lundurine A–D,4 and vinblastine.5 Generally, the construction of medium-sized compounds has been challenging in organic synthesis due to unfavorable entropy and transannular interactions.6 It is impressive that significant strategies including cycloaddition,7 cycloisomerization,8 and ring expansion9 have been invented for the generation of eight- and nine-membered nitrogen-containing heterocycles.
Recently, we have developed a diastereoselective protocol to prepare indole-annulated eight-membered lactams through light-driven alkylative ring-opening of spiroindolines, a type of dearomative Heck product of easily available β-carbolines.10 DFT calculations and mechanistic experiments support that a cationic C–C fragmentation should be favorable rather than a homolytic C–C fragmentation, in which a tertiary cation intermediate might be involved (Scheme 1a).11 Because a tertiary carbon cation could be formed regioselectively through direct protonation of an alkene, we envisioned an alternative to indole-annulated medium-sized lactams by protonation-induced ring-opening of the spiroindolines (Scheme 1b). The key issues of the transformation include the choice of Brønsted acids, the tolerance of the indole ring, and the nucleophile to trap the iminium intermediate. Furthermore, if this can be realized, a deuterative ring-opening would be feasible by employing deuterated acids and deuterated nucleophiles, which provides an unprecedented protocol to prepare deuterated indole-containing medium-sized heterocycles.12 Here, we report our experimental results on the reaction design.
Scheme 1. Reaction Design.
Results and Discussion
We commenced the study by reacting spiroindole 1a with methanol using acetic acid as a promoter. The anticipated ring-opening reaction did not take place even after heating in 1,2-dichloroethane at 60 °C for 12 h, probably due to the relatively weak acidity (Table 1, entry 1). However, in the presence of stronger Brønsted acids such as trifluoroacetic acid, hydrochloride, and methanesulfonic acid, the spiroindoline was converted successfully to eight-membered lactam 2a (Table 1, entries 2–4). The structure of 2a was confirmed unequivocally by single-crystal X-ray diffraction (Figure 1). It was impressive that 2a was isolated in 89% yield under the promotion of methanesulfonic acid even when the ring-opening reaction was performed at room temperature. Control experiments showed that 0.2 equiv of methanesulfonic acid is appropriate for the transformation (entries 5 and 6). Further screenings of solvents by fixing methanesulfonic acid and methanol demonstrated that lower yields were obtained in dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, and toluene, while the reaction was completely inhibited in acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide (Table 1, entries 9–14).
Table 1. Optimization of the Protonation-Induced Ring-Opening of Spiroindoline 1aa.
| entry | acid | x | solvent | temp. (°C) | time (h) | yield (%)b |
|---|---|---|---|---|---|---|
| 1 | HOAc | 1.0 | DCE | 60 | 12 | |
| 2 | TFA | 1.0 | DCE | 60 | 2 | 68 |
| 3c | HCl | 1.0 | DCE | 60 | 2 | 80 |
| 4 | MsOH | 1.0 | DCE | rt | 2 | 89 |
| 5 | MsOH | 0.2 | DCE | rt | 2 | 85 |
| 6 | MsOH | 0.1 | DCE | rt | 12 | 70 |
| 7 | MsOH | 0.2 | DCM | rt | 2 | 81 |
| 8 | MsOH | 0.2 | CHCl3 | rt | 2 | 63 |
| 9 | MsOH | 0.2 | dioxane | rt | 2 | 25 |
| 10 | MsOH | 0.2 | THF | rt | 2 | 24 |
| 11 | MsOH | 0.2 | toluene | rt | 2 | 58 |
| 12 | MsOH | 0.2 | MeCN | rt | 2 | |
| 13 | MsOH | 0.2 | DMF | rt | 2 | |
| 14 | MsOH | 0.2 | DMSO | rt | 2 |
Reaction conditions: spiroindoline 1a (0.05 mmol), acid (x equiv), methanol (0.05 mmol), and degassed solvent (0.25 mL) were stirred in a sealed vial.
Isolated yield after column purification.
20% HCl in water.
Figure 1.
X-ray crystal structure of 2a (30% probability levels).
The scope of the protonation-induced C–C bond fragmentation was next examined (Scheme 2). Like spiroindoline 1a, spiroindolines with electron-donating and electron-withdrawing substituents (Me, MeO, F, Cl) located at ortho, meta, and para positions of the benzamide ring, participated in the ring-opening reaction with methanol smoothly, affording indole-annulated eight-membered lactams 2b–2k in yields ranging from 76 to 90%. It seems that the electron-donating group might be more favorable than the electron-withdrawing group for the transformation. Different substituents (MeO, Cl, Me) on the indole ring were also compatible, affording lactams 2l–2n in a comparable efficiency. Replacing the benzyl group on the nitrogen of the indole ring by a methyl group did not interfere with the conversion, affording lactam 2o in 91% yield. Spiroindoline 1a reacted with heteroatom-containing nucleophiles with increasing steric hindrance such as ethanol, benzyl alcohol, isopropanol, and 4-methylbenzenethiol in a similar manner, affording lactams 2p–2s in good yields. Carbon nucleophiles including 2-naphthol and indole engaged in the ring-opening reaction to afford lactams 2t and 2u in 82 and 70% yields, respectively.
Scheme 2. Scope of Indole-Annulated Eight-Membered Lactamsa.
Reaction conditions: a mixture containing spiroindoline 1 (0.05 mmol), methanesulfonic acid (0.01 mmol), nucleophile (0.05 mmol), and degassed 1,2-dichloroethane (0.25 mL) was stirred in a sealed vial at room temperature for 2 h. Isolated yield after column purification.
We further tested the feasibility of deuteration-induced ring-opening of spiroindolines by employing commercially available deuterated Brønsted acid and deuterated nucleophile. To our delight, the ring-opening of spiroindoline 1a was observed at 60 °C under the promotion of deuterated trifluoroacetic acid and deuterated methanol, affording indole-annulated eight-membered lactam 3a in 70% yield (Table 2, entry 1). The assignment of different hydrogens of lactam 3a was identified by a series of NMR studies. Further NOE experiments of lactam 3a supported that hydrogens a, d, and e are close in space, in which the cross-peaks of hydrogen a and e, a and d had strong intensities (Figure 2). Based on the integration of peaks on the 1H NMR spectra of 3a, we found that hydrogens c and d were partially deuterated with 49 and 48% deuterium installation. When deuterated hydrochloride was employed as Brønsted acid, the medium-sized lactam was isolated in 83% yield of 49 and 46% deuterium contents (Table 2, entry 2). It is worth mentioning that the competitive nucleophilic addition of D2O toward the iminium intermediate did not happen, highlighting that deuterated methanol performed as a benign nucleophile. Inferior results were obtained in dichloromethane, chloroform, toluene, 1,4-dioxane, and THF, and no conversions were observed in acetonitrile, DMF, and DMSO (Table 1, entries 3–10), which are consistent with those encountered in the protonation-induced ring-opening reaction.
Table 2. Optimization of the Deuteration-Induced Ring-Opening of Spiroindoline 1aa.
| deuterium
content |
|||||||
|---|---|---|---|---|---|---|---|
| entry | deuterated acid | solvent | temp. (°C) | t (h) | yield (%)b | Hc (%)c | Hd (%)c |
| 1 | CF3COOD | DCE | 60 | 2 | 70 | 49 | 48 |
| 2 | DCl (20% in D2O) | DCE | 60 | 2 | 83 | 49 | 46 |
| 3 | DCl (20% in D2O) | DCM | 40 | 8 | 72 | 48 | 45 |
| 4 | DCl (20% in D2O) | CHCl3 | 60 | 2 | 61 | 45 | 41 |
| 5 | DCl (20% in D2O) | toluene | 60 | 2 | 50 | 45 | 40 |
| 6 | DCl (20% in D2O) | dioxane | 60 | 2 | 28 | 43 | 41 |
| 7 | DCl (20% in D2O) | THF | 60 | 2 | 29 | 42 | 39 |
| 8 | DCl (20% in D2O) | MeCN | 60 | 2 | |||
| 9 | DCl (20% in D2O) | DMF | 60 | 2 | |||
| 10 | DCl (20% in D2O) | DMSO | 60 | 2 | |||
Reaction conditions: spiroindoline 1a (0.05 mmol), deuterated acid (0.01 mmol), CD3OD (0.05 mmol), 1,2-dichloroethane (degassed, 0.25 mL), 60 °C, 2 h.
Isolated yields after column purification.
The deuterium content was calculated by the integration of peaks shown on the 1H NMR spectra.
Figure 2.
2D NOESY spectra of compound 3a with a mixing time of 700 ms.
By fixing the combination of deuterated hydrochloride and deuterated methanol, the deuteration-induced ring-opening of spiroindoline 1a was extended (Scheme 3). Other candidates with methoxy, methyl, chlorine, and fluorine groups located at different positions on the benzamide and indoline rings as well as the nitrogen of the indoline afforded lactams 3b–3o in good to excellent yields. The deuterium content ratio of two hydrogens on the eight-membered ring is close to 1:1, except for that of compounds 3b and 3c. It was suggested that in most cases, nondiastereoselective deuteration of the alkene in spiroindolines is predominant, while the ortho substituent on the benzamide ring leads to a diastereoselective deuteration, which makes one diastereomer of 3b or 3c excess.
Scheme 3. Scope of Deuterated Indole-Annulated Eight-Membered Lactams.
Reaction conditions: a mixture containing spiroindoline 1 (0.05 mmol), deuterated hydrochloride (20% in D2O, 0.01 mmol), deuterated methanol (0.05 mmol), degassed 1,2-dichloroethane (0.25 mL) was stirred at 60 °C for 2 h. Isolated yield after column purification.
Based on the protonation/deuteration-promoted ring-opening reaction, indole-annulated nine-membered lactams 5a–5d can be prepared from spiroindoline 4 (Scheme 4). As illustrated, under the promotion of methanesulfonic acid, spiroindoline 4 reacted with oxygen and carbon nucleophiles to afford lactams 5a–5c in excellent yields, in which methoxy, 2-naphthol, and indole were installed to the side chain of the nine-membered lactams. In the presence of deuterated hydrochloride and methanol, lactam 5d was obtained in 88% yield with 58 and 41% deuterium installation.
Scheme 4. Access to Indole-Annulated Nine-Membered Lactams from Spiroindoline 4.
Conclusions
In summary, we have established a protocol to prepare indole-annulated eight- and nine-membered lactams by taking advantage of protonation-induced ring-opening of spiroindolines. Under the promotion of methanesulfonic acid, spiroindolines reacted with different hetero and carbon nucleophiles to afford medium-sized lactams with side chains containing alkoxy, thiol ether, 2-naphthol, and indole groups. In the presence of deuterated hydrochloride and deuterated methanol, a deuterative ring-opening of spiroindolines proceeded smoothly to afford deuterated medium-sized lactams. Further investigations on the diastereoselective deuteration-induced ring-opening of spiroindolines are underway.
Experimental Section
General Information
1H NMR spectra was obtained at 400 MHz. 2H NMR spectra were recorded at a frequency of 92 MHz. 13C NMR spectra were obtained at 100 MHz, and 19F NMR spectra were obtained at 376 MHz. Spectra were recorded in a CDCl3 solution using the residual protonated solvent as the internal standard, and J values are given in hertz. IR spectra were recorded on a Fourier transform infrared spectrometer and listed in cm–1. High-resolution mass spectral analyses (HRMS) were performed on a Q-TOF-MS spectrometer. All air moisture-sensitive reactions were conducted in oven-dried glassware under a nitrogen atmosphere using dry and degassed solvents. Flash column chromatography was performed over silica gel (300–400 mesh). All commercially available reagents were used without further purification. Spiroindolines were prepared according to the known procedure.10
General Procedure A for the Synthesis of Indole-Annulated Medium-Sized Lactams
To a dry 1.5 mL glass bottle, spiroindoline 1 or 4 (0.05 mmol) and degassed DCE (0.25 mL) were added successively. Then, a nucleophile (50 μL, 0.05 mmol, 1 mol/L DCE solution) and MsOH (10 μL, 0.01 mmol, 1 mol/L DCE solution) were added. The reaction mixture was stirred at room temperature for 2 h. The solution was concentrated under vacuum to afford a residue, which was purified by column chromatography on silica gel to afford lactam 2 or 5a–5c.
General Procedure B for the Synthesis of Deuterated Indole-Annulated Medium-Sized Lactams
To a dry 1.5 mL glass bottle, spiroindoline 1 or 4 (0.05 mmol) and degassed DCE (0.25 mL) were added successively. Then, CD3OD (50 μL, 0.05 mmol, 1 mol/L DCE solution) and DCl (20% in D2O, 2 μL, 0.01 mmol) were added. The reaction mixture was stirred at 60 °C for 2 h. The solution was concentrated under vacuum to afford a residue, which was purified by chromatography on silica gel to afford lactam 3 or 5d.
13-Benzyl-6-(methoxymethyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2a)
According to procedure A, lactam 2a was obtained from spiroindoline 1a (18.2 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (16.3 mg, 85% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 101–103 °C. 1H NMR (400 MHz, CDCl3) δ 7.61–7.50 (m, 2H), 7.44 (td, J = 7.5, 1.3 Hz, 1H), 7.36 (td, J = 7.6, 1.5 Hz, 1H), 7.28–7.11 (m, 7H), 6.99–6.94 (m, 2H), 5.17 (d, J = 16.9 Hz, 1H), 5.10–4.98 (m, 2H), 4.88 (d, J = 10.3 Hz, 1H), 3.88 (td, J = 14.2, 4.6 Hz, 1H), 3.68–3.49 (m, 2H), 3.15 (s, 3H), 2.92 (ddd, J = 16.5, 4.4, 1.2 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.3, 138.0, 137.6, 137.5, 134.0, 130.6, 129.3, 129.2, 129.0, 128.7, 128.6, 128.2, 127.2, 126.1, 122.7, 119.9, 118.4, 110.6, 109.4, 75.6, 56.2, 47.6, 44.9, 24.4 ppm. IR (film) νmax 1644, 1460, 1442, 1346, 1178, 1081, 1015, 962, 906, 727, 698 cm–1. HRMS (ESI) m/z calcd for C26H24N2NaO2 419.1730 [M + Na]+, found 419.1732.
13-Benzyl-6-(methoxymethyl)-4-methyl-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2b)
According to procedure A, lactam 2b was obtained from spiroindoline 1b (18.9 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (17.8 mg, 87% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 166–168 °C. 1H NMR (400 MHz, CDCl3) δ 7.59–7.53 (m, 1H), 7.29–7.17 (m, 5H), 7.16–7.09 (m, 3H), 7.05–6.98 (m, 3H), 5.23 (d, J = 16.9 Hz, 1H), 5.16–5.07 (m, 2H), 4.79 (d, J = 10.4 Hz, 1H), 3.88–3.79 (m, 1H), 3.68–3.47 (m, 2H), 3.19 (s, 3H), 2.91–2.80 (m, 1H), 2.41 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 171.6, 138.1, 137.4, 137.0, 135.5, 134.6, 130.8, 129.2, 128.7, 128.7, 128.5, 128.0, 127.1, 126.2, 122.5, 119.7, 118.2, 110.7, 109.0, 74.9, 56.3, 47.7, 44.4, 24.0, 19.8 ppm. IR (film) νmax 1645, 1451, 1421, 1349, 1180, 1195, 1078, 1024, 907, 727, 699 cm–1. HRMS (ESI) m/z calcd for C27H26N2O2 433.1886 [M + Na]+, found 433.1883.
13-Benzyl-4-chloro-6-(methoxymethyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2c)
According to procedure A, lactam 2c was obtained from spiroindoline 1c (20.0 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (16.4 mg, 76% yield, eluent: petroleum ether/ethyl acetate = 2/1). Mp 182–184 °C. 1H NMR (400 MHz, CD2Cl2) δ 7.60–7.56 (m, 1H), 7.52–7.41 (m, 3H), 7.29–7.24 (m, 1H), 7.23–7.06 (m, 5H), 6.93–6.83 (m, 2H), 5.22 (d, J = 16.8 Hz, 1H), 5.11 (d, J = 16.9 Hz, 1H), 4.97 (dd, J = 10.2, 1.1 Hz, 1H), 4.86 (d, J = 10.2 Hz, 1H), 3.86 (td, J = 14.2, 4.4 Hz, 1H), 3.67–3.45 (m, 2H), 3.12 (s, 3H), 2.96–2.80 (m, 1H) ppm. 13C NMR (100 MHz, CD2Cl2) δ 172.4, 138.4, 138.1, 137.8, 134.4, 131.0, 129.6, 129.5, 129.3, 129.1, 128.9, 128.4, 127.4, 126.5, 122.8, 120.1, 118.8, 110.9, 110.1, 76.0, 56.3, 47.7, 45.3, 24.8 ppm. IR (film) νmax 1653, 1469, 1443, 1418, 1360, 1095, 1017, 726, 661, 648 cm–1. HRMS (ESI) m/z calcd for C26H23ClN2NaO2 453.1340 [M + Na]+, found 453.1337.
13-Benzyl-6-(methoxymethyl)-3-methyl-6,7,8,13-tetrahydro-5H-benzo[6,7]azocin[5,4-b]indol-5-one (2d)
According to procedure A, lactam 2d was obtained from spiroindoline 1d (18.9 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (18.5 mg, 90% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 73–75 °C. 1H NMR (400 MHz, CDCl3) δ 7.61–7.52 (m, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.27–7.12 (m, 7H), 7.07 (d, J = 7.9 Hz, 1H), 7.00–6.95 (m, 2H), 5.17 (d, J = 16.9 Hz, 1H), 5.11–4.99 (m, 2H), 4.86 (d, J = 10.3 Hz, 1H), 3.90 (td, J = 14.3, 4.6 Hz, 1H), 3.67–3.46 (m, 2H), 3.16 (s, 3H), 2.91 (ddd, J = 16.5, 4.4, 1.2 Hz, 1H), 2.39 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.5, 139.1, 138.1, 137.5, 137.3, 134.2, 130.5, 130.1, 128.7, 128.7, 128.6, 127.1, 126.2, 126.1, 122.5, 119.8, 118.3, 110.6, 109.1, 75.5, 56.2, 47.6, 44.8, 24.3, 21.2 ppm. IR (film) νmax 1643, 1464, 1440, 1349, 1174, 1092, 1015, 907, 727, 699 cm–1. HRMS (ESI) m/z calcd for C27H26N2NaO2 433.1886 [M + Na]+, found 433.1885.
13-Benzyl-3-chloro-6-(methoxymethyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2e)
According to procedure A, lactam 2a was obtained from spiroindoline 1e (20.0 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (17.5 mg, 81% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 65–67 °C. 1H NMR (400 MHz, CDCl3) δ 7.60–7.56 (m, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.33 (dd, J = 8.3, 2.2 Hz, 1H), 7.28–7.13 (m, 6H), 7.10 (d, J = 8.3 Hz, 1H), 6.98–6.91 (m, 2H), 5.17 (d, J = 17.0 Hz, 1H), 5.09–4.97 (m, 2H), 4.86 (d, J = 10.3 Hz, 1H), 3.87 (td, J = 14.4, 4.3 Hz, 1H), 3.71–3.48 (m, 2H), 3.14 (s, 3H), 2.92 (ddd, J = 16.6, 4.4, 1.3 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 170.8, 138.9, 137.8, 137.8, 135.1, 132.8, 131.9, 129.4, 128.8, 128.4, 128.3, 127.7, 127.3, 126.0, 123.0, 120.0, 118.5, 110.6, 109.9, 75.6, 56.3, 47.6, 44.9, 24.3 ppm. IR (film) νmax 1651, 1464, 1441, 1350, 1180, 1093, 1015, 910, 732, 698 cm–1. HRMS (ESI) m/z calcd for C26H23ClN2NaO2 453.1340 [M + Na]+, found 453.1338.
13-Benzyl-3-fluoro-6-(methoxymethyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2f)
According to procedure A, lactam 2f was obtained from spiroindoline 1f (19.1 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (16.4 mg, 79% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 76–77 °C. 1H NMR (400 MHz, CDCl3) δ 7.61–7.54 (m, 1H), 7.28–7.12 (m, 8H), 7.06 (td, J = 8.3, 2.7 Hz, 1H), 6.99–6.92 (m, 2H), 5.17 (d, J = 17.0 Hz, 1H), 5.09–4.99 (m, 2H), 4.86 (d, J = 10.3 Hz, 1H), 3.86 (td, J = 14.5, 4.4 Hz, 1H), 3.71–3.48 (m, 2H), 3.14 (s, 3H), 2.92 (ddd, J = 16.5, 4.5, 1.3 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 170.87, 163.98, 161.49, 139.46 (d, J = 8.1 Hz), 137.73 (d, J = 19.2 Hz), 132.96, 132.57 (d, J = 8.1 Hz), 128.75, 128.42, 127.26, 125.97, 125.32 (d, J = 3.0 Hz), 122.82, 119.96, 118.39, 116.52 (d, J = 12.1 Hz), 115.36 (d, J = 23.2 Hz), 110.55, 109.53, 75.65, 56.27, 47.55, 44.93, 24.27. 19F NMR (376 MHz, CDCl3) δ −111.48 (s, 1F) ppm. IR (film) νmax 1647, 1464, 1441, 1347, 1306, 1270, 1201, 1175, 1088, 1015, 962, 908, 728, 699 cm–1. HRMS (ESI) m/z calcd for C26H23FN2NaO2 437.1636 [M + Na]+, found 437.1633.
13-Benzyl-3-methoxy-6-(methoxymethyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2g)
According to procedure A, lactam 2g was obtained from spiroindoline 1g (19.7 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (18.8 mg, 88% yield, eluent: petroleum ether/ethyl acetate = 3/2). Mp 66–68 °C. 1H NMR (400 MHz, CDCl3) δ 7.61–7.50 (m, 1H), 7.28–7.11 (m, 6H), 7.10–7.04 (m, 2H), 7.01–6.95 (m, 2H), 6.89 (dd, J = 8.6, 2.7 Hz, 1H), 5.17 (d, J = 17.0 Hz, 1H), 5.09–4.99 (m, 2H), 4.85 (d, J = 10.2 Hz, 1H), 3.91 (td, J = 14.5, 4.6 Hz, 1H), 3.85 (s, 3H), 3.69–3.46 (m, 2H), 3.15 (s, 3H), 2.91 (ddd, J = 16.4, 4.5, 1.3 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.1, 160.0, 138.7, 138.1, 137.4, 134.0, 131.9, 128.7, 128.6, 127.1, 126.1, 122.4, 121.4, 119.7, 118.2, 115.8, 112.7, 110.5, 108.9, 75.6, 56.2, 55.5, 47.5, 45.0, 24.3 ppm. IR (film) νmax 1644, 1464, 1452, 1431, 1349, 1315, 1293, 1229, 1182, 1083, 1032, 1014, 908, 727, 699 cm–1. HRMS (ESI) m/z calcd for C27H26N2NaO3 449.1836 [M + Na]+, found 449.1833.
13-Benzyl-2,3-dimethoxy-6-(methoxymethyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2h)
According to procedure A, lactam 2h was obtained from spiroindoline 1h (21.2 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (18.5 mg, 81% yield, eluent: petroleum ether/ethyl acetate = 1/1). Mp 89–90 °C. 1H NMR (400 MHz, CDCl3) δ 7.60 (dt, J = 6.9, 1.4 Hz, 1H), 7.33–7.13 (m, 6H), 7.10–7.00 (m, 3H), 6.53 (s, 1H), 5.21 (d, J = 17.5 Hz, 1H), 5.05 (dd, J = 10.1, 1.1 Hz, 1H), 4.96 (d, J = 17.5 Hz, 1H), 4.82 (d, J = 10.1 Hz, 1H), 3.99 (dd, J = 14.8, 4.2 Hz, 1H), 3.93 (s, 3H), 3.70–3.47 (m, 2H), 3.19 (s, 3H), 3.18 (s, 3H), 2.94 (ddd, J = 16.6, 4.3, 1.4 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.3, 149.3, 149.2, 138.8, 137.9, 134.2, 129.2, 128.9, 128.4, 127.1, 125.8, 122.7, 121.8, 119.9, 118.4, 113.1, 110.9, 110.1, 108.9, 75.7, 56.2, 56.1, 55.1, 47.7, 45.0, 24.2 ppm. IR (film) νmax 1641, 1604, 1515, 1465, 1429, 1350, 1267, 1249, 1222, 1205, 1167, 1082, 1043, 910, 729, 699 cm–1. HRMS (ESI) m/z calcd for C28H28N2NaO4 479.1941 [M + Na]+, found 479.1939.
13-Benzyl-6-(methoxymethyl)-2-methyl-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2i)
According to procedure A, lactam 2i was obtained from spiroindoline 1i (18.9 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (17.0 mg, 83% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 57–58 °C. 1H NMR (400 MHz, CDCl3) δ 7.62–7.54 (m, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.26–7.11 (m, 7H), 7.02–6.95 (m, 2H), 6.92–6.87 (m, 1H), 5.20 (d, J = 16.8 Hz, 1H), 5.06–4.94 (m, 2H), 4.86 (d, J = 10.2 Hz, 1H), 3.90 (td, J = 14.3, 4.4 Hz, 1H), 3.68–3.46 (m, 2H), 3.14 (s, 3H), 2.90 (ddd, J = 16.4, 4.4, 1.2 Hz, 1H), 2.19 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.5, 139.2, 138.3, 137.8, 134.5, 134.3, 131.4, 129.6, 129.1, 128.6, 128.5, 128.2, 127.1, 126.2, 122.6, 119.8, 118.4, 110.4, 109.4, 75.6, 56.1, 47.7, 44.9, 24.3, 21.1 ppm. IR (film) νmax 1643, 1465, 1453, 1428, 1349, 11178, 1091, 1022, 908, 828, 727, 707 cm–1. HRMS (ESI) m/z calcd for C27H26N2NaO2 433.1886 [M + Na]+, found 433.1885.
13-Benzyl-2-fluoro-6-(methoxymethyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2j)
According to procedure A, lactam 2j was obtained from spiroindoline 1j (19.1 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (16.6 mg, 80% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 194–196 °C. 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 7.6, 1.3 Hz, 1H), 7.52 (dd, J = 8.5, 5.7 Hz, 1H), 7.29–7.09 (m, 7H), 6.98–6.91 (m, 2H), 6.87 (dd, J = 9.5, 2.6 Hz, 1H), 5.20 (d, J = 16.9 Hz, 1H), 5.07 (d, J = 16.9 Hz, 1H), 5.00 (dd, J = 10.3, 1.0 Hz, 1H), 4.88 (d, J = 10.3 Hz, 1H), 3.87 (td, J = 14.3, 4.4 Hz, 1H), 3.68–3.49 (m, 2H), 3.13 (s, 3H), 2.93 (ddd, J = 16.5, 4.3, 1.2 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 171.45, 163.85, 161.36, 137.81, 137.63, 133.63 (d, J = 3.0 Hz), 132.67 (d, J = 2.0 Hz), 131.65 (d, J = 8.1 Hz), 130.36 (d, J = 9.1 Hz), 128.77, 128.37, 127.34, 126.02, 123.08, 120.05, 118.56, 117.46 (d, J = 22.2 Hz), 116.12 (d, J = 22.2 Hz), 110.62, 110.19, 75.74, 56.22, 47.70, 44.91, 24.36 ppm. 19F NMR (376 MHz, CDCl3) δ −110.52 (td, J = 8.7, 5.8 Hz, 1F) ppm. IR (film) νmax 1647, 1606, 1465, 1453, 1431, 1346, 1179, 1090, 1021, 909, 729, 699 cm–1. HRMS (ESI) m/z calcd for C26H23FN2NaO2 437.1636 [M + Na]+, found 437.1634.
13-Benzyl-2-methoxy-6-(methoxymethyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2k)
According to procedure A, lactam 2k was obtained from spiroindoline 1k (19.7 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (18.3 mg, 86% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 67–69 °C. 1H NMR (400 MHz, CDCl3) δ 7.60 (dt, J = 7.1, 1.4 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.30–7.13 (m, 6H), 7.06–6.99 (m, 2H), 6.95 (dd, J = 8.6, 2.6 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 5.21 (d, J = 17.2 Hz, 1H), 5.07–4.97 (m, 2H), 4.85 (d, J = 10.3 Hz, 1H), 3.98–3.87 (m, 1H), 3.67–3.48 (m, 2H), 3.34 (s, 3H), 3.16 (s, 3H), 2.93 (ddd, J = 16.5, 4.4, 1.2 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.4, 159.9, 138.5, 137.9, 134.1, 130.7, 129.9, 129.5, 128.8, 128.4, 127.1, 125.9, 122.8, 119.9, 118.5, 116.0, 114.5, 110.4, 109.5, 75.6, 56.1, 54.8, 47.6, 44.8, 24.3 ppm. IR (film) νmax 1639, 1602, 1465, 1431, 1348, 1307, 1239, 1121, 1177, 1090, 1048, 1022, 907, 727, 698 cm–1. HRMS (ESI) m/z calcd for C27H26N2NaO3 449.1836 [M + Na]+, found 449.1834.
13-Benzyl-6-(methoxymethyl)-10-methyl-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2l)
According to procedure A, lactam 2l was obtained from spiroindoline 1l (19.1 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (17.6 mg, 86% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 62–64 °C. 1H NMR (400 MHz, CDCl3) δ 7.56–7.50 (m, 1H), 7.43 (td, J = 7.5, 1.3 Hz, 1H), 7.39–7.31 (m, 2H), 7.27–7.14 (m, 4H), 7.07–6.92 (m, 4H), 5.14 (d, J = 16.9 Hz, 1H), 5.08–4.99 (m, 2H), 4.86 (d, J = 10.2 Hz, 1H), 3.96–3.79 (m, 1H), 3.68–3.43 (m, 2H), 3.17 (s, 3H), 2.89 (ddd, J = 16.5, 4.4, 1.3 Hz, 1H), 2.46 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.4, 138.1, 137.4, 136.0, 134.1, 130.5, 129.4, 129.2, 129.1, 128.9, 128.8, 128.7, 128.2, 127.1, 126.1, 124.2, 118.1, 110.3, 108.9, 75.5, 56.2, 47.7, 44.8, 24.3, 21.5 ppm. IR (film) νmax 1644, 1466, 1442, 1420, 1349, 1309, 1180, 1091, 1036, 1014, 907, 790, 774, 727, 699 cm–1. HRMS (ESI) m/z calcd for C27H26N2NaO2 433.1886 [M + Na]+, found 433.1884.
13-Benzyl-10-chloro-6-(methoxymethyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2m)
According to procedure A, lactam 2m was obtained from spiroindoline 1m (20.0 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (15.7 mg, 73% yield, eluent: petroleum ether/ethyl acetate = 2/1). Mp 63–65 °C. 1H NMR (400 MHz, CDCl3) δ 7.54 (dt, J = 4.4, 1.8 Hz, 2H), 7.47 (td, J = 7.5, 1.3 Hz, 1H), 7.38 (td, J = 7.5, 1.5 Hz, 1H), 7.28–7.16 (m, 4H), 7.11 (dd, J = 8.7, 2.0 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.93 (dd, J = 7.6, 1.8 Hz, 2H), 5.15 (d, J = 16.9 Hz, 1H), 5.09–4.96 (m, 2H), 4.91 (d, J = 10.3 Hz, 1H), 3.86 (td, J = 14.5, 4.4 Hz, 1H), 3.62 (ddd, J = 15.0, 6.1, 1.4 Hz, 1H), 3.47 (ddd, J = 16.5, 13.9, 6.2 Hz, 1H), 3.14 (s, 3H), 2.88 (ddd, J = 16.5, 4.5, 1.3 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.2, 137.5, 137.5, 135.9, 135.4, 130.4, 129.6, 129.4, 129.3, 128.8, 128.7, 128.2, 127.3, 126.0, 125.6, 122.9, 117.9, 111.7, 109.1, 75.7, 56.3, 47.7, 45.0, 24.4 ppm. IR (film) νmax 1644, 1466, 1440, 1420, 1179, 1091, 1036, 1013, 908, 729, 700 cm–1. HRMS (ESI) m/z calcd for C26H23ClN2NaO2 453.1340 [M + Na]+, found 453.1340.
13-Benzyl-10-methoxy-6-(methoxymethyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2n)
According to procedure A, lactam 2n was obtained from spiroindoline 1n (19.7 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (17.7 mg, 83% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 60–62 °C. 1H NMR (400 MHz, CDCl3) δ 7.56–7.49 (m, 1H), 7.44 (td, J = 7.5, 1.3 Hz, 1H), 7.37 (td, J = 7.5, 1.5 Hz, 1H), 7.28–7.15 (m, 4H), 7.06–6.99 (m, 2H), 6.99–6.93 (m, 2H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 5.13 (d, J = 16.9 Hz, 1H), 5.07–4.99 (m, 2H), 4.91 (d, J = 10.3 Hz, 1H), 3.93–3.84 (m, 4H), 3.62 (ddd, J = 15.0, 6.1, 1.4 Hz, 1H), 3.49 (ddd, J = 16.4, 13.9, 6.1 Hz, 1H), 3.16 (s, 3H), 2.89 (ddd, J = 16.5, 4.4, 1.4 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.3, 154.4, 138.0, 137.4, 134.7, 132.9, 130.5, 129.3, 129.3, 128.9, 128.7, 128.2, 127.1, 126.1, 112.6, 111.4, 109.0, 100.3, 75.7, 56.2, 55.9, 47.7, 44.9, 24.5 ppm. IR (film) νmax 1647, 1483, 1466, 1442, 1291, 1208, 1172, 1091, 1046, 1028, 909, 774, 729, 700 cm–1. HRMS (ESI) m/z calcd for C27H26N2NaO3 449.1836 [M + Na]+, found 449.1833.
6-(Methoxymethyl)-13-methyl-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2o)
According to procedure A, lactam 2o was obtained from spiroindoline 1o (14.4 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (14.6 mg, 85% yield, eluent: petroleum ether/ethyl acetate = 2/1). Mp 55–57 °C. 1H NMR (400 MHz, CDCl3) δ 7.60–7.45 (m, 4H), 7.34–7.23 (m, 3H), 7.15 (ddd, J = 7.9, 6.7, 1.3 Hz, 1H), 5.07 (dd, J = 10.2, 1.2 Hz, 1H), 4.78 (d, J = 10.2 Hz, 1H), 3.90–3.82 (m, 1H), 3.62 (ddd, J = 15.0, 6.0, 1.5 Hz, 1H), 3.55–3.45 (m, 4H), 3.19 (s, 3H), 2.88 (ddd, J = 16.6, 4.3, 1.4 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.4, 138.0, 137.2, 133.8, 131.0, 129.4, 129.3, 128.8, 128.2, 128.1, 122.5, 119.5, 118.3, 109.5, 108.8, 75.3, 56.2, 44.6, 31.0, 24.1 ppm. IR (film) νmax 1644, 1467, 1444, 1421, 1359, 1089, 1036, 1011, 910, 737, 648 cm–1. HRMS (ESI) m/z calcd for C20H20N2NaO2 343.1417 [M + Na]+, found 343.1415.
13-Benzyl-6-(ethoxymethyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2p)
According to procedure A, lactam 2p was obtained from spiroindoline 1a (18.2 mg, 0.05 mmol) and ethanol (2.3 mg, 0.05 mmol) as a pale yellow solid (15.3 mg, 74% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 56–58 °C. 1H NMR (400 MHz, CDCl3) δ 7.61–7.56 (m, 1H), 7.53 (dd, J = 7.6, 1.5 Hz, 1H), 7.44 (td, J = 7.5, 1.3 Hz, 1H), 7.36 (td, J = 7.6, 1.5 Hz, 1H), 7.27–7.10 (m, 7H), 6.99–6.92 (m, 2H), 5.17 (d, J = 16.9 Hz, 1H), 5.13–5.02 (m, 2H), 4.96 (d, J = 10.5 Hz, 1H), 3.89 (td, J = 14.3, 4.4 Hz, 1H), 3.70–3.50 (m, 2H), 3.41 (dq, J = 9.5, 7.0 Hz, 1H), 3.27 (dq, J = 9.5, 7.0 Hz, 1H), 2.92 (ddd, J = 16.5, 4.4, 1.2 Hz, 1H), 1.00 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.2, 138.0, 137.6, 137.5, 134.0, 130.6, 129.2, 128.9, 128.7, 128.5, 128.1, 127.1, 126.1, 122.7, 119.8, 118.4, 110.6, 109.5, 74.2, 64.2, 47.6, 45.0, 24.4, 15.0 ppm. IR (film) νmax 2973, 2925, 1644, 1464, 1443, 1420, 1386, 1349, 1319, 1182, 1089, 1036, 1014, 909, 729, 698 cm–1. HRMS (ESI) m/z calcd for C27H26N2NaO2 433.1886 [M + Na]+, found 433.1890.
13-Benzyl-6-((benzyloxy)methyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2q)
According to procedure A, lactam 2q was obtained from spiroindoline 1a (18.2 mg, 0.05 mmol) and benzyl alcohol (5.4 mg, 0.05 mmol) as a pale yellow solid (19.5 mg, 83% yield, eluent: petroleum ether/ethyl acetate = 2/1). Mp 61–63 °C. 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 7.7, 1.4 Hz, 2H), 7.44 (td, J = 7.5, 1.3 Hz, 1H), 7.41–7.34 (m, 1H), 7.27–7.14 (m, 9H), 7.14–7.03 (m, 3H), 7.00–6.91 (m, 2H), 5.25–5.00 (m, 4H), 4.39 (d, J = 11.6 Hz, 1H), 4.28 (d, J = 11.6 Hz, 1H), 3.91 (td, J = 14.4, 4.4 Hz, 1H), 3.73–3.48 (m, 2H), 2.92 (ddd, J = 16.5, 4.4, 1.3 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.3, 137.9, 137.8, 137.6, 137.4, 134.0, 130.6, 129.3, 129.3, 128.9, 128.7, 128.5, 128.3, 128.2, 127.9, 127.6, 127.2, 126.1, 122.7, 119.9, 118.6, 110.63, 109.6, 74.6, 71.1, 65.4, 47.7, 45.4, 24.5 ppm. IR (film) νmax 2923, 1645, 1464, 1442, 1420, 1378, 1349, 1319, 1071, 1017, 908, 728, 696 cm–1. HRMS (ESI) m/z calcd for C32H28N2NaO2 495.2043 [M + Na]+, found 495.2045.
13-Benzyl-6-(isopropoxymethyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2r)
According to procedure A, lactam 2r was obtained from spiroindoline 1a (18.2 mg, 0.05 mmol) and 2-propanol (3.0 mg, 0.05 mmol) as a pale yellow solid (16.3 mg, 77% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 67–69 °C. 1H NMR (400 MHz, CDCl3) δ 7.57 (dt, J = 6.8, 1.4 Hz, 1H), 7.52 (dd, J = 7.6, 1.5 Hz, 1H), 7.44 (td, J = 7.5, 1.3 Hz, 1H), 7.36 (td, J = 7.6, 1.5 Hz, 1H), 7.28–7.10 (m, 7H), 7.00–6.88 (m, 2H), 5.22–4.99 (m, 2H), 4.84 (d, J = 10.6 Hz, 1H), 3.94–3.79 (m, 1H), 3.77–3.44 (m, 3H), 2.92 (ddd, J = 16.5, 4.2, 1.5 Hz, 1H), 1.15 (d, J = 6.1 Hz, 3H), 1.00 (d, J = 6.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 171.9, 138.0, 137.6, 137.5, 134.0, 130.6, 129.2, 128.9, 128.6, 128.5, 128.1, 127.1, 126.1, 122.6, 119.7, 118.5, 110.6, 109.5, 71.7, 69.4, 47.6, 44.4, 24.1, 22.3, 22.2 ppm. IR (film) νmax 2970, 2924, 1644, 1464, 1443, 1420, 1367, 1180, 1065, 1036, 1015, 908, 731, 699 cm–1. HRMS (ESI) m/z calcd for C28H28N2NaO2 447.2043 [M + Na]+, found 447.2046.
13-Benzyl-6-((p-tolylthio)methyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2s)
According to procedure A, lactam 2s was obtained from spiroindoline 1a (18.2 mg, 0.05 mmol) and methyl p-tolyl sulfide (6.9 mg, 0.05 mmol) as a pale yellow solid (21.0 mg, 87% yield, eluent: petroleum ether/ethyl acetate = 1/1). Mp 67–69 °C. 1H NMR (400 MHz, CDCl3) δ 7.59–7.50 (m, 1H), 7.40–7.27 (m, 4H), 7.26–7.04 (m, 10H), 6.99–6.92 (m, 2H), 5.61 (dd, J = 13.4, 1.1 Hz, 1H), 5.13 (d, J = 17.0 Hz, 1H), 5.00 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 13.3 Hz, 1H), 3.89–3.71 (m, 2H), 3.45 (ddd, J = 16.7, 12.3, 7.5 Hz, 1H), 2.88 (ddd, J = 16.7, 3.7, 2.0 Hz, 1H), 2.33 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 170.9, 137.9, 137.6, 137.6, 137.2, 134.0, 132.5, 130.4, 129.8, 129.2, 129.1, 128.8, 128.7, 128.5, 128.0, 127.1, 126.1, 122.7, 119.8, 118.4, 110.7, 109.0, 48.6, 47.6, 43.9, 23.3, 21.2 ppm. IR (film) νmax 2919, 1640, 1493, 1464, 1443, 1419, 1349, 1274, 1249, 1182, 1142, 1022, 908, 870, 730, 698 cm–1. HRMS (ESI) m/z calcd for C32H28N2NaOS 511.1815 [M + Na]+, found 511.1816.
13-Benzyl-6-((2-hydroxynaphthalen-1-yl)methyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2t)
According to procedure A, lactam 2t was obtained from spiroindoline 1a (18.2 mg, 0.05 mmol) and 2-hydroxynaphthalene (7.2 mg, 0.05 mmol) as a white solid (20.8 mg, 82% yield, eluent: petroleum ether/ethyl acetate = 1/2). Mp 231–233 °C. 1H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.81 (dd, J = 8.2, 1.3 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.65–7.54 (m, 2H), 7.53–7.47 (m, 1H), 7.46–7.32 (m, 3H), 7.30–7.11 (m, 8H), 7.01–6.90 (m, 2H), 5.20 (dd, J = 16.2, 12.2 Hz, 2H), 5.05 (d, J = 17.0 Hz, 1H), 4.85 (d, J = 15.4 Hz, 1H), 3.93–3.54 (m, 3H), 2.99 (dd, J = 15.7, 3.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 173.7, 155.7, 137.9, 137.7, 135.7, 134.0, 133.9, 130.7, 130.6, 129.9, 129.7, 129.2, 129.0, 128.9, 128.8, 128.2, 127.2, 127.2, 126.0, 122.9, 122.7, 120.8, 120.0, 119.9, 118.3, 113.0, 110.7, 108.7, 47.7, 46.0, 38.5, 23.1 ppm. IR (film) νmax 3067, 1598, 1582, 1514, 1465, 1452, 1438, 1360, 1348, 1317, 1294, 1273, 1212, 1182, 1042, 815, 758, 747, 729 cm–1. HRMS (ESI) m/z calcd for C35H28N2NaO2 531.2043 [M + Na]+, found 531.2042.
6-((1H-Indol-3-yl)methyl)-13-benzyl-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one (2u)
According to procedure A, lactam 2u was obtained from spiroindoline 1a (18.2 mg, 0.05 mmol) and indole (5.9 mg, 0.05 mmol) as a white solid (16.8 mg, 70% yield, eluent: petroleum ether/ethyl acetate = 1/2). Mp 164–166 °C. 1H NMR (400 MHz, CDCl3) δ 8.27–8.14 (m, 1H), 7.77 (dd, J = 7.9, 1.2 Hz, 1H), 7.57 (dd, J = 7.7, 1.4 Hz, 1H), 7.47–6.86 (m, 16H), 5.35 (d, J = 14.8 Hz, 1H), 5.15 (d, J = 17.0 Hz, 1H), 5.04 (d, J = 17.0 Hz, 1H), 4.37 (d, J = 14.8 Hz, 1H), 3.84–3.65 (m, 1H), 3.52–3.28 (m, 2H), 2.87–2.68 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 170.9, 138.1, 138.1, 137.5, 136.3, 134.2, 130.4, 129.3, 128.9, 128.9, 128.7, 128.6, 128.0, 127.1, 127.0, 126.2, 124.1, 122.5, 122.3, 121.9, 121.8, 119.9, 119.6, 119.6, 119.2, 119.1, 118.2, 111.8, 111.2, 111.1, 110.6, 109.2, 47.6, 44.6, 38.8, 23.4 ppm. IR (film) νmax 3271, 3057, 2923, 1613, 1495, 1464, 1450, 1423, 1350, 1279, 1183, 1024, 907, 729, 699 cm–1. HRMS (ESI) m/z calcd for C33H27N3NaO 504.2046 [M + Na]+, found 504.2048.
(±)-aS-13-Benzyl-6-((methoxy-d3)methyl-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3a)
According to procedure B, lactam 3a was obtained from spiroindoline 1a (18.2 mg, 0.05 mmol) as a pale yellow solid (16.6 mg, 83% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 108–109 °C. 1H NMR (400 MHz, CDCl3) δ 7.61–7.56 (m, 1H), 7.53 (dd, J = 7.7, 1.5 Hz, 1H), 7.45 (td, J = 7.5, 1.3 Hz, 1H), 7.36 (td, J = 7.6, 1.5 Hz, 1H), 7.26–7.12 (m, 7H), 7.01–6.93 (m, 2H), 5.17 (d, J = 17.0 Hz, 1H), 5.10–4.96 (m, 2H), 4.88 (dd, J = 10.3, 2.0 Hz, 1H), 3.94–3.81 (m, 1H), 3.62 (ddd, J = 14.9, 3.7, 2.3 Hz, 1H), 3.53 (dd, J = 13.8, 6.1 Hz, 0.51H), 2.96–2.87 (m, 0.54H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.4, 138.0, 137.6, 137.5, 134.1, 130.6, 129.3, 129.2, 129.0, 128.7, 128.6 (q, J = 3.0 Hz), 128.2, 127.2, 126.1, 122.7 119.9, 118.4, 110.6, 109.4, 75.5, 47.6, 44.8, 24.1 (q, J = 18.2 Hz) ppm. IR (film) νmax 1648, 1463, 1448, 1350, 1183, 1089, 1008, 967, 906, 728, 700 cm–1. HRMS (ESI) m/z calcd for C26H20D4N2NaO2 423.1981 [M + Na]+, found 423.1983.
(±)-aS-13-Benzyl-6-((methoxy-d3)methyl)-4-methyl-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3b)
According to procedure B, lactam 3b was obtained from spiroindoline 1b (18.9 mg, 0.05 mmol) as a pale yellow solid (17.0 mg, 82% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 171–173 °C. 1H NMR (400 MHz, CDCl3) δ 7.58–7.53 (m, 1H), 7.29–7.17 (m, 5H), 7.17–7.09 (m, 3H), 7.06–6.97 (m, 3H), 5.23 (d, J = 16.9 Hz, 1H), 5.16–5.05 (m, 2H), 4.79 (d, J = 10.4 Hz, 1H), 3.91–3.75 (m, 1H), 3.62 (dd, J = 14.9, 6.4 Hz, 1H), 3.52 (dd, J = 13.8, 6.4 Hz, 0.88H), 2.86 (dd, J = 16.1, 4.3 Hz, 0.2H), 2.41 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 171.6, 138.1, 137.4, 137.0, 135.5, 134.7, 130.8, 129.2, 128.8, 128.7, 128.5, 128.0, 127.1, 126.2, 122.5, 119.7, 118.2, 110.7, 109.0 (d, J = 6.1 Hz), 74.9, 47.7, 44.3 (d, J = 5.1 Hz), 23.8 (q, J = 19.2 Hz), 19.8 ppm. IR (film) νmax 1645, 1451, 1423, 1346, 1098, 1025, 907, 728, 698 cm–1. HRMS (ESI) m/z calcd for C27H22D4N2NaO2 437.2138 [M + Na]+, found 437.2136.
(±)-aS-13-Benzyl-4-chloro-6-((methoxy-d3)methyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3c)
According to procedure B, lactam 3c was obtained from spiroindoline 1c (20.0 mg, 0.05 mmol) as a pale yellow solid (15.6 mg, 72% yield, eluent: petroleum ether/ethyl acetate = 2/1). Mp 195–196 °C. 1H NMR (400 MHz, CDCl3) δ 7.57 (dt, J = 7.3, 1.4 Hz, 1H), 7.47 (dd, J = 8.1, 1.1 Hz, 1H), 7.30–7.21 (m, 4H), 7.21–7.11 (m, 3H), 7.08 (dd, J = 7.7, 1.1 Hz, 1H), 7.05–7.00 (m, 2H), 5.24 (d, J = 17.0 Hz, 1H), 5.19–5.07 (m, 2H), 4.77 (d, J = 10.5 Hz, 1H), 3.80 (ddd, J = 15.0, 13.8, 1.1 Hz, 1H), 3.69 (dd, J = 15.1, 6.5 Hz, 1H), 3.54 (dd, J = 13.8, 6.5 Hz, 0.82H), 2.88 (ddd, J = 16.6, 4.7, 1.5 Hz, 0.19H) ppm. 13C NMR (100 MHz, CDCl3) δ 168.8, 137.8, 137.6, 136.5, 133.2, 131.4, 131.3, 130.0, 129.5, 128.9, 128.8, 128.7, 127.3, 126.1, 123.0, 120.0, 118.4, 110.7, 109.9 (d, J = 5.1 Hz), 74.7, 47.8, 44.1 (d, J = 5.1 Hz), 23.8 (q, J = 19.2 Hz) ppm. IR (film) νmax 1655, 1440, 1419, 1345, 1229, 1099, 1018, 910, 729, 699 cm–1. HRMS (ESI) m/z calcd for C26H19D4ClN2NaO2 457.1591 [M + Na]+, found 457.1590.
(±)-aS-13-Benzyl-6-((methoxy-d3)methyl)-3-methyl-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3d)
According to procedure B, lactam 3d was obtained from spiroindoline 1d (18.9 mg, 0.05 mmol) as a pale yellow solid (18.6 mg, 90% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 88–90 °C. 1H NMR (400 MHz, CDCl3) δ 7.60–7.53 (m, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.27–7.10 (m, 7H), 7.07 (d, J = 7.9 Hz, 1H), 7.00–6.94 (m, 2H), 5.17 (d, J = 16.9 Hz, 1H), 5.12–4.99 (m, 2H), 4.86 (dd, J = 10.3, 2.0 Hz, 1H), 3.90 (ddd, J = 14.4, 9.1, 4.8 Hz, 1H), 3.62 (ddd, J = 14.9, 3.7, 2.3 Hz, 1H), 3.55–3.46 (m, 0.52 H), 2.92 (dd, J = 19.0, 4.0 Hz, 0.61H), 2.40 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.6, 148.9, 139.1, 138.1, 137.5, 137.3, 130.5, 130.1, 129.9 (d, J = 6.1 Hz), 128.7, 128.7, 128.6, 127.1, 126.7, 126.2, 126.1 (d, J = 2.0 Hz), 125.2, 122.5, 119.8, 118.3, 110.6, 109.1 (t, J = 3.0 Hz), 76.7, 75.5 (d, J = 2.0 Hz), 47.5, 44.8 (t, J = 5.1 Hz), 24.1 (q, J = 18.2 Hz), 21.2 ppm. IR (film) νmax 1644, 1464, 1437, 1348, 1307, 1097, 1022, 908, 830, 730, 698 cm–1. HRMS (ESI) m/z calcd for C27H22D4N2NaO2 437.2138 [M + Na]+, found 437.2137.
(±)-aS-13-Benzyl-3-chloro-6-((methoxy-d3)methyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3e)
According to procedure B, lactam 3e was obtained from spiroindoline 1e (20.0 mg, 0.05 mmol) as a pale yellow solid (18.5 mg, 85% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 72–73 °C. 1H NMR (400 MHz, CDCl3) δ 7.58 (dt, J = 6.7, 1.6 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.32 (dd, J = 8.3, 2.3 Hz, 1H), 7.30–7.06 (m, 7H), 7.04–6.88 (m, 2H), 5.17 (d, J = 17.0 Hz, 1H), 5.10–4.95 (m, 2H), 4.87 (dd, J = 10.3, 1.9 Hz, 1H), 3.86 (ddd, J = 14.5, 9.2, 4.8 Hz, 1H), 3.64 (ddd, J = 15.0, 3.8, 2.3 Hz, 1H), 3.59–3.48 (m, 0.47H), 2.92 (ddd, J = 15.3, 4.4, 1.5 Hz, 0.53H) ppm. 13C NMR (100 MHz, CDCl3) δ 170.8, 138.9, 137.8, 135.1, 132.8, 132.8, 131.9, 129.4, 128.8, 128.5 (d, J = 3.0 Hz), 128.3, 127.7, 127.3, 126.0, 123.0, 120.0, 118.5, 110.6, 109.9, 109.9 (t, J = 3.0 Hz), 75.6 (d, J = 2.0 Hz), 47.6, 44.8 (t, J = 5.1 Hz), 24.2 (q, J = 19.2 Hz) ppm. IR (film) νmax 1648, 1463, 1437, 1348, 1223, 1098, 1020, 908, 832, 730, 697 cm–1. HRMS (ESI) m/z calcd for C26H19D4ClN2NaO2 457.1591 [M + Na]+, found 457.1591.
(±)-aS-13-Benzyl-3-fluoro-6-((methoxy-d3)methyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3f)
According to procedure B, lactam 3f was obtained from spiroindoline 1f (19.7 mg, 0.05 mmol) as a pale yellow solid (16.3 mg, 78% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 87–89 °C. 1H NMR (400 MHz, CDCl3) δ 7.64–7.49 (m, 1H), 7.30–7.10 (m, 8H), 7.06 (td, J = 8.3, 2.7 Hz, 1H), 7.00–6.89 (m, 2H), 5.17 (d, J = 17.0 Hz, 1H), 5.09–4.95 (m, 2H), 4.87 (dd, J = 10.3, 1.9 Hz, 1H), 3.86 (ddd, J = 14.4, 9.2, 4.7 Hz, 1H), 3.65 (ddd, J = 15.0, 3.8, 2.3 Hz, 1H), 3.59–3.49 (m, 0.51H), 2.92 (dd, J = 15.5, 3.7 Hz, 0.55H) ppm. 13C NMR (100 MHz, CDCl3) δ 170.9, 164.0, 161.5, 139.5 (d, J = 8.1 Hz), 137.7 (d, J = 20.2 Hz), 133.0, 132.6 (d, J = 8.1 Hz), 128.8, 128.4 (d, J = 3.0 Hz), 127.3, 126.0, 125.3 (d, J = 3.0 Hz), 122.8, 120.0, 118.4, 116.5 (d, J = 21.2 Hz), 115.4 (d, J = 23.2 Hz), 110.6, 109.5, 75.6, 47.6, 44.9, 24.1 (q, J = 19.2 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ −111.48 (s, 1F) ppm. IR (film) νmax 1648, 1464, 1439, 1346, 1298, 1270, 1202, 197, 1021, 908, 833, 730, 698 cm–1. HRMS (ESI) m/z calcd for C26H19D4FN2NaO2 441.1887 [M + Na]+, found 441.1885.
(±)-aS-13-Benzyl-3-methoxy-6-((methoxy-d3)methyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3g)
According to procedure B, lactam 3g was obtained from spiroindoline 1g (19.7 mg, 0.05 mmol) as a pale yellow solid (19.4 mg, 90% yield, eluent: petroleum ether/ethyl acetate = 3/2). Mp 80–81 °C. 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 8.2, 1.8 Hz, 1H), 7.27–7.18 (m, 3H), 7.16–7.11 (m, 3H), 7.10–7.03 (m, 2H), 7.01–6.94 (m, 2H), 6.89 (dd, J = 8.6, 2.7 Hz, 1H), 5.17 (d, J = 16.9 Hz, 1H), 5.11–4.97 (m, 2H), 4.86 (dd, J = 10.2, 1.9 Hz, 1H), 3.90 (ddd, J = 14.5, 9.2, 4.8 Hz, 1H), 3.85 (s, 3H), 3.63 (ddd, J = 15.0, 3.8, 2.4 Hz, 1H), 3.56–3.45 (m, 0.46H), 2.96–2.85 (m, 0.54H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.1, 160.0, 138.7, 138.1, 137.5, 134.0, 131.9, 128.7, 128.6 (d, J = 3.0 Hz), 127.1, 126.1, 122.4, 121.4, 119.7, 118.2, 115.8 (d, J = 3.0 Hz), 112.7, 110.5, 108.8 (t, J = 3.0 Hz), 75.6, 55.5, 47.5, 44.9 (d, J = 5.1 Hz), 24.1 (q, J = 18.2 Hz) ppm. IR (film) νmax 1644, 1464, 1452, 1431, 1349, 1315, 1293, 1229, 1182, 1083, 1032, 1014, 908, 727, 699 cm–1. HRMS (ESI) m/z calcd for C27H22D4N2NaO3 453.2087 [M + Na]+, found 453.2085.
(±)-aS-13-Benzyl-2,3-dimethoxy-6-((methoxy-d3)methyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3h)
According to procedure B, lactam 3h was obtained from spiroindoline 1h (21.2 mg, 0.05 mmol) as a pale yellow solid (18.4 mg, 83% yield, eluent: petroleum ether/ethyl acetate = 1/1). Mp 101–103 °C. 1H NMR (400 MHz, CDCl3) δ 7.60 (dt, J = 6.9, 1.5 Hz, 1H), 7.34–7.25 (m, 3H), 7.25–7.14 (m, 4H), 7.12–6.97 (m, 3H), 6.53 (s, 1H), 5.21 (d, J = 17.5 Hz, 1H), 5.04 (ddd, J = 10.1, 2.7, 1.1 Hz, 1H), 4.96 (d, J = 17.5 Hz, 1H), 4.82 (dd, J = 10.1, 2.0 Hz, 1H), 4.00–3.93 (m, 4H), 3.64 (ddd, J = 14.9, 3.7, 2.3 Hz, 1H), 3.55–3.46 (m, 0.52H), 2.98–2.91 (m, 0.59H), 3.18 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.3, 149.3, 149.2, 138.8, 137.9, 134.2, 134.2, 129.2, 128.9, 128.4 (d, J = 3.0 Hz), 127.1, 125.8, 122.7, 121.8, 119.9, 118.4, 113.1, 110.9, 110.1, 108.9 (t, J = 3.0 Hz), 75.6, 56.1, 55.1, 47.7, 44.9 (d, J = 6.1 Hz), 24.0 (q, J = 16.2 Hz) ppm. IR (film) νmax 1640, 1604, 1515, 1465, 1432, 1262, 1247, 1206, 1183, 1096, 1025, 911, 729, 698 cm–1. HRMS (ESI) m/z calcd for C28H24D4N2NaO4 483.2192 [M + Na]+, found 483.2191.
(±)-aS-13-Benzyl-6-((methoxy-d3)methyl)-2-methyl-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3i)
According to procedure B, lactam 3i was obtained from spiroindoline 1i (18.9 mg, 0.05 mmol) as a pale yellow solid (17.6 mg, 85% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 68–70 °C. 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 7.3, 1.4 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.29–7.11 (m, 7H), 7.04–6.94 (m, 2H), 6.92–6.85 (m, 1H), 5.20 (d, J = 16.9 Hz, 1H), 5.07–4.95 (m, 2H), 4.86 (dd, J = 10.2, 2.0 Hz, 1H), 3.97–3.82 (m, 1H), 3.61 (ddd, J = 14.9, 3.7, 2.3 Hz, 1H), 3.55–3.47 (m, 0.52H), 2.90 (dd, J = 15.8, 3.8 Hz, 0.56H), 2.19 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.5, 139.2, 138.3, 137.7, 134.5, 134.3, 131.4, 129.6, 129.1, 128.6, 128.5 (d, J = 3.0 Hz), 128.2, 127.1, 126.4, 122.6, 119.8, 118.4, 110.4, 109.3 (d, J = 3.0 Hz), 75.6 (d, J = 2.0 Hz), 47.7, 44.9 (d, J = 5.1 Hz), 24.1 (q, J = 18.2 Hz), 21.1 ppm. IR (film) νmax 1642, 1464, 1452, 1432, 1348, 1095, 1023, 908, 829, 728, 699 cm–1. HRMS (ESI) m/z calcd for C27H22D4N2NaO2 437.2138 [M + Na]+, found 437.2136.
(±)-aS-13-Benzyl-2-fluoro-6-((methoxy-d3)methyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3j)
According to procedure B, lactam 3j was obtained from spiroindoline 1j (19.1 mg, 0.05 mmol) as a pale yellow solid (16.7 mg, 80% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 212–213 °C. 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 7.6, 1.3 Hz, 1H), 7.52 (dd, J = 8.5, 5.8 Hz, 1H), 7.29–7.09 (m, 7H), 6.98–6.91 (m, 2H), 6.87 (dd, J = 9.4, 2.5 Hz, 1H), 5.20 (d, J = 16.9 Hz, 1H), 5.07 (d, J = 16.9 Hz, 1H), 4.99 (ddd, J = 10.3, 2.7, 1.0 Hz, 1H), 4.88 (dd, J = 10.3, 2.0 Hz, 1H), 3.86 (ddd, J = 14.4, 9.1, 4.7 Hz, 1H), 3.64 (ddd, J = 15.0, 3.7, 2.3 Hz, 1H), 3.59–3.50 (m, 0.52H), 2.96–2.89 (m, 0.58H) ppm. 13C NMR (100 MHz, CDCl3) δ 171.5, 163.9, 161.4, 137.7 (d, J = 17.2 Hz), 133.6, 132.7, 131.7 (d, J = 8.1 Hz), 130.4 (d, J = 9.1 Hz), 128.8, 128.4 (d, J = 3.0 Hz), 127.3, 126.0, 123.1, 120.1, 118.6, 117.5 (d, J = 22.2 Hz), 116.1 (d, J = 22.2 Hz), 110.6, 110.2 (d, J = 3.0 Hz), 75.7, 47.7, 44.9, 24.2 (q, J = 18.2 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ −110.52 (s, 1F) ppm. IR (film) νmax 1644, 1605, 1464, 1453, 1434, 1345, 1294, 1262, 1232, 1189, 1099, 1022, 909, 728, 699 cm–1. HRMS (ESI) m/z calcd for C26H19D4FN2NaO2 441.1887 [M + Na]+, found 441.1887.
(±)-aS-13-Benzyl-2-methoxy-6-((methoxy-d3)methyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3k)
According to procedure B, lactam 3k was obtained from spiroindoline 1k (19.7 mg, 0.05 mmol) as a pale yellow solid (18.9 mg, 88% yield, eluent: petroleum ether/ethyl acetate = 3/2). Mp 83–84 °C. 1H NMR (400 MHz, CDCl3) δ 7.60 (dt, J = 7.1, 1.4 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.32–7.13 (m, 6H), 7.07–6.99 (m, 2H), 6.95 (dd, J = 8.5, 2.6 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 5.21 (d, J = 17.2 Hz, 1H), 5.09–4.96 (m, 2H), 4.85 (dd, J = 10.2, 2.1 Hz, 1H), 3.92 (ddd, J = 14.4, 9.1, 4.7 Hz, 1H), 3.62 (ddd, J = 14.9, 3.7, 2.2 Hz, 1H), 3.57–3.48 (m, 0.52H), 2.97–2.88 (m, 0.56H)], 3.34 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.4, 159.9, 138.5, 137.9, 134.1, 130.7, 129.9, 129.5 (d, J = 1.0 Hz), 128.8, 128.4 (d, J = 3.0 Hz), 127.1, 125.9, 122.8, 119.9, 118.5 (d, J = 2.0 Hz), 116.0, 114.5, 110.4, 109.5 (t, J = 3.0 Hz), 75.6, 54.8, 47.8, 44.8 (t, J = 5.1 Hz), 24.1 (q, J = 19.2 Hz) ppm. IR (film) νmax 1642, 1602, 1465, 1433, 1308, 1237, 1214, 1094, 1021, 909, 730, 700 cm–1. HRMS (ESI) m/z calcd for C27H22D4N2NaO3 453.2087 [M + Na]+, found 453.2085.
(±)-aS-13-Benzyl-6-((methoxy-d3)methyl)-10-methyl-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3l)
According to procedure B, lactam 3l was obtained from spiroindoline 1l (18.9 mg, 0.05 mmol) as a pale yellow solid (18.4 mg, 89% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 77–78 °C. 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 7.6, 1.5 Hz, 1H), 7.43 (td, J = 7.5, 1.3 Hz, 1H), 7.39–7.32 (m, 2H), 7.27–7.15 (m, 4H), 7.07–6.92 (m, 4H), 5.14 (d, J = 16.9 Hz, 1H), 5.09–4.99 (m, 2H), 4.86 (dd, J = 10.3, 1.9 Hz, 1H), 3.86 (ddd, J = 14.4, 9.2, 4.8 Hz, 1H), 3.62 (ddd, J = 15.0, 3.8, 2.3 Hz, 1H), 3.54–3.45 (m, 0.51H), 2.94–2.85 (m, 0.57H), 2.46 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 138.1, 137.5, 136.0, 134.1 (d, J = 2.0 Hz), 130.5, 129.4, 129.2, 129.1, 128.9, 128.8 (d, J = 3.0 Hz), 128.6, 128.2, 127.1, 126.1, 124.2, 118.1, 108.9 (t, J = 3.0 Hz), 75.5 (d, J = 2.0 Hz), 47.6, 44.8 (d, J = 6.1 Hz), 24.1 (q, J = 18.2 Hz), 21.5 ppm. IR (film) νmax 1648, 1466, 1443, 1421, 1351, 1306, 1098, 1019, 909, 791, 773, 729, 699 cm–1. HRMS (ESI) m/z calcd for C27H22D4N2NaO2 437.2138 [M + Na]+, found 437.2135.
(±)-aS-13-Benzyl-10-chloro-6-((methoxy-d3)methyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3m)
According to procedure B, lactam 3m was obtained from spiroindoline 1m (20.0 mg, 0.05 mmol) as a pale yellow solid (15.0 mg, 69% yield, eluent: petroleum ether/ethyl acetate = 2/1). Mp 73–74 °C. 1H NMR (400 MHz, CDCl3) δ 7.54 (td, J = 3.6, 2.8, 1.5 Hz, 2H), 7.47 (td, J = 7.5, 1.3 Hz, 1H), 7.38 (td, J = 7.6, 1.6 Hz, 1H), 7.28–7.16 (m, 4H), 7.11 (dd, J = 8.7, 2.0 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.93 (dd, J = 7.8, 1.7 Hz, 2H), 5.15 (d, J = 16.9 Hz, 1H), 5.09–4.95 (m, 2H), 4.91 (dd, J = 10.3, 2.0 Hz, 1H), 3.85 (ddd, J = 14.5, 9.2, 4.8 Hz, 1H), 3.61 (ddd, J = 15.1, 3.8, 2.4 Hz, 1H), 3.50–3.40 (m, 0.52H), 2.88 (ddd, J = 14.8, 4.4, 1.9 Hz, 0.57H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.2, 137.5, 137.5, 135.9, 135.4 (d, J = 2.0 Hz), 129.6 (d, J = 3.0 Hz), 129.4, 129.3, 128.8, 128.7, 128.2, 127.3, 126.0, 125.6, 122.9, 117.9, 111.7, 109.1 (t, J = 3.0 Hz), 75.7, 47.7, 44.9 (d, J = 5.1 Hz), 24.2 (q, J = 18.2 Hz) ppm. IR (film) νmax 1644, 1465, 1440, 1421, 1351, 1032, 1096, 1018, 908, 788, 765, 728, 699 cm–1. HRMS (ESI) m/z calcd for C26H19D4ClN2NaO2 457.1591 [M + Na]+, found 457.1592.
(±)-aS-13-Benzyl-10-methoxy-6-((methoxy-d3)methyl)-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3n)
According to procedure B, lactam 3n was obtained from spiroindoline 1n (19.7 mg, 0.05 mmol) as a pale yellow solid (18.1 mg, 84% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 80–81 °C. 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 7.6, 1.5 Hz, 1H), 7.37 (td, J = 7.5, 1.3 Hz, 1H), 7.29 (td, J = 7.5, 1.5 Hz, 1H), 7.20–7.09 (m, 5H), 7.00–6.92 (m, 1H), 6.91–6.86 (m, 2H), 6.75 (d, J = 8.9 Hz, 1H), 5.06 (d, J = 16.9 Hz, 1H), 5.01–4.91 (m, 2H), 4.84 (dd, J = 10.3, 2.1 Hz, 1H), 3.84–3.77 (m, 4H), 3.55 (ddd, J = 15.0, 3.8, 2.3 Hz, 1H), 3.43–3.35 (m, 0.49H), 2.87–2.77 (m, 0.52H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.3, 154.3, 138.0, 137.4, 134.7, 132.9, 130.5, 129.3, 129.3, 128.9, 128.7, 128.2, 127.1, 126.1, 112.6, 111.4, 111.3, 109.0, 100.3, 75.6, 55.9, 47.7, 44.9, 24.3 (q, J = 17.2 Hz) ppm. IR (film) νmax 1648, 1477, 1466, 1433, 1304, 1209, 1097, 1053, 1019, 911, 787, 772, 732, 700 cm–1. HRMS (ESI) m/z calcd for C27H22D4N2NaO3 453.2087 [M + Na]+, found 453.2086.
(±)-aS-6-((Methoxy-d3)methyl)-13-methyl-6,7,8,13-tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-one-8-d (3o)
According to procedure B, lactam 3o was obtained from spiroindoline 1o (14.4 mg, 0.05 mmol) as a pale yellow solid (14.8 mg, 91% yield, eluent: petroleum ether/ethyl acetate = 2/1). Mp 61–63 °C. 1H NMR (400 MHz, CDCl3) δ 7.61–7.44 (m, 4H), 7.36–7.22 (m, 3H), 7.15 (ddd, J = 7.9, 6.7, 1.2 Hz, 1H), 5.06 (ddd, J = 10.2, 2.7, 1.1 Hz, 1H), 4.78 (dd, J = 10.2, 1.8 Hz, 1H), 3.93–3.79 (m, 1H), 3.62 (ddd, J = 15.0, 3.7, 2.2 Hz, 1H), 3.51 (s, 3H), 3.50–3.46 (m, 0.55H), 2.92–2.82 (m, 0.53H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.4, 138.0, 137.2, 133.9 (d, J = 2.0 Hz), 131.0, 129.4, 129.3, 128.8, 128.2, 128.1 (d, J = 3.0 Hz), 122.5, 119.5, 118.3, 109.5, 108.8 (t, J = 3.0 Hz), 75.3, 44.5, 31.0, 24.4 (q, J = 19.2 Hz) ppm. IR (film) νmax 1643, 1467, 1444, 1422, 1358, 1232, 1097, 1031, 1012, 910, 734, 645 cm–1. HRMS (ESI) m/z calcd for C20H16D4N2NaO2 347.1668 [M + Na]+, found 347.1667.
14-Benzyl-6-(methoxymethyl)-7,8,9,14-tetrahydrobenzo[3,4]azonino[5,6-b]indol-5(6H)-one (5a)
According to procedure A, lactam 5a was obtained from spiroindoline 4 (18.9 mg, 0.05 mmol) and methanol (1.65 mg, 0.05 mmol) as a pale yellow solid (18.1 mg, 88% yield, eluent: petroleum ether/ethyl acetate = 3/1). Mp 47–49 °C. 1H NMR (400 MHz, CDCl3) δ 7.62–7.56 (m, 1H), 7.48 (td, J = 7.6, 1.2 Hz, 1H), 7.39 (dd, J = 7.5, 1.4 Hz, 1H), 7.29 (td, J = 7.6, 1.4 Hz, 1H), 7.24–7.17 (m, 3H), 7.16–7.07 (m, 4H), 7.00–6.91 (m, 2H), 5.23 (d, J = 16.9 Hz, 1H), 4.86 (d, J = 16.9 Hz, 1H), 4.72 (dd, J = 10.4, 1.0 Hz, 1H), 4.57 (d, J = 10.4 Hz, 1H), 3.53–3.30 (m, 2H), 3.12 (dddd, J = 14.5, 5.2, 2.3, 1.0 Hz, 1H), 2.81 (s, 3H), 2.36 (ddd, J = 14.5, 13.0, 2.5 Hz, 1H), 2.02 (dddt, J = 15.2, 13.2, 11.0, 2.2 Hz, 1H), 1.73–1.67 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 171.7, 140.7, 138.6, 136.7, 134.7, 130.9, 129.52, 129.0, 128.5, 128.2, 127.1, 127.0, 126.3, 124.8, 122.0, 119.4, 118.1, 114.5, 110.2, 75.5, 55.8, 49.8, 47.5, 27.2, 24.5 ppm. IR (film) νmax 2923, 1640, 1460, 1442, 1421, 1388, 1367, 1351, 1329, 1178, 1094, 1063, 1030, 762, 731, 696 cm–1. HRMS (ESI) m/z calcd for C27H26N2NaO2 433.1886 [M + Na]+, found 433.1886.
14-Benzyl-6-((2-hydroxynaphthalen-1-yl)methyl)-7,8,9,14-tetrahydrobenzo[3,4]azonino[5,6-b]indol-5(6H)-one (5b)
According to procedure A, lactam 5b was obtained from spiroindoline 4 (18.9 mg, 0.05 mmol) and 2-hydroxynaphthalene (7.2 mg, 0.05 mmol) as a white solid (23.6 mg, 91% yield, eluent: petroleum ether/ethyl acetate = 1/1). Mp 258–260 °C. 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.45 (q, J = 7.6 Hz, 2H), 7.36 (d, J = 7.5 Hz, 1H), 7.34–7.07 (m, 9H), 7.07–6.90 (m, 3H), 5.30 (d, J = 16.9 Hz, 1H), 5.01–4.75 (m, 2H), 4.55 (d, J = 15.5 Hz, 1H), 3.54–3.29 (m, 2H), 3.15 (dd, J = 13.9, 4.6 Hz, 1H), 2.45–2.30 (m, 1H), 2.20 (q, J = 12.8 Hz, 1H), 1.74 (t, J = 10.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.7, 155.6, 139.2, 138.5, 136.8, 134.4, 134.0, 130.9, 130.5, 129.6, 129.3, 129.0, 128.7, 128.6, 128.5, 127.1, 126.9, 126.7, 126.2, 125.4, 122.5, 122.2, 121.0, 119.9, 119.6, 118.0, 114.0, 112.7, 110.4, 50.3, 47.6, 38.1, 25.8, 24.3 ppm. IR (film) νmax 3141, 1590, 1579, 1507, 1497, 1461, 1435, 1409, 1368, 1347, 1272, 1251, 817, 743, 729 cm–1. HRMS (ESI) m/z calcd for C36H30N2NaO2 545.2199 [M + Na]+, found 545.2200.
6-((1H-Indol-3-yl)methyl)-14-benzyl-7,8,9,14-tetrahydrobenzo[3,4]azonino[5,6-b]indol-5(6H)-one (5c)
According to procedure A, lactam 5c was obtained from spiroindoline 4 (18.9 mg, 0.05 mmol) and indole (5.9 mg, 0.05 mmol) as a white solid (21.0 mg, 85% yield, eluent: petroleum ether/ethyl acetate = 1/1). Mp 164–166 °C. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.7 Hz, 1H), 7.86 (s, 1H), 7.34–7.19 (m, 5H), 7.19–7.02 (m, 4H), 6.92 (td, J = 7.5, 4.9 Hz, 2H), 6.65 (q, J = 8.0 Hz, 2H), 6.52 (d, J = 7.8 Hz, 1H), 6.34 (d, J = 8.3 Hz, 1H), 6.28 (d, J = 7.8 Hz, 1H), 6.15 (d, J = 2.7 Hz, 1H), 4.58 (td, J = 12.3, 7.1 Hz, 1H), 4.21 (d, J = 16.2 Hz, 1H), 4.03 (d, J = 16.2 Hz, 1H), 3.89 (d, J = 13.3 Hz, 1H), 3.47 (d, J = 13.3 Hz, 1H), 3.15 (dd, J = 13.1, 7.2 Hz, 1H), 2.64 (d, J = 13.2 Hz, 1H), 2.49 (dd, J = 15.6, 7.1 Hz, 1H), 2.35–2.15 (m, 1H), 2.07–1.89 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 167.4, 150.7, 140.9, 138.3, 136.0, 133.1, 131.0, 128.7, 128.6, 128.4, 127.9, 126.7, 126.3, 126.1, 125.9, 124.3, 123.7, 121.0, 120.5, 120.2, 119.4, 119.3, 110.5, 110.2, 58.6, 48.7, 46.8, 46.5, 22.6 ppm. IR (film) νmax 3306, 2928, 1641, 1602, 1481, 1459, 1421, 1348, 1296, 1236, 731, 707, 697 cm–1. HRMS (ESI) m/z calcd for C34H29N3NaO 518.2203 [M + Na]+, found 518.2205.
(±)-aS-14-Benzyl-6-((methoxy-d3)methyl)-7,8,9,14-tetrahydrobenzo[3,4]azonino[5,6-b]indol-5(6H)-one-9-d (5d)
According to procedure B, lactam 5d was obtained from spiroindoline 4 (18.9 mg, 0.05 mmol) as a pale yellow solid (18.6 mg, 90% yield, eluent: petroleum ether/ethyl acetate = 2/1). Mp 44–46 °C. 1H NMR (400 MHz, CDCl3) δ 7.62–7.56 (m, 1H), 7.47 (td, J = 7.5, 1.2 Hz, 1H), 7.39 (dd, J = 7.7, 1.4 Hz, 1H), 7.29 (td, J = 7.6, 1.4 Hz, 1H), 7.25–7.16 (m, 3H), 7.15–7.09 (m, 4H), 7.00–6.92 (m, 2H), 5.22 (d, J = 16.9 Hz, 1H), 4.86 (d, J = 16.9 Hz, 1H), 4.71 (dd, J = 10.4, 0.9 Hz, 1H), 4.57 (d, J = 10.3 Hz, 1H), 3.56–3.32 (m, 2H), 3.18–3.06 (m, 0.41H), 2.36 (ddd, J = 15.4, 13.1, 2.5 Hz, 0.40H)], 2.09–1.92 (m, 1H), 1.77–1.56 (m, 1H). ppm. 13C NMR (100 MHz, CDCl3) δ 171.7, 140.7, 138.6, 136.7, 134.7, 134.6, 130.9, 129.5, 129.0, 128.5, 128.2, 127.1, 127.0, 126.3, 126.2, 124.8, 122.0, 119.4, 118.1, 114.4, 110.2, 75.5, 49.8, 49.7, 47.5, 27.1, 27.1 (t, J = 10.1 Hz), 24.2 (q, J = 19.2 Hz) ppm. IR (film) νmax 2918, 1639, 1460, 1422, 1390, 1350, 1306, 1265, 1098 1056, 1028, 1013, 761, 730, 695 cm–1. HRMS (ESI) m/z calcd for C27H22D4N2NaO2 437.2138 [M + Na]+, found 437.2138.
Acknowledgments
The work was financially supported by the National Natural Science Foundation of China (21871132, 21572098) and the National Key Research and Development Program of China (2018YFC0310900).
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c04261.
Copies of 1H and 13C NMR spectra of all new compounds (PDF)
Accession Codes
CCDC 2087324 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
The authors declare no competing financial interest.
Supplementary Material
References
- Riemer B.; Hofer O.; Greger H. Tryptamine Derived Amides from Clausena indica. Phytochemistry 1997, 45, 337–341. 10.1016/S0031-9422(96)00848-5. [DOI] [Google Scholar]
- Steyn P. S. The Structures of Five Diketopiperazines from Aspergillus ustus. Tetrahedron 1973, 29, 107–120. 10.1016/S0040-4020(01)99384-6. [DOI] [Google Scholar]
- Hayashi H.; Furutsuka K.; Shiono Y. Okaramines H and I, New Okaramine Congeners, from Aspergillus aculeatus. J. Nat. Prod. 1999, 62, 315–317. 10.1021/np9802623. [DOI] [PubMed] [Google Scholar]
- a Kam T. S.; Yoganathan K.; Chuah C. H. Lundurines A, B and C, new indole alkaloids with a novel carbon skeleton containing a cyclopropyl moiety. Tetrahedron Lett. 1995, 36, 759–762. 10.1016/0040-4039(94)02361-E. [DOI] [Google Scholar]; b Kam T. S.; Lim K. H.; Yoganathan K.; Hayashi M.; Komiyama K. Lundurines A-D, cytotoxic indole alkaloids incorporating a cyclopropyl moiety from Kopsia tenuis and revision of the structures of tenuisines A-C. Tetrahedron 2004, 60, 10739–10745. 10.1016/j.tet.2004.08.091. [DOI] [Google Scholar]
- Neuss N.; Neuss M. N.. In The Alkaloids; Brossi A.; Suffness M., Eds.; Academic: San Diego, 1990; Vol. 37, p 229. [Google Scholar]
- Illuminati G.; Mandolini L. Ring Closure Reactions of Bifunctional Chain Molecules. Acc. Chem. Res. 1981, 14, 95–102. 10.1021/ar00064a001. [DOI] [Google Scholar]
- For selected cycloaddition reactions, see:; a Wang Y.-N.; Yang L.-C.; Rong Z.-Q.; Liu T.-L.; Liu R.; Zhao Y. Pd-Catalyzed Enantioselective [6+4] Cycloaddition of Vinyl Oxetanes with Azadienes to Access Ten-Membered Heterocycles. Angew. Chem., Int. Ed. 2018, 57, 1596–1600. 10.1002/anie.201711648. [DOI] [PubMed] [Google Scholar]; b Wu A.; Feng Q.; Sung H. H. Y.; Williams I. D.; Sun J. Synthesis of Eight-Membered Lactams through Formal [6+2] Cyclization of Siloxy Alkynes and Vinylazetidines. Angew. Chem., Int. Ed. 2019, 58, 6776–6780. 10.1002/anie.201902866. [DOI] [PubMed] [Google Scholar]; c Boyd O.; Wang G.-W.; Sokolova O. O.; Calow A. D. J.; Bertrand S. M.; Bower J. F. Modular Access to Eight-Membered N-Heterocycles by Directed Carbonylative C-C Bond Activation of Aminocyclopropanes. Angew. Chem., Int. Ed. 2019, 58, 18844–18848. 10.1002/anie.201910276. [DOI] [PubMed] [Google Scholar]
- For selected cycloisomerization reactions, see:; a Baran P. S.; Corey E. J. A Short Synthetic Route to (+)-Austamide, (+)-Deoxyisoaustamide, and (+)-Hydratoaustamide from a Common Precursor by a Novel Palladium-Mediated Indole →Dihydroindoloazocine Cyclization. J. Am. Chem. Soc. 2002, 124, 7904–7905. 10.1021/ja026663t. [DOI] [PubMed] [Google Scholar]; b Baran P. S.; Guerrero C. A.; Corey E. J. Short, Enantioselective Total Synthesis of Okaramine N. J. Am. Chem. Soc. 2003, 125, 5628–5629. 10.1021/ja034491+. [DOI] [PubMed] [Google Scholar]; c Kirillova M. S.; Muratore M. E.; Dorel R.; Echavarren A. M. Concise Total Synthesis of Lundurines A-C Enabled by Gold Catalysis and a Homodienyl Retro-Ene/Ene Isomerization. J. Am. Chem. Soc. 2016, 138, 3671–3674. 10.1021/jacs.6b01428. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Miloserdov F. M.; Kirillova M. S.; Muratore M. E.; Echavarren A. M. Unified Total Synthesis of Pyrroloazocine Indole Alkaloids Sheds Light on Their Biosynthetic Relationship. J. Am. Chem. Soc. 2018, 140, 5393–5400. 10.1021/jacs.7b13484. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Zhou B.; Li L.; Zhu X.-Q.; Yan J.-Z.; Guo Y.-L.; Ye L.-W. Yttrium-Catalyzed Intramolecular Hydroalkoxylation/Claisen Rearrangement Sequence: Efficient Synthesis of Medium-Sized Lactams. Angew. Chem., Int. Ed. 2017, 56, 4015–4019. 10.1002/anie.201700596. [DOI] [PubMed] [Google Scholar]; f Zhou B.; Zhang Y.-Q.; Zhang K.; Yang M.-Y.; Chen Y.-B.; Li Y.; Peng Q.; Zhu S.-F.; Zhou Q.-L.; Ye L.-W. Stereoselective synthesis of medium lactams enabled by metal-free hydroalkoxylation/stereospecific [1,3]-rearrangement. Nat. Commun. 2019, 10, 3234 10.1038/s41467-019-11245-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- For selected ring-expansion reactions, see; a Ishikawa H.; Colby D. A.; Boger D. L. Direct Coupling of Catharanthine and Vindoline to Provide Vinblastine: Total Synthesis of (+)- and ent-(-)-Vinblastine. J. Am. Chem. Soc. 2008, 130, 420–421. 10.1021/ja078192m. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Gotoh H.; Sears J. E.; Eschenmoser A.; Boger D. L. New Insights into the Mechanism and an Expanded Scope of the Fe(III)-Mediated Vinblastine Coupling Reaction. J. Am. Chem. Soc. 2012, 134, 13240–13243. 10.1021/ja306229x. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Ishikawa H.; Colby D. A.; Seto S.; Va P.; Tam A.; Kakei H.; Rayl T. J.; Hwang I.; Boger D. L. Total Synthesis of Vinblastine, Vincristine, Related Natural Products, and Key Structural Analogues. J. Am. Chem. Soc. 2009, 131, 4904–4916. 10.1021/ja809842b. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Beatty J. W.; Stephenson C. R. J. Synthesis of (-)-Pseudotabersonine, (-)-Pseudovincadifformine, and (+)-Coronaridine Enabled by Photoredox Catalysis in Flow. J. Am. Chem. Soc. 2014, 136, 10270–10273. 10.1021/ja506170g. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Zhang L.; Wang Y.; Yao Z. J.; Wang S.; Yu Z. X. Kinetic or Dynamic Control on a Bifurcating Potential Energy Surface? An Experimental and DFT Study of Gold-Catalyzed Ring Expansion and Spirocyclization of 2-Propargyl-β-tetrahydrocarbolines. J. Am. Chem. Soc. 2015, 137, 13290–13300. 10.1021/jacs.5b05971. [DOI] [PubMed] [Google Scholar]; f Huang L.; Dai L.-X.; You S.-L. Enantioselective Synthesis of Indole-Annulated Medium-Sized Rings. J. Am. Chem. Soc. 2016, 138, 5793–5796. 10.1021/jacs.6b02678. [DOI] [PubMed] [Google Scholar]; g Hall J. E.; Matlock J. V.; Ward J. W.; Gray K. V.; Clayden J. Medium-Ring Nitrogen Heterocycles through Migratory Ring Expansion of Metalated Ureas. Angew. Chem., Int. Ed. 2016, 55, 11153–11157. 10.1002/anie.201605714. [DOI] [PubMed] [Google Scholar]; h Costil R.; Lefebvre Q.; Clayden J. Medium-Sized-Ring Analogues of Dibenzodiazepines by a Conformationally Induced Smiles Ring Expansion. Angew. Chem., Int. Ed. 2017, 56, 14602–14606. 10.1002/anie.201708991. [DOI] [PubMed] [Google Scholar]; i Wang N.; Gu Q.-S.; Li Z.-L.; Li Z.; Guo Y.-L.; Guo Z.; Liu X.-Y. Direct Photocatalytic Synthesis of Medium-Sized Lactams by C-C Bond Cleavage. Angew. Chem., Int. Ed. 2018, 57, 14225–14229. 10.1002/anie.201808890. [DOI] [PubMed] [Google Scholar]; j Lawer A.; Rossi-Ashton J. A.; Stephens T. C.; Challis B. J.; Epton R. G.; Lynam J. M.; Unsworth W. P. Internal Nucleophilic Catalyst Mediated Cyclisation/Ring Expansion Cascades for the Synthesis of Medium-Sized Lactones and Lactams. Angew. Chem., Int. Ed. 2019, 58, 13942–13947. 10.1002/anie.201907206. [DOI] [PubMed] [Google Scholar]
- a Qiao J.; Zhao W.; Liang Y.; Yao Z.-J.; Wang S. Diastereose-lective Access to Tetracyclic Eight-Membered Lactams through a Dearomative Heck Reaction and an Alkylative Ring-Opening Driven by the Photoexcited Spiroindolines. Chem. - Eur. J. 2021, 27, 6308–6314. 10.1002/chem.202005369. [DOI] [PubMed] [Google Scholar]; b Li H.-H.; Ye S.-H.; Chen Y.-B.; Luo W.-F.; Qian P.-C.; Ye L.-W. Efficient and Divergent Synthesis of Medium-Sized Lactams through Zinc-Catalyzed Oxidative Cyclization of Indoly Ynamides. Chin. J. Chem. 2020, 38, 263–268. 10.1002/cjoc.201900478. [DOI] [Google Scholar]; c Zhu B.-H.; Zheng Y.-X.; Kang W.; Deng C.; Zhou J.-M.; Ye L.-W.. Catalytic hydrative cyclization of aldehyde-ynamide with water for synthesis of medium-sized lactams. China: Chem. 2021, 10.1007/s11426-021-1069-7. [DOI]
- For selected reviews on C–C bond fragmentation, see:; a Morcillo S. P. Radical-Promoted C-C Bond Cleavage: A Deconstructive Approach for Selective Functionalization. Angew. Chem., Int. Ed. 2019, 58, 14044–14054. 10.1002/anie.201905218. [DOI] [PubMed] [Google Scholar]; b Drahl M. A.; Manpadi M.; Williams L. J. C-C Fragmentation: Origins and Recent Applications. Angew. Chem., Int. Ed. 2013, 52, 11222–11251. 10.1002/anie.201209833. [DOI] [PubMed] [Google Scholar]; c Prantz K.; Mulzer J. Synthetic Applications of the Carbonyl Generating Grob Fragmentation. Chem. Rev. 2010, 110, 3741–3766. 10.1021/cr900386h. [DOI] [PubMed] [Google Scholar]; d Grob C. A. Mechanisms and Stereochemistry of Heterolytic Fragmentation. Angew. Chem., Int. Ed. 1969, 8, 535–546. 10.1002/anie.196905351. [DOI] [Google Scholar]
- Atzrodt J.; Derdau V.; Kerr W. J.; Reid M. Deuterium and Tritium-Labelled Compounds: Applications in the Life Sciences. Angew. Chem., Int. Ed. 2018, 57, 1758–1784. 10.1002/anie.201704146. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.