Cesium carbonate promoted cascade reaction involving DMF as a reactant for the synthesis of dihydropyrrolizino[3,2-b]indol-10-ones

Abstract

We presented a cesium carbonate promoted cascade reaction of N-tosyl-2-(2-bromophenylacetyl)pyrroles with DMF to synthesize dihydropyrrolizino[3,2-b]indol-10-ones. The transformation involved three successive bond formations without the aid of an exogenous transition metal catalyst or ligand.

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Introduction

Transition metal catalyzed cross-coupling reactions for carbon–carbon and carbon–heteroatom bond formation¹ have become the most powerful tool in modern organic synthesis. Despite the remarkable advances, however, transition metal catalyzed cross-coupling reactions still confront challenges such as expensiveness of metal catalysts and ligands, high catalyst loading, and difficulties in removing trace amounts of toxic transition metal residues from the products. Therefore, the development of transition metal free protocols to fulfill the classic transition metal catalyzed cross-coupling reactions is highly appealing.² Pioneered by Itami's initial report in 2008,^3a great progress has been made in the field of transition metal free biaryl couplings.³ However, there are only a few reports on transition metal free carbon–heteroatom bond forming reactions.⁴

N,N-Dimethylformamide (DMF) is an aprotic polar solvent commonly employed in organic reactions. Besides, DMF has been used as a promising reagent in organic transformation as a source of various units such as –CN, –CHO, –CONMe₂, –OCHO, –NMe₂, –O, etc. in transition metal catalyzed reactions.^5,6 Herein, we report novel base promoted cascade reactions involving DMF as a reactant/solvent for the construction of dihydropyrrolizino[3,2-b]indol-10-ones.

Results and discussion

Previously, we developed a valuable approach toward the synthesis of 9H-pyrrolo[1,2-a]indol-9-ones via detosylation and in situ palladium catalyzed C–N bond formation of 2-bromophenyl N-tosylpyrrol-2-yl ketones.⁷ We further envisioned that under the reaction conditions, the one-carbon homologue 2-(2-bromophenyl)acetyl-N-tosylpyrroles, which was easily accessed by TFAA-mediated acylation of N-tosylpyrrole with 2-(2-bromophenyl)acetic acids,⁸ might give rise to the formation of pyrrolo[1,2-a]quinolines, a class of compounds possessing important biological activities⁹ (Scheme 1). However, alkyne 2 was the only product obtained after heating a mixture of 1, Pd(PPh₃)₄, Cs₂CO₃ and DMF at 120 °C for 12 h. Literature search indicated that a similar transformation was previously reported.¹⁰

Scheme 1 Synthesis of alkyne 2.

To bypass alkyne formation, we next subjected 3a to the aforementioned reaction conditions (Scheme 2). The reaction proceeded cleanly and resulted, quite surprisingly, in the formation of dihydropyrrolizino[3,2-b]indol-10-one 4a in 82% isolated yield. The structure of 4a was unambiguously confirmed by X-ray single crystal diffraction,¹¹ and no trace of the 4a,9b-trans isomer was evident by NMR. Repetition of the reaction in deuterated DMF clearly indicated that the product 4a-D arose from the reaction of 3a with the solvent (Fig. 1).

Scheme 2 Synthesis of dihydropyrrolizino[3,2-b]indol-10-one 4a.

Fig. 1 Deuterated product 4a-D.

Inspired by the results, we then turned our attention to the synthesis of dihydropyrrolizino[3,2-b]indol-10-ones. Using 3a as a substrate, the results for reaction condition optimization are shown in Table 1. The reaction proceeded smoothly in the presence of a variety of palladium catalysts and Cs₂CO₃ as the base to give 4a in good to excellent isolated yields (entries 1–5). It was subsequently found that Cs₂CO₃ alone, without any exogenous palladium catalyst, could efficiently promote the reaction to provide 4a in 72% isolated yield, together with a small amount of dihydropyrrolizinone 5 (entry 6). The relative stereochemistry of 5 was assigned on the basis of NOE correlation. Extension of the reaction time to 24 h resulted in the exclusive formation of 4a in 87% isolated yield (entry 7). Furthermore, the isolated 5 could be transformed into 4a by exposure to the reaction conditions, indicating that 5 was an intermediate for the formation of 4a from 3a (Scheme 3). The bases were then screened and Cs₂CO₃ remained the best choice (entries 7–12). With Cs₂CO₃ as the optimized base, it was found that the reaction could hardly be driven to completion at temperatures below 120 °C (entries 13–15). Although elevated temperature favored the formation of 4a, no improvement was observed at a temperature higher than 120 °C (entry 16 vs. 7).

Scheme 3 Transformation of compound 5 to 4a.

Table 1 Optimization of reaction conditions for the synthesis of dihydropyrrolizino[3,2-b]indol-10-one 4a

Entry	Catalyst^a	Base^b	Temp. (°C)	4a Yield^c (%)	5 Yield^c (%)
a 0.05 equiv. b 2.0 equiv. c Isolated yield. d Reaction time: 12 h. e Reaction time: 24 h. f The starting material was completely reacted. g No reaction, starting material recovered. h 10% starting material recovered. i Another product was also isolated (structure not determined), which on heating could be transformed into 5 (80 °C) or 4a (120 °C).
1^d	Pd(PPh3)4	Cs2CO3	120	82	—
2^d	Pd2(dba)3	Cs2CO3	120	84	—
3^d	Pd[P(^tBu)3]2	Cs2CO3	120	63	—
4^d	Pd(PPh3)2Cl2	Cs2CO3	120	80	—
5^d	Pd(dppf)Cl2	Cs2CO3	120	63	—
6^d	—	Cs2CO3	120	72	7
7^e	—	Cs2CO3	120	87	—
8^e	—	K2CO3	120	67	—
9^e^,^f	—	KO^tBu	120	—	—
10^e^,^g	—	DBU	120	—	—
11^e^,^h	—	K3PO4	120	40	—
12^e	—	LiHMDS	120	20	—
13^e^,^i	—	Cs2CO3	80	—	28
14^e	—	Cs2CO3	100	41	20
15^e	—	Cs2CO3	110	72	14
16^e	—	Cs2CO3	130	86	—

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Next, the substrate scope was explored and the results are shown in Table 2. When the methyl substituent in 3a was replaced with a more bulky ethyl, benzyl or 2-bromobenzyl group, the products 4b–d could be obtained in excellent yields. The structure of 4d was unambiguously confirmed by X-ray single crystal diffraction¹² and no trace of the alternative [6-6-5-5]-tetrahydropyrrolizino[3,2-b]quinolin-11-one was observed. The reaction of the substrate with a 3-azidopropyl group was less satisfactory and gave a mixture of products from which 4e was isolated in 32% yield. Under the reaction conditions, both dimeric products 4f and 4g could be obtained eventlessly in moderate yield. A variety of substituted bromobenzene derivatives, as well as bromonaphthalene could all participate in the desired reaction to give 4h–m in good to excellent yields. It should be indicated that the substrate bearing two electron-donating methoxy groups reacted rather slowly. Apart from 4l (50%), 28% of the intermediate 6 was also isolated. Substituted pyrrolyl derivative 4n could also be successfully synthesized, but in 42% isolated yield only, probably due to increased steric hindrance for the nucleophilic attack of pyrrolyl nitrogen to DMF.

Table 2 Substrate scope

Reaction conditions: 3a–n (0.4 mmol), Cs₂CO₃ (0.8 mmol), DMF (4 mL), 120 °C, nitrogen, 24 h.

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The limitations of the current method were revealed when we were testing the reaction of 3a with other amides. The reaction of 3a with the enolizable N,N-dimethylacetamide gave a mixture of products. The desired 4a′ could be isolated, but only in a disappointing 7% yield (Scheme 4). Another product separated from the reaction system was pyrrolo[1,2-a]quinolin-4-one 7 (15%). The reaction of 3a with N-methylformamide or N,N-dimethylbenzamide (dioxane as a solvent) also failed to deliver the desired dihydropyrrolizino[3,2-b]indol-10-ones. The detosylation product 8 (Scheme 5) was exclusively formed in the former case, while no isolable product could be obtained in the latter case.

Scheme 4 Results for the reaction of 3a with N,N-dimethylacetamide.

Scheme 5 Control experiments.

Finally, to gain a deep insight into the reaction mechanism, we carried out some control experiments (Scheme 5). First, the unprotected acylpyrrole 8 did not react with DMF under the reaction conditions to provide any trace of 4a or 5, indicating that the tosyl protecting group is crucial to the formation of 5. Second, the reaction of 9 with DMF gave rise to the formation of dihydropyrrolizinone 10 (28%), together with 15% of the unreacted starting material recovered. No trace of 4a was observed. This result ruled out the mechanism for C–N bond formation via a benzyne intermediate. Third, when the reaction of 3a with DMF was performed in the presence of a radical scavenger (TEMPO), the yield of the product 4a was not reduced. This result ruled out the mechanism for C–N bond formation via a radical pathway.

Based on the results obtained above, a plausible mechanism is depicted in Scheme 6. The enolization of 3a provided I which attacked DMF to give intermediate II. Intramolecular tosyl group transfer and nucleophilic substitution provided 5 in which the methyl and dimethylamino groups were in a cis relationship. 5 was in equilibrium with the sterically disfavored III. Once III was formed, the dimethylamino group was in an ideal position to displace the bromide following a typical S_NAr mechanism to give V.^4d,g,13 Finally, nucleophilic attack of the methyl group attached on nitrogen with the displaced bromide or base furnished 4a.

Scheme 6 Proposed mechanism.

Conclusions

In summary, we have developed an efficient and environmentally friendly Cs₂CO₃-mediated cascade reaction for the synthesis of dihydropyrrolizino[3,2-b]indol-10-ones. The reaction mechanism involved consecutive nucleophilic attack of DMF with enolate and pyrrolyl nitrogen, followed by transition metal free C–N bond formation.

Experimental section

General

Melting points were determined on an XT4A hot-stage apparatus and are uncorrected. IR spectra were obtained using a PerkinElmer FT/IR spectrometer. ¹H and ¹³C NMR spectra were obtained on an Agilent AV400 instrument. High-resolution mass spectra were recorded on a Micromass Q-TOF mass spectrometer. The X-ray diffraction (XRD) patterns of the samples were recorded on a Rigaku B/Max-RB diffractometer.

2-[(2-Bromophenyl)ethynyl]-1H-pyrrole (2)

A mixture of 2-(2-bromophenyl)-1-(1-tosyl-1H-pyrrol-2-yl)ethan-1-one (167 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol), Pd(PPh₃)₄ (5 mg, 0.004 mmol) and DMF (4.0 mL) under nitrogen was heated at 120 °C for 12 h. The cooled mixture was partitioned between EtOAc (10 mL) and H₂O (20 mL). The separated aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (30 mL), then dried (Na₂SO₄), filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (5% EtOAc in petroleum ether) to afford 2 (72 mg, 73%) as a gray oil; ¹H NMR (CDCl₃, 400 MHz): δ = 8.45 (s, 1H), 7.58 (dd, J = 8.1, 0.9 Hz, 1H), 7.49 (dd, J = 7.7, 1.6 Hz, 1H), 7.26 (m, 1H), 7.14 (td, J = 7.8, 1.6 Hz, 1H), 6.82 (m, 1H), 6.60 (m, 1H), 6.24 (m, 1H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 132.9, 132.5, 129.2, 127.2, 125.6, 125.0, 120.2, 115.6, 112.7, 109.8, 89.3, 86.7 ppm; IR (neat, cm⁻¹) ν_max 3416, 2204, 1431, 1043, 1088, 1025; HRMS (ESI): m/z calcd for C₁₂H₉⁷⁹BrN [M + H]⁺: 245.9913; found 245.9917.

General procedure for the preparation of 4a–n, 5, 6 and 10

A sealed tube was charged with 2-(2-bromophenyl)-1-(N-tosyl-2-pyrrolyl)propan-1-one (1.0 mmol), Cs₂CO₃ (2.0 mmol) and DMF (10 mL). The reaction system was recharged with nitrogen three times. The reaction mixture was heated at 120 °C for 24 h and cooled. The mixture was partitioned between EtOAc (20 mL) and H₂O (40 mL). The separated aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (100 mL), then dried (Na₂SO₄), filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc) to afford the products 4a–n, 5, 6 and 10.

5,9b-Dimethyl-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one (4a)

The title compound was prepared according to the general procedure by stirring a mixture of 2-(2-bromophenyl)-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (173 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to afford 4a (83 mg, 87%) as a colorless solid; mp 145–146 °C; ¹H NMR (DMSO-d₆, 400 MHz): δ = 7.59 (d, J = 0.8 Hz, 1H), 7.17 (d, J = 7.3 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.71–6.68 (m, 2H), 6.58 (dd, J = 3.6, 2.4 Hz, 1H), 6.52 (d, J = 7.9 Hz, 1H), 5.92 (s, 1H), 3.16 (s, 3H), 1.52 (s, 3H) ppm; ¹³C NMR (DMSO-d₆, 100 MHz): δ = 188.8, 148.5, 130.4, 129.2, 128.8, 123.9, 122.7, 118.1, 117.2, 107.9, 106.5, 83.2, 62.0, 31.8, 20.1 ppm; IR (neat, cm⁻¹) ν_max 1688, 1493, 1360, 1279, 1217, 1048; HRMS (ESI): m/z calcd for C₁₅H₁₄N₂ONa [M + Na]⁺: 261.0998; found 261.0996.

9b-Methyl-5-(methyl-d₃)-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one-4a-d (4a-D)

The title compound was prepared according to the general procedure by stirring a mixture of 2-(2-bromophenyl)-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (173 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF-d₇ (2.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to afford 4a-D (74 mg, 76%) as a colorless solid; mp 132–133 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.36 (dd, J = 7.4, 0.8 Hz, 1H), 7.17–7.12 (m, 2H), 6.76 (td, J = 7.5, 0.9 Hz, 1H), 6.73 (dd, J = 3.9, 1.0 Hz, 1H), 6.54 (dd, J = 3.9, 2.3 Hz, 1H), 6.42 (d, J = 7.9 Hz, 1H), 5.61 (s, 0.34H), 1.64 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 189.5, 148.4, 131.5, 129.4, 129.0, 123.6, 122.2, 119.0, 117.6, 108.7, 106.4, 83.8 (t, J_D–C = 25.4 Hz), 62.8, 31.4 (m), 20.6 ppm; IR (neat, cm⁻¹) ν_max 1688, 1601, 1487, 1359, 1288, 1047, 1011; HRMS (ESI): m/z calcd for C₁₅H₁₀D₄N₂ONa [M + Na]⁺: 265.1249; found 265.1246.

9b-Ethyl-5-methyl-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one (4b)

The title compound was prepared according to the general procedure by stirring a mixture of 2-(2-bromophenyl)-1-(1-tosyl-1H-pyrrol-2-yl)butan-1-one (179 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to afford 4b (94 mg, 93%) as a colorless solid; mp 137–138 °C; ¹H NMR (DMSO-d₆, 400 MHz): δ = 7.60 (d, J = 1.8 Hz, 1H), 7.16–7.10 (m, 2H), 6.70–6.66 (m, 2H), 6.57 (dd, J = 3.8, 2.4 Hz, 1H), 6.51 (d, J = 7.8 Hz, 1H), 6.05 (s, 1H), 3.15 (s, 3H), 2.05 (dq, J = 14.4, 7.2 Hz, 1H), 1.90 (dq, J = 14.4, 7.2 Hz, 1H), 0.77 (t, J = 7.4 Hz, 3H) ppm; ¹³C NMR (DMSO-d₆, 100 MHz): δ = 188.6, 149.0, 131.0, 129.3, 127.2, 124.0, 122.8, 118.0, 117.1, 107.7, 106.5, 80.7, 67.1, 31.8, 26.7, 8.8 ppm; IR (neat, cm⁻¹) ν_max 1682, 1604, 1525, 1492, 1455, 1275, 1219; HRMS (ESI): m/z calcd for C₁₆H₁₆N₂ONa [M + Na]⁺: 275.1155; found 275.1156.

9b-Benzyl-5-methyl-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one (4c)

The title compound was prepared according to the general procedure by stirring a mixture of 2-(2-bromophenyl)-3-phenyl-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (203 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to afford 4c (112 mg, 89%) as a colorless solid; mp 154–155 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.49 (dd, J = 7.5, 1.2 Hz, 1H), 7.19–7.12 (m, 4H), 7.04–7.07 (m, 2H), 7.01 (dd, J = 2.2, 0.8 Hz, 1H), 6.81 (td, J = 7.5, 0.7 Hz, 1H), 6.68 (dd, J = 3.9, 0.8 Hz, 1H), 6.45 (dd, J = 3.9, 2.2 Hz, 1H), 6.38 (d, J = 7.9 Hz, 1H), 5.62 (s, 1H), 3.62 (d, J = 14.0 Hz, 1H), 3.12 (d, J = 14.0 Hz, 1H), 3.00 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 188.5, 148.7, 136.6, 132.0, 129.7, 129.6, 128.5, 128.1, 127.0, 123.9, 122.4, 119.1, 117.4, 108.5, 107.0, 80.9, 68.2, 40.0, 32.5 ppm; IR (neat, cm⁻¹) ν_max 1697, 1487, 1367, 1281, 1222, 1061, 1024; HRMS (ESI): m/z calcd for C₂₁H₁₈N₂ONa [M + Na]⁺: 337.1311; found 337.1313.

9b-(2-Bromobenzyl)-5-methyl-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one (4d)

The title compound was prepared according to the general procedure by stirring a mixture of 2,3-bis(2-bromophenyl)-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (235 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to afford 4d (142 mg, 90%) as a colorless solid; mp 135–136 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.51 (dd, J = 7.9, 1.3 Hz, 1H), 7.46 (dd, J = 7.5, 0.9 Hz, 1H), 7.20–7.16 (m, 2H), 7.08 (td, J = 7.5, 1.4 Hz, 1H), 7.04–6.99 (m, 2H), 6.80 (td, J = 7.5, 0.8 Hz, 1H), 6.68 (dd, J = 3.9, 1.0 Hz, 1H), 6.45 (dd, J = 3.9, 2.3 Hz, 1H), 6.42 (d, J = 7.9 Hz, 1H), 5.76 (s, 1H), 3.82 (d, J = 14.2 Hz, 1H), 3.37 (d, J = 14.2 Hz, 1H), 3.11 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 188.1, 148.5, 136.3, 133.0, 132.0, 132.0, 129.8, 128.8, 128.0, 127.9, 125.4, 123.8, 122.5, 119.1, 117.5, 108.6, 107.0, 80.8, 68.2, 38.6, 32.6 ppm; IR (neat, cm⁻¹) ν_max 1698, 1488, 1365, 1277, 1215, 1021; HRMS (ESI): m/z calcd for C₂₁H₁₇⁷⁹BrN₂ONa [M + Na]⁺: 415.0416; found 415.0429.

9b-(3-Azidopropyl)-5-methyl-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one (4e)

The title compound was prepared according to the general procedure by stirring a mixture of 5-azido-2-(2-bromophenyl)-1-(1-tosyl-1H-pyrrol-2-yl)pentan-1-one (200 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (3% EtOAc in petroleum ether) to afford 4e (39 mg, 32%) as a colorless solid; mp 102–103 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.33 (dd, J = 7.4, 0.7 Hz, 1H), 7.18–7.14 (m, 2H), 6.77 (td, J = 7.4, 0.6 Hz, 1H), 6.73 (dd, J = 3.9, 0.8 Hz, 1H), 6.54 (dd, J = 3.9, 2.4 Hz, 1H), 6.42 (d, J = 7.9 Hz, 1H), 5.72 (s, 1H), 3.31–3.20 (m, 2H), 3.17 (s, 3H), 2.19–2.08 (m, 2H), 1.61–1.40 (m, 2H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 188.5, 148.7, 131.8, 129.7, 127.1, 123.7, 122.5, 119.2, 117.7, 108.8, 106.6, 81.8, 66.8, 51.4, 32.2, 31.4, 24.5 ppm; IR (neat, cm⁻¹) ν_max 2093, 1694, 1490, 1364, 1283, 1245, 1220, 1055; HRMS (ESI): m/z calcd for C₁₇H₁₇N₅ONa [M + Na]⁺: 330.1325; found 330.1340.

9b,9b′-(Hexane-1,6-diyl)bis[5-methyl-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one] (4f)

The title compound was prepared according to the general procedure by stirring a mixture of 2,9-bis(2-bromophenyl)-1,10-bis(1-tosyl-1H-pyrrol-2-yl)decane-1,10-dione (367 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (3% EtOAc in petroleum ether) to afford 4f (113 mg, 53%) as a colorless solid; mp 176–177 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.30 (d, J = 7.4 Hz, 2H), 7.15–7.11 (m, 4H), 6.74 (t, J = 7.5 Hz, 2H), 6.70 (dd, J = 3.9, 0.9 Hz, 2H), 6.52 (dd, J = 7.6, 2.3 Hz, 2H), 6.39 (dd, J = 7.8, 3.3 Hz, 2H), 5.70 (s, 2H), 3.16 (s, 6H), 2.10–1.90 (m, 4H), 1.28–1.17 (m, 8H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 189.3, 148.6, 131.9, 129.4, 127.8, 123.6, 122.3, 119.0, 117.5, 108.5, 106.4, 81.8, 67.4, 34.3, 32.3, 29.4, 24.5 ppm; IR (neat, cm⁻¹) ν_max 1691, 1278, 1121, 1054; HRMS (ESI): m/z calcd for C₃₄H₃₄N₄O₂Na [M + Na]⁺: 553.2574; found 553.2574.

9b,9b′-[1,4-Phenylenebis(methylene)]bis{5-methyl-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one} (4g)

The title compound was prepared according to the general procedure by stirring a mixture of 2-(2-bromophenyl)-3-(4-(2-(2-bromophenyl)-3-oxo-3-(1-tosyl-1H-pyrrol-2-yl)propyl)phenyl)-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (375 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (3% EtOAc in petroleum ether) to afford 4g (119 mg, 54%) as a colorless solid; mp 226–228 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.43 (d, J = 7.3 Hz, 2H), 7.13 (t, J = 7.6 Hz, 2H), 6.96 (m, 2H), 6.85 (s, 4H), 6.77 (t, J = 7.4 Hz, 2H), 6.66 (d, J = 3.7 Hz, 2H), 6.44 (m, 2H), 6.32 (d, J = 7.9 Hz, 2H), 5.49 (s, 2H), 3.47 (d, J = 14.0 Hz, 2H), 3.04 (d, J = 14.0 Hz, 2H), 2.90 (s, 6H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 188.4, 148.8, 135.1, 131.9, 129.7, 129.6, 127.9, 123.8, 122.3, 119.1, 117.4, 108.5, 107.0, 81.0, 68.1, 39.6, 32.6 ppm; IR (neat, cm⁻¹) ν_max 1687, 1607, 1497, 1359, 1280, 1225; HRMS (ESI): m/z calcd for C₃₆H₃₀N₄O₂Na [M + Na]⁺: 573.2261; found 573.2248.

8-Fluoro-5,9b-dimethyl-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one (4h)

The title compound was prepared according to the general procedure by stirring a mixture of 2-(2-bromo-5-fluorophenyl)-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (180 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to afford 4h (89 mg, 87%) as a colorless solid; mp 108–109 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.16 (dd, J = 2.4, 0.9 Hz, 1H), 7.09 (dd, J = 8.1, 2.6 Hz, 1H), 6.83 (td, J = 8.8, 2.4 Hz, 1H), 6.75 (dd, J = 3.9, 0.9 Hz, 1H), 6.56 (dd, J = 3.9, 2.4 Hz, 1H), 6.30 (dd, J = 8.6, 4.0 Hz, 1H), 5.62 (s, 1H), 3.16 (s, 3H), 1.63 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 188.8, 157.2 (d, J_F–C = 235.1 Hz), 144.6 (d, J_F–C = 1.4 Hz), 131.2, 130.4 (d, J_F–C = 8.3 Hz), 122.4, 117.8, 115.4 (d, J_F–C = 23.3 Hz), 111.3 (d, J_F–C = 24.9 Hz), 109.0, 106.7 (d, J_F–C = 8.1 Hz), 84.8, 62.8 (d, J_F–C = 2.0 Hz), 32.8, 20.5 ppm; IR (neat, cm⁻¹) ν_max 1693, 1494, 1364, 1288, 1265, 1225, 1056, 1008; HRMS (ESI): m/z calcd for C₁₅H₁₃FN₂ONa [M + Na]⁺: 279.0904; found 279.0896.

8-Chloro-5,9b-dimethyl-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one (4i)

The title compound was prepared according to the general procedure by stirring a mixture of 2-(2-bromo-5-chlorophenyl)-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (187 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to afford 4i (98 mg, 90%) as a colorless solid; mp 143–145 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.31 (d, J = 2.2 Hz, 1H), 7.16 (dd, J = 2.4, 0.9 Hz, 1H), 7.07 (dd, J = 8.4, 2.2 Hz, 1H), 6.73 (dd, J = 3.9, 0.9 Hz, 1H), 6.55 (dd, J = 3.9, 2.4 Hz, 1H), 6.30 (d, J = 8.4 Hz, 1H), 5.62 (s, 1H), 3.15 (s, 3H), 1.61 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 188.6, 147.0, 131.1, 130.6, 129.1, 123.8, 123.7, 122.4, 117.9, 109.0, 107.2, 84.3, 62.7, 32.3, 20.6 ppm; IR (neat, cm⁻¹) ν_max 1698, 1493, 1369, 1271, 1055; HRMS (ESI): m/z calcd for C₁₅H₁₃³⁵ClN₂ONa [M + Na]⁺: 295.0609; found 295.0606.

5,9b-Dimethyl-8-(trifluoromethyl)-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one (4j)

The title compound was prepared according to the general procedure by stirring a mixture of 2-(2-bromo-5-(trifluoromethyl)phenyl)-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (200 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to afford 4j (91 mg, 75%) as a colorless solid; mp 165–166 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.57 (d, J = 1.2 Hz, 1H), 7.40 (dd, J = 8.3, 1.2 Hz, 1H), 7.18 (dd, J = 2.4, 0.9 Hz, 1H), 6.75 (dd, J = 3.9, 0.9 Hz, 1H), 6.57 (dd, J = 3.9, 2.4 Hz, 1H), 6.42 (d, J = 8.3 Hz, 1H), 5.69 (s, 1H), 3.22 (s, 3H), 1.66 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 188.4, 150.8, 131.0, 129.3, 127.3 (q, J_F–C = 3.8 Hz), 124.9 (q, J_F–C = 269.1 Hz), 122.3, 120.9 (q, J_F–C = 32.4 Hz), 120.8 (q, J_F–C = 3.6 Hz), 118.1, 109.3, 105.6, 84.2, 62.5, 31.9, 20.8 ppm; IR (neat, cm⁻¹) ν_max 1696, 1618, 1321, 1279, 1095, 1068, 1056; HRMS (ESI): m/z calcd for C₁₆H₁₃F₃N₂ONa [M + Na]⁺: 329.0872; found 329.0873.

7-Fluoro-5,9b-dimethyl-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one (4k)

The title compound was prepared according to the general procedure by stirring a mixture of 2-(2-bromo-4-fluorophenyl)-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (180 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to afford 4k (95 mg, 93%) as a colorless solid; mp 164–165 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.25 (dd, J = 8.2, 5.5 Hz, 1H), 7.15 (dd, J = 2.3, 0.8 Hz, 1H), 6.75 (dd, J = 3.9, 0.8 Hz, 1H), 6.56 (dd, J = 3.9, 2.3 Hz, 1H), 6.41 (ddd, J = 9.5, 8.2, 2.3 Hz, 1H), 6.11 (dd, J = 9.8, 2.3 Hz, 1H), 5.64 (s, 1H), 3.16 (s, 3H), 1.62 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 189.2, 164.8 (d, J_F–C = 242.1 Hz), 149.9 (d, J_F–C = 11.9 Hz), 131.3, 124.5 (d, J_F–C = 2.2 Hz), 124.3 (d, J_F–C = 10.7 Hz), 122.1, 117.8, 109.0, 105.0 (d, J_F–C = 22.9 Hz), 94.6 (d, J_F–C = 27.4 Hz), 84.7, 62.3, 32.1, 20.8 ppm; IR (neat, cm⁻¹) ν_max 1691, 1495, 1244, 1219, 1092, 1051, 1017; HRMS (ESI): m/z calcd for C₁₅H₁₃FN₂ONa [M + Na]⁺: 279.0904; found 279.0906.

7,8-Dimethoxy-5,9b-dimethyl-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one (4l) and 2-(2-bromo-4,5-dimethoxyphenyl)-2-methyl-3-(dimethylamino)-2,3-dihydro-1H-pyrrolizin-1-one (6)

A mixture of 2-(2-bromo-4,5-dimethoxyphenyl)-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (197 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) was stirred at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (3% EtOAc in petroleum ether) to afford 4l (60 mg, 50%) and 6 (44 mg, 28%) both as colorless solids.

Compound 4l showed: mp 137–138 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.14 (d, J = 2.4 Hz, 1H), 6.96 (s, 1H), 6.73 (d, J = 3.8 Hz, 1H), 6.55 (dd, J = 3.8, 2.4 Hz, 1H), 6.09 (s, 1H), 5.57 (s, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.17 (s, 3H), 1.62 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 189.7, 150.9, 143.0, 142.8, 131.4, 122.2, 119.7, 117.5, 108.6, 108.4, 93.1, 85.1, 62.8, 57.1, 56.3, 33.3, 20.5 ppm; IR (neat, cm⁻¹) ν_max 1690, 1506, 1220, 1205, 1050, 1022; HRMS (ESI): m/z calcd for C₁₇H₁₉N₂O₃ [M + H]⁺: 299.1390; found 299.1386.

Compound 6 showed: mp 91–92 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.07 (s, 1H), 6.99 (d, J = 2.2 Hz, 1H), 6.83 (d, J = 3.9 Hz, 1H), 6.72 (s, 1H), 6.50 (dd, J = 3.9, 2.2 Hz, 1H), 5.75 (s, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 2.26 (s, 6H), 1.75 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 193.0, 148.3, 146.9, 134.6, 132.7, 123.6, 118.2, 116.4, 112.7, 112.6, 108.0, 84.1, 62.5, 56.2, 56.0, 40.4, 18.1 ppm; IR (neat, cm⁻¹) ν_max 1698, 1500, 1361, 1249, 1204, 1162; HRMS (ESI): m/z calcd for C₁₈H₂₂⁷⁹BrN₂O₃ [M + H]⁺: 393.0808; found 393.0818.

6b,12-Dimethyl-11a,12-dihydrobenzo[g]pyrrolizino[3,2-b]indol-7(6bH)-one (4m)

The title compound was prepared according to the general procedure by stirring a mixture of 2-(1-bromonaphthalen-2-yl)-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (193 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (3% EtOAc in petroleum ether) to afford 4m (81 mg, 70%) as a colorless solid; mp 216–218 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 8.02 (m, 1H), 7.78 (m, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.40–7.37 (m, 2H), 7.25 (m, 1H), 6.67 (dd, J = 3.9, 0.9 Hz, 1H), 6.53 (dd, J = 3.9, 2.4 Hz, 1H), 5.53 (s, 1H), 3.56 (s, 3H), 1.74 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 189.6, 145.6, 135.4, 130.5, 129.1, 127.2, 125.7, 125.2, 123.0, 122.8, 122.1, 121.2, 117.7, 108.3, 88.8, 63.8, 42.4, 21.7 ppm; IR (neat, cm⁻¹) ν_max 1687, 1362, 1303, 1277, 1058; HRMS (ESI): m/z calcd for C₁₉H₁₆N₂ONa [M + Na]⁺: 311.1155; found 311.1151.

3-Ethyl-5,9b-dimethyl-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one (4n)

The title compound was prepared according to the general procedure by stirring a mixture of 2-(2-bromophenyl)-1-(5-ethyl-1-tosyl-1H-pyrrol-2-yl)propan-1-one (184 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (3% EtOAc in petroleum ether) to afford 4n (45 mg, 42%) as a colorless solid; mp 71–72 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.39 (d, J = 7.4 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.82 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 3.9 Hz, 1H), 6.52 (d, J = 7.9 Hz, 1H), 6.34 (d, J = 3.9 Hz, 1H), 5.47 (s, 1H), 3.24 (s, 3H), 2.84 (q, J = 7.5 Hz, 2H), 1.64 (s, 3H), 1.37 (t, J = 7.5 Hz, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 188.8, 150.1, 139.5, 130.0, 129.9, 129.3, 123.6, 120.0, 115.3, 109.6, 108.8, 86.3, 63.6, 37.4, 22.4, 20.7, 12.8 ppm; IR (neat, cm⁻¹) ν_max 1687, 1487, 1355, 1274, 1260, 1222, 1017; HRMS (ESI): m/z calcd for C₁₇H₁₉N₂O [M + H]⁺: 267.1492; found 267.1494.

2-(2-Bromophenyl)-2-methyl-3-(dimethylamino)-2,3-dihydro-1H-pyrrolizin-1-one (5)

The title compound was prepared according to the general procedure by stirring a mixture of 2-(2-bromophenyl)-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (173 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 80 °C for 24 h. The crude product was purified by column chromatography on silica gel (3% EtOAc in petroleum ether) to afford 5 (37 mg, 28%) as a colorless solid; mp 130–132 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.62 (dd, J = 7.8, 1.4 Hz, 1H), 7.22–7.14 (m, 2H), 7.06 (td, J = 7.8, 2.0 Hz, 1H), 6.98 (dd, J = 2.2, 1.0 Hz, 1H), 6.83 (dd, J = 4.0, 1.0 Hz, 1H), 6.49 (dd, J = 4.0, 2.2 Hz, 1H), 5.74 (s, 1H), 2.26 (s, 6H), 1.78 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 191.8, 141.5, 134.7, 131.8, 128.7, 127.8, 126.8, 122.5, 121.9, 115.4, 107.1, 82.9, 62.0, 39.4, 17.0 ppm; IR (neat, cm⁻¹) ν_max 1684, 1362, 1053, 1038, 1016; HRMS (ESI): m/z calcd for C₁₆H₁₇⁷⁹BrN₂ONa [M + Na]⁺: 355.0416; found 355.0415.

2-(3-Bromophenyl)-2-methyl-3-(dimethylamino)-2,3-dihydro-1H-pyrrolizin-1-one (10)

The title compound was prepared according to the general procedure by stirring a mixture of 2-(3-bromophenyl)-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (173 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and DMF (4.0 mL) at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (3% EtOAc in petroleum ether) to afford 10 (37 mg, 28%) as a colorless solid; mp 78–79 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.36 (m, 1H), 7.33 (dt, J = 7.3, 1.8 Hz, 1H), 7.14–7.08 (m, 2H), 7.06 (dd, J = 2.3, 1.0 Hz, 1H), 6.82 (dd, J = 3.9, 1.0 Hz, 1H), 6.54 (dd, J = 3.9, 2.3 Hz, 1H), 5.30 (s, 1H), 2.24 (s, 6H), 1.62 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 191.7, 147.0, 132.4, 130.4, 130.2, 129.2, 124.6, 123.9, 123.0, 116.8, 108.7, 85.9, 61.3, 40.8, 18.6 ppm; IR (neat, cm⁻¹) ν_max 1693, 1527, 1363, 1269, 1047, 1035; HRMS (ESI): m/z calcd for C₁₆H₁₇⁷⁹BrN₂ONa [M + Na]⁺: 355.0416; found 355.0414.

4a,5,9b-Trimethyl-5,9b-dihydropyrrolizino[3,2-b]indol-10(4aH)-one (4a′) and 5-methyl-5-[1-(dimethylamino)vinyl]pyrrolo[1,2-a]quinolin-4(5H)-one (7)

A mixture of 2-(2-bromophenyl)-1-(1-tosyl-1H-pyrrol-2-yl)propan-1-one (173 mg, 0.4 mmol), Cs₂CO₃ (261 mg, 0.8 mmol) and N,N-dimethylacetamide (4.0 mL) was stirred at 120 °C for 24 h. The crude product was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to afford 4a′ (7 mg, 7%) and 7 (16 mg, 15%) both as colorless solids.

Compound 4a′ showed: mp 117–118 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.34 (d, J = 7.4 Hz, 1H), 7.12 (td, J = 7.7, 1.2 Hz, 1H), 7.10 (dd, J = 2.3, 0.9 Hz, 1H), 6.75 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 3.9 Hz, 1H), 6.49 (dd, J = 3.9, 2.3 Hz, 1H), 6.39 (d, J = 7.9 Hz, 1H), 3.06 (s, 3H), 1.77 (s, 3H), 1.53 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 189.1, 147.8, 131.3, 129.2, 128.8, 123.5, 120.8, 119.1, 116.9, 108.2, 106.3, 86.2, 65.4, 28.7, 21.0, 17.6 ppm; IR (neat, cm⁻¹) ν_max 1682, 1603, 1530, 1488, 1362, 1291, 1019; HRMS (ESI): m/z calcd for C₁₆H₁₇N₂O [M + H]⁺: 253.1335; found 253.1325.

Compound 7 showed: mp 86–88 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.52 (dd, J = 7.6, 1.6 Hz, 1H), 7.34–7.25 (m, 2H), 7.22 (dt, J = 7.6, 1.6 Hz, 1H), 7.16 (dd, J = 2.6, 1.0 Hz, 1H), 6.74 (d, J = 3.6 Hz, 1H), 6.55 (dd, J = 3.6, 2.6 Hz, 1H), 4.96 (d, J = 2.4 Hz, 1H), 4.25 (d, J = 2.4 Hz, 1H), 2.22 (s, 3H), 2.06 (s, 3H), 1.74 (s, 3H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ = 189.8, 152.1, 150.3, 140.7, 133.2, 129.0, 127.5, 126.6, 124.4, 116.9, 115.6, 106.5, 90.0, 57.8, 45.6, 43.5, 23.7 ppm; IR (neat, cm⁻¹) ν_max 1693, 1658, 1450, 1417, 1370, 1305; HRMS (ESI): m/z calcd for C₁₇H₁₉N₂O [M + H]⁺: 267.1492; found 267.1485.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to the NSFC (#81330075; #21172202) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1542588 and 1543830. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7qo00771j

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