A catalyst-free, efficient green MCR protocol for access to functionalized γ-carbolines in water

Abstract

A general, mild, efficient and practical approach for the construction of functionalized γ-carboline derivatives has been successfully realized in water through a one-pot three-component reaction involving several aryl/hetero-aryl/alkyl/alkenyl/alkynyl/ferrocenyl aldehydes, 3-formyl indole derivatives and ammonium acetate as a cheap N-source. The most important feature of the current methodology is that this hetero-annulation reaction of indole to γ-carboline can occur in good to excellent yields with wider substrate scope at room temperature in water, starting from simple inexpensive raw materials under catalyst-free and oxidant-free conditions. Moreover, a facile access to pentacyclic quinolinone fused carboline derivative has been achieved through our methodology.

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Introduction

Multi-component reactions are unarguably one of the most practical, atom-economical and efficient synthetic techniques for the rapid construction of a wide range of pharmacologically interesting frameworks from simple readily available raw materials through a one-pot multiple bond forming process.¹ Thus, when such a strategy is conducted in water at ambient temperature without using any external catalysts and volatile/carcinogenic organic solvents, reaction conditions should be considered nearly perfect in terms of safety, health, cost-effectiveness, energy conservation and eco-sustainable points of view.² On the other hand, the highly efficient synthesis of multi-functionalized γ-carboline derivatives has been subject of growing interest in recent years since this tricyclic scaffold played a crucial role in several biological processes and showed broad spectrum of biological activities including anti-cancer, antibiotic, antipsychotic, anti-Alzheimer etc.³ In order to evaluate the biological activities, many synthetic and medicinal chemists have developed several tools for the preparations of these moieties.^4,5 Among them, one-shot hetero-annulation reactions of indoles to γ-carbolines catalyzed by transition metal-salts have been recognized tremendously as alternative powerful synthetic protocols in recent years. For instance, Larock et al.,^5a–c Jiao^5d and Jeganmohan^5e groups have independently developed the one-shot attractive synthetic protocols for the constructions of γ-carboline scaffolds via iminoannulation reactions between alkynes and 2-halo-3-iminoindoles or 3-iminoindoles using Pd(0)/Pd(II)/Ru(II)-catalysts under heating conditions (Scheme 1a and b). In 2012, Rh(III) catalyzed one-pot three-component hetero-annulation reaction of 3-carbonyl indoles, NH₂OH·HCl with alkynes for the preparation of γ-carbolines has been developed by Hua et al.^5f Furthermore, an innovative route to N-imino-γ-carboline ylides has been realized by Zhan et al. via Ag(I) catalyzed imino-heteroannulation of propargyl alcohol with 3-indolyl hydrazone derivative (Scheme 1c).^5g Despite the great advances, many reported protocols entail several disadvantageous such as the use of toxic and expensive metals, harmful and volatile organic solvents, excess amount of strong oxidants, difficult operation, higher reaction temperature, unsatisfactory yields, poor atom-economy, specific substrate scope etc. Therefore, it would be highly meaningful to develop an alternative one-pot, catalyst-free, efficient and environment friendly protocol for the synthesis of pharmacologically interesting γ-carboline scaffolds in water at room temperature by utilizing cheap and easily available starting materials.

Scheme 1 Various one-pot hetero-annulation approaches of indoles to γ-carbolines.

As part of our continued research goal towards the newer synthetic transformations for the access to biologically interesting various N-heterocycles in a practical manner,⁶ we recently reported on organocatalytic two-step synthetic method for the preparation of substituted γ-carboline derivatives starting from 3-formyl indoles in DMSO medium using L-proline as a catalyst (Scheme 1d).^6a Against these backgrounds, we envisioned that this reaction may be conveniently performed in a one-pot manner without using any catalyst in water medium, thereby enhancing the substrate scope and structural complexity of final γ-carbolines. Here we wish to report a mild (room temperature), easy, catalyst-free, green and efficient one-pot MCR technique for the preparation of a wide range of functionalized γ-carbolines by employing 2-substituted-3-formyl-1H-indoles, aldehydes and ammonium acetate as N-source in water at room temperature under aerobic conditions (Scheme 1e).

Results and discussion

To access the desired γ-carboline, we have performed the model reaction between 2-(2-oxo-2-phenylethyl)-1H-indole-3-carbaldehyde (1a), benzaldehyde (2a) and ammonium acetate as N-source in DMSO at room temperature under air. Indeed, after 14 h, the expected γ-carboline 3aa was isolated in excellent yield 90%. The structure of product was ascertained by its spectroscopic data (¹H, ¹³C NMR and HRMS). This fascinating result inspired us to examine this MCR in more detail. In this context, we examined the reaction in various common solvents such as DMF, DCM, toluene, MeCN, THF and 1,4-dioxane, EtOH, MeOH and H₂O. To our satisfaction, this reaction proceeded very well not only in organic solvents but also in water. Consequently, similar kinds of yields (84–89%, entries 2–10) of γ-carboline 3aa were observed. However, it was witnessed that the rate of the reaction in water was much slower than organic solvents (14 h vs. 24 h, entries 1–9 vs. entry 10). In spite of, water was chosen as a best solvent for this hetero-annulation reaction due to its unique beneficial features such as environment friendly, extremely cheap, non-flammable, non-toxic, and most abundant in nature. Next, we screened this reaction by employing a variety of commercially available ammonium salts as the N-sources in water. Results clearly addressed that the NH₄OAc, HCO₂NH₄ and NH₄SCN offered superior yields (89%, 85% and 75% respectively, entries 10–12) than other basic (NH₄OH, NH₄HCO₃ and (NH₄)₂CO₃) and acidic salts (NH₄Cl and (NH₄)₂SO₄) tested for this annulation reaction (entries 13–17). The probable reason is that ammonium salts (entries 10–12) of weak acids (corresponding counteranion AcO⁻, HCO₂⁻ and SCN⁻) and weak base may easily dissociate into the ammonia in reaction media as compared to the corresponding basic (counteranion HO⁻, HCO₃⁻ and CO₃²⁻, entries 15–17) and acidic (counteranion Cl⁻ and SO₄²⁻, entries 13 and 14) ammonium salts.⁷ Finally, NH₄OAc being less expensive compared to NH₄HCO₂, was opted as a best N-supplier (Table 1).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Salt	Time (h)	Yield^b (%)
a Unless otherwise to be noted, all the reactions were conducted with 2-(2-oxo-2-phenylethyl)-1H-indole-3-carbaldehyde (1a, 0.2 mmol), PhCHO (2a, 0.24 mmol) and ammonium salt (0.22 mmol) in specified solvent (0.5 mL) at room temperature under air.b Isolated yield after column chromatography.
1	DMSO	NH4OAc	14	90
2	DMF	NH4OAc	14	88
3	DCM	NH4OAc	14	85
4	Toluene	NH4OAc	14	86
5	MeCN	NH4OAc	14	90
6	THF	NH4OAc	14	89
7	1,4-Dioxane	NH4OAc	14	84
8	EtOH	NH4OAc	14	88
9	MeOH	NH4OAc	14	87
10	Water	NH4OAc	24	89
11	Water	HCO2NH4	24	85
12	Water	NH4SCN	24	75
13	Water	(NH4)2CO3	24	57
14	Water	NH4HCO3	24	60
15	Water	NH4OH	24	42
16	Water	(NH4)2SO4	24	30
17	Water	NH4Cl	24	36

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A mechanistic insight of this catalyst-free one-pot aqueous MCR is proposed as depicted in Scheme 2. Similarly, benzaldehyde (2a) may react with ammonium acetate to form iminium ion 2a′ which is subsequently nucleophilic attacked by keto–enol 1á to generate Mannich adduct 4. Finally, γ-carboline 3aa is formed from intermediate 4 via an intramolecular imination reaction, followed by oxidation of tricyclic intermediate 5 under aerobic conditions as follows in Path A. Alternatively, the intermediate 4 may be possible to convert into the corresponding Knoevenagel condensation product 4a (ref. 6a) by elimination of ammonium acetate (Path B). Afterwards, the latter react with ammonium acetate to form imine intermediate 4a′ which upon intramolecular cyclization and subsequent aerial oxidation lead to 3aa. However, the detailed understanding the mode of reaction requires additional efforts.

Scheme 2 Proposed mechanism for one-pot three-component hetero-annulation reaction.

With optimization reaction in hand, we thoroughly investigated the scope and generality of this MCR by taking a variety of aromatic/hetero-aromatic/aliphatic aldehydes (2a–r), 2-(2-oxo-2-arylethyl)-1H-indole-3-carbaldehydes (1a–c) with ammonium acetate under our established reaction conditions. Results are summarized in Table 2. Incorporation of several substituents such as electron rich (Me, OMe, OBn) and electron poor (Br, Cl, F, CF₃, NO₂, CN) at ortho-, meta- and para-positions on aryl rings of aromatic aldehydes did not show any significant impact on the rate of the reactions when substrate 1a was used. Consequently, after 24 h, all these reactions led to the corresponding functionalized γ-carbolines in good to excellent yields (3ab–3am, 79–89%). Furthermore, several challenging electrophiles like hetero-aryl, alkyl and ferrocenyl aldehydes also participated well with substrate 1a under identical conditions (except 3ar, at 50 °C) to furnish the anticipated products in satisfactory yields (66–76%, 3an–3ar).

Table 2 The scope of the reaction between 2-(2-oxo-2-arylethyl)-1H-indole-3-carbaldehydes (1a–c) and aldehydes (2a–r)

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Similarly, by this procedure, substituted indole derivatives 1b–c also underwent spotless reactions with a variety of structurally diverse aryl, hetero-aryl and alkyl aldehydes to furnish the corresponding products in good to high yields (72–86%, 3ba–3cn).

In order to explore the further possible substrate scope, we decided to use other indole analogues such as 2-(3-formyl-1H-indol-2-yl)acetates (1d–e) under our standard conditions. As can be seen from Table 3, the indole derivatives 1d–e annulated not only with a benzaldehyde but also with several aromatic aldehydes having a wide range of functional groups namely Me, OMe, OBn, Cl, Br, NO₂, NHBoc on the aromatic rings in a practical manner, leading to the corresponding substituted γ-carbolines (3da–3ds and 3ea) in high to excellent yields (81–91%). Similarly, several hetero-aromatic aldehydes (2-furyl, 2-thiophenyl and 3-indolyl) were found to be appropriate electrophiles for this transformation. As a consequence, after 24 h, all these reactions produced the corresponding desired γ-carbolines (3dn, 3eo and 3dt) in nearly perfect yields (81–85%). It is noteworthy to mention that all the above γ-carbolines (3da–3dt) had also been synthesized previously from same starting material 1d by adopting two-step method involving L-proline as a catalyst.^6a However, the combined yields (60–80%, two-step) of corresponding products are considerably (10–24%) lower than those obtained (81–91%, Table 3) by this present procedure with much shorter times (96 h vs. 24 h). Therefore, the present conditions are superior in terms of yields, times and green chemistry point of view. Moreover, by this current one-shot procedure, the substrates 1d–e were actively engaged with a variety of 1°- and 2°-aliphatic aldehydes and resulted in good to high yields (79–86%) of corresponding 3-alkylated γ-carboline precursors (3dq–3dw & 3ev–3ex). Most importantly, ferrocenecaboxaldehyde also worked equally well with substrates 1d–e to afford the interesting ferrocenyl functionalized γ-carbolines in 78–82% yields. It is fruitful to mention that a large number of sensitive functional groups including Me, OMe, OBn, Cl, Br, NO₂, NHBoc, NHCbz, CO₂Me, thiophene, furan, indole, ferrocene etc. remained unaltered in our mild conditions.

Table 3 The scope of the reaction between methyl 2-(3-formyl-1H-indol-2-yl)acetate derivatives (1d–e) and aldehydes (2a–y)

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Furthermore, this catalyst-free one-pot MCR was then applied to the synthesis of synthetically challenging (E)-2-styryl-substituted γ-carboline frameworks. In this regard, we performed the reactions between several β-aryl/alkyl-substituted acroleins with diverse steric and stereoelectronic environments, NH₄OAc and indole derivatives (1d–e) in our imposed conditions. Surprisingly, instead of 1,4-addition products, we have isolated exclusively (E)-2-styryl-substituted γ-carbolines (3daa–3eaa) in highly satisfactory yields (75–87%, Table 4). Notably, this is the first successful report for the one-pot synthesis of (E)-2-styryl-substituted γ-carboline scaffolds in an efficient and eco-friendly manner.

Table 4 One-pot synthesis of (E)-2-styryl-substituted γ-carboline frameworks (3daa–3eaa)

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After successfully employing β-substituted acroleins as electrophiles, we then inspired to substitute them with a more complicated electrophile like β-arylpropargylaldehyde in the reaction with indole derivatives 1d–e under our present conditions. To our pleasant surprise, the same (E)-2-styryl-substituted γ-carbolines (3da–3ea) were obtained in mediocre yields (39–45%, Scheme 3) with a single isomer. Therefore, it is a great opportunity for the construction of these heterocycles by using either alkenyl aldehydes or alkynyl aldehydes as electrophiles.

Scheme 3 One-pot hetero-annulation reaction of alkynyl aldehydes with indole derivatives (1d–e).

Finally, the current one-pot hetero-annulation process can be applied to the synthesis of biologically interesting quinolinone fused heterocyclic scaffolds⁸ in 76–79% yields from the reaction of indole derivatives 1d–e, aromatic aldehyde 2t and ammonium acetate in DMSO at heating conditions as shown in Scheme 4.

Scheme 4 One-pot synthesis of pentacyclic quinolinone fused γ-carbolines (6–7).

Experimental

All reactions were carried out under air and monitored by TLC using Merck 60 F₂₅₄ pre coated silica gel plates (0.25 mm thickness) and the products were visualized by UV detection. Flash chromatography was carried out with silica-gel (200–300 mesh). ¹H and ¹³C NMR spectra were recorded on a Bruker Avance (III) 400 MHz spectrometer. Data for ¹H NMR are reported as a chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, q = quartet, m = multiplet), coupling constant J (Hz), integration, and assignment, data for ¹³C are reported as a chemical shift. High resolutions mass spectral analyses (HRMS) were carried out using ESI-TOF-MS. All the starting materials were either synthesized by literature procedure or purchased from commercial sources.

Representative experimental procedure for the synthesis of phenyl(3-phenyl-5H-pyrido[4,3-b]indol-4-yl)methanone (3aa)

A heterogeneous mixture of 2-(2-oxo-2-phenylethyl)-1H-indole-3-carbaldehyde (52.6 mg, 0.2 mmol, 1a), benzaldehyde (25.2 mg, 0.24 mmol, 2a) and ammonium acetate (16.97 mg; 0.22 mmol) in water (0.5 mL) at room temperature was stirred for 24 h under air. After that, the reaction mixture was concentrated under vacuum to leave the crude residue which was purified by column chromatography over silica-gel using ethyl acetate/hexane (1 : 10) as an eluent to furnish the pure γ-carboline (3aa, 61.9 mg) in 89% yield.

All the products in Tables 2–4 and Scheme 3 were synthesized by following procedure. All the unknown products were characterized by its spectroscopic data (¹H, ¹³C NMR and HRMS).

Phenyl(3-phenyl-5H-pyrido[4,3-b]indol-4-yl)methanone (3aa)

Yield 89%; ¹H NMR (400 MHz, CDCl₃) δ 9.48 (br s, 1H), 9.40 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.45–7.48 (m, 5H), 7.29–7.33 (m, 1H), 7.18–7.22 (m, 2H), 7.40–7.11 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 198.2, 155.3, 144.8, 143.6, 140.3, 140.1, 137.9, 132.6, 130.4, 129.5, 128.5, 128.1, 128.0, 127.5, 121.5, 121.2, 120.9, 119.8, 115.3, 111.5; HRMS (ESI) m/z calcd for C₂₄H₁₆N₂O[M + H]⁺: 349.1335; found 349.1332.

Phenyl{3-(4-methylphenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3ab)

Yield 87%; ¹H NMR (400 MHz, CDCl₃) δ 9.53 (br s, 1H), 9.45 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.50–7.55 (m, 4H), 7.43 (d, J = 8.0 Hz, 2H), 7.34–7.39 (m, 1H), 7.27–7.31 (m, 1H), 7.12–7.16 (m, 2H), 6.95 (d, J = 7.6 Hz, 2H), 2.20 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 198.2, 155.3, 144.8, 143.5, 140.0, 138.4, 137.8, 137.5, 132.5, 130.3, 129.5, 128.8, 127.9, 127.3, 121.4, 121.3, 120.8, 119.5, 115.0, 111.5, 21.1; HRMS (ESI) m/z calcd for C₂₅H₁₈N₂O[M + H]⁺: 363.1498; found 363.1492.

Phenyl{3-(4-methoxyphenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3ac)

Yield 84%; ¹H NMR (400 MHz, CDCl₃) δ 9.59 (br s, 1H), 9.36 (s, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.40–7.47 (m, 6H), 7.06–7.28 (m, 4H), 6.60 (d, J = 7.2 Hz, 2H), 3.61 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 198.2, 159.9, 154.8, 144.8, 143.5, 140.0, 137.8, 132.9, 132.6, 131.7, 129.5, 128.0, 127.3, 121.4, 120.7; 119.4, 114.8, 113.6, 111.5, 55.2; HRMS (ESI) m/z calcd for C₂₅H₁₈N₂O₂[M + H]⁺: 379.1441; found 379.1444.

Phenyl{3-(2,5-dimethoxyphenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3ad)

Yield 81%; ¹H NMR (400 MHz, CDCl₃) δ 9.65 (br s, 1H), 9.47 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.51–7.57 (m, 4H), 7.28–7.38 (m, 3H), 7.15–7.19 (m, 2H), 6.62 (d, J = 7.6 Hz, 1H), 6.36 (d, J = 8.8 Hz, 1H), 3.79 (s, 3H), 3.52 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 197.1, 153.6, 151.3, 150.2, 144.4, 143.8, 140.1, 137.6, 132.2, 130.1, 129.2, 127.5, 127.4, 121.3, 121.1, 120.8, 120.1, 116.8, 116.0, 111.4, 111.2, 55.9, 54.9; HRMS (ESI) m/z calcd for C₂₆H₂₀N₂O₃ [M + H]⁺: 409.1552; found 409.1559.

Phenyl{3-(3-methoxy-4-benzyloxyphenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3ae)

Yield 79%; ¹H NMR (400 MHz, CDCl₃) δ ¹H NMR (400 MHz, CDCl₃) δ 9.50 (br s, 1H), 9.41 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.50–7.54 (m, 4H), 7.38–7.42 (m, 2H), 7.31–7.37 (m, 5H), 7.11–7.19 (m, 3H), 6.95–6.98 (m, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.04 (s, 2H), 3.85 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 198.2, 154.8, 149.3, 148.6, 144.9, 143.3, 140.1, 137.9, 136.8, 133.7, 132.5, 129.3, 128.5, 128.0, 127.8, 127.4, 127.1, 123.8, 121.5, 121.3, 120.8, 119.5, 115.0, 113.6, 113.5, 111.5, 70.8, 56.0; HRMS (ESI) m/z calculated for C₃₂H₂₄N₂O₃ [M + H]⁺: 485.1869; found 485.1860.

Phenyl{3-(4-bromophenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3af)

Yield 88%; ¹H NMR (400 MHz, CDCl₃) δ 9.49 (br s, 1H), 9.45 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.53–7.60 (m, 4H), 7.28–7.43 (m, 6H), 7.14–7.21 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 197.9, 153.8, 144.7, 143.6, 140.1, 139.4, 137.7, 132.9, 131.8, 131.2, 129.5, 128.2, 127.7, 123.1, 121.6, 121.1, 120.9, 120.0, 115.3, 111.6; HRMS (ESI) m/z calcd for C₂₄H₁₅BrN₂O [M + H]⁺: 427.0441, 429.0421; found 427.0441; 429.0426.

Phenyl{3-(4-chlorophenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3ag)

Yield 88%; ¹H NMR (400 MHz, CDCl₃) δ 9.56 (br s, 1H), 9.46 (s, 1H), 8.21 (d, J = 4.8 Hz, 1H), 7.47–7.53 (m, 6H), 7.34–7.31 (m, 2H), 7.13–7.18 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 197.9, 153.7, 144.7, 143.5, 140.1, 138.7, 137.7, 134.7, 132.9, 131.5, 129.5, 128.3, 128.2, 127.7, 121.6, 121.1, 120.1, 120.0, 115.3, 111.6; HRMS (ESI) m/z calcd for C₂₄H₁₅ClN₂O [M + H]⁺: 383.0946; found 383.0947.

Phenyl{3-(2-chlorophenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3ah)

Yield 84%; ¹H NMR (400 MHz, CDCl₃) δ 9.75 (br s, 1H), 9.49 (s, 1H), 8.23 (d, J = 7.2 Hz, 1H), 7.52–7.56 (m, 4H), 7.27–7.42 (m, 3H), 7.15–7.19 (m, 2H), 7.08–7.11 (m, 2H), 7.00–7.03 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 198.0, 153.0, 144.4, 143.7, 140.2, 139.3, 138.4, 133.2, 132.8, 132.3, 129.6, 129.07, 127.7, 127.7, 126.4, 121.6, 121.0, 121.0, 120.4, 116.6, 111.6; HRMS (ESI) m/z calcd for C₂₄H₁₅ClN₂O [M + H]⁺: 383.0946; found 383.0948.

Phenyl{3-(4-fluorophenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3ai)

Yield 85%; ¹H NMR (400 MHz, CDCl₃) δ 9.46 (br s, 1H), 9.38 (s, 1H), 8.14 (d, J = 7.6 Hz, 1H), 7.46–7.49 (m, 6H), 7.23–7.33 (m, 2H), 7.08–7.13 (m, 2H) 6.76–6.80 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 198.0, 161.9, 154.0, 144.8, 143.6, 140.1, 137.8, 136.6, 132.8, 132.2, 132.1, 129.4, 128.1, 127.6, 121.6, 121.2, 120.9, 119.9, 115.2, 115.0, 111.5; HRMS (ESI) m/z calcd for C₂₄H₁₅FN₂O [M + H]⁺: 367.1250; found 367.1241.

Phenyl{3-(4-trifluoromethylphenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3aj)

Yield 89%; ¹H NMR (400 MHz, CDCl₃) δ 9.57 (br s, 1H), 9.48 (s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 7.64–7.66 (m, 2H), 7.50–7.54 (m, 4H), 7.39–7.41 (m, 3H) 7.29–7.30 (m, 1H), 7.14–7.17 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 197.8, 153.6, 144.6, 143.7, 140.2, 137.7, 133.0, 130.6, 130.3, 130.0, 129.4, 128.6, 128.2, 127.8, 124.9 (m), 122.5, 121.7, 121.0, 120.4, 115.7, 111.6; HRMS (ESI) m/z calcd for C₂₅H₁₅F₃N₂O [M + H]⁺: 417.1208; found 417.1209.

Phenyl{3-(4-nitrophenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3ak)

Yield 85%; ¹H NMR (400 MHz, CDCl₃) δ 9.57 (br s, 1H), 9.49 (s, 1H), 8.24 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 7.6 Hz, 2H), 7.72 (d, J = 7.6 Hz, 2H), 7.53–7.56 (m, 4H), 7.31–7.44 (m, 2H), 7.16–7.19 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 197.4, 152.3, 147.3, 146.6, 143.7, 140.3, 139.4, 137.7, 133.3, 131.1, 129.5, 128.3, 128.1, 123.2, 121.9, 121.1, 120.9, 120.7, 115.9, 111.7; HRMS (ESI) m/z calcd for C₂₄H₁₅N₃O₃ [M + H]⁺: 394.1186; found 394.1189.

Phenyl{3-(2-nitrophenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3al)

Yield 82%; ¹H NMR (400 MHz, CDCl₃) δ 9.64 (br s, 1H), 9.36 (s, 1H), 8.20 (d, J = 7.2 Hz, 1H), 7.78–7.80 (m, 2H), 7.41–7.56 (m, 2H), 7.30–7.40 (m, 1H),7.17–7.26 (m, 7H); ¹³C NMR (100 MHz, CDCl₃) δ 197.5, 151.5, 148.8, 144.6, 143.8, 140.1, 138.4, 135.4, 133.4, 132.8, 131.7, 129.2, 129.0, 128.1, 127.8, 124.6, 121.7, 121.0, 120.9, 120.4, 116.0, 111.6; HRMS (ESI) m/z calcd for C₂₄H₁₅N₃O₃ [M + Na]⁺ 416.1006; found 416.1009.

Phenyl{3-(4-cyanophenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3am)

Yield 84%; ¹H NMR (400 MHz, CDCl₃) δ 9.54 (br s, 1H), 9.48 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.65–7.67 (m, 2H), 7.53–7.59 (m, 4H), 7.40–7.46 (m, 3H), 7.33–7.37 (m, 1H), 7.16–7.20 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ; 197.4, 152.8, 144.7, 144.5, 143.7, 140.3, 137.6, 133.2, 131.8, 130.9, 129.5, 128.3, 128.0, 121.8, 121.1, 120.9, 120.6, 118.6, 115.8, 111.9, 111.7; HRMS (ESI) m/z calcd for C₂₅H₁₅N₃O [M + H]⁺ 374.1293; found 374.1282.

Phenyl{3-(2-furyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3an)

Yield 75%; ¹H NMR (400 MHz, CDCl₃) δ 9.38 (s, 1H), 9.30 (br s, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.73–7.71 (m, 2H), 7.28–7.51 (m, 6H), 7.17–7.13 (s, 1H), 6.92 (s, 1H), 6.29 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 196.8, 152.9, 144.0, 143.9, 143.7, 143.6, 140.1, 138.1, 132.9, 128.7, 128.4, 127.5, 121.8, 121.3, 120.8, 119.7, 113.6, 112.1, 111.7, 111.5; HRMS (ESI) m/z calcd for C₂₂H₁₄N₂O₂ [M + H]⁺ 339.1134; found 339.1140.

Phenyl{3-(2-thiophenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3ao)

Yield 76%; ¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (br s, 1H), 9.45 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H) 7.75 (d, J = 7.6 Hz, 2H), 7.28–7.62 (m, 7H), 6.88–6.96 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 196.0, 144.0, 143.7, 143.1, 142.1, 140.8, 136.3, 134.3, 129.3, 129.1, 128.7, 127.9, 127.2, 127.0, 120.8, 120.8, 120.3, 118.7, 115.0, 112.0; HRMS (ESI) m/z calcd forC₂₂H₁₄N₂OS [M + H]⁺ 355.0905; found 355.0899.

Phenyl{3-(4-butyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3ap)

Yield 73%; ¹H NMR (400 MHz, CDCl₃) δ 9.31 (br s, 1H), 8.90 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.82–7.84 (m, 2H), 7.62–7.66 (m, 1H), 7.41–7.52 (m, 4H), 7.32–7.36 (m, 1H), 2.73 (t, J = 8.0 Hz, 2H), 1.60–1.68 (m, 2H), 1.10–1.19 (m, 2H), 0.75 (t, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 197.7, 156.9, 143.8, 143.5, 139.6, 138.6, 133.7, 129.4, 128.9, 127.1, 121.3, 121.20, 120.6, 118.9, 116.3, 111.3, 37.0, 32.7, 22.5, 13.7; HRMS (ESI) m/z calcd for C₂₂H₂₀N₂O [M + H]⁺ 329.1648; found 329.1645.

Phenyl{3-(3-propyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3aq)

Yield 73%; ¹H NMR (400 MHz, CDCl₃) δ 9.30 (s, 1H), 8.92 (s, 1H), 8.14 (d, J = 7.6 Hz, 1H), 7.82–7.83 (m, 2H), 7.62–7.65 (m, 1H), 7.41–7.51 (m, 4H), 7.32–7.35 (m, 1H), 2.72 (t, J = 7.6 Hz, 2H), 1.67–1.71 (m, 2H), 0.76 (t, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 197.7, 156.7, 143.7, 143.6, 139.6, 138.6, 133.7, 129.4, 128.9, 127.1, 121.3, 120.6, 119.0, 116.4, 111.3, 39.3, 23.8, 13.9; HRMS (ESI) m/z calculated for C₂₁H₁₈N₂O [M + H]⁺ 315.1492; found 315.1485.

Phenyl(3-ferrocenyl-5H-pyrido[4,3-b]indol-4-yl)methanone (3ar)

Yield 66%; ¹H NMR (400 MHz, CDCl₃) δ 9.36 (s, 1H), 9.16 (br s, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.2 Hz, 2H), 7.47–7.50 (m, 2H), 7.33–7.41 (m, 2H), 7.22–7.24 (m, 2H), 4.61 (s, 2H), 4.11 (s, 2H), 4.01 (s, 5H); HRMS (ESI) m/z calcd for C₂₈H₂₀FeN₂O [M + H]⁺: 457.1003; found 457.1051.

4-Methylphenyl(3-phenyl-5H-pyrido[4,3-b]indol-4-yl)methanone (3ba)

Yield 84%; ¹H NMR (400 MHz, CDCl₃) δ 9.46 (br s, 1H), 9.39 (s, 1H), 8.21 (d, J = 7.9 Hz, 2H), 7.46–7.57 (m, 6H), 7.36–7.39 (m, 1H), 7.14–7.20 (m, 3H), 6.94–6.96 (d, J = 7.76 Hz, 2H), 2.24 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 197.7, 156.3, 144.8, 143.5, 140.0, 138.4, 137.9, 137.5, 132.5, 130.3, 129.5, 128.8, 128.0, 127.3, 121.4, 120.8, 119.5, 115.0, 111.5, 21.7; HRMS (ESI) m/z calcd for C₂₅H₁₈N₂O[M + H]⁺ 363.1492; found 363.1496.

4-Methylphenyl{3-(4-methoxyphenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3bc)

Yield 82%; ¹H NMR (400 MHz, acetone-d₆) δ 11.22 (br s, 1H), 9.60 (s, 1H), 8.41 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.04 Hz, 1H), 7.54–7.60 (m, 5H), 7.39–7.43 (m, 1H), 7.10 (d, J = 7.5 Hz, 2H), 6.80 (d, J = 7.3 Hz, 2H), 3.71 (s, 3H), 2.26 (s, 3H); ¹³C NMR (100 MHz, acetone-d₆) δ 195.4, 161.5, 150.6, 145.3, 142.2, 141.2, 135.4, 132.4, 130.6, 130.5, 129.9, 129.0, 128.8, 122.6, 122.0, 121.9, 120.3, 117.5, 114.5, 113.2, 55.6, 21.5; HRMS (ESI) m/z calcd for C₂₆H₂₀N₂O₂ [M + H]⁺: 393.1598; found 393.1594.

4-Methylphenyl{3-(4-bromophenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3bf)

Yield 84%; ¹H NMR (400 MHz, CDCl₃) δ 9.39 (br s, 2H), 8.14 (d, J = 3.6 Hz, 1H), 7.32–7.53 (m, 7H), 7.20–7.26 (m, 2H), 6.92–6.94 (m, 2H), 2.22 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 196.0, 151.9, 143.6, 143.2, 142.1, 139.1, 137.7, 133.7, 130.7, 130.3, 128.7, 128.1, 128.0, 126.7, 122.2, 120.6, 120.0, 118.9, 114.6, 110.6, 20.6; HRMS (ESI) m/z calcd for C₂₅H₁₇BrN₂O [M + H]⁺ 441.0603, 443.0582; found 441.0610, 443.0588.

4-Methylphenyl{3-(4-nitrophenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3bk)

Yield 83%; ¹H NMR (400 MHz, CDCl₃) δ 9.47 (br s, 2H), 8.22 (d, J = 6.0 Hz, 1H), 8.02–8.05 (m, 2H), 7.73–7.76 (m, 2H), 7.41–7.54 (m, 5H), 6.97–6.99 (m, 2H), 2.25 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 196.7, 151.7, 147.3, 146.6, 144.6, 144.3, 143.5, 140.2, 134.8, 131.0, 129.7, 129.1, 128.0, 123.2, 121.8, 121.1, 120.9, 120.6, 116.2, 111.65, 21.6; HRMS (ESI) m/z calcd for C₂₅H₁₇N₃O₃ [M + H]⁺: 408.1343; found 408.1347.

4-Methylphenyl{3-(4-cyanophenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3bl)

Yield 86%; ¹H NMR (400 MHz, CDCl₃) δ 9.46 (br s, 2H), 8.21 (d, J = 7.92 Hz, 1H), 7.68 (d, J = 7.8 Hz, 2H), 7.38–7.57 (m, 7H), 6.98 (d, J = 7.76 Hz, 2H), 2.28 (s, 3H); ³C NMR (100 MHz, CDCl₃) δ 196.8, 152.4, 144.9, 144.5, 144.4, 143.6, 140.3, 134.9, 131.8, 130.8, 129.8, 129.1, 128.0, 121.8, 121.0, 121.0, 120.5, 118.7, 116.1, 111.8, 111.7, 21.7; HRMS (ESI) m/z calcd forC₂₆H₁₇N₃O [M + H]⁺: 388.1445; found 388.1444.

4-Methylphenyl (3-butyl-5H-pyrido[4,3-b]indol-4-yl)methanone (3bp)

Yield 72%; ¹H NMR (400 MHz, CDCl₃) δ 9.22 (br s, 1H), 8.81 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.65–7.67 (d, J = 7.2 Hz, 2H), 7.33–7.41 (m, 2H), 7.20–7.28 (m, 3H), 2.69 (t, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.55–1.59 (m, 2H), 1.07–1.12 (m, 2H), 0.69 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 197.0, 156.5, 144.9, 143.6, 143.2, 139.6, 135.8, 129.7, 127.1, 123.1, 121.3, 120.6, 118.9116.6, 111.3, 36.8, 32.7, 22.5, 21.8, 13.75; HRMS (ESI) m/z calcd for C₂₃H₂₂N₂O [M + H]⁺ 343.1810, found 343.1787.

4-Methoxyphenyl(3-phenyl-5H-pyrido[4,3-b]indol-4-yl)methanone (3ca)

Yield 85%; ¹H NMR (400 MHz, CDCl₃) δ 9.59 (br s, 1H), 9.36 (s, 1H), 8.10 (d, J = 7.04 Hz, 1H), 7.40–7.47 (m, 6H), 7.19–7.28 (m, 2H), 7.05–7.08 (m, 2H), 6.60 (d, J = 7.2 Hz, 2H), 3.61 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ ¹³C NMR (100 MHz, CDCl₃) δ 196.2, 163.3, 154.2, 144.5, 143.2, 140.3, 140.1, 132.0, 130.4, 130.2, 128.4, 128.2, 127.4, 121.3, 121.2, 120.8, 119.7, 115.9, 113.4, 111.5, 55.3; HRMS (ESI) m/z calcd for C₂₅H₁₈N₂O₂ [M + H]⁺ 379.1442; found 379.1441.

4-Methoxyphenyl{3-(4-methylphenyl-5H-pyrido[4,3-b]indol-4-yl)methanone (3cb)

Yield 81%; ¹H NMR (400 MHz, CDCl₃) δ 9.42 (br s, 1H), 9.37 (s, 1H), 8.17 (d, J = 7.8 Hz, 2H), 7.58–7.60 (d, J = 7.8 Hz, 2H), 7.45–7.50 (m, 4H), 7.33–7.37 (m, 1H), 6.99 (d, J = 7.8 Hz, 2H), 6.65 (d, J = 8.28 Hz, 2H), 3.74 (s, 3H), 2.23 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 196.3, 163.3, 154.3, 154.3, 144.6, 143.2, 140.0, 138.4, 132.1, 130.4, 128.9, 127.3, 121.4, 120.8, 119.5115.6, 113.4, 111.4, 55.4, 21.2; HRMS (ESI) m/z calcd for C₂₆H₂₀N₂O₂ [M + H]⁺: 393.1598; found 393.1594.

4-Methoxyphenyl{3-(4-methoxyphenyl-5H-pyrido[4,3-b]indol-4-yl)methanone (3cc)

Yield 77%; ¹H NMR (400 MHz, CDCl₃) δ 9.41 (br s, 1H), 9.38 (s, 1H), 8.17 (d, J = 7.8 Hz, 2H), 7.53–7.60 (m, 4H), 7.45–7.49 (m, 2H), 7.33–7.37 (m, 1H), 6.72 (d, J = 8.04 Hz, 2H), 6.65 (d, J = 8.2 Hz, 2H), 3.74 (s, 3H), 3.72 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 196.3, 163.3, 159.9, 153.9, 144.6, 143.2, 140.0, 133.0, 132.0, 131.5, 130.3, 127.2, 121.3, 120.7, 119.3115.3, 113.9, 113.4, 111.4, 55.3, 55.2; HRMS (ESI) m/z calcd for C₂₆H₂₀N₂O₃ [M + H]⁺ 409.1547; found 409.1578.

4-Methoxyphenyl{3-(2,5-dimethoxyphenyl-5H-pyrido[4,3-b]indol-4-yl)methanone (3cd)

Yield 75%; ¹H NMR (400 MHz, CDCl₃) δ 9.52 (br s, 1H), 9.45 (s, 1H), 8.18 (d, J = 7.8 Hz, 2H), 7.59–7.62 (d, J = 8.52 Hz, 2H), 7.47–7.55 (m, 2H), 7.34–7.37 (m, 1H), 7.26–7.28 (m, 1H), 6.65–6.67 (m, 3H), 6.43 (d, J = 9.0 Hz, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.51 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 195.3, 163.0, 153.7, 150.8, 150.3, 144.3, 143.5, 140.2, 131.8, 130.2, 130.1, 127.4, 121.3, 120.8, 120.8120.2, 120.0, 117.0, 116.6, 116.0, 115.7, 113.0, 112.9, 111.4, 111.3, 56.0, 55.4, 55.0; HRMS (ESI) m/z calcd for C₂₇H₂₂N₂O₄ [M + H]⁺: 439.1652; found 439.1666.

4-Methoxyphenyl{3-(4-chlorophenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3cg)

Yield 86%; ¹H NMR (400 MHz, CDCl₃) δ 9.43 (s, 1H), 9.27 (br s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.50–7.58 (m, 6H), 7.36–7.40 (m, 1H), 7.18 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 3.78 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 195.9, 163.6, 152.7, 144.4, 143.2, 140.1, 138.8, 138.7, 134.7, 132.1, 131.4, 130.1, 128.4, 127.6, 127.5, 121.6, 120.9, 119.9, 113.6, 111.5, 55.5; (ESI) m/z calcd for C₂₅H₁₇N₂O₂Cl [M + H]⁺: 413.1053; found 413.1051.

4-Methoxyphenyl{3-(4-nitrophenyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3ck)

Yield 81%; ¹H NMR (400 MHz, CDCl₃) δ 9.45 (br s, 2H), 8.21 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.76–7.78 (m, 2H), 7.49–7.57 (m, 4H), 7.37–7.41 (m, 1H), 6.66 (d, J = 7.6 Hz, 2H), 3.74 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 195.3, 163.9, 151.3, 147.4, 146.6, 144.1, 143.4, 140.3, 132.1, 130.9, 130.0, 127.9, 123.3, 121.7, 121.0, 120.9, 120.5, 116.5, 113.7, 111.6, 55.4; HRMS (ESI) m/z calcd for C₂₅H₁₇N₃O₄ [M + H]⁺: 424.1291; found 424.1292.

4-Methoxyphenyl{3-(2-furyl)-5H-pyrido[4,3-b]indol-4-yl}methanone (3cn)

Yield 73%; ¹H NMR (400 MHz, CDCl₃) δ 9.28 (br s, 1H), 9.16 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.04 Hz, 2H), 7.36–7.47 (m, 2H), 7.26–7.28 (m, 1H), 7.13 (s, 1H), 6.85 (s, 1H), 6.70 (d, J = 8.0 Hz, 2H), 6.25 (s, 1H), 3.72 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 193.9, 162.5, 151.9, 142.7, 142.6, 142.3, 142.1, 139.0, 130.3, 129.7, 126.4, 120.4, 120.3119.7, 118.5, 113.1, 112.7, 111.0, 110.4, 54.4; HRMS (ESI) m/z calcd for C₂₃H₁₆N₂O₃ [M + H]⁺ 369.1286; found: 369.1239.

Methyl 3-phenyl-5H-pyrido[4,3-b]indole-4-carboxylate (3da)^6a

Yield 90%.

Methyl 3-(4-methylphenyl)-5H-pyrido[4,3-b]indole-4-carboxylate (3db)^6a

Yield 88%.

Methyl 3-(4-methoxyphenyl)-5H-pyrido[4,3-b]indole-4-carboxylate (3dc)^6a

Yield 84%.

Methyl 3-(3-methoxy-4-benzyloxyphenyl)-5H-pyrido[4,3-b]indole-4-carboxylate (3de)^6a

Yield 82%.

Methyl 3-(4-bromophenyl)-5H-pyrido[4,3-b]indole-4-carboxylate (3df)^6a

Yield 88%.

Methyl 3-(4-chlorophenyl)-5H-pyrido[4,3-b]indole-4-carboxylate (3dg)^6a

Yield 91%.

Methyl 3-(2-nitrophenyl)-5H-pyrido[4,3-b]indole-4-carboxylate (3dl)^6a

Yield 87%.

Methyl 3-{2-(tetr-butoxycarbonyl)aminophenyl}-5H-pyrido[4,3-b]indole-4-carboxylate (3ds)^6a

Yield 78%.

Methyl 3-(2-furyl)-5H-pyrido[4,3-b]indole-4-carboxylate (3dn)^6a

Yield 84%.

Methyl 3-{1-(tetr-butoxycarbonyl)-1H-indol-3yl}-5H-pyrido[4,3-b]indole-4-carboxylate (3dt)^6a

Yield 81%.

Methyl 3-ferrocenyl-5H-pyrido[4,3-b]indole-4-carboxylate (3dr)

Yield 78%; ¹H NMR (400 MHz, CDCl₃) δ 9.45 (br s, 1H), 9.27 (s, 1H), 8.12 (d, J = 7.76 Hz, 1H) 7.50 (m, 2H), 7.34 (m, 1H), 4.83 (s, 2H), 4.41 (s, 2H), 4.07 (s, 5H), 3.86 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.1, 155.6, 144.4, 143.1, 139.7, 126.9, 121.3, 120.4, 117.9, 111.3, 107.6, 85.7, 70.3, 70.0, 69.1, 52.0; HRMS (ESI) m/z calcd for C₂₃H₁₈FeN₂O₂ [M + H]⁺: 411.0796; found 411.0790.

Methyl 3-propyl-5H-pyrido[4,3-b]indole-4-carboxylate (3dq)^6a

Yield 83%.

Methyl 3-(2-phenylethyl)-5H-pyrido[4,3-b]indole-4-carboxylate (3du)^6a

Yield 86%.

Methyl 3-{2-(tert-butoxycarbonyl)aminoethyl}-5H-pyrido[4,3-b]indole-4-carboxylate (3dv)

Yield 79%; ¹H NMR (400 MHz, CDCl₃) δ 10.03 (br s, 1H), 9.24 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.48–7.52 (m, 2H), 7.32–7.36 (m, 1H), 5.37 (br s, 1H), 4.07 (s, 3H), 3.64–3.66 (m, 2H), 3.52–3.53 (m, 2H), 1.40 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 167.9, 157.5, 156.0, 145.5, 143.9, 139.6, 127.3, 121.4, 120.9, 120.6, 119.7, 111.4, 107.7, 78.8, 52.4, 39.9, 37.6, 28.4; HRMS (ESI) m/z calcd for C₂₀H₂₃N₃O₄ [M + H]⁺: 370.1767; found 370.1760.

Methyl 3-{1-(benzyloxycarbonyl)aminomethyl}-5H-pyrido[4,3-b]indole-4-carboxylate (3dw)

Yield 74%; ¹H NMR (400 MHz, CDCl₃) δ 10.12 (br s, 1H), 9.20 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.51–7.55 (m, 2H), 7.31–7.43 (m, 6H), 6.85 (br s, 1H), 5.19 (s, 2H), 4.99 (d, J = 4.8 Hz, 2H), 4.06 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.4, 156.5, 153.1, 145.6, 143.3, 139.8, 136.8, 128.5, 128.1, 128.0, 127.7, 121.5, 120.8, 120.7, 120.6, 111.5, 106.04, 66.7, 52.5, 45.8; HRMS (ESI) m/z calcd for C₂₂H₁₉N₃O₄ [M + H]⁺: 390.1448; found 390.1447.

Methyl 8-bromo-3-phenyl-5H-pyrido[4,3-b]indole-4-carboxylate (3ea)

Yield 91%; ¹H NMR (400 MHz, CDCl₃) δ 9.92 (br s, 1H), 9.33 (s, 1H), 8.29 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 6.4 Hz, 2H), 7.42–7.44 (m, 4H), 3.70 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.3, 157.5, 145.5, 144.0, 141.5, 138.5, 130.3, 129.1, 128.3, 127.9, 123.7, 122.9, 118.8, 114.4, 112.9, 107.8, 52.0; HRMS (ESI) m/z calcd for C₁₉H₁₃BrN₂O₂ [M + H]⁺: 381.0239, 383.0218; found 381.0233, 383.0215.

Methyl 8-bromo-3-(2-tert-butoxycarbonylaminoethyl)-5H-pyrido[4,3-b]indole-4-carboxylate (3ev)

Yield 81%; ¹H NMR (400 MHz, DMSO-d₆) δ 11.65 (br s, 1H), 9.39 (s, 1H), 8.48 (s, 1H), 7.59–7.65 (m, 2H), 6.78 (br s, 1H), 3.99 (s, 3H), 3.34 (s, 4H), 1.32 (s, 9H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.3, 156.9, 155.4, 144.8, 143.6, 138.9, 129.4, 123.1, 122.3, 118.0, 114.1, 112.8, 118.5, 77.3, 52.3, 52.2, 37.0, 28.2; HRMS (ESI) m/z calcd for C₂₀H₂₂BrN₃O₄ [M + H]⁺: 448.0872, 450.0851; found 448.0865, 450.0850.

Methyl 8-bromo-3-isopropyl-5H-pyrido[4,3-b]indole-4-carboxylate (3ex)

Yield 85%; ¹H NMR (400 MHz, CDCl₃) δ 9.93 (br s, 1H), 9.29 (s, 1H), 8.22 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 4.12–4.19 (m, 1H), 4.08 (s, 3H), 1.40 (s, 3H), 1.39 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.0, 145.6, 144.4, 138.1, 129.9, 123.3, 123.0, 118.0, 114.2, 112.7, 107.0, 52.4, 32.8, 22.8; HRMS (ESI) m/z calcd for C₁₆H₁₅BrN₂O₂ [M + H]⁺: 347.0390, 349.0370; found 347.0395, 349.0374.

Methyl 8-bromo-3-(2-thiophenyl)-5H-pyrido[4,3-b]indole-4-carboxylate (3eo)

Yield 85%; ¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (br s, 1H), 9.41 (s, 1H), 8.52 (s, 1H), 7.57–7.68 (m, 3H), 7.31 (d, J = 3.6 Hz, 1H), 7.13–7.15 (m, 1H), 3.95 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 167.1, 145.4, 144.1, 143.4, 142.7, 139.4, 129.7, 128.9, 128.1, 126.8, 123.5, 122.4, 117.9, 114.0, 113.0, 108.4, 52.9; HRMS (ESI) m/z calcd for C₁₇H₁₁BrN₂O₂S [M + H]⁺: 386.9791, 388.9772; found 386.9797, 388.9777.

Methyl 8-bromo-3-ferrocenyl-5H-pyrido[4,3-b]indole-4-carboxylate (3er)

Yield 82%; ¹H NMR (400 MHz, CDCl₃) δ 9.48 (br s, 1H), 9.21 (s, 1H), 8.23 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 4.82 (s, 2H), 4.42 (s, 2H), 4.06 (s, 5H), 3.85 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.9, 156.6, 144.8, 143.4, 138.3, 129.6, 123.4, 123.2, 116.9, 114.2, 112.7, 107.6, 85.5, 70.4, 70.1, 69.3, 51.9; HRMS (ESI) m/z calcd for C₂₃H₁₇BrFeN₂O₂ [M + H]⁺: 488.9901, 490.9881; found 488.9982, 490.9821.

(E)-Methyl 3-styryl-5H-pyrido[4,3-b]indole-4-carboxylate (3daa)

Yield 82%; ¹H NMR (400 MHz, CDCl₃) δ 9.97 (br s, 1H), 9.32 (s, 1H), 8.34 (d, J = 16.0 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 16.0 Hz, 1H), 7.66–7.68 (m, 2H), 7.48–7.51 (m, 2H), 7.32–7.41 (m, 4H), 4.13 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.7, 152.5, 145.1, 144.3, 139.5, 137.2, 135.8, 128.7, 128.3, 127.5, 127.2, 126.7, 121.4, 121.2, 120.5, 119.5, 111.3, 106.3, 52.5; HRMS (ESI) m/z calcd for C₂₁H₁₆N₂O₂ [M + H]⁺: 329.1285; found 329.1287.

(E)-Methyl 3-(4-methylstyryl)-5H-pyrido[4,3-b]indole-4-carboxylate (3dab)

Yield 85%; ¹H NMR (400 MHz, CDCl₃) δ 9.97 (br s, 1H), 9.31 (s, 1H), 8.30 (d, J = 15.8 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 15.8 Hz, 1H), 7.47–7.57 (m, 4H), 7.32–7.36 (m, 1H), 7.20 (d, J = 7.8 Hz, 2H), 4.13 (s, 3H), 2.38 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.8, 152.8, 145.2, 144.4, 139.5, 138.4, 135.8, 134.5, 229.4, 127.4, 127.0, 125.8, 121.3, 121.2, 120.4, 119.3, 111.3, 106.1, 52.4, 21.4; HRMS (ESI) m/z calcd for C₂₂H₁₈N₂O₂ [M + H]⁺: 343.1441; found 343.1442.

(E)-Methyl 3-(4-methoxystyryl)-5H-pyrido[4,3-b]indole-4-carboxylate (3dac)

Yield 81%; ¹H NMR (400 MHz, CDCl₃) δ 9.96 (br s, 1H), 9.33 (s, 1H), 8.42 (d, J = 15.8 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 15.8 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.49–7.55 (m, 2H), 7.34–7.38 (m, 1H), 4.15 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.8, 159.9, 153.0, 145.2, 144.4, 139.6, 135.5, 130.6, 130.2, 128.9, 127.0, 124.6, 121.3, 121.3, 120.4, 119.2, 114.1, 111.3, 55.3, 52.4; HRMS (ESI) m/z calcd for C₂₂H₁₈N₂O₃ [M + H]⁺: 359.1390; found 359.1398.

(E)-Methyl 3-(3-methoxy-4-benzyloxystyryl)-5H-pyrido[4,3-b]indole-4-carboxylate (3dad)

Yield 78%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.96 (br s, 1H), 9.30 (s, 1H), 8.21 (d, J = 15.8 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 15.8 Hz, 1H), 7.44–7.53 (m, 4H), 7.29–7.40 (m, 4H), 7.18–7.21 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 5.20 (s, 2H), 4.12 (s, 3H), 3.97 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.7, 152.8, 149.6, 148.7, 145.1, 144.3, 139.5, 136.9, 135.6, 130.9, 128.5, 127.8, 127.2, 127.0, 125.0, 121.3, 121.2, 120.6, 120.4, 119.2, 113.8, 111.3, 110.7, 105.9, 70.9, 55.9, 52.3; HRMS (ESI) m/z calcd for C₂₉H₂₄N₂O₄ [M + H]⁺: 465.1809; found 465.1814.

(E)-Methyl 3-(4-trifluorostyryl)-5H-pyrido[4,3-b]indole-4-carboxylate (3dae)

Yield 84%; ¹H NMR (400 MHz, CDCl₃) δ 9.96 (br s, 1H), 9.33 (s, 1H), 8.42 (d, J = 15.8 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 15.8 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.49–7.55 (m, 2H), 7.34–7.38 (m, 1H), 4.15 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.5, 151.8, 144.9, 144.4, 140.8, 139.6, 134.0, 129.1, 127.4, 127.4, 125.6 (m), 121.5, 121.0, 120.6, 119.9, 111.4, 106.7, 52.5; HRMS (ESI) m/z calcd for C₂₂H₁₅F₃N₂O₂ [M + H]⁺: 397.1164; found 397.1170.

(E)-Methyl 3-(4-fluorostyryl)-5H-pyrido[4,3-b]indole-4-carboxylate (3daf)

Yield 87%; ¹H NMR (400 MHz, CDCl₃) δ 9.95 (br s, 1H), 9.31 (s, 1H), 8.26 (d, J = 16.0 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 16.0 Hz, 1H), 7.61–7.65 (m, 2H), 7.48–7.54 (m, 2H), 7.33–7.36 (m, 1H), 7.06–7.11 (m, 2H), 4.14 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.5, 162.7 (d, J = 240 Hz), 152.4, 144.9, 144.2, 139.5, 134.5, 133.5, 129.0, 127.1, 126.4, 121.1, 120.4, 119.5, 115.7, 115.5, 111.3, 106.1, 52.4; HRMS (ESI) m/z calcd for C₂₁H₁₅FN₂O₂ [M + H]⁺: 347.1190. found 347.1196.

(E)-methyl 3-(4-nitrostyryl)-5H-pyrido[4,3-b]indole-4-carboxylate (3dag)

Yield 82%; ¹H NMR (400 MHz, DMSO-d₆)δ 11.67 (br s, 1H), 9.50 (s, 1H), 8.40 (d, J = 16.0 Hz, 1H), 8.25–8.29 (m, 3H), 8.05 (d, J = 16.0 Hz, 1H), 7.93 (d, J = 7.6 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.50–7.55 (m, 1H), 7.30–7.34 (m, 1H), 4.08 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.2, 149.6, 146.7, 144.5, 143.5, 142.9, 140.6, 131.9, 130.7, 128.0, 127.4, 124.2, 121.0, 120.7, 120.4, 119.8, 112.3, 108.5, 52.7; HRMS (ESI) m/z calcd for C₂₁H₁₅N₃O₄ [M + H]⁺: 374.1141; found 374.1148.

(E)-Methyl 3-pentenyl-5H-pyrido[4,3-b]indole-4-carboxylate (3dah)

Yield 75%; ¹H NMR (400 MHz, CDCl₃) δ 9.94 (br s, 1H), 9.26 (s, 1H), 8.10 (d, J = 8 0.0 Hz, 1H), 7.47–7.54 (m, 3H), 7.30–7.34 (m, 1H), 7.10–7.14 (m, 1H), 4.08 (s, 3H), 2.32–2.37 (m, 2H), 1.58–1.65 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.9, 153.0, 145.2, 144.3, 139.3, 128.5, 126.9, 121.3, 121.2, 120.4, 119.2, 111.2, 111.3, 105.6, 52.2, 35.4, 22.2, 13.9; HRMS (ESI) m/z calcd for C₁₈H₁₈N₂O₂ [M + H]⁺: 295.1447. found 295.1443.

(E)-Methyl 8-bromo-3-styryl-5H-pyrido[4,3-b]indole-4-carboxylate (3eaa)

Yield 79%; ¹H NMR (400 MHz, CDCl₃) δ 10.02 (br s, 1H), 9.26 (s, 1H), 8.33 (d, J = 15.8 Hz, 1H), 8.26 (s, 1H), 8.03 (d, J = 15.8 Hz, 1H), 7.58–7.68 (m, 3H), 7.30–7.42 (m, 4H), 4.14 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.7, 145.6, 144.8, 138.2, 137.2, 136.5, 130.0, 128.7, 128.5, 128.4, 127.6, 126.5, 123.3, 123.0, 118.6, 114.8, 112.8, 106.4, 52.6; HRMS (ESI) m/z calcd for C₂₁H₁₅BrN₂O₂ [M + H]⁺: 407.2679, 409.0375; found 407.2671, 409.0384.

tert-Butyl 1-oxo-1H-benzo[h]indolo[3,2-c][1,6]naphthyridine-2(13H)-carboxylate (6)

Yield 76%; ¹H NMR (400 MHz, CDCl₃) δ 10.63 (br s,1H), 9.58 (s, 1H), 8.97 (d, J = 8.04 Hz, 1H), 8.19 (d, J = 7.76 Hz, 1H), 7.50–7.61 (m, 3H), 7.41–7.46 (m, 1H), 7.35–7.39 (m, 1H), 7.23–7.25 (m, 1H), 1.78 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 161.0, 150.7, 147.7, 146.8, 143.0, 139.7, 135.1, 130.7, 127.2, 125.9, 123.9, 121.7, 121.0, 120.6, 119.4, 114.1, 111.9, 105.4, 87.0, 27.7; HRMS (ESI) m/z calcd for C₂₃H₁₉N₃O₃ [M + H]⁺: 386.1505; found 386.1499.

tert-Butyl 10-bromo-1-oxo-1H-benzo[h]indolo[3,2-c][1,6]naphthyridine-2(13H)-carboxylate (7)

Yield 79%; ¹H NMR (400 MHz, CDCl₃) δ 10.68 (br s, 1H), 9.57 (s, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.35 (s, 1H), 7.60–7.65 (m, 2H), 7.45–7.49 (m, 2H), 7.25 (s, 1H), 1.77 (s, 9H); HRMS (ESI) m/z calcd for C₂₃H₁₈BrN₃O₃ [M + H]⁺: 464.0604, 466.0585; found 464.0560, 466.0564.

Conclusions

In summary, we have developed a general, catalyst-free, simple, mild, convenient and green method for the synthesis of biologically interesting functionalized γ-carboline derivatives via a one-pot three-component hetero-annulation reaction between 3-formyl indoles, aromatic/hetero-aromatic/alkyl/alkenyl/alkynyl/ferrocenyl aldehydes and ammonium acetate as an inexpensive N-supplier in water at room temperature under aerobic conditions. Our current MCR technique provides good to excellent yields of title compounds, thus it ensures a broad substrate scope and allows a wide range of synthetically useful functional groups. Very interestingly, this chemistry could be applied for the synthesis of same (E)-2-styryl-substituted γ-carboline derivatives by employing either alkenyl aldehydes or alkynyl aldehydes. In addition, the quinolinone fused γ-carboline derivatives have been achieved in a practical manner through our methodology. Further exploration into the potential substrates scope and test their biological activities are in progress in our laboratory which will be documented in due course.

Acknowledgements

The authors thank the DST, Govt. of India research grant (Project no. SB/S1/OC-19/2013). S. Biswas is thankful to his UGC fellowship. Authors are also thankful to Mr K. Pandey for recording the NMR spectra.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of all unknown compounds ¹H and ¹³C NMR spectra are attached. See DOI: 10.1039/c5ra08422a

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