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Proceeding Paper

Multicomponet Synthesis of Pyrrolo [3,4-a] Carbazole-1,3-Diones †

by
Ana Bornadiego
,
Ana G. Neo
,
Jesús Díaz
* and
Carlos F. Marcos
*
Departamento de Química Orgánica e Inorgánica, Facultad de Veterinaria, Universidad de Extremadura, Avda, Universidad, s/n, 10003 Cáceres, Spain
*
Authors to whom correspondence should be addressed.
†
Presented at the 23rd International Electronic Conference on Synthetic Organic Chemistry, 15 November–15 December 2019; Available online: https://ecsoc-23.sciforum.net/.
Proceedings 2019, 41(1), 50; https://doi.org/10.3390/ecsoc-23-06525
Published: 14 November 2019
(This article belongs to the Proceedings of The 23rd International Electronic Conference on Synthetic Organic Chemistry)
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Versions Notes

Abstract

:
Pyrrolocarbazoles are important structural motives present in many natural products and pharmaceuticals. Particularly, pyrrolo [3,4-a] carbazole-1,3-diones have attracted much attention as analogues of bioactive compounds, such as anticancer agent granulatimide. Surprisingly, only a few methods for the synthesis of these compounds have been reported in the literature, and they are almost limited to the Diel–Alder cycloaddition of 3-vinylindoles. We have recently developed a multicomponent synthesis of polysubstituted anilines starting from α,β-unsaturated carbonyls, isocyanides and dienophiles. Here we report the application of this tandem [4 + 1]–[4 + 2] cycloaddition procedure for the synthesis of 4-amino-5-arylisoindoline-1,3-diones, which are then cyclized by means of a metal catalyzed intramolecular C-N coupling, affording structurally diverse, natural product-like pyrrolo [3,4-a] carbazole-1,3-diones with high yields and selectivities.

1. Introduction

Carbazole is a privileged heterocyclic structure, present in a wide range of naturally occurring alkaloids [1,2] and pharmacologically active compounds [3,4,5,6]. Carbazoles have also found important applications as photoactive organic functional materials, such as organic light-emitting diodes (OLEDs) [7,8] and organic photovoltaic devices [9,10].
Particularly, indolocarbazoles and the related pyrrolocarbazoles have attracted much interest for their biological properties [11]. For example, naturally occurring Staurosporin (1), Rebeccamycin (2) and Granulatimide (3) are lead structures in the development of novel anticancer agents due to their potent kinase inhibitor activities [12] (Figure 1). Furthermore, some pyrrolo [3,4-a] carbazoles have been developed as checkpoint kinase 1 inhibitors structurally related to granulatimide [13], and topoisomerase II poisons [14].
Surprisingly, little attention has been paid to the synthesis of pyrrolo [3,4-a] carbazoles, in spite of the many reports on the synthesis of some of their isomers, such as 3,6-dihydropyrrolo [2,3-c] carbazoles [15]. Most of the methods to obtain [3,4-a] carbazoles are based on the Diels–Alder cycloaddition of 3-vinylindoles [13,14,16,17], which often requires harsh reaction conditions and non-readily available starting materials [12,13,15,16]. Thus, it is vital to develop new efficient and flexible syntheses of these important heterocyclic structures.
Here, we propose a two-step synthesis of pyrrolo [3,4-a] carbazoles by the succession of a tandem [4 + 1]–[4 + 2] cycloaddition of isocyanides, α,β-unsaturated carbonyls and maleimide dienophiles, followed by a metal catalyzed intramolecular C-N coupling of the resulting 4-amino-5-arylisoindoline-1,3-diones. Pyrrololo [3,4-a] carbazoles 11 [18] and 17a [19] and their isoindole precursors have been previously reported by us, while pyrrololo [3,4-a] carbazole 17b is a novel compound.

2. Results and Discussion

In a first approach, (E)-methyl 4-(2-bromophenyl)-2-oxobut-3-enoate (4), benzyl isocyanide (5a) and N-phenylmaleimide (6) were heated in toluene at 100 °C in the presence of a catalytic amount of yttrium trifluoromethanesulfonate (Scheme 1). In these conditions, methyl 7-(benzylamino)-6-(2-bromophenyl)-1,3-dioxo-2-phenylisoindoline-4-carboxylate (7) was obtained in 55% yield, as a yellow solid [18].
The mechanism, outlined in Scheme 2, involves the [4 + 1] cycloaddition of α,β-unsaturated carbonyl (4) and isocyanide (5) to give unstable aminofuran (8). This is trapped in situ by maleimide (6) by means of a Diels–Alder reaction, leading to 7-oxabicyclo [2.2.1] heptene (9). Finally, oxygen ring opening and aromatization affords isoindole (7).
Copper catalyzed intramolecular N–C coupling of isoindole 7 was efficiently achieved under microwave activation in toluene, in the presence of Cs2CO3 and 30% mol of L-Boc-proline. Thus, pyrrolocarbazole 11 was obtained in an excellent yield (Scheme 3) [18].
Structural diversity on final pyrrolocarbazoles could be increased by generating the starting α,β-unsaturated carbonyl compounds in situ. Notably, the Knoevenagel condensation of cyclic 1,3-dicarbonyls (12) and aldehydes (13) can readily generate α,β-unsaturated carbonyl compounds (14). Cycloaddition of these resulting heterodienes (14) with isocyanides (5) is known to afford 2-aminofuranes (15) [20,21], and subsequent Diels–Alder reaction with dienophiles (6) present in the reaction medium could purportedly afford tricyclic isoindoles (16) in the same pot (Scheme 4).
Thus, equimolar amounts of dimedone (12), p-nitrobenzaldehyde (13), cyclohexyl isocyanide (5b) and N-phenylmaleimide (6) were stirred in refluxing acetonitrile for 22 h, affording the expected. 4-(cyclohexylamino)-8,8-dimethyl-5-(4-nitrophenyl)-2-phenyl-8,9-dihydro-1H-benzo[e]isoindole-1,3,6(2H,7H)-trione (16a) with a 90% yield (Scheme 4) [19]. Interestingly, in contrast with our previous results, the addition of catalytic Y(OTf)3 [18] did not improve the reaction. Analogously, the reaction with benzyl isocyanide (5c) affords the corresponding pentylaminoisoindole (16b).
In this case, dehydrogenative N-C bond forming cyclization of the cycloadducts (16a,b) yields straightforwardly natural product-like pyrrolocarbazoles (17a,b). Thus, isoindoline-1,3-dione (16a) was subjected to a palladium catalysed dehydrogenative cyclization, using phenyliodine (III) diacetate (PIDA) as an external oxidant [22,23,24,25]. The reaction is completed under microwave irradiation at 110 °C in hexafluoroisopropanol (HFIP) in just one minute, affording pyrrolocarbazole 17a in 58% yield (Scheme 5) [19]. Analogously, pyrrolocarbazole 17b was obtained in similar conditions from isoindoline 16b. Pyrrolo[3,4-a]carbazole-1,3-diones (17a,b) can be considered analogues of granulatimide (3) in which the position of the imidazole ring is occupied by a pyrrole-2,5-dione, while a cyclohexanone is the place of the pyrrole-2,5-dione [26]. Remarkably, these complex pentacyclic compounds are readily and efficiently synthesized from simple starting materials in a two-step reaction sequence.

3. Conclusions

In conclusion, we have effectively designed a straightforward and versatile synthesis of natural product-like pyrrolo [3,4-a] carbazole-1,3-diones. This two-step method involves a multicomponent tandem succession of [4 + 1] and [4 + 2] cycloadditions, ring opening and aromatization, followed by an intramolecular metal catalysed N-C coupling. Moreover, the first step can be combined in the same pot with a Knoevenagel condensation, substantially increasing the structural diversity attainable by this procedure.
Initially, intermediate 4-amino-5-(2-bromoaryl) isoindoline-1,3-diones were cyclized in the presence of catalytic CuI to give the corresponding pyrrolocarbazoles. Successfully, we developed a significantly improved procedure that does not require a halogen on the aryl group. Conversely, an aryl C-H is efficiently coupled with an amino N, in the presence of catalytic Pd(OAc)2 under the oxidative action of PIDA, in just one minute under microwave irradiation.
In this way, biologically important pyrrolocarbazoles, which would otherwise require long and complex syntheses, can be easily obtained in a high yielding, convergent and atom economic process involving readily available starting materials.

4. Experimental Section

Synthesis of methyl 7-(benzylamino)-6-(2-bromophenyl)-1,3-dioxo-2-phenylisoindoline-4-carboxylate (7): To a solution of (E)-methyl 4-(2-bromophenyl)-2-oxobut-3-enoate 4 (81 mg, 0.3 mmol) in dry toluene (1.2 mL), yttrium trifluoromethanesulfonate (8 mg, 5% mol), benzyl isocyanide 5a (66 µL, 0.54 mmol, 1.8 equivalent) and N-phenylmaleimide 6 (62 mg, 0.36 mmol, 1.2 equivalent) were added under a nitrogen atmosphere. The resulting mixture was heated 3 h at 100 °C. The reaction was cooled to rt, 10% HCl (5 mL) was added and the organic phase was extracted with CH2Cl2, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica gel, hexane–EtOAc gradient), and isoindoline 7 (55%) was obtained as a yellow solid; mp: 175–177 °C; IR (cm−1) 3428, 2962, 1766, 1696, 1620; 1H NMR (500 MHz, CDCl3) δ 8.31 (s, NH), 7.62 (s, 1H), 6.95–6.94 (m, 2H), 6.81–6.69 (m, 5H), 3.96 (s, 3H), 3.22 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 169.50 (C), 165.60 (C), 164.56 (C), 147.55 (C), 140.89 (CH), 140.03 (C), 137.97 (C), 132.69 (CH), 131.80 (CH), 131.62 (C), 131.49 (C), 130.87 (C), 130.23 (CH), 129.21 (CH), 128.86 (CH), 128.24 (CH), 127.82 (CH), 127.44 (CH), 127.39 (CH), 126.86 (CH), 124.65 (C), 117.12 (C), 113.32 (C), 52.61 (CH2), 49.03 (CH3); MS (EI) m/z (%) 542 (M+, 15), 540 (M+, 16), 461 (27), 429 (43), 383 (10), 91 (100); HRMS (EI) calculated for C29H21N2O4Br: 540.0685; found: 540.0681.
Synthesis of methyl 10-benzyl-1,3-dioxo-2-phenyl-1,2,3,10-tetrahydropyrrolo [3,4-a] carbazole-4-carboxylate (11): A solution of isoindoline 7 (16 mg, 0.03 mmol), CuI (2 mg, 0.010 mmol, 35% mol), Cs2CO3 (19 mg, 0.06 mmol, 2 equivalent) and L-Boc-proline (2 mg, 0.009 mmol, 31% mol) in toluene (1 mL) was heated for 1 h at 130 °C in a microwave oven. The crude product was filtered through a short pad of SiO2 and washed with CH2Cl2. The solvents were removed in the rotary evaporator to give pyrrolocarbazole 11 (94%), obtained as a yellow solid; mp: 226–228 °C; IR (cm−1) 2923, 1762, 1702, 1493, 1269, 1170, 804; 1H NMR (500 MHz, CDCl3) δ 8.67 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.59–7.53 (m, 1H), 7.51–7.46 (m, 2H), 7.45–7.41 (m, 3H), 7.41–7.36 (m, 2H), 7.25–7.17 (m, 3H), 7.05 (d, J = 6.7 Hz, 2H), 6.40 (s, 2H), 4.05 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.56 (C), 166.57 (C), 165.80 (C), 143.34 (C), 137.65 (C), 137.48 (C), 131.75 (C), 130.15 (C), 129.19 (CH), 128.87 (CH), 128.29 (CH), 127.96 (C), 127.49 (CH), 127.13 (CH), 126.27 (CH), 126.22 (CH), 122.55 (C), 121.90 (CH), 121.40 (C), 121.21 (CH), 113.92 (C), 111.31 (CH), 53.17 (CH3), 50.48 (CH2); MS (CI) m/z (%) 461 (M+ + 1, 21), 429 (21), 339 (3), 199 (17), 91 (100); HRMS (EI) calculated for C29H20N2O4: 460.1423; found: 460.1423.
Synthesis of 4-(Cyclohexylamino)-8,8-dimethyl-5-(4-nitrophenyl)-2-phenyl-8,9-dihydro-1H-benzo[e]isoindole-1,3,6(2H,7H)-trione (16a): To a solution of dimedone 12 (140 mg, 1 mmol) in dry acetonitrile (2 mL), p-nitrobenzalaldehyde 13 (151 mg, 1 mmol), N-phenylmaleimide 6 (173 mg, 1 mmol) and cyclohexyl isocyanide 5b (137 µL, 1.1 mmol) were successively added. The resulting mixture was stirred and heated to reflux under a nitrogen atmosphere until the starting materials were consumed, as judged by tlc. The precipitate was then filtered and washed with a mixture of cyclohexane and ethyl acetate. To the resulting washed mixture, a 1 N HCl solution was added and extracted with ethyl acetate. The organic layer was evaporated and then subjected to column chromatography (silica gel, gradient from cyclohexane to cyclohexane-EtOAc 70:30). The fractions obtained by filtration and chromatography were combined, giving the desired product 16a (28 h, 398 –mg, 73%); mp: 197–206 °C; IR (cm–1): 3433, 2956, 1751, 1702, 1596; 1H NMR (500 MHz, CDCl3): δ 8.24 (d, J = 8.3 Hz, 2H), 7.52 (t, J = 7.5 Hz, 2H), 7.43 (d, J = 7.6 Hz, 3H), 7.33 (t, J = 9.9 Hz, 2H), 7.22 (d, J = 6.9 Hz, 3H), 6.98 (d, J = 6.3 Hz, 2H), 6.85 (s, 1H), 3.81 (s, 2H), 3.37 (s, 2H), 2.46 (s, 2H), 1.11 (s, 6H) ppm; 13C{1H} NMR (126 MHz, CDCl3): 198.2 (C), 168.2 (C), 166.9 (C), 147.4 (C), 145.7 (C), 145.4 (C), 138.5 (C), 137.5 (C), 134.7 (C), 134.3 (CH), 132.5 (C), 131.5 (C), 130.4 (CH), 129.3 (CH), 129.2 (C), 128.8 (CH), 128.4 (CH), 127.8 (CH), 127.3 (CH), 126.7 (CH), 126.2 (CH), 123.7 (CH), 117.8 (C), 54.5 (CH2), 51.0 (CH2), 38.8 (CH2), 33.6 (C), 28.4 (CH3) ppm; HRMS (ESI-Q-TOF) m/z: [M + H]+ calculated for C33H28N3O5 546.2023; found: 546.2031.
Synthesis of 4-(Benzylamino)-8,8-dimethyl-5-(4-nitrophenyl)-2-phenyl-8,9-dihydro-1H-benzo[e]isoindole-1,3,6(2H,7H)-trione (16b): Following the above described procedure for 16a, the compound 16b was obtained from dimedone (12), 1-benzylisocyanide (5a), N-phenylmaleimide (6) and 4-nitrobenzaldehyde (13) as an orange solid (13 h, 226 mg, 43%); mp: 68–74 °C; IR (cm−1): 3397, 2956, 1755, 1702, 1598; 1H NMR (500 MHz, CDCl3): δ 8.30 (d, J = 8.7 Hz, 2H), 7.55–7.50 (m, 2H), 7.43 (d, J = 7.7 Hz, 3H), 7.41–7.38 (m, 2H), 3.35 (s, 2H), 2.47 (t, J = 7 Hz, 2H), 2.47 (s, 2H), 1.30 (quin, 2H), 1.19–1.04 (m, 5H), 1.11 (s, 6H), 0.80 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): 198.4 (C), 168.5 (C), 167.0 (C), 147,3 (C), 146.4 (C), 146.1 (C), 137.4 (C), 134.0 (C), 131.6 (C), 131.5 (C), 130.4 (CH), 129.3 (CH), 129.0 (C), 128.4 (CH), 126.7 (CH), 123.6 (CH), 116.8 (C), 54.5 (CH2), 46.9 (CH2), 38.7 (CH2), 33.6 (C), 30.3 (CH2), 28.7 (CH2), 28.4 (CH3), 22.3 (CH2), 14.00 (CH3) ppm; HRMS (ESI-Q-TOF) m/z: [M + H]+ calculated for C31H32N3O5: 526.2336; found: 526.2334.
Synthesis of 12-Cyclohexyl-5,5-dimethyl-10-nitro-2-phenyl-4,5,6,12-tetrahydrobenzo[c]pyrrolo [3,4-a] carbazole-1,3,7(2H)-trione (17a): A solution of isoindole 16a (92 mg, 0.17 mmol), PIDA (203 mg, 3.7 equivalent) and Pd(OAc)2 (4 mg, 10% mol) and Ph3P (10 mg, 22% mol) in HFIP (1 mL) was heated to 110 °C under microwave irradiation for 1 minute. The crude mixture was evaporated to dryness and then subjected to column chromatography (silica gel, gradient from cyclohexane to cyclohexane-EtOAc 70:30) to give the indolocarbazole 17a, obtained as an orange solid (53 mg, 58% yield).; mp: 287–302 °C; IR (cm−1): 3449, 2939, 2858, 1760, 1708, 1523; 1H NMR (500 MHz, CDCl3): δ 9.16 (d, J = 9.2 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.12 (dd, J = 9.2, 2.1 Hz, 1H), 7.59–7.54 (m, 2H), 7.48 (m, 3H), 6.12 (tt, J = 12.4, 3.8 Hz, 1H), 3.62 (s, 2H), 2.83 (s, 2H), 2.44 (dq, J = 12.4, 3.4 Hz, 2H), 2.11–1.95 (m, 4H), 1.84 (d, J = 13.1 Hz, 1H), 1.67 (ddd, J = 16.1, 13.1, 3.3 Hz, 3H), 1.51–1.38 (m, 1H), 1.21 (s, 6H) ppm; 13C{1H} NMR (126 MHz, CDCl3): 199.8 (C), 167.6 (C), 166.1 (C), 146.8 (C), 141.8 (C), 139.3 (C), 134.9 (C), 134.4 (C), 131.6 (C), 129.4 (CH), 128.7 (CH), 128.3 (C), 128.2 (CH), 127.4 (CH), 127.3 (C), 127.0 (C), 117.8 (C), 114.8 (CH), 109.0 (CH), 59.6 (CH), 54.4 (CH2), 39.5 (CH2), 34.1 (C), 31.5 (CH2), 28.6 (CH3), 26.1 (CH2), 25.5 (CH2) ppm; HRMS (ESI-Q-TOF) m/z: [M + H]+ calculated for C32H30N3O5: 536.2180; found: 536.2168.
Synthesis of 12-Benzyl-5,5-dimethyl-10-nitro-2-phenyl-4,5,6,12-tetrahydrobenzo[c]pyrrolo [3,4-a] carbazole-1,3,7(2H)-trione (17b): Following the above described procedure for 17a, the compound 17b was obtained from 16b as an orange solid (11 mg, 12 % yield); mp: 249–257 °C; IR (cm−1): 3444, 2957, 1762, 1711, 1516; 1H NMR (500 MHz, CDCl3): δ 9.29 (d, J = 9.1 Hz, 2H), 8.19 (dd, J = 9.1 Hz, J = 2.1, 2H), 7.55 (t, J = 7.7 Hz, 2H), 7.47–7.44 (m, 3H), 7.26–7.24 (m, 3H), 7.04 (d, J = 7.7 Hz, 2H), 6.54 (s, 2H), 3.66 (s, 2H), 2.89 (s, 2H), 1.26 (s, 6H) ppm; 13C{1H} NMR (126 MHz, CDCl3): 199.5 (C), 163.7 (C), 165.8 (C), 147.8 (C), 143.4 (C), 138.5 (C), 136.7 (C), 135.2 (C), 134.1 (C), 131.3 (C), 129.2 (CH), 128.9 (CH), 128.5 (CH), 128.4 (CH), 128.2 (C), 127.7 (CH), 127.2 (C), 127.0 (CH). 126.1 (C), 125.9 (CH), 117.7 (C), 115.5 (CH), 106.0 (CH), 54.3 (CH2), 50.5 (CH2), 39.4 (CH2), 33.9 (C), 28.5 (CH3) ppm; HRMS (ESI-Q-TOF) m/z: [M + H]+ calculated for C33H26N3O5: 544.1872; found: 544.1867.

Acknowledgments

We thank the financial support from Junta de Extremadura and FEDER (IB16095).

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Proceedings 41 00050 g001
Figure 1. Bioactive isoindolopyrroles.
Figure 1. Bioactive isoindolopyrroles.
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Scheme 1. Tandem [4 + 1]/[4 + 2] synthesis of isoindoline-1,3-dione (7).
Scheme 1. Tandem [4 + 1]/[4 + 2] synthesis of isoindoline-1,3-dione (7).
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Scheme 2. Proposed mechanism for the tandem [4 + 1]/[4 + 2] cycloaddition.
Scheme 2. Proposed mechanism for the tandem [4 + 1]/[4 + 2] cycloaddition.
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Scheme 3. Synthesis of pyrrolo [3,4-a] carbazole (11).
Scheme 3. Synthesis of pyrrolo [3,4-a] carbazole (11).
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Scheme 4. Four-component synthesis of isoindoline-1,3-dione (16).
Scheme 4. Four-component synthesis of isoindoline-1,3-dione (16).
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Scheme 5. Synthesis of pyrrolo [3,4-a]carbazole (17).
Scheme 5. Synthesis of pyrrolo [3,4-a]carbazole (17).
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Bornadiego, A.; Neo, A.G.; Díaz, J.; Marcos, C.F. Multicomponet Synthesis of Pyrrolo [3,4-a] Carbazole-1,3-Diones. Proceedings 2019, 41, 50. https://doi.org/10.3390/ecsoc-23-06525

AMA Style

Bornadiego A, Neo AG, Díaz J, Marcos CF. Multicomponet Synthesis of Pyrrolo [3,4-a] Carbazole-1,3-Diones. Proceedings. 2019; 41(1):50. https://doi.org/10.3390/ecsoc-23-06525

Chicago/Turabian Style

Bornadiego, Ana, Ana G. Neo, Jesús Díaz, and Carlos F. Marcos. 2019. "Multicomponet Synthesis of Pyrrolo [3,4-a] Carbazole-1,3-Diones" Proceedings 41, no. 1: 50. https://doi.org/10.3390/ecsoc-23-06525

APA Style

Bornadiego, A., Neo, A. G., Díaz, J., & Marcos, C. F. (2019). Multicomponet Synthesis of Pyrrolo [3,4-a] Carbazole-1,3-Diones. Proceedings, 41(1), 50. https://doi.org/10.3390/ecsoc-23-06525

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