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Synthesis 2023; 55(02): 289-296
DOI: 10.1055/a-1878-8597
paper
Special Issue dedicated to Prof. Alain Krief

A Practical Approach to 6H-Indol-6-ones Enables the Formal Synthesis of γ-Lycorane

Yang Chen
a   Yunnan Key Laboratory of Southern Medicinal Resources, School of Chinese Materia Medica, Yunnan University of Chinese Medicine, 1076 Yuhua Road, Kunming, 650500, P. R. of China
,
Xin-Ting Hu
a   Yunnan Key Laboratory of Southern Medicinal Resources, School of Chinese Materia Medica, Yunnan University of Chinese Medicine, 1076 Yuhua Road, Kunming, 650500, P. R. of China
,
Xiao-Yan Xie
a   Yunnan Key Laboratory of Southern Medicinal Resources, School of Chinese Materia Medica, Yunnan University of Chinese Medicine, 1076 Yuhua Road, Kunming, 650500, P. R. of China
,
Dashan Li
a   Yunnan Key Laboratory of Southern Medicinal Resources, School of Chinese Materia Medica, Yunnan University of Chinese Medicine, 1076 Yuhua Road, Kunming, 650500, P. R. of China
,
Chun-Xia Zheng
a   Yunnan Key Laboratory of Southern Medicinal Resources, School of Chinese Materia Medica, Yunnan University of Chinese Medicine, 1076 Yuhua Road, Kunming, 650500, P. R. of China
,
You-Xi Zhang
b   School of Chemistry and Chemical Engineering, Yunnan Normal University, 798 Jvxian Street, Kunming, 650500, P. R. of China
,
Wen-Jing Wang
a   Yunnan Key Laboratory of Southern Medicinal Resources, School of Chinese Materia Medica, Yunnan University of Chinese Medicine, 1076 Yuhua Road, Kunming, 650500, P. R. of China
,
Rui Zhan∗
b   School of Chemistry and Chemical Engineering, Yunnan Normal University, 798 Jvxian Street, Kunming, 650500, P. R. of China
,
Li-Dong Shao  ∗
a   Yunnan Key Laboratory of Southern Medicinal Resources, School of Chinese Materia Medica, Yunnan University of Chinese Medicine, 1076 Yuhua Road, Kunming, 650500, P. R. of China
› Author Affiliations

The authors gratefully acknowledge financial support from the National­ Natural Science of Foundation of China (81960631), the Yunnan­ Fundamental Research Project (202001AS070038), the Ten Thousand Talent Plans for Young Top-Notch Talents of Yunnan Province (R.Z. and L.-D.S.), and the Start-up Fund of Yunnan University of Chinese Medicine (2019YZG03).
› Further Information
 
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Abstract

We represented herein a two-step synthesis of 1-methyl-6H-indol-6-one which is an N-containing 6/5 fused bicyclic building blocks in Amaryllidaceae alkaloids. The key step featured is a ‘one-pot’ ozonolysis/reductive amination/cyclization of allylated cyclohexa-1,3-dione to give bicyclic compounds. Moreover, the formal total synthesis of natural product γ-lycorane could be achieved through a photo-promoted cyclization/oxidation cascade reaction from the resulting bicyclic intermediate.


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Key words

1-methyl-6H-indol-6-one - two-step synthesis - one-pot - Amaryllidaceae alkaloids - γ-lycorane

1-Substituted 6H-indol-6-one 1 [1] (Figure [1]) is an N-heterobicyclic enone, which is the core skeleton of biologically active benzylphenethylamine-type alkaloids[2] widely found in Amaryllidaceae alkaloids, for example, lycorane (1a), lycorine (1b), lycoris (1c), kirkine (1d), fortucine (1e), and others.[3] Due to the important biological activities and the attractive chemical structures of these alkaloids, extensive advances in their total synthesis have been achieved.[4] Moreover, Aubé and co-workers found that simple derivatives of 1 showed druglike properties with the similar natural alkaloids, which might be served as leads for further development.[5]

Zoom Image
Figure 1 Representative natural products with 6H-indol-6-one cores and methods for their synthesis

Due to the high relevance of bicyclic building blocks 1 to the corresponding natural products syntheses and drug development, its preparation has been extensively studied. In the 1970s, Bryson’s intramolecular nucleophilic substitution of β-enamino ketone 2 [6] and Kibayashi’s direct Birch reduction of 3 [7] were found to be effective for the preparation of 1 (Figure [1]). Later, Michael and co-workers reported that 1 could be prepared through an acid-promoted cyclization from intermediate 4, which was synthesized by the condensation of 1-methylpyrrolidine-2-thione with Nazarov reagent.[8] Recently, Bower and co-workers developed a Rh(I)-catalyzed [3+1+2] cyclization of highly functionalized intermediate 5, leading to 1 within four steps starting from cyclopropanamine.[9] Herein, we present a facile synthetic route to this important bicyclic compound through a key ‘one-pot’ ozonolysis/reductive amination/cyclization based on Zhang’s intermediate 6,[10] which could be prepared on a gram-scale according to the Zhang’s protocol from cyclohexa-1,3-dione or our modified method (vide infra).

Our synthesis of 1 started with the preparation of cyclized precursors 7a–7c through the nucleophilic substitution of 6a–6c with 1-chloro-2-iodoethane (Scheme [1]). Unfortunately, all tested bases like lithium hexamethyldisilazanide (LiHMDS)/hexamethylphosphoramide (HMPA), lithium diisopropylamide (LDA)/HMPA, nBuLi, NaH, and K2CO3 failed to give any of the desired products. We supposed that the highly active 1-chloro-2-iodoethane was not stable enough to survive for a sufficient period required for the nucleophilic substitution reaction in the presence of a strong base.

Zoom Image
Scheme 1 Unsuccessful attempts to synthesis of cyclized precursors 7a–7c

Thus, the synthetic plan was changed to the preparation of 7d, which was obtained by direct condensation of 6a with 2-(methylamino)ethanol in quantitative yields after workup with K2CO3/MeOH (Scheme [2a]). Converting 7d into active methyl sulfonate was realized using triethylamine (TEA)/methanesulfonyl chloride (MsCl), which gave methyl sulfonate 8a in 90% yield. In the presence of NaI, 8a was transformed into the corresponding iodide 8b in 89% yield. With 8a and 8b in hand, cyclization conditions were screened by varying the bases (Scheme [2b]). Treatment of 8a with excess LiHMDS led to complete decomposition of the starting materials (Scheme [2b], entry 1). Utilizing Mariano’s observation[11] and applying thermodynamic anion-forming conditions to the cyclization with a lower excess LiHMDS (1.5 eq.) furnished α-alkylated product 9a in 20% yield (Scheme [2b], entry 2). Adding HMPA (1.5 eq.) to this system did not give the desired γ-alkylated product (Scheme [2b], entry 3).[12] Similarly, using 8b as the substrate, 9a was harvested in 46% yield when lowering the deprotonation temperature to –78 °C and reacting at 0 °C (Scheme [2b], entry 4), whereas harsh conditions (Cs2CO3, 120 °C) in a sealed reaction tube led to 9a in 16% yield (Scheme [2b], entry 5). We speculated that the unexpected product 9a might be resulted from the potential intramolecular interactions between the lithium cation with the O atom (R = Ms in 8a) or the I atom (R = I in 8b) in γ-enolate anion i , which located the side chain at reacting center nearby the α-position.

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Scheme 2 Unsuccessful attempts to the cyclization of 8a and 8b (a), selected conditions for base screening (b)

On the basis of these unsuccessful attempts, we envisioned that introduction of the N atom at a late stage through the reductive amination/cyclization of the corresponding aldehyde based on intermediate 6 would be more reasonable and effective (Scheme [3]).

Zoom Image
Scheme 3 Final synthetic route to 1-substituted 6H-indol-6-ones 1f–1i

Table 1 Selected Optimizations for ‘One-Pot’ Ozonolysis/Reductive Amination/Cyclizationa

Entry

Conditions

Yield (%)

Ozonolysis

Reductive amination/cyclization

 1

6 (0.33 mmol), O3 (1 min), DCM (10 mL), –78 °C; Me2S (10 eq.), rt, 2 h

NH2Me (2 M in THF, 1.0 eq.), NaBH3CN (1.0 eq.), 0 °C, 5 h;

evaporated DCM, then AcOH (3 mL), 90 °C, 12 h

1f (13)

 2

6 (0.33 mmol), O3 (1 min), DCM (10 mL), –78 °C; Me2S (10 eq.), rt, 2 h

NH2Me (2 M in THF, 1.0 eq.), NaBH3CN (1.0 eq.), 0 °C, 2 h;

evaporated DCM, then AcOH (3 mL), 90 °C, 12 h

1f (10)

 3

6 (0.33 mmol), O3 (5 min), DCM (10 mL), –78 °C; Me2S (10 eq.), rt, 2 h

NH2Me (2 M in THF, 1.0 eq.), NaBH3CN (1.0 eq.), 0 °C, 5 h;

evaporated DCM, then AcOH (3 mL), 90 °C, 12 h

decomposed

 4

6 (0.33 mmol), O3 (1 min), DCM/MeOH (10 mL, 5:1), –78 °C; Me2S (10 eq.), rt, 2 h

NH2Me (2 M in THF, 1.0 eq.), NaBH3CN (1.0 eq.), 0 °C, 5 h;

evaporated solvent, then AcOH (3 mL), 90 °C, 12 h

decomposed

 5

6 (0.33 mmol), O3 (1 min), DCM (10 mL), –78 °C; Me2S (10 eq.), rt, 2 h

evaporated DCM, then THF (4 mL), MeNH2·HCl (1.5 eq.), rt, 8 h;

then NaBH3CN (2.0 eq.), rt, 12 h

1f (28)

 6

6 (1.32 mmol), O3 (1 min), DCM (30 mL), –78 °C; Me2S (10 eq.), rt, 2 h

evaporated DCM, then THF (10 mL), MeNH2·HCl (1.5 eq.), rt, 8 h;

then NaBH3CN (2.0 eq.), rt, 12 h

1f (25)

 7

11b (0.33 mmol), O3 (1 min), DCM (10 mL), –78 °C; Me2S (10 eq.), rt, 2 h

evaporated DCM, then EtOAc (3 mL), 2N HCl (2 mL), rt, 2 h; MeNH2·HCl (1.5 eq.), rt, 8 h;

then NaBH3CN (2.0 eq.), rt, 12 h

1f (8)

 8

11b (0.33 mmol), O3 (1 min), DCM (10 mL), –78 °C; Me2S (10 eq.), rt, 2 h;

evaporated DCM, then THF (4 mL), MeNH2·HCl (1.5 eq.), rt, 8 h;

then NaBH3CN (2.0 eq.), rt, 12 h;

then EtOAc (3 mL), 2N HCl (2 mL), reflux, 2 h

decomposed

 9

10 (0.33 mmol) as entry 5

as entry 5

1g (40)

10

6 (0.33 mmol) as entry 5

piperonylamine hydrochloride (1.5 eq.) instead of MeNH2·HCl

1h (23)

11

6 (0.33 mmol) as entry 5

6-bromopiperonylamine hydrochloride (1.5 eq.) instead of MeNH2·HCl

1i (16)

a The yields shown are isolated yields after flash chromatography column on silica gel; the red color in entries 2–5 is used to highlight the variations based on entry 1; the blue color in entries 6–11 is used to highlight the variations based on entry 5.

As shown in Scheme [3], intermediate 6 was obtained in 70% yield by following Zhang’s protocol.[10] Actually, we found a modified method that underwent O-methylation (6b),[13] α′-allylation (11b), and hydrolysis was more efficient, giving 6 on a gram-scale in 76% overall yield. The same procedure was applied to seven-membered ring giving 10 in 35% overall yield. Next, the ‘one-pot’ ozonolysis/reductive amination/cyclization sequence was examined using 6 and 11b as the substrates (Table [1]). Initially, we found that short-time (30 s) bubbling with O3 into the reaction system resulted in trace products, and decomposition of the starting materials were detected when using OsO4 and K2OsO4 in place of O3 (Table S1, supporting information).[13a] [14] Consequently, bubbling the reaction system with O3 for 1 min followed by Me2S reduction gave the corresponding aldehyde intermediate, which underwent reductive amination/cyclization (NH2Me, NaBH3CN, AcOH) to furnish 1 in 10–13% yield (entries 1 and 2). Increasing O3 bubbling time to 5 min until the presentation of ‘blue’ color or replacement of DCM with DCM/MeOH (5:1, v/v) led to decomposition of the starting materials (entries 3 and 4). Delightedly, the yield of 1 was improved up to 28% by using THF as the solvent and MeNH2·HCl as the nitrogen source in the reductive amination step (entries 5 and 6). Whereas, 11b was less effective in this ‘one-pot’ sequence compared to 6 (entries 7 and 8). By varying the alkenes (6 or 10) and amines, bicyclic compounds 1g–1i could be also prepared (entries 9–11). Further attempts to formation different bicyclic compounds 1j (6/6) and 1k (7/6) by tuning the chain length of the corresponding bromides failed due to the extremely low yields of the α′-alkylation with 4-bromobut-1-ene (for details see Table S2, Supporting Information).

Pleasingly, bicyclic compounds 1h and 1i seemed to be advanced synthetic intermediate towards γ-lycorane, especially 1i was successfully transformed to 12a in the presence of LiNEt2 which likely underwent the intramolecular addition to the corresponding benzyne intermediate (Scheme [4]).[15] However, under the standard Pd-catalyzed conditions like Pd(OAc)2/Cu(OAc)2, Pd(OAc)2/P(p-tol-Ph)3 or with varied phosphine ligands as well as UV or visible light irradiation,[16] both 1h and 1i failed to convert into cyclized product 12a in our additional attempts (data not shown). Treatment of 1h with bromine in DCM gave α-bromide 1l in 81% yield. Delightedly, irradiation of 1l with UV lamp (254 nm) in anhydrous MeCN/TEA under a argon atmosphere gave trace amount of 12c (entry 1, Table S3, Supporting Information), of which the imine intermediate 12b (M+, m/z = 268.0968) could be detected by MS in reaction mixture (for details see the Supporting Information). Further optimization of the conditions revealed that the moisture and oxygen/air were of advantage to this cyclization/oxidation cascade (Table S3, Supporting Information), indicating this transformation maybe undergo the photo-promoted radical cyclization[7] [17] and subsequent aerobic oxidation.[18] Finally, the Kibayashi intermediate 12c was obtained in 41% yield, which could be further converted into natural product γ-lycorane in two steps.[16]

Zoom Image
Scheme 4 Formal total synthesis of γ-lycorane

In summary, we have developed a straightforward route to 1-methyl-6H-indol-6-one (1) from simple commercial building blocks. The key ‘one-pot’ transformation could be realized in the absence of metal, base, and acid. The common intermediates 6 and 10 could be obtained in 76% and 35% yield on a gram-scale according to our modified method. Finally, natural product γ-lycorane could be prepared from bicyclic intermediate 1h through a photo-promoted cyclization/oxidation cascade. Our findings will facilitate the novel synthetic approaches to benzylphenethylamine-type alkaloids.

All reactions were carried out under an atmosphere of argon in dry flask, and were monitored by analytical thin-layer chromatography (TLC), which was visualized by UV light (254 nm). All solvents were obtained from commercial sources and were purified according to standard procedures. Ozonolysis was performed on a Lanzihuan LZH-205 ozonator (120 W) with oxygen inlet (3 L/min). Irradiation experiments was performed on a SDAG OG-S801 UV light (36 W) or OSRAM HQL high-pressure mercury lamp (250 W). Melting points were obtained on a SGW® X-4B apparatus (cover glass) and are uncorrected. Purification of products was accomplished by flash column chromatography using silica gel (200–300 mesh) or basic alumina (200–300 mesh). All NMR spectra were recorded with a Bruker AVANCE III 500 MHz or AVANCE III 600 MHz (1H NMR) spectrometer and 125 MHz or 150 MHz (13C NMR) in CDCl3; the solvent signals were used as reference (CDCl3: δC= 77.2; residual CHCl3 in CDCl3: δH = 7.26). HRMS (ESI) data were recorded on an Agilent 6540 Q-TOF spectrometer. IR spectroscopy was performed with KBr pellets on an Affinity-1S spectrophotometer (Agilent).


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3-Methoxycyclohex-2-en-1-one (6b)

According to the literature,[13b] cyclohexa-1,3-dione (6a; 5.0 g, 39.7 mmol), methanol (8 mL, 198.5 mmol), and pTSA·H2O (75.0 mg, 0.4 mmol) were refluxed in toluene (20 mL) for 12 h. The solvent was evaporated, and EtOAc (40 mL) was added to dissolve the residue and it was washed with sat. aq NaHCO3 solution (20 mL × 3). The aqueous solution was extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine, dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure to give 6b as yellow oil in quantitative yield, which was directly used in the next step without purification; Rf = 0.35 (petroleum ether/EtOAc 2:1).

IR (KBr): 2960, 2931, 1644, 1603, 1376, 1221, 1135, 1005, 853 cm–1.

1H NMR (500 MHz): δ = 5.34 (s, 1 H), 3.66 (s, 3 H), 2.38 (t, J = 6.3 Hz, 2 H), 2.32 (dd, J = 7.2, 6.0 Hz, 2 H), 1.98–1.93 (m, 2 H).

13C NMR (125 MHz): δ = 199.9, 178.8, 102.4, 55.7, 36.8, 28.9, 21.3.

HRMS (ESI): m/z [M + H]+ calcd for C7H11O2: 127.0754; found: 127.0753.


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3-(Methylamino)cyclohex-2-en-1-one (6c)

According to the literature,[19] cyclohexa-1,3-dione (6a; 100 mg, 0.89 mmol) was dissolved in AcOH (1 mL), and NH2Me (0.76 mL, 2 M in THF, 1.52 mmol) was added. The reaction was sealed and stirred at 90 °C for 33 h. The solvent was evaporated, Flash chromatography of the residue (silica gel, DCM/MeOH 30:1) gave 6c (91 mg, 82%) as a yellow amorphous powder; Rf = 0.55 (DCM/MeOH 7:1).

IR (KBr): 3357, 3248, 3083, 1657, 1543, 1195, 764, 520 cm–1.

1H NMR (500 MHz): δ = 5.59 (brs, 1 H), 5.05 (s, 1 H), 2.76 (d, J = 5.0 Hz, 3 H), 2.34 (t, J = 6.2 Hz, 2 H), 2.28 (t, J = 6.5 Hz, 2 H), 1.93 (p, J = 6.4 Hz, 2 H).

13C NMR (125 MHz): δ = 197.3, 166.2, 96.1, 36.5, 29.6, 29.6, 22.1.

HRMS (ESI): m/z [M + H]+ calcd for C7H12NO: 126.0913; found: 126.0914.


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3-((2-Hydroxyethyl)(methyl)amino)cyclohex-2-en-1-one (7d)

Cyclohexa-1,3-dione (6a; 200 mg, 1.79 mmol) was dissolved in AcOH (2 mL), and 2-(methylamino)ethan-1-ol (0.31 mL, 3.81 mmol) was added, and the reaction was sealed and stirred at 90 °C for 21 h. The AcOH was evaporated, and then MeOH (2 mL) was added followed by K2CO3 (247 mg, 1.79 mmol). The reaction was stirred at rt for 2 h. The mixture was filtered through Celite® and concentrated under reduced pressure. Flash chromatography of the residue (silica gel, DCM/MeOH 10:1) gave 7d as yellow oil in quantitative yield; Rf = 0.45 (DCM/MeOH 7:1).

IR (KBr): 2948, 2883, 1541, 1418, 1191, 1051, 811, 639 cm–1.

1H NMR (500 MHz): δ = 5.10 (s, 1 H), 4.26 (brs, 1 H), 3.73 (t, J = 5.6 Hz, 2 H), 3.43 (t, J = 5.6 Hz, 2 H), 2.97 (s, 3 H), 2.48 (t, J = 6.4 Hz, 2 H), 2.19 (t, J = 6.5 Hz, 2 H), 1.91 (p, J = 6.4 Hz, 2 H).

13C NMR (125 MHz): δ = 197.2, 167.0, 98.3, 59.5, 54.1, 38.8, 35.3, 26.9, 22.1.

HRMS (ESI): m/z [M + H]+ calcd for C9H16NO2: 170.1176; found: 170.1176.


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2-(Methyl(3-oxocyclohex-1-en-1-yl)amino)ethyl Methanesulfonate (8a)

To a solution of 7d (100 mg, 0.59 mmol) in dry DCM (2 mL) was added triethylamine (0.16 mL, 1.18 mmol) at 0 °C followed by addition of methanesulfonyl chloride (69 μL, 0.89 mmol), and the mixture was allowed to warm up to rt and stirred for 1 h. The reaction was diluted with water (10 mL) and extracted with DCM (10 mL × 5). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography of the residue (silica gel, DCM/MeOH 30:1) gave 8a (131 mg, 90%) as a yellow oil; Rf  = 0.50 (DCM/MeOH 7:1).

IR (KBr): 3010, 2935, 1601, 1558, 1351, 1271, 1174, 969, 527 cm–1.

1H NMR (500 MHz): δ = 5.14 (s, 1 H), 4.32 (t, J = 6.1 Hz, 2 H), 3.64 (t, J = 6.1 Hz, 2 H), 3.01 (s, 6 H), 2.46 (t, J = 6.2 Hz, 2 H), 2.26 (t, J = 6.5 Hz, 2 H), 2.01–1.94 (m, 2 H).

13C NMR (125 MHz): δ = 197.2, 165.1, 99.8, 66.1, 50.8, 39.0, 37.8, 35.6, 26.9, 22.1.

HRMS (ESI): m/z [M + H]+ calcd for C10H18NO4S: 248.0951; found: 248.0947.


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((2-Iodoethyl)(methyl)amino)cyclohex-2-en-1-one (8b)

A solution of 8a (30 mg, 0.12 mmol) and NaI (45.0 mg, 0.3 mmol) in acetone (2 mL) was refluxed for 12 h. The reaction was diluted with water (5 mL) and extracted with DCM (10 mL × 3). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography of the residue (silica gel, DCM/MeOH 30:1) gave 8b (29.4 mg, 89%) as a yellow oil; Rf = 0.50 (DCM/MeOH 10:1).

IR (KBr): 2948, 2883, 1593, 1541, 1415, 1265, 1167, 934, 811 cm–1.

1H NMR (500 MHz): δ = 5.18 (s, 1 H), 3.64 (t, J = 7.7 Hz, 2 H), 3.19 (t, J = 7.7 Hz, 2 H), 2.98 (s, 3 H), 2.45 (t, J = 6.2 Hz, 2 H), 2.28 (t, J = 6.5 Hz, 2 H), 2.00 (p, J = 6.4 Hz, 2 H).

13C NMR (125 MHz): δ = 197.3, 164.4, 99.7, 54.2, 38.2, 35.6, 26.8, 22.2, 0.1.

HRMS (ESI): m/z [M + H]+ calcd for C9H15INO: 280.0193; found: 280.0190.


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4-Methyl-1,2,3,5,6,7-hexahydro-4H-indol-4-one (9a); Scheme [2b], Entry 2

To a solution of 8a (60 mg, 0.24 mmol) in dry THF (2 mL) was added dropwise of LiHMDS (0.36 mL, 1 M in THF, 0.36 mmol) at 0 °C. After stirring at 0 °C for 0.5 h, the reaction was allowed to warm up to rt and stirring for 20 h. The reaction was quenched with water (1 mL), diluted with water (5 mL), and the aqueous solution was extracted with DCM (5 mL × 3). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. Silica gel was soaked with diethylamine/DCM (1:100) for 10 min, and flash chromatography of the residue over the silica gel using DCM/MeOH (30:1) gave 9a (7.2 mg, 20%) as a yellow oil (for detailed procedures for Scheme [2], see the Supporting Information); Rf = 0.40 (DCM/MeOH 10:1).

IR (KBr): 2939, 2868, 1523, 1415, 1295, 1191, 978, 641 cm–1.

1H NMR (500 MHz): δ = 3.56–3.50 (m, 2 H), 2.90 (s, 3 H), 2.76 (t, J = 9.6 Hz, 2 H), 2.34–2.30 (m, 2 H), 2.30–2.27 (m, 2 H), 1.98 (p, J = 6.4 Hz, 2 H).

13C NMR (125 MHz): δ = 190.3, 169.6, 109.6, 54.5, 35.3, 33.4, 24.2, 22.7, 22.3.

HRMS (ESI): m/z [M + H]+ calcd for C9H14NO: 152.1070; found: 152.1067.


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3-Allylcyclohexane-1,3-dione (6) from 6a

According to the literature,[10] to a solution of cyclohexa-1,3-dione (6a; 1.0 g, 8.9 mmol) in dry THF/HMPA (20 mL, 4:1) was added dropwise LDA (8.9 mL, 2 M in 22% THF/35% n-heptane/14% ethylbenzene, 17.8 mmol) at –78 °C. After stirring for 1 h at –78 °C, the reaction was warmed to –40 °C, and 3-bromoprop-1-ene (0.8 mL, 9.3 mmol) was added quickly by syringe. The reaction was allowed to warm up to rt and stirred for 10 h. The reaction was diluted with 5% aq HCl (20 mL), and the aqueous phase was extracted with Et2O (20 mL × 3). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography of the residue (silica gel, petroleum ether/EtOAc 1:1) gave 6 (0.95 g, 70%) as yellow oil.


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3-Allylcyclohexane-1,3-dione (6) from 11b

To a solution of 11b (5.0 g, 30.1 mmol) in EtOAc (80 mL) was added 2N HCl (40 mL, 80.0 mmol), and the reaction was refluxed for 11 h. NaHCO3 powder was added portionwise to the reaction until no bubbles were produced at 0 °C. EtOAc (30 mL) was added to the mixture, and the organic layer was washed with sat. aq NaHCO3 solution (15 mL × 3). The aqueous solutions were extracted with EtOAc (10 mL × 5). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography of the residue (silica gel, petroleum ether/EtOAc 1:1) gave 6 (4.2 g, 92%); Rf = 0.3 (petroleum ether/EtOAc 1:1).

IR (KBr): 2935, 1575, 1415, 1346, 1267, 1193, 915, 848 cm–1.

1H NMR (600 MHz): δ = 5.83–5.72 (m, 1 H), 5.46 (s, 0.35 H), 5.13–5.03 (m, 2 H), 3.49–3.37 (m, 1.28 H), 2.73–2.61 (m, 1 H), 2.60–2.54 (m, 1 H), 2.48–2.34 (m, 1 H), 2.23–2.01 (m, 2 H), 1.81–1.52 (m, 1 H).

13C NMR (150 MHz): δ = 204.3, 204.3, 136.0, 135.1, 117.7, 117.3, 104.3, 58.4, 49.0, 41.8, 39.8, 34.6, 33.5, 30.0, 25.5, 24.0.

HRMS (ESI): m/z [M + H]+ calcd for C9H13O2: 153.0961; found: 153.0958.


#

6-Allyl-3-methoxycyclohex-2-en-1-one (11b)

To a solution of 6b (5.0 g, 39.7 mmol) in dry THF (60 mL) was added dropwise LiHMDS (47.6 mL, 1 M in THF, 47.6 mmol) at –78 °C. After stirring for 1 h at –78 °C, 3-bromoprop-1-ene (3.6 mL, 41.7 mmol) was added. The reaction was allowed to warm up to rt and stirred for 20 h. The reaction was quenched with water (10 mL), diluted with water (20 mL), and the aqueous solution was extracted with EtOAc (30 mL × 3). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography of the residue (silica gel, petroleum ether/EtOAc 8:1) gave 11b (5.5 g, 84%) as a yellow oil; Rf = 0.5 (petroleum ether/EtOAc 2:1).

IR (KBr): 3077, 2978, 2943, 1655, 1612, 1381, 1197, 841 cm–1.

1H NMR (500 MHz): δ = 5.83–5.72 (m, 1 H), 5.34 (s, 1 H), 5.09–4.99 (m, 2 H), 3.67 (s, 3 H), 2.67–2.60 (m, 1 H), 2.44–2.39 (m, 2 H), 2.28–2.21 (m, 1 H), 2.17–2.10 (m, 1 H), 2.10–2.02 (m, 1 H), 1.73–1.67 (m, 1 H).

13C NMR (125 MHz): δ = 200.7, 178.0, 136.5, 116.8, 102.0, 55.8, 44.8, 34.1, 28.0, 25.9.

HRMS (ESI): m/z [M + H]+ calcd for C10H15O2: 167.1067; found: 167.1069.


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3-Methoxycyclohept-2-en-1-one (10b)

According to the procedure for the synthesis of 6b, cycloheptane-1,3-dione (10a; 1.0 g, 7.9 mmol), methanol (2.4 mL), pTSA·H2O (30.4 mg, 0.16 mmol), and anhyd MgSO4 (5 g) were refluxed in toluene (10 mL) for 12 h. The mixture was filtered to remove MgSO4 and concentrated under reduced pressure. EtOAc (10 mL) was added to dissolve the residue, washed with sat. aq NaHCO3 solution (10 mL × 3). The aqueous solution was extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine, dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure to give the oily residue which was purified by flash chromatography (silica gel, DCM/acetone 50:1) to give 10b (0.77 g, 70%) as colorless oil; Rf = 0.60 (DCM/acetone 20:1).

IR (KBr): 1608, 1456, 1377, 1202, 1141, 995, 822, 563 cm–1.

1H NMR (500 MHz): δ = 5.38 (s, 1 H), 3.60 (s, 3 H), 2.59–2.53 (m, 4 H), 1.86–1.77 (m, 4 H).

13C NMR (125 MHz): δ = 202.4, 176.9, 105.6, 55.9, 41.9, 33.0, 23.7, 21.5.

HRMS (ESI): m/z [M + H]+ calcd for C8H13O2: 141.0910; found: 141.0907.


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7-Allyl-3-methoxycyclohept-2-en-1-one (10c)

According to the procedure for the synthesis of 11b, to a solution of 10b (300.0 mg, 2.14 mmol) in dry THF (7 mL) was added dropwise LiHMDS (2.6 mL, 1 M in THF, 2.57 mmol) at –78 °C. After stirring for 1 h at –78 °C, 3-bromoprop-1-ene (0.22 mL, 2.57 mmol) was added. The reaction was allowed to warm up to rt and stirred for 20 h. The reaction was quenched with water (2 mL), diluted with water (10 mL), and the aqueous solution was extracted with EtOAc (10 mL × 3). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography of the residue (silica gel, petroleum ether/EtOAc 8:1) gave 11b (215.7 mg, 56%) as a slightly yellow oil; Rf = 0.68 (petroleum ether/EtOAc 2:1).

IR (KBr): 1648, 1610, 1381, 1191, 997, 913, 841, 643 cm–1.

1H NMR (500 MHz): δ = 5.85–5.73 (m, 1 H), 5.39 (s, 1 H), 5.03 (dq, J = 17.3, 1.9 Hz, 1 H), 4.99 (ddt, J = 10.2, 2.2, 1.1 Hz, 1 H), 3.60 (s, 3 H), 2.69–2.55 (m, 3 H), 2.47–2.38 (m, 1 H), 2.13–2.05 (m, 1 H), 1.96–1.85 (m, 2 H), 1.75–1.65 (m, 1 H), 1.48–1.40 (m, 1 H).

13C NMR (125 MHz): δ = 202.7, 177.0, 137.1, 116.2, 105.7, 55.7, 49.3, 35.6, 33.1, 28.4, 23.5.

HRMS (ESI): m/z [M + H]+ calcd for C11H17O2: 181.1223; found: 181.1218.


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4-Allylcycloheptane-1,3-dione (10)

According to the procedure for the synthesis of 6, to a solution of 10c (468.0 mg, 2.6 mmol) in EtOAc (10 mL) was added 2 N HCl (13 mL, 26.0 mmol) and the mixture was stirred at rt for 18 h. NaHCO3 powder was added portionwise to the reaction until no bubbles were produced at 0 °C. EtOAc (5 mL) was added to the mixture, and the organic layer was washed with sat. aq NaHCO3 solution (10 mL × 3). The aqueous solutions were extracted with EtOAc (10 mL × 5). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography of the residue (silica gel, petroleum ether/EtOAc 8:1) gave 10 (401 mg, 93%) as a slightly yellow oil; Rf = 0.60 (petroleum ether/EtOAc 2:1).

IR (KBr): 1720, 1700, 1448, 1340, 1219, 1141, 999, 919 cm–1.

1H NMR (500 MHz): δ = 5.74–5.64 (m, 1 H), 5.07–5.00 (m, 2 H), 3.54 (s, 2 H), 2.72–2.63 (m, 1 H), 2.59–2.50 (m, 2 H), 2.50–2.46 (m, 1 H), 2.13–2.04 (m, 2 H), 2.04–1.98 (m, 1 H), 1.94–1.83 (m, 1 H), 1.66–1.55 (m, 1 H).

13C NMR (125 MHz): δ = 206.9, 205.3, 135.4, 117.3, 67.2, 59.6, 52.6, 43.6, 35.3, 32.0, 23.7.

HRMS (ESI): m/z [M + H]+ calcd for C10H15O2: 167.1067; found: 167.1072.


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1-Methyl-1,2,3,3a,4,5-hexahydro-6H-indol-6-one (1f)


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Table [1], Entry 1

To a solution of 6 (50 mg, 0.33 mmol) in DCM (10 mL) was bubbled with O3 by using an ozone generator at –78 °C for 1 min. After stirring for 1 min at –78 °C, Me2S (242 μL, 3.3 mmol) was added at –78 °C, and the reaction was allowed to warm up to rt and stirred for 2 h. Then NH2Me (0.17 mL, 2 M in THF, 0.33 mmol) and NaBH3CN (20.8 mg, 0.33 mmol) were added to the reaction at 0 °C, and the mixture was stirred at 0 °C for 5 h. The DCM was evaporated, and AcOH (3 mL) was added to dissolve the residue. The reaction was sealed and stirred at 90 °C for 12 h, then AcOH was evaporated and the reaction diluted with water (5 mL) and extracted with DCM (10 mL × 5). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. Silica gel was soaked with diethylamine/DCM (1:100) for 10 min, and flash chromatography of the residue over the silica gel using DCM/MeOH (30:1) gave 1f (4.2 mg, 13%) as a yellow oil; Rf = 0.40 (DCM/MeOH 10:1).

IR (KBr): 2939, 2872, 1556, 1416, 1305, 1254, 800, 434 cm–1.

1H NMR (500 MHz): δ = 4.95 (s, 1 H), 3.55 (td, J = 10.5, 6.0 Hz, 1 H), 3.39 (t, J = 9.5 Hz, 1 H), 2.84 (s, 3 H), 2.39–2.25 (m, 2 H), 2.21–2.14 (m, 2 H), 2.14–2.08 (m, 1 H), 1.68–1.57 (m, 2 H).

13C NMR (125 MHz): δ = 196.4, 170.7, 91.8, 54.7, 42.2, 36.2, 32.6, 28.9, 28.5.

HRMS (ESI): m/z [M + H]+ calcd for C9H14NO: 152.1070; found: 152.1067.


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Table [1], Entry 2

Following the procedure of entry 1, the time of reduction amination was reduced to 2 h, 10% of 1f was obtained.


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Table [1], Entry 3

Following the procedure of entry 1, the time of ozonolysis was extended to 5 min. TLC analysis revealed that the starting material had decomposed.


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Table [1], Entry 4

Following the procedure of entry 1, using DCM/MeOH (10 mL, 5:1) as the co-solvents of ozonolysis, TLC analysis revealed that the starting material had decomposed.


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Table [1], Entry 5

Following the procedure of entry 1, after the ozonolysis was complete (1 min), Me2S (242 μL, 3.3 mmol) was added at –78 °C, and the reaction was allowed to warm up to rt and stirred for 2 h. Then the solvent DCM was evaporated, the residue was dissolved in THF (4 mL), and MeNH2·HCl (33.4 mg, 0.495 mmol) was added and the mixture was stirred at rt for 8 h. After that, NaBH3CN (41.6 mg, 0.66 mmol) were added to the reaction and it was stirred at rt for additional 12 h. The mixture was diluted with water (5 mL) and extracted with DCM (10 mL × 5). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. Silica gel was soaked with diethylamine/DCM (1:100) for 10 min, and flash chromatography of the residue over the silica gel using DCM/MeOH (30:1) gave 1f (13.7 mg, 28%).


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Table [1], Entry 6 (Scale-Up Experiment)

Following the procedure of entry 5 increasing the loading of 6 (200 mg, 1.32 mmol) in DCM (30 mL) gave 25% of 1f.


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Table [1], Entry 7

Following the procedure of entry 5 using 11b as the substrate, after the ozonolysis was complete (1 min), Me2S (242 μL, 3.3 mmol) was added at –78 °C, and the reaction was allowed to warm up to rt and stirred for 2 h. Then the solvent DCM was evaporated, the residue was dissolved in EtOAc (3 mL), and 2N HCl (2 mL) was added. The resulting mixture was stirred for at rt for 2 h. MeNH2·HCl (33.4 mg, 0.495 mmol) was added and the mixture was stirred at rt for 8 h. After that, NaBH3CN (41.6 mg, 0.66 mmol) was added to the reaction and it was stirred at rt for additional 12 h. The solvent was evaporated and the residue was diluted with water (5 mL) and extracted with DCM (10 mL × 5). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. Silica gel was soaked with diethylamine/DCM (1:100) for 10 min, and flash chromatography of the residue over the silica gel using DCM/MeOH (30:1) gave 1f in 8% yield.


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Table [1], Entry 8

Following the procedure of entry 7, changing the order of reductive amination/cyclization and hydrolysis. The TLC analysis revealed that the starting material had decomposed.


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Table [1], Entry 9

Following the procedure of entry 5 using 10 (50 mg, 0.3 mmol) as substrate, 40% of 1g was obtained as a yellow oil; Rf = 0.40 (DCM/MeOH 10:1).

IR (KBr): 1579, 1411, 1264, 1189, 1085, 923, 798, 649 cm–1.

1H NMR (500 MHz): δ = 5.09 (s, 1 H), 3.50–3.37 (m, 2 H), 3.15 (qd, J = 10.8, 6.4 Hz, 1 H), 2.82 (s, 3 H), 2.72–2.62 (m, 1 H), 2.50–2.41 (m, 1 H), 2.23 (ddt, J = 12.7, 8.6, 4.1 Hz, 1 H), 2.04–1.97 (m, 1 H), 1.89–1.82 (m, 2 H), 1.72–1.58 (m, 2 H).

13C NMR (125 MHz): δ = 199.2, 169.2, 96.0, 54.0, 43.9, 41.1, 33.8, 31.5, 29.0, 22.1.

HRMS (ESI): m/z [M + H]+ calcd for C10H16NO: 166.1226; found: 166.1229.


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Table [1], Entry 10

Following the procedure of entry 5 using piperonylamine hydrochloride (1.5 eq.) as nitrogen source, 23% of 1h was obtained as a yellow solid; mp 142–143 °C; Rf = 0.48 (DCM/MeOH 10:1).

IR (KBr): 2919, 1579, 1444, 1247, 1038, 924, 807, 731 cm–1.

1H NMR (500 MHz): δ = 6.75 (d, J = 7.7 Hz, 1 H), 6.68 (d, J = 7.6 Hz, 2 H), 5.94 (s, 2 H), 5.47 (s, 1 H), 4.35–4.23 (m, 2 H), 3.54–3.44 (m, 1 H), 3.45–3.36 (m, 1 H), 2.98–2.85 (m, 1 H), 2.59–2.49 (m, 1 H), 2.48–2.38 (m, 1 H), 2.24–2.13 (m, 2 H), 1.76–1.66 (m, 1 H), 1.65–1.55 (m, 1 H).

13C NMR (125 MHz): δ = 197.7, 173.2, 148.3, 147.6, 129.0, 121.6, 108.7, 108.3, 101.4, 92.9, 52.6, 49.9, 42.6, 35.9, 28.7, 28.3.

HRMS (ESI): m/z [M + H]+ calcd for C16H18NO3: 272.1281; found: 272.1283.


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Table [1], Entry 11

Following the procedure of entry 5 using 6-bromopiperonylamine hydrochloride (1.5 eq.) as nitrogen source, 16% of 1i was obtained as a white solid; mp 169–170 °C; Rf = 0.50 (DCM/MeOH 10:1).

IR (KBr): 3027, 2928, 1586, 1480, 1247, 1036, 937, 801 cm–1.

1H NMR (500 MHz): δ = 7.00 (s, 1 H), 6.62 (s, 1 H), 5.97 (s, 2 H), 5.32 (brs, 1 H), 4.45–4.35 (m, 2 H), 3.55–3.44 (m, 1 H), 3.44–3.36 (m, 1 H), 3.02–2.86 (m, 1 H), 2.57–2.36 (m, 2 H), 2.26–2.14 (m, 2 H), 1.76–1.59 (m, 2 H).

13C NMR (125 MHz): δ = 197.6, 171.5, 148.4, 148.0, 127.3, 114.3, 113.2, 109.0, 102.2, 93.3, 52.7, 50.0, 42.3, 36.0, 28.9, 28.4.

HRMS (ESI): m/z [M + H]+ calcd for C16H17BrNO3: 350.0386; found: 350.0383.


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1-(Benzo[d][1,3]dioxol-5-ylmethyl)-7-bromo-1,2,3,3a,4,5-hexahydro-6H-indol-6-one (1l)

To a solution of 1h (100 mg, 0.37 mmol) in DCM (3 mL) was added dropwise bromine/DCM (1:9; 190 μL, 0.37 mmol) at –20 °C and the mixture was stirred for 1 h. The reaction was quenched with sat. aq Na2S2O3 solution (5 mL), diluted with water (5 mL), and the aqueous solution was extracted with DCM (10 mL × 3). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography of the residue (silica gel, DCM/acetone 30:1) gave 1l (104.3 mg, 81%) as a white solid; mp 133–134 °C; Rf = 0.50 (DCM/acetone 10:1).

IR (KBr): 2928, 1627, 1545, 1260, 1043, 801, 693, 520 cm–1.

1H NMR (600 MHz, CDCl3): δ = 6.77 (d, J = 5.6 Hz, 2 H), 6.71 (d, J = 8.0 Hz, 1 H), 5.95 (d, J = 2.4 Hz, 2 H), 5.13–5.02 (m, 2 H), 3.52–3.44 (m, 1 H), 3.41–3.35 (m, 1 H), 3.08–3.00 (m, 1 H), 2.68 (d, J = 16.9 Hz, 1 H), 2.54–2.44 (m, 1 H), 2.15–2.07 (m, 2 H), 1.77–1.61 (m, 2 H).

13C NMR (150 MHz, CDCl3): δ = 189.7, 163.9, 148.2, 147.3, 130.5, 121.1, 108.4, 108.1, 101.3, 88.2, 54.3, 50.9, 47.4, 37.0, 28.3, 27.5.

HRMS (ESI): m/z [M + H]+ calcd for C16H17BrNO3: 350.0386; found: 350.0383.


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3,3a,4,5-Tetrahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridine-1,7(2H)-dione (12c)

A 10-mL round-bottom quartz flask was charged with a stir bar, 1l (10 mg, 0.029 mmol), triethylamine (28 μL, 0.197 mmol), and THF/H2O (10:1; 4 mL). The reaction was irradiated at 254 nm at rt for 4 h. The solvent was evaporated; flash chromatography of the residue (basic alumina, DCM/acetone 100:1) gave 12c (3.6 mg, 41%) as a white amorphous solid; Rf = 0.55 (DCM/acetone 10:1).

IR (KBr): 2924, 1634, 1433, 1247, 1034, 936, 882, 798 cm–1.

1H NMR (500 MHz): δ = 8.66 (s, 1 H), 7.70 (s, 1 H), 6.09 (s, 2 H), 4.51 (dd, J = 12.3, 8.8 Hz, 1 H), 3.99 (td, J = 12.0, 6.2 Hz, 1 H), 3.48 (tdd, J = 12.2, 7.4, 4.9 Hz, 1 H), 2.76–2.69 (m, 1 H), 2.67–2.59 (m, 1 H), 2.51 (dt, J = 13.0, 6.8 Hz, 1 H), 2.36 (dtd, J = 12.4, 4.9, 2.4 Hz, 1 H), 2.00–1.85 (m, 2 H).

13C NMR (125 MHz): δ = 195.4, 160.4, 158.6, 153.0, 147.5, 132.1, 120.9, 107.6, 105.4, 104.5, 102.1, 48.8, 42.0, 39.1, 29.6, 28.3.

HRMS (ESI): m/z [M + H]+ calcd for C16H14NO4: 284.0917; found: 284.0920.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1878-8597.
  • Supporting Information

Corresponding Authors

Rui Zhan
School of Chemistry and Chemical Engineering, Yunnan Normal University
798 Jvxian Street, Kunming, 650500
P. R. of China   

Li-Dong Shao
Yunnan Key Laboratory of Southern Medicinal Resources, School of Chinese Materia Medica, Yunnan University of Chinese Medicine
1076 Yuhua Road, Kunming, 650500
P. R. of China   

Publication History

Received: 27 May 2022

Accepted after revision: 20 June 2022

Accepted Manuscript online:
20 June 2022

Article published online:
11 August 2022

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Zoom Image
Figure 1 Representative natural products with 6H-indol-6-one cores and methods for their synthesis
Zoom Image
Scheme 1 Unsuccessful attempts to synthesis of cyclized precursors 7a–7c
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Scheme 2 Unsuccessful attempts to the cyclization of 8a and 8b (a), selected conditions for base screening (b)
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Scheme 3 Final synthetic route to 1-substituted 6H-indol-6-ones 1f–1i
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Scheme 4 Formal total synthesis of γ-lycorane