Metal halide hydrates as lewis acid catalysts for the conjugated friedel-crafts reactions of indoles and activated olefins

ARTICLE

Metal halide hydrates as lewis acid catalysts for the conjugated friedel-crafts reactions of indoles and activated olefins

Cristiane S. Schwalm; Marco Antonio Ceschi; Dennis Russowsky^*

Instituto de Química, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9500, 91501-970 Porto Alegre-RS, Brazil

ABSTRACT

Metal halide hydrates such as SnCl₂·2H₂O, MnCl₂·4H₂O, SrCl₂·6H₂O, CrCl₂·6H₂O, CoCl₂·6H₂O e CeCl₃·7H₂O were investigated as mild Lewis acids catalysts for the conjugate Friedel-Crafts reaction between indoles and activated olefins. The reactions were carried out with aliphatic unsaturated ketones over a period of days at room temperature, while chalcones reacted only under reflux conditions. The reactions with nitrostyrenes were either performed in solvent or under solventless conditions. In all cases reasonable to good yields were obtained.

Keywords: Friedel-Crafts, indoles, activated olefins, metal halide hydrates, Lewis acids, Michael addition

RESUMO

O uso de haletos metálicos hidratados, tais como, SnCl₂·2H₂O, MnCl₂·4H₂O, SrCl₂·6H₂O, CrCl₂·6H₂O, CoCl₂·6H₂O e CeCl₃·7H₂O como catalisadores ácidos de Lewis foi investigado nas reações conjugadas tipo Friedel-Crafts entre indóis e olefinas ativadas. A utilização de enonas alifáticas forneceu as respectivas β-indolilcetonas à temperatura ambiente em longos tempos de reação, enquanto que nas reações com chalconas foi necessário o uso de condições de refluxo em isopropanol. As reações dos indóis com nitroestirenos foram efetuadas tanto em fase líquida como em condições sem solvente. Em todos os casos estudados foram obtidos rendimentos de razoáveis a bons.

Introduction

The investigation of synthetic methodologies for the preparation of 3-substituted indole derivatives has been a continuous challenge in the chemistry of heterocyclic compounds.^1-3

The C₃ alkylation reaction of indoles through the conjugated Friedel-Crafts (CFC) reaction has received much attention in the last decade.^4-6 Not only they allow access to advanced building blocks in the synthesis of natural compounds, but also their diverse biological properties of derivatives have pharmaceutical applications.^7-11

Over the past few years a range of methods for the preparation of β-indolylketones by CFC reaction of indoles with α,β-unsaturated ketones has appeared in the literature in which both Brønsted or Lewis acidic catalysts have successfully been employed. However, in the curse of Brønsted acid catalysis, many procedures involve strong acidic conditions, expensive reagents, longer reaction times, low yields, complex handling procedures and problematic side reactions, such as dimerization and polymerization.¹²

On the other hand, the employment of suitable metal halides such as InCl₃,¹³ InBr₃,¹⁴ SmI₃,¹⁵ GaI₃,¹⁶ SbCl₃,¹⁷ ScCl₃,¹⁸ AlCl₃,¹⁹ ZrCl₄,²⁰ and HfCl₄¹⁸ as Lewis acid catalysts have attracted attention due to their ability to efficiently activate the α,β-unsaturated carbonyl system for the CFC reaction. However, many of them are moisture sensitive needing a careful handling and the achievement of a substitute is welcome. Additionally, others environmentally-benign, oxygen and/or moisture tolerant Lewis acids such as Yb(OTf)₃,⁷ Sc(OTf)₃,²¹ Bi(OTf)₃,²² Hf(OTf)₄,²¹ and Zr(OTf)₄²³ have been applied to this transformation, but they are expensive.

A few previous uses of metal salt hydrates such as: NaAuCl₄·2H₂O,²⁴ ZrOCl₂·8H₂O,²⁵ RuCl₃·nH₂O²⁶ and Fe(BF₄)₂·6H₂O²⁷ have been reported.

As a part of our ongoing investigation searching for moisture compatible Lewis acids, including their use in protic solvents, for the synthesis of small molecules of biological interest,^28-36 we decide to investigate the metal halide hydrates as a potential catalysts for the CFC reaction. We have earlier demonstrated the successful use of SnCl₂·2H₂O as an alcoholic compatible Lewis acid catalyst for the multicomponent dihydropyrimidinone synthesis.³⁷ The Lewis acidity of SnCl₂·2H₂O has been reported by others in different reactions types.^38-40

Although the hydrogen Brønsted acid catalysis has been suggested by Spencer as the main process when a metal halide is used as a Lewis catalyst in aqueous (or protic alcoholic) solvents,⁴¹ other authors postulated the water-tolerance of many metal halides. Kobayashi suggests that the certain metal halides are able to complex with the electrophile before the hydrolysis occurs. These characteristics depends on the hydrolysis constant (K_h) within a certain range and a high water-exchange rate constant (WERC).⁴² On the other hand, Fringuelli et al.⁴³ report the use of AlCl₃, TiCl₄, and SnCl₄ as the Lewis acids catalysts in aqueous solvent. Although the authors agree with the fast hydrolysis of metal salts, they affirm that the hydrated metal cation remains as the effective species as Lewis acid catalyst.

Recent studies of Lindstrom⁴⁴ show that the water tightly coordinated to the metal halide become more labile upon complexation of an organic ligand (electrophile), leading to a higher rate of exchange with substrate molecules and consequently to higher reaction rates.

The SnCl₂·2H₂O was employed as a Lewis acid catalyst in the esterification of oleic acid. The authors proved the ethanol-compatibility of the catalyst as a Lewis acid through the recovery of SnCl₂·2H₂O and verified that the catalytic activity of the recovered SnCl₂·2H₂O remains unaltered in successive reactions with oleic acid.⁴⁵

Based on these previous studies, we report in this paper, our efforts to apply a series of metal halide hydrates such as: SnCl₂·2H₂O, MnCl₂·4H₂O, SrCl₂·6H₂O, CoCl₂·6H₂O and CrCl₃·6H₂O as Lewis acid catalysts for the CFC reaction of indoles and activated olefins, carried out in benign alcoholic solvents.

Results and Discussion

Reactions of indoles with alkylidene-alkylketones

In our first experiment, we investigated the use of various metal halide hydrates as Lewis acid catalysts in the reaction of indole (1a) and 4-hexen-3-one (2a) under different alcoholic solvents, temperatures and catalyst loading. In all experiments the desired β-indolylketone 3a was obtained in good yield (Scheme 1).

As shown in Table 1, the yield of the product 3a was quite good when the reaction was carried out in i-PrOH at room temperature. The reaction proceeded cleanly⁴⁶ as observed by comparative TLC and i-PrOH was chosen as the default solvent for the other reactions (c.f. entries 1-3).

For the SnCl₂·2H₂O, the increase of the catalyst loading did not improve the yields and the catalytic amount of 10 mol% was chosen as the default load of the catalyst (entries 3, 4 and 5, respectively).

Although long reaction times were required, in general, reasonable to good yields were observed when MnCl₂·4H₂O, SrCl₂·6H₂O, CoCl₂·6H₂O were used as catalysts in experiments carried out at room temperature (entries 6, 7 and 8). On the other hand, shorter reaction times of 3-5 h and refluxing conditions were enough to complete the consumption of the reagents when SnCl₂·2H₂O, CoCl₂·6H₂O and CrCl₂·6H₂O were used (entries 9, 10 and 11, respectively).

Due to the easy availability, good stability and low cost, SnCl₂·2H₂O was chosen as the default catalyst. Its use as a Lewis acid catalyst in the reaction of indoles 1a-c and ketones 2a-e afforded the respective β-indolylketones 3b-m in reasonable to good yields (Scheme 2). The results are summarized in the Table 2.

As can be observed, the yields of adducts 3 were high, except for the cases where cyclohexenone was used as the Michael acceptor in the reactions with indole 1a (entries 4 and 9, respectively). In both cases, we were able to isolate variable amounts of two other side products, which showed a strong absorption in UV-light (254 nm).

We believe that the side products are generated by a second attack of an indole molecule to the initial β-indolylketone formed. Alternatively, a third molecule of indole could be added to the bis-indolyl adduct 3n and 3o to form the tris-indolyl adduct 3p and 3q, respectively, as reported recently by Shi et al.²³ (Figure 1).

All of the yields refer to isolated products after purification by column chromatography and the ¹H NMR, ¹³C NMR and IR spectral data were in accordance with the proposed structures.

Reactions of indoles with arylidene-phenylketones

Next, we investigated the conjugated Friedel-Crafts reaction of indoles 1a-c with chalcones⁴⁷2f-i in presence of SnCl₂·2H₂O as the catalyst and i-PrOH as the solvent (Scheme 2).

In contrast with alkylidene-alkylketones, the chalcone 2f was not reactive with indole 1a at room temperature over 144 h, even at 50 mol% catalyst loading (cf. entries 1-3, Table 3). On the other hand, the use of reflux conditions led to the formation of the desired adduct 3r after 5 h in good yield (entry 4). Other catalysts such as MnCl₂·4H₂O, SrCl₂·6H₂O, CoCl₂·6H₂O and CeCl₃·7H₂O were also effective (entries 5 and 8).

The chalcones 2f-i were reacted under the previous reaction conditions and the β-indolylchalcones 3r-z were obtained in reasonable to good yields after purification by column chromatography (entries 9-15). The lower reactivity of chalcones may be attributed to their inferior electrophilicity as well as the increase of steric hindrance at the β-position of the ketone.

Reactions of indoles with nitrostyrenes

Due to the success of previous experiments we decided to investigate the CFC reactions of indoles 1a-c with nitroolefins 4a-g. The nitroolefins are recognized as excellent Michael aceptors^48,49 and their derivatives are important intermediates in organic synthesis due to the synthetic versatility of the nitro-group as precursor of other organic functionalities.^50-52 First, we investigated the reaction of indole 1a wiyh nitrostyrene 4a carried out under the reactions conditions described above (i-PrOH, room temperature and 10 mol% of SnCl₂·2H₂O). Unfortunately, no product was formed even after 6 days. A second experiment was carried out under reflux conditions over 5 h and total consumption of the starting materials was observed. The TLC analysis revealed the presence of very polar mixture of byproducts⁵³ which were not identified. After purification by chromatography, product 5a was obtained in only 54% yield (Scheme 3).

With the aim of improving the chemo-selectivity of the reaction and the yields of the products, the catalyst was changed to CoCl₂·6H₂O, which had been successfully applied previously (see Table 1 entry 10 and Table 3, entry 7, respectively).

The reaction was carried out in i-PrOH under reflux conditions for 2 h, when total consumption of the starting material was observed by TLC. After purification by chromatography, the nitro-adduct 5a was isolated in 95% yield (Table 4, entry 1).

At this point we decided to investigate a set of different solvents. The experiments were carried out in polar protic solvents such as MeOH and EtOH; polar non protic solvents such as THF, CH₃CN and CH₂Cl₂ and in the non polar non protic solvent such as C₆H₆. The results are shown in Table 4.

As can be seen, the best result was achieved when the reaction was carried out under reflux of i-PrOH (Table 4, entry 1). On the other hand, the reaction did not proceed in CH₂Cl₂ (entry 6). It should be noted that the yield of product 5a in the reaction performed in C₆H₆ was similar to those obtained in MeOH or EtOH (entries 7, 2 and 3, respectively).

Solventless CFC reactions of indoles with nitrostyrenes

Due to the constant search for environmentally-friendly protocols that avoid the collateral production of wastes in the synthetic organic chemistry, many efforts have been made to develop organic reactions in solventless conditions.^54-56

Therefore, we decided to investigate the viability of CFC reaction of indoles and nitrostyrenes catalyzed by metal halide hydrates under solventless conditions. The results are summarized in Table 5.

The best result was achieved when CoCl₂·6H₂O was employed over 15 min at 100 °C (entry 1). Good yields were also achieved with CrCl₃·6H₂O and CeCl₃·7H₂O with little increase of the reaction times (entries 2 and 3). The employment of MnCl₂·4H₂O, NiCl₂·6H₂O or SrCl₂·6H₂O showed lower activity and an increase of the reaction time was needed to complete the consumption of the reagents (entries 4-6, respectively). In presence of SnCl₂·2H₂O, even over prolonged time, poor yield was obtained (entry 7).

To explore the generality of the solventless conjugated Friedel-Crafts reaction, we synthesized a set of nitrostyrene derivatives through a methodology reported in the literature.⁵⁷ Reaction of nitromethane with various aromatic aldehydes in the presence of ammonium acetate under heating (Scheme 4) afforded the respective nitroolefins 4a-g in 65-89% yields, after recrystallization (Figure 2).

The solventless CFC reactions were carried out under the same conditions disclosed above and afforded the respective nitro adducts 5b-q. The results are summarized in Table 6.

In general, all reactions afforded the nitro-adducts in good yields. The reactivity of the nitroolefin 4d was lower for both indoles 1a and 1b (entries 3 and 10, respectively). This may be due to the strong electron releasing effect of the N,N-dimethyl group attached at 4-position of the aromatic ring. Also, the steric hindrance caused by the bulky naphtyl group could be responsible for de increase of the reaction times with the indoles 1a and 1c and the nitroolefin 4f

(entry 5 and 15, respectively).

Synthesis of β-carboline derivative via Pictet-Spengler reaction

To demonstrate the synthetic utility of the nitro adduct intermediate 5a we performed the transformation of the nitro group into an amino group by reduction in the presence of NH₄OAc and catalytic amounts of Pd/C.⁵⁸ The triptamine derivative 8 was obtained in 90% yield as a crude product.

After the treatment of compound 8 with benzaldehyde under the Pictet-Spengler reaction conditions, the β-Carboline derivative 9 was isolated as a diastereomeric mixture of 87:13 ratios. After purification by chromatography, the compound 9-trans was isolated in 70% yield. The relative trans configuration of the major distereoisomer was inferred by comparison of the ¹H NMR data with the reported literature (Scheme 5).⁵⁹

Conclusions

We have demonstrated that many metal halides hydrates are able to catalyze the conjugate Friedel-Crafts reaction of indoles and activated olefins in good to excellent yields. The alcoholic solvents were superior and i-PrOH was found to be the best choice.

For the reactions with aliphatic enones longer reaction times were needed for those reaction carried out at room temperature, whereas shorter times were observed under refluxing conditions. The metal halide hydrates SnCl₂·2H₂O, MnCl₂·4H₂O, CrCl₂·6H₂O, CoCl₂·6H₂O were all effective.

Chalcones as Michael acceptors afforded the desired adducts only under refluxing conditions using SnCl₂·2H₂O as catalysts.

For the reaction with of nitroolefins, refluxing conditions are imperative under the liquid phase. Here, the alcoholic i-PrOH was superior. On the other hand, SnCl₂·2H₂O leads to the formation of several byproducts and therefore it was abandoned. The best results were achieved in the presence of CoCl₂·6H₂O. These reactions were also investigated in the absence of solvents under 100 °C. The metal halide hydrates CoCl₂·6H₂O, CrCl₃·6H₂O, CeCl₃·7H₂O, MnCl₂·4H₂O, NiCl₂·6H₂O and SrCl₂·6H₂O were all effective in the reaction, but with different reaction times. The CoCl₂·6H₂O, CrCl₃·6H₂O and CeCl₃·7H₂O were the most effective catalysts. In summary, we have demonstrated the use of cheaper and easy to handle metal halide hydrates as Lewis acids catalysts in the conjugated Friedel-Crafts reaction under enviromentally benign alcoholic solvents or under eco-friendly solventless protocols.

Experimental

All reactions were carried out under air. The chalcones⁴⁷ (2f-i) and the nitrostyrenes⁵⁷ (4a-g) were prepared according to the literature. All other reagents and solvents were purchased from commercial suppliers and used without further purification except hexane which was distilled prior to use. The ¹H and ¹³C NMR spectra were recorded in CDCl₃ on a Varian VNMRS spectrometer at 300 MHz and 75 MHz, respectively. The chemical shifts (δ) are reported in ppm relative to TMS (0.00 ppm) for ¹H NMR and to the central line of CDCl₃ (77.0 ppm) for ¹³C NMR. Coupling constants J are reported in Hertz (Hz). IR spectra were recorded on a FTIR-Varian 640-IR spectrometer. Melting points were measured on an Olympus BX41 microscope equipped with a Mettler-Toledo FP82HT hot stage (Mettler-Toledo FP90 controller) and are uncorrected. Reactions were monitored using thin layer chromatography (TLC) carried out on Merck silica gel 60 F₂₅₄ precoated aluminium plates. The visualization was achieved under UV light (254 nm) or staining with I₂. Chromatographic separations were achieved on silica gel columns (70-230 mesh, Aldrich) using gradient of hexanes/ethyl acetate as eluent.

General procedure for the synthesis of β-indolylketones 3a-m

In a 25 mL round-bottom flask, equipped with magnetic stirrer were added the indoles 1a-c (1.0 mmol), the α,β-unsaturated ketones 2a-e (1.1 mmol) and SnCl₂·2H₂O (0.1 mmol) in i-PrOH (2 mL). The reaction mixture was stirred at room temperature for the appropriate time shown in the Table 2. After the completion of the reaction, monitored by TLC, the solvent was removed under vacuum and the crude products 3a-m were purified by column chromatography using a gradient of hexanes/ethyl acetate as eluent.

5-(1H-Indol-3-yl)hexan-3-one (3a):⁶⁰ 96%, viscous brown oil; ¹H NMR (300 MHz, CDCl₃) δ 8.25 (br s, 1H), 7.63 (m, 1H), 7.28 (m, 1H), 7.18-7.04 (m, 2H), 6.82 (s, 1H), 3.62 (m, 1H), 2.86 (dd, J 15.9 and 6.3 Hz, 1H), 2.64 (dd, J 15.9 and 8.1 Hz, 1H), 2.31 (q, J 7.2 Hz, 2H), 1.34 (d, J 6,9 Hz, 3H), 0.96 (t, J 7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 211.8, 136.4, 126.0, 121.7, 120.5, 120.2, 118.9, 118.9, 111.3, 50.1, 36.3, 26.9, 21.1, 7,6; IR ν_max/cm^-1 (neat, film) 3411 (NH), 2971, 1705 (C=O), 1458, 1375, 1354, 1341, 743.

1-(1H-Indol-3-yl)pentan-3-one (3b):⁶¹ 96%, brown solid, mp 86-87 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.20 (br s, 1H), 7.56 (d, J 7.8 Hz, 1H), 7.27 (d, J 8.1Hz, 1H), 7.20-7.05 (m, 2H), 6.89 (d, J 1.8 Hz, 1H), 3.03 (t, J 7.2 Hz, 2H), 2.77 (t, J 7.2 Hz, 2H), 2.26 (q, J 7.5 Hz, 2H), 1.01 (t, J 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 211.8, 136.2, 127.0, 121.8, 121.5, 119.0, 118.5, 114.9, 111.2, 42.7, 35.9, 19.3, 7.7; IR ν_max/cm^-1 (KBr) 3323 (NH), 1704 (C=O), 1458, 736.

4-(1H-Indol-3-yl)nonan-2-one (3c):⁶⁰ 96%, viscous brown oil; ¹H NMR (300 MHz, CDCl₃) δ 8.09 (br s, 1H), 7.64 (d, J 7.8 Hz, 1H), 7.31 (d, J 7.8 Hz, 1H), 7.21-7.05 (m, 2H), 6.91 (d, J 2.4 Hz, 1H), 3.43 (m, 1H), 2.88 (dd, J 15.9 and 7.5 Hz, 1H), 2.78 (dd, J 15.9 and 6.9 Hz, 1H), 2.00 (s, 3H), 1.62-1.82 (m, 2H), 1.23 (br s, 6H), 0.81 (br s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 209.2, 136.5, 126.5, 121.8, 121.2, 119.2, 119.1, 118.8, 111.3, 50.2, 35.8, 32.9, 31.8, 30.4, 27.2, 22.5, 14.0; IR ν_max/cm^-1 (neat, film) 3412 (NH), 2956, 2928, 2856, 1707 (C=O), 1458, 1357, 742 .

3-(1H-Indol-3-yl)-cyclopentanone (3d):⁶¹ 96%, viscous brown oil; ¹H NMR (300 MHz, CDCl₃) δ 8.34 (br s, 1H), 7.60 (d, J 7.8 Hz, 1H), 7.32 (dd, J 7.8 and 0.9 Hz, 1H), 7.19 (dt, J 7.5 and 1.2 Hz, 1H), 7.12 (dt, J 7.5 and 1.2 Hz, 1H), 6.88 (d, J 1.8 Hz, 1H), 3.65 (m, 1H), 2.72 (dd, J 18.0 and 7.2 Hz, 1H), 2.65-2.17 (m, 4H), 2.17-1.98 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 220.0, 136.6, 126.5, 122.1, 120.0, 119.2, 118.9, 118.2, 111.3, 45.2, 38.1, 33.6, 29.7; IR ν_max/cm^-1 (neat, film) 3410 (NH), 1734 (C=O), 1458, 1401, 1230, 1169, 744.

3-(1H-Indol-3-yl)-cyclohexenone (3e):⁶⁰ 40%, viscous brown oil; ¹H NMR (300 MHz, CDCl₃) δ 8.18 (br s, 1H), 7.61 (d, J 7.8 Hz, 1H), 7.34 (d, J 8.1 Hz, 1H), 7.20 (t, J 7.5 Hz, 1H), 7.11 (t, J 7.5 Hz, 1H), 6.94 (d, J 1.5 Hz, 1H), 3.43 (m, 1H), 2.92-2.72 (m, 1H), 2.72-2.57 (m, 1H), 2.57-2.33 (m, 2H), 2.33-2.16 (m, 1H), 2.16-1.62 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 212.1, 136.4, 126.0, 122.1, 120.4, 119.5, 119.2, 118.9, 111.3, 48.0, 41.5, 35.9, 31.6, 24.8;

IR ν_max/cm^-1 (neat, film) 3411 (NH), 2971, 1705 (C=O), 1458, 1375, 1354, 1340, 743.

5-(5-Methoxy-1H-indol-3-yl)hexan-3-one (3f):⁶² 98%, viscous brown oil; ¹H NMR (300 MHz, CDCl₃) δ 8.29 (br s, 1H), 7.16 (d, J 8.7 Hz, 1H), 7.06 (d, J 2.1 Hz, 1H), 6.86 (d, J 2.1 Hz, 1H), 6.83 (dd, J 8.7 and 2.1 Hz, 1H), 3.84 (s, 3H), 3.59 (m, 1H), 2.86 (dd, J 15.9 and 6.0 Hz, 1H), 2.65 (dd, J 15.9 and 8.4 Hz, 1H), 2.32 (q, J 7.2 Hz, 2H), 1.34 (d, J 6.9 Hz, 3H), 0,98 (t, J 7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 211.6; 153.5, 131.6, 126.4; 121.0; 120.4, 112.0, 111.7, 100.9, 55.8, 50.0, 36.3, 26.8, 21.1, 7.5; IR ν_max/cm^-1 (neat, film) 3407 (NH), 3383, 2964, 1705 (C=O).

1-(5-Methoxy-1H-indol-3-yl)-pentan-3-one (3g): 80%, brown solid, mp 94-95 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.89 (br s, 1H), 7.24 (d, J 8.7 Hz, 1H), 7.02 (d, J 2.4 Hz, 1H), 6.96 (d, J 2.4 Hz, 1H), 6.85 (dd, J 8.7 and 2.4 Hz, 1H), 3.87 (s, 3H), 3.02 (t, J 7.5 Hz, 2H), 2.81 (t, J 7.5 Hz, 2H), 2.42 (q, J 7.2 Hz, 2H), 1.05 (t, J 7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 211.5, 153.9, 131.4, 127.6, 122.2, 115.1, 112.2, 111.8, 100.6, 56.0, 42.6, 36.1, 19.4, 7.8; IR ν_max/cm^-1 (KBr) 3340 (NH), 1704 (C=O), 1487, 1456, 1211, 1173, 806. HRMS(ESI⁺, m/Na⁺) Found: 254.11510. Calc. for C₁₄H₁₇O₂N/Na⁺ : 254.11515.

4-(5-Methoxy-1H-indol-3-yl)-nonan-2-one (3h):⁶⁰ 90%, viscous brown oil; ¹H NMR (300 MHz, CDCl₃) δ 8.35 (br s, 1H), 7.16 (d, J 8.7 Hz, 1H), 7.08 (d, J 2.4Hz, 1H), 6.87 (d, J 2.4Hz, 1H), 6.82 (dd, J 8.7 and 2.4 Hz, 1H), 3.85 (s, 3H), 3.42 (m, 1H), 2.85 (dd, J 15.9 and 7.5 Hz, 1H), 2.76 (dd, J 15.9 and 6.9 Hz, 1H), 2.00 (s, 3H), 1.60-1.80 (m, 2H), 1.38-1,07 (br s, 6H), 0.81 (br s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 209.3, 153.4, 131.7, 126.8, 122.0, 118.3, 111.9, 111.5, 101.2, 55.8, 50.0, 35.7, 32.6, 31.7, 30.3, 27.1, 22.4, 13.9; IR ν_max/cm^-1 (neat, film) 3408 (NH), 2954, 2929, 1707 (C=O), 1484, 1457, 1215.

3-(5-Methoxy-1H-indol-3-yl)-cyclopentanone (3i): viscous brown oil, 95%; ¹H NMR (300 MHz, CDCl₃) δ 8.45 (br s, 1H), 7.21 (d, J 8.7 Hz, 1H), 7.05 (d, J 2.4 Hz, 1H), 6.88 (d, J 2.1 Hz, 1H), 6.87 (dd, J 8.7 and 2.1 Hz, 1H), 3.85 (s, 3H), 3.62 (m, 1H), 2.72 (dd, J 18.0 and 7.2 Hz, 1H), 2.55-2.22 (m, 4H), 2.15-1.98 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 219.8, 153.5, 131.7, 126.8, 120.8, 117.7, 112.0, 111.9, 100.9, 55.8, 45.1, 37.9, 33.4, 29.5; IR ν_max/cm^-1 (neat, film) 3408 (NH), 1736 (C=O), 1485, 1457, 1440, 1212, 1167.

3-(5-Methoxy-1H-indol-3-yl)-cyclohexanone (3j):⁵⁸ 41%, viscous brown oil,; ¹H NMR (300 MHz, CDCl₃)

δ 8.11 (br s, 1H), 7.24 (d, J 8.7, 1H), 7.03 (d, J 2.4 Hz, 1H), 6.95 (d, J 2.1 Hz, 1H), 6.94 (dd, J 8.7 and 2.4 Hz, 1H), 3.84 (s, 3H), 3.39 (m, 1H), 2.86-2.73 (m, 1H), 2.63-2.51 (m, 1H), 2.51-2.33 (m, 2H), 2.33-2.20 (m, 1H), 2.13-1.73 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 212.0, 153.8, 131.6, 126.4, 121.2, 119.2, 112.2, 112.0, 110.9, 56.0, 48.0, 41.5, 35.8, 31.5, 24.9; IR ν_max/cm^-1 (neat, film) 3406 (NH), 2360, 1701 (C=O), 1484, 1456, 1216, 1171.

5-(2-Methyl-1H-indol-3-yl)-hexan-3-one (3k): 88%, viscous brown oil; ¹H NMR (300 MHz, CDCl₃) δ 7.96 (br. s, 1H), 7.59 (m, 1H), 7.17-7.10 (m, 1H), 7.09-6.98 (m, 2H), 3.55 (m, 1H), 2.97 (dd, J 15.6 and 7.8 Hz), 2.76 (dd, J 15.6 and 7.2 Hz), 2.32-2.21 (m, 5H), 1.39 (d, J 7.2 Hz, 3H), 0.87 (d, J 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 211.8, 135.4, 130.4, 126.8, 120.3, 118.7, 118.6, 114.6, 110.5, 49.1, 36.5, 27.1, 21.0, 11.6, 7.5; IR ν_max/cm^-1 (neat, film) 3400 (NH), 2969, 2933, 1705 (C=O), 1461, 742. HRMS (ESI⁺, m/Na⁺) Found: 252.13575. Calc. for C₁₅H₁₉ON/Na⁺: 252.13589.

1-(2-Methyl-1H-indol-3-yl)pentan-3-one (3l): 97%, viscous brown oil; ¹H NMR (300 MHz, CDCl₃) δ 7.91 (br s, 1H), 7.44 (m, 1H), 7.20-6.94 (m, 3H), 2.95 (t, J 7.2 Hz, 2H), 2.68 (t, J 7.2 Hz, 2H), 2.35-2.20 (m, 5H), 0.97 (t, J 7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 211.9, 135.1, 131.1, 128.0, 120.6, 118.8, 117.5, 110.3, 110.0, 42.7, 36.1, 18.4, 11.2, 7.6; IR ν_max/cm^-1 (neat, film) 3400 (NH), 2975, 2936, 2919, 1708 (C=O), 1462, 742. HRMS (ESI⁺, m/Na⁺) Found: 238.12015. Calc. for C₁₄H₁₇ON/Na⁺: 238.12024.

3-(2-Methyl-1H-indol-3-yl)-cyclopentanone (3m)^:46 81%, yellow solid; mp 135-136 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.98 (br s, 1H), 7.53 (d, J 7.5 Hz, 1H), 7.28 (d, J 7.8 Hz, 1H), 7.23-7.00 (m, 2H), 3.59 (m, 1H), 2.87-2.20 (m, 10H); ¹³C NMR (75 MHz, CDCl₃) δ 219.8, 135.5, 130.9, 126.7, 120.9, 119.1, 118.6, 111.8, 110.7, 44.3, 39.4, 34.5, 29.7, 12.1; IR ν_max/cm^-1 (KBr) 3342 (NH), 2961, 2897, 1729 (C=O), 1461, 1231, 1137, 743.

General procedure for the synthesis of β-indolylchalcones 3r-z

In a 25 mL round-bottom flask, equipped with a reflux condenser and magnetic stirrer were added the indoles 1a-c (1.0 mmol), the chalcones 2f-i (1.1 mmol), and SnCl₂·2H₂O (0.1 mmol) in i-PrOH (2 mL). The reaction mixture was heated to reflux and stirred for the appropriate time showed in the Table 3. After the completion of the reaction, monitored by TLC, the solvent was removed under vaccum and the crude products 3r-z were purified by column chromatography using hexanes/ethyl acetate as eluant.

3-(1H-Indol-3-yl)-1,3-diphenylpropan-1-one (3r):⁶⁴ 96%,brownish solid, mp 130-131 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.03 (br s, 1H), 7.91 (d, J 7.5 Hz, 2H), 7.51 (t, J 7.2 Hz, 1H), 7.46-7.06 (m, 10H), 6.99 (t, J 7.2 Hz, 1H), 6.90 (s, 1H), 5.05 (m, 1H), 3.80 (dd, J 16.8 and 6.9 Hz, 1H), 3.70 (dd, J 16.8 and 7.8 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃,) δ 198.7, 144.2, 137.0, 136.6, 133.0, 128.5, 128.4, 128.1, 127.8, 126.5, 126.2, 122.0, 121.4, 119.4, 119.3, 119.1, 111.1, 45.2, 38.2; IR ν_max/cm^-1 (KBr) 3411 (NH), 1681 (C=O), 1456, 1448, 745, 700.

3-(1H-Indol-3-yl)-3-(naphthalen-1-yl)-1-phenyl-propan -1-one (3s): 60%, brownish solid, mp 97-98 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.29 (m, 1H), 7.96-7.80 (m, 4H), 7.68 (d, J 7.5 Hz, 1H), 7.54-7.17 (m, 9H), 7.09 (m, 1H), 6.96 (m, 1H), 6.70 (s, 1H), 5.92 (m, 1H), 3.94 (dd, J 17.4 and 7.8 Hz, 1H), 3.73 (dd,

J 17.4 and 6.3 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃,) δ 198.5, 139.9, 137.0, 136.6, 134.0, 133.1, 131.4, 128.8, 128.6, 128.0, 127.0, 126.6, 126.1, 125.5, 125.3, 124.4, 123.6, 122.2, 122.0, 119.4, 119.3, 118.9, 111.2, 44.6, 33.2; IR ν_max/cm^-1 (KBr) 3412 (NH), 3055, 1681 (C=O), 1596, 1448, 1337, 1269, 780, 743; HRMS (ESI⁺, m/Na⁺) Found: 398.15161.Calc. for C₂₇H₂₁ON/Na⁺: 398.15154.

3-(1H-Indol-3-yl)-3-(4-methoxyphenyl)-1-phenyl-propan-1-one (3t):⁶⁴ 80%, brownish solid, mp 114-115 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.00 (br s, 1H), 7.92 (d, J 7.8 Hz, 2H), 7.53 (t, J 7.5 Hz, 1H), 7.47-7.36 (m, 3H), 7.29 (d, J 7.8 Hz, 1H), 7.25 (d, J 8.4 Hz, 2H), 7.13 (t, J 7.5 Hz, 1H), 7.00 (t, J 7.5, 1H), 6.95 (d, J 1.5 Hz, 1H), 6.78 (d, J 8.4 Hz, 2H), 5.01 (t, J 6.9 Hz, 1H), 3.83-3.63 (m, 5H); δ ¹³C NMR (75 MHz, CDCl₃,) 198.8, 157.9, 137.1, 136.6, 136.3, 133.0, 128.7, 128.5, 128.1, 126.5, 122.0, 121.3, 119.5, 119.3, 113.7, 111.1, 55.1, 45.3, 37.4; IR ν_max/cm^-1 (KBr) 3420 (NH), 1670 (C=O), 1510, 1249, 1177, 1031, 746.

3-(1H-Indol-3-yl)-1-phenyl-3-(thiophen-2-yl)-propan-1-one (3u):⁶⁵ 74%, brown solid, mp 153-154 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.02 (br s, 1H), 7.93 (d, J 8.1 Hz, 2H), 7.53 (t, J 7.5 Hz, 2H), 7.42 (t, J 7.5 Hz, 2H), 7.31 (d, J 8.1 Hz, 1H), 7.20-7.00 (m, 4H), 6.95-6.83 (m, 2H), 5.36 (t, J 7.2 Hz, 1H), 3.83 (d, J 7.2 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃,) δ 198.1, 148.7, 137.0, 136.5, 133.1, 128.6, 128.1, 126.5, 126.2, 124.2, 123.4, 122.2, 121.6, 119.5, 119.4, 119.0, 111.2, 46.1, 33.5; IR ν_max/cm^-1 (KBr) 3409 (NH), 3057, 1682 (C=O), 1268, 743, 689.

3-(5-Methoxy-1H-indol-3-yl)-1,3-diphenylpropan-1-one (3v):⁶⁶ 96%, yellow solid, mp 136-137 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.02 (br s, 1H), 7.92 (d, J 7.2 Hz, 2H), 7.6-7.1 (m, 9H), 6.92 (d, J 1.5 Hz, 1H), 6.85-6.73 (m, 2H), 5.00 (m, 1H), 3.84-3.64 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 198.7, 153.7, 144.1, 137.1, 133.0, 131.7, 128.5, 128.4, 128.1, 127.8, 127.0, 126.2, 122.2, 118.8, 112.1, 111.8, 101.4, 55.7, 45.1, 38.2; IR ν_max/cm^-1 (KBr) 3366 (NH), 1679 (C=O), 1485, 1457, 1448, 1214, 1170, 723.

3-(5-Methoxy-1H-indol-3-yl)-3-(naphthalen-1-yl)-1-phenylpropan-1-one (3w): 95%, pale brown solid, mp 156-157 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.35-8.26 (m, 1H), 7.94 (d, J 7.8 Hz, 2H), 7.90-7.78 (m, 2H), 7.70 (d, J 6.9 Hz, 1H), 7.58-7.29 (m, 7H), 7.15 (d, J 9.0 Hz, 1H), 6.85 (d, J 2.1 Hz, 1H), 6.82-6.74 (m, 2H), 5.88 (m, 1H), 3.95 (dd,

J 17.4 and 7.8 Hz, 1H), 3.79 (dd, J 17.4 and 6.3 Hz, 1H), 3.66 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 198.5, 153.8, 139.8, 137.1, 134.1, 133.1, 131.8, 131.5, 128.6, 128.5, 128.1, 127.1, 127.0, 126.1, 125.5, 125.3, 124.3, 123.6, 122.9, 118.8, 112.2, 111.8, 101.3; 55.8, 44.6, 33.2; IR ν_max/cm^-1 (KBr) 3412 (NH), 1680 (C=O), 1484, 1212, 780; HRMS (ESI⁺, m/Na⁺) Found: 428.16208. Calc. for C₂₈H₂₃O₂N/Na⁺ : 428.16210.

3-(5-Methoxy-1H-indol-3-yl)-3-(4-methoxyphenyl)-1-phenylpropan-1-one (3x): 95%, brown solid, mp 70-71 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.02 (br s, 1H), 7.91 (d, J 7.8Hz, 2H), 7.52 (t, J 7.8 Hz, 1H), 7.40 (t, J 7.5 Hz, 2H), 7.24 (d, J 8.7 Hz, 2H), 7.14 (d, J 8.7Hz, 1H), 6.90 (s, 1H), 6.83 (d, J 2.1 Hz, 1H), 6.77 (d, J 8.4 Hz, 3H), 4.95 (t, J 7.2 Hz, 1H), 3.81-3.61 (m, 8H); ¹³C NMR (75 MHz, CDCl₃) δ 198.9, 157.9, 153.6, 137.1, 136.2, 133.0, 131.7, 128.7, 128.5, 128.0, 126.9, 122.1, 119.1, 113.7, 112.0, 111.8, 101.4, 55.7, 55.1, 45.2, 37.4; IR ν_max/cm^-1 (KBr) 3400 (NH), 2929, 1683 (C=O), 1509, 1485, 1247, 1212, 1175, 1033; HRMS (ESI⁺, m/ Na⁺) Found: 408.15689. Calc. for C₂₅H₂₃O₃N/Na⁺ : 408.15702.

3-(5-Methoxy-1H-indol-3-yl)-1-phenyl-3-(thiophen-2-yl)propan-1-one (3y): 92%, pale yellow solid, mp 153-154 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.98-7.88 (m, 3H), 7.54 (m, 1H), 7.43 (m, 2H), 7.21 (d, J 8.7 Hz, 1H), 7.10 (m, 1H), 7.04 (d, J 2.4 Hz, 1H), 6.95 (d, J 2.4 Hz, 1H), 6.94-6.85 (m, 2H), 6.83 (dd, J 8.7 and 2.4 Hz, 1H), 5.32 (m, 1H), 3.82-3.75 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 198.1, 153.9, 148.7, 137.0, 133.1, 131.6, 128.6, 128.1, 126.7, 126.5, 124.2, 123.5, 122.3, 118.8, 112.3, 111.9, 101.3, 55.9, 46.0, 33.4; IR ν_max/cm^-1 (KBr) 3382 (NH), 1680 (C=O), 1485, 1438, 1213, 1171, 732; HRMS (ESI⁺, m/Na⁺) Found: 384.10283. Calc. for C₂₂H₁₉O₂N/Na⁺ : 384.10287.

3-(2-Methyl-1H-indol-3-yl)-1,3-diphenylpropan-1-one (3z):⁴⁶ 96%, brownish solid, mp 130-131 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.03 (br s, 1H), 7.91 (d, J 7.5 Hz, 2H), 7.51 (t, J 7.2 Hz, 1H), 7.46-7.06 (m, 10H), 6.99 (t, J 7.2 Hz, 1H), 6.90 (s, 1H), 5.05 (m, 1H), 3.80 (dd, J 16.8 and 6.9 Hz, 1H), 3.70 (dd, J 16.8 and 7.8 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 198.7, 144.2, 137.0, 136.6, 133.0, 128.5, 128.4, 128.1, 127.8, 126.5, 126.2, 122.0, 121.4, 119.4, 119.3, 119.1, 111.1, 45.2, 38.2; IR ν_max/cm^-1 (KBr) 3411 (NH), 1681 (C=O), 1456, 1448, 745, 700.

Procedure for the synthesis of nitro-adducts 5a in i-PrOH

In a 25 mL round botton flask equipped with a reflux condenser, and magnetic stirrer was added the indole 1a (1.0 mmol), the nitroolefin 4a (1.1 mmol), and the CoCl₂·6H₂O (0.1 mmol) in i-PrOH (2 mL). The reaction mixture was heated to reflux temperature of i-PrOH and stirred for 2 h. After the completion of the reaction, monitored by TLC, the solvent was removed under vaccum and the crude product 5a was purified by column chromatography using a mixture of hexanes/ethyl acetate 70:30 (v/v) as eluent.

3-(2-Nitro-1-phenylethyl)-1H-indole (5a):⁶² 97%, brownish solid, mp 99-100 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.84 (br s, 1H), 7.37 (d, J 8.1 Hz, 1H), 7.25-7.05 (m, 7H), 7.00 (t, J 7.2 Hz, 1H), 6.72 (d, J 1.8 Hz, 1H), 5.08 (m, 1H), 4.87 (dd, J 12.3 and 7.5 Hz, 1H), 4.76 (dd, J 12.3 and 8.4 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 139.1, 136.2, 128.7, 127.6, 127.3, 125.8, 122.3, 121.5, 119.6, 118.6, 113.7, 111.3, 79.3, 41.3; IR ν_max/cm^-1 (KBr) 3401 (NH), 3052, 1536, 1455, 1424, 1377, 1097, 750, 704.

General procedure for the synthesis of nitro-adducts 5b-q under solventless conditions

In a 25 mL round-botton flask equiped with a reflux condenser, and magnetic stirrer, were added the indoles 1a-c (1.0 mmol), the nitroolefins 4b-g (1.1 mmol) and CoCl₂·6H₂O (0.1 mmol). The reactional flask was placed in a 100 °C pre-heated silicone oil bath and was stirred for the appropriate time showed in the Table 6. After the completion of the reaction, monitored by TLC, the crude product 5b-q were purified by column chromatography using a mixture of hexanes/ethyl acetate.

3-(1-(4-Methoxyphenyl)-2-nitroethyl)-1H-indole (5b):⁶⁷ 92%, brownish solid, mp 146-147 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.10 (br s, 1H), 7.43 (d, J 8.1 Hz, 1H), 7.35 (d, J 8.1 Hz, 1H), 7.24 (d, J 8.4 Hz, 2H), 7.19 (t, J 7.5 Hz, 1H), 7.07 (t, J 7.5 Hz, 1H), 7.01 (d, J 1.5 Hz, 1H), 6.84 (d, J 8.4 Hz, 2H), 5.14 (m, 1H), 5.04 (dd, J 12.3 and 7.5 Hz, 1H), 4.89 (dd, J 12.3 and 8.4 Hz, 1H), 3.77 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 158.8, 136.5, 131.2, 128.8, 126.1, 122.6, 121.4, 119.9, 119.0, 114.8, 114.3, 111.3, 79.7, 55.2, 40.8; IR ν_max/cm^-1 (KBr) 3379 (NH), 1547, 1511, 1463, 1422, 1377, 1245, 1029, 750.

3-(1-(4-Fluorophenyl)-2-nitroethyl)-1H-indole (5c):⁶⁷ 97%, orange solid, mp 77-78 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.10 (br s, 1H), 7.39 (d, J 7.8 Hz, 1H), 7.37-7.16 (m, 4H), 7.11-6.95 (m, 4H), 5.16 (m, 1H), 5.04 (dd, J 12.6 and 7.5 Hz, 1H), 4.89 (dd, J 12.6 and 8.7 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 162.1 (d, J 245 Hz), 136.5, 134.9 (d, J 3 Hz), 129.3 (d, J 8 Hz), 125.9, 122.8, 121.4, 120.0, 118.8, 115.8 (d, J 21 Hz), 114.2, 111.4, 79.5, 40.8; IR ν_max/cm^-1 (KBr) 3371 (NH), 1542, 1508, 1430, 1378, 1224, 748.

4-(1-(1H-Indol-3-yl)-2-nitroethyl)-N,N-dimethylaniline (5d):⁶⁸ 98%, pink solid, mp 131-133 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.09 (br s, 1H); 7.46 (d, J 8.1 Hz, 1H); 7.35 (d, J 8.1 Hz, 1H); 7.24-7.00 (m, 5H); 6.71 (d, J 8.4 Hz, 2H); 5.10 (m, 1H); 5.03 (dd, J 11.7 and 7.5 Hz, 1H); 4.88 (dd, J 11.7 and 8.4 Hz, 1H); 2.92 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 149.8; 136.5; 128.4; 126.7; 126.2; 122.5; 121.4; 119.8; 119.1; 115.1; 112.7; 111.3; 79.9; 40.8; 40.5; IR ν_max/cm^-1 (KBr) 3434 (NH), 2916, 1611, 1519, 1379, 817, 743.

3-(1-(3,4-Dimethoxyphenyl)-2-nitroethyl)-1H-indole (5e):⁶⁹ 90%, orange solid, mp 79-80 ºC; ¹H NMR (300 MHz, CDCl3) δ 8.27 (br s, 1H), 7.43 (d, J 7.8 Hz, 1H), 7.28 (d, J 8.1 Hz, 1H), 7.16 (t, J 7.5 Hz, 1H), 7.05 (t, J 7.5 Hz, 1H), 6.93 (s, 1H), 6.87-6.80 (m, 2H), 6.76 (d, J 8.1 Hz, 1H), 5.11 (m, 1H), 5.00 (dd, J 12.3 and 7.5 Hz, 1H), 4.87 (dd, J 12.3 and 8.4 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H); ¹³C NMR (75 MHz, CDCl3) δ 149.0, 148.2, 136.4, 131.7, 125.9, 122.4, 121.5, 119.7, 119.6, 118.7, 114.2, 111.4, 111.3, 111.1, 79.6, 55.7, 41.1; IR ν_max/cm^-1 (KBr) 3405 (NH), 1549, 1515, 1262, 1141, 1023, 745.

3-(1-(Naphthalen-1-yl)-2-nitroethyl)-1H-indole (5f):⁶⁷ 97%, redish solid, mp 140-142 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.27 (d, J 8.4 Hz), 8.05 (br s, 1H, NH), 7.91-7.86 (m, 1H), 7.82-7.74 (m, 1H), 7.59-7.32 (m, 6H), 7.23-7.15 (m, 1H), 7.09-6.97 (m, 2H), 6.07 (m, 1H), 5.12 (dd,

J 12.9 and 8.1 Hz, 1H), 5.07 (dd, J 12.9 and 7.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 136.6, 134.6, 134.2, 131.1, 129.1, 128.3, 126.8, 126.1, 125.9, 125.3, 124.6, 122.7, 122.6, 120.0, 118.8, 114.3, 111.4, 78.5, 37.0; IR ν_max/cm^-1 (KBr) 3420 (NH), 1545, 1509, 1458, 1381, 796, 777, 743.

3-(2-Nitro-1-(thiophen-2-yl)ethyl)-1H-indole (5g):⁶⁹ 98%, brown solid, mp 86-87 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.03 (br s, 1H), 7.49 (d, J 8.1 Hz, 1H), 7.29 (d, J 8.1 Hz, 1H), 7.22-7.05 (m, 3H), 6.98 (d, J 2.7 Hz, 1H), 6.96-6.87 (m, 2H), 5.42 (m, J 7.8 Hz, 1H), 4.99 (dd,

J 12.3 and 8.1 Hz, 1H), 4.92 (dd, J 12.3 and 8.1 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 142.8, 136.2, 126.9, 125.5, 125.1, 124.8, 122.5, 121.9, 119.9, 118.6, 113.6, 111.5, 79.8, 36.7; IR ν_max/cm^-1 (KBr) 3416 (NH), 1550, 1455, 1433, 1418, 1377, 747, 720.

5-Methoxy-3-(2-nitro-1-phenylethyl)-1H-indole (5h):⁶⁷ 95%, brownish solid, mp 130-131 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.02 (br s, 1H), 7.32-7.15 (m, 6H), 6.93 (s, 1H), 6.86-6.80 (m, 2H), 5.11 (m, 1H), 5.00 (dd, J 12.3 and 7.5 Hz, 1H), 4.89 (dd, J 12.3 and 8.4 Hz, 1H), 3.75 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 154.0, 139.1, 131.5, 128.8, 127.7, 127.5, 126.5, 122.3, 113.9, 112.6, 112.1, 100.7, 79.4, 55.8, 41.4; IR ν_max/cm^-1 (KBr) 3447 (NH), 1548, 1482, 1453, 1440, 1379, 1209, 1177.

5-Methoxy-3-(1-(4-methoxyphenyl)-2-nitroethyl)-1H-indole (5i): 86%, pale yellow solid, mp 141-142 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.00 (br s, 1H), 7.28-7.21 (m, 3H), 6.99 (d, J 2.1 Hz, 1H), 6.88-6.82 (m, 4H), 5.09 (m, 1H), 5.02 (dd, J 11.7 and 7.2 Hz, 1H), 4.88 (dd, J 11.7 and 7.8 Hz, 1H), 3.77 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 158.9, 154.2, 131.6, 131.1, 128.8, 126.6, 122.1, 114.4, 114.3, 112.7, 112.1, 100.9, 79.7, 55.8, 55.2, 40.8; IR ν_max/cm^-1 (KBr) 3434 (NH), 2959, 1545, 1513, 1480, 1456, 1247, 1208.

3-(1-(4-Fluorophenyl)-2-nitroethyl)-5-methoxy-1H-indole (5j): 96%, brown solid, mp 102-103 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.11 (br s, 1H); 7.28-7.20 (m, 2H), 7.17 (d, J 8.7 Hz, 1H), 7.00-6.88 (m, 3H), 6.83 (dd, J 8.7 and 2.4 Hz, 1H), 6.78 (d, J 2.1 Hz, 1H), 5.08 (m, 1H), 4.97 (dd, J 12.3 and 7.5 Hz, 1H), 4.83 (dd, J 12.3 and 8.4 Hz, 1H), 3.74 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 161.9 (d, J 2.4 Hz), 154.0, 134.8 (d, J 3 Hz), 131.5, 129.3 (d, J 8 Hz), 126.3, 122.1, 115.7 (d, J 21 Hz), 113.6, 112.6, 112.2, 100.7, 79.4, 55.7, 40.7; IR ν_max/cm^-1 (KBr) 3434 (NH), 1551, 1509, 1482, 1454, 1439, 1377, 1226, 1207, 808.

4-(1-(5-Methoxy-1H-indol-3-yl)-2-nitroethyl)-N,N-dimethylaniline (5k): 87%, pink solid, mp 134-135 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.99 (br s, 1H), 7.23 (d, J 8.1 Hz, 1H), 7.21-7.14 (m, 2H), 6.96 (d, J 2.4 Hz, 1H), 6.87 (d, J 2.4 Hz, 1H), 6.83 (dd, J 8.7 and 2.4 Hz, 1H), 6.68 (d, J 9 Hz, 2H), 5.07-4.95 (m, 2H), 4.92-4.80 (m, 1H), 3.77 (s, 3H), 2.90 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 154.0, 149.7, 131.6, 128.4, 126.9, 126.6, 122.2, 114.7, 112.9, 112.5, 112.0, 101.0, 79.8, 55.8, 40.7, 40.6; IR ν_max/cm^-1 (KBr) 3408 (NH), 1616, 1541, 1524, 1484, 1376, 1210, 1201. HRMS (ESI⁺) Found: 340.16545. Calc. for C₁₉H₂₁O₃N₃ : 340.16557.

3-(1-(3,4-Dimethoxyphenyl)-2-nitroethyl)-5-methoxy-1H-indole (5l): 98%, brownish solid, mp 131-132 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.31 (br s, 1H), 7.15 (d, J 8.7 Hz, 1H), 6.94-6.74 (m, 6H), 5.06 (m, 1H), 4.98 (dd, J 11.7 and 7.2 Hz, 1H), 4.86 (dd, J 11.7 and 8.4 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.75 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 153.9, 149.0, 148.1, 131.6, 131.5, 126.4, 122.2, 119.6, 113.8, 112.3, 112.1, 111.2, 111.1, 100.7, 79.5, 55.7, 55.7, 55.6, 41.1; IR ν_max/cm^-1 (KBr) 3436 (NH), 2955, 2931, 2830, 1544, 1510, 1259, 1020. HRMS (ESI⁺, m/Na⁺) Found: 379.12635. Calc. for C₁₉H₂₀O₅N₂ /Na⁺: 379.12644.

5-Methoxy-3-(1-(naphthalen-1-yl)-2-nitroethyl)-1H-indole (5m): 98%, brown solid, mp 76-77 °C. ¹H NMR (300 MHz, CDCl₃) δ 8.25 (d, J 8.1 Hz, 1H), 7.97 (br s, 1H), 7.92-7.74 (m, 2H), 7.58-7.17 (m, 5H), 6.95-6.81 (m, 3H), 6.00 (t, J 7.8 Hz, 1H), 5.08 (d, J 7.8 Hz, 2H), 3.71 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 154.2, 134.6, 134.2, 131.7, 131.2, 129.1, 128.3, 126.8, 126.6, 125.9, 125.3, 124.5, 123.3, 122.7, 114.0, 112.7, 112.1, 100.7, 78.5, 55.8, 37.0; IR ν_max/cm^-1 (KBr) 3420 (NH), 1549, 1484, 1457, 1437, 1376, 1213, 800.

5-Methoxy-3-(2-nitro-1-(thiophen-2-yl)ethyl)-1H-indole (5n): 93%, greenish brown solid, mp 83-85 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.15 (br s, 1H), 7.26-7.20 (m, 2H), 7.06-6.89 (m, 5H), 5.45 (m, 1H), 5.04 (dd,

J 12.6 and 7.5 Hz, 1H), 4.99 (dd, J 12.6 and 8.1 Hz, 1H), 3.85 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 154.1, 142.9, 131.4, 126.9, 126.1, 125.1, 124.8, 113.5, 112.6, 112.2, 100.6, 79.9, 55.8, 36.8; IR ν_max/cm^-1 (KBr) 3336 (NH), 2929, 2829, 1551, 1489, 1436, 1376, 1214, 716; HRMS (ESI⁺, m/ Na⁺) Found: 325.06167. Calc. for C₁₅H₁₄O₃N₂ S/Na⁺: 325.06174.

2-Methyl-3-(2-nitro-1-phenylethyl)-1H-indole (5o):⁶⁷ 94%, pale pink solid, mp 102-103 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (br s, 1H), 7.35 (d, J 7.8 Hz, 1H), 7.32-7.16 (m, 6H), 7.08 (m, 1H), 7.00 (m, 1H), 5.23-5.04 (m, 3H), 2.28 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 139.5, 135.3, 132.8, 128.7; 127.2, 127.0, 126.8, 121.2, 119.6, 118.5, 110.7, 108.7, 78.6, 40.4, 11.8; IR ν_max/cm^-1 (KBr) 3403 (NH), 1550, 1459, 1428, 1377, 743, 700.

2-Methyl-3-(1-(naphthalen-1-yl)-2-nitroethyl)-1H-indole (5p): 94%, pale yellow solid, mp 150-151 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.11 (m, 1H), 7.89-7.82 (m, 2H), 7.79 (d, J 8.1 Hz, 1H), 7.60 (d, J 7.2 Hz, 1H), 7.55 (d, J 7.2 Hz, 1H), 7.52-7.39 (m, 3H), 7.28-7.21 (m, 1H), 7.15-7.03 (m, 2H), 5.92 (m, 1H), 5.25 (dd, J 12.9 and 6.9 Hz, 1H), 5.19 (dd, J 12.9 and 8.7 Hz, 1H), 2.27 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 135.3, 134.5, 134.1, 132.9, 131.3, 129.1, 128.3, 127.3, 126.6, 125.8, 125.1, 124.3, 123.0, 121.4, 119.8, 118.4, 110.7, 108.3, 78.0, 37.4, 12.3; IR ν_max/cm^-1 (KBr) 3415, 3348, 2921, 2870, 1453, 903, 742; HRMS (ESI⁺, m/Na⁺) Found: 353.12611. Calc.for C₂₁H₁₈O₂N₂ /Na⁺: 353.12605.

2-Methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-1H-indole (5q): 98%, greenish brown solid, mp 89-91 °C ¹H NMR (300 MHz, CDCl₃) δ 7.75 (br s, 1H); 7.32 (d, J 7.8 Hz, 1H), 7.16-6.95 (m, 4H), 6.87-6.80 (m, 2H), 5.29 (dd, J 9.0 and 6.6 Hz, 1H), 5.10 (dd, J 12.3 and 6.6 Hz, 1H), 4.99 (dd, J 12.3 and 9.0 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 143.2, 135.2, 133.0, 126.7, 126.1, 124.6, 124.2, 121.1, 119.5, 118.4, 110.7, 108.1, 78.7, 36.4, 11.4; IR ν_max/cm^-1 (neat, film) 3404 (NH), 1551, 1460, 1427, 1378, 745, 702; HRMS (ESI⁺, m/Na⁺) Found: 309.06671. Calc. for C₁₅H₁₄O₂N₂ S/Na⁺: 309.06682.

Preparation of the triptamine derivative 8

To a stirred solution of compound 5a (266.3 mg, 1 mmol) in CH₃OH (5 mL) were sequentially added Pd/C 10% (52mg) and HCOONH₄ (315.3 mg, 5 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered on a celite pad, washed several times with CH₃OH and the solvent removed on a rotatory evaporator. To the white residue was added saturated Na₂CO₃(aq) until pH 8 was reached and then the aqueous mixture was extracted twice with EtOAc. The combined organic phases were dried over MgSO₄, filtered and the solvent removed under vacuum, affording compound 8. The crude product was used in the next step without further purification.

2-(1H-Indol-3-yl)-2-phenylethanamine (8):⁵⁸ 90%, pale brown solid, mp 129-130 °C. ¹H NMR (300 MHz, CDCl₃) δ 8.33 (br s, 1H), 7.45 (d, J 7.8 Hz, 1H), 7.35-7.10 (m, 7H), 7.02 (t, J 7.5 Hz, 2H), 4.25 (m, 1H), 3.42 (dd, J 12.6 and 7.2 Hz, 1H), 3.27 (dd, J 12.6 and 7.8 Hz, 1H), 1.71 (br s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 142.9, 136.5, 128.5, 128.1, 127.0, 126.4, 122.1, 121.3, 119.4, 119.3, 117.4, 111.1, 47.1, 46.7; IR ν_max/cm^-1 (KBr) 3415, 3348, 2921, 2870, 1453, 903, 742.

Preparation of β-carboline derivative 9

To a suspension of MgSO₄ (240 mg) and compound 8 (70.9 mg, 0.3 mmol) in CH₂Cl₂ (2 mL) was added benzaldehyde (37 μL, 0.36 mmol, 1.2 equiv.) at room temperature and the mixture was stirred at room temperature for 1 h. The suspension was cooled to 0 °C and TFA (45 μL 0.6 mmol, 2.0 equiv.) was slowly added. The reaction was stirred at room temperature for 72 h. The reaction was quenched by addition of sat. NaHCO₃ at 0 °C until pH 8 was reached. After filtration over celite, the filtrate was extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried over anhydrous MgSO₄, filtered and the solvent evaporated under vacuum. The ¹H NMR analysis of the crude product showed a mixture of two diastereoisomers in 87:13 ratio. The 1,4-trans relative configuration for the major isomer was assumed based on literature data. The crude product was purified by column chromatography using a mixture of hexanes/ethyl acetate 75:25 (v/v) as eluent. After purification only the major isomer was observed in the ¹H NMR spectra.

trans-1,4-Diphenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole (9-trans):⁵⁹ 70%, pale brown solid, mp 184-185 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.70 (br s, 1H), 7.40-7.21 (m, 10 H), 7.18 (d, J 8.1 Hz, 1H), 7.06 (m, 1H), 6.90-6.78 (m, 2H), 5.25 (s, 1H), 4.37 (m, 1H), 3.53 (dd, J 12.6 and 5.1 Hz, 1H), 3.02 (dd, J 12.6 and 8.7 Hz, 1H), 1.91 (br s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 143.0, 141.4, 135.9, 135.8, 128.9, 128.6, 128.4, 128.3, 126.7, 126.5, 121.5, 119.8, 119.3, 112.5, 110.7, 58.2, 52.9, 41.7; IR ν_max/cm^-1 (KBr) 3405, 3319, 3052, 3019, 2952, 2811, 1451, 1273, 750, 697.

Supplementary Information

The spectroscopic ¹H NMR, ¹³C NMR, IR data as well as the HRMS of selected compounds are provided as supplementary information and available free of charge at http://jbcs.sbq.org.br, as PDF file.

Acknowledgments

The authors thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for the financial support (D. R., Grant Universal No. 484615/2007-6). C. S. S. acknowledges the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for the graduate fellowship. We would like to thank Prof. Dr. Marcos N. Eberlin and MSc Clécio F. Klitzke from the Thomson Mass Spectrometry Laboratory of Instituto de Química-UNICAMP, for the HRMS analysis, and also Prof. Dr. Luiz Carlos Dias for his generosity reading and suggesting improvements to this work.

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Submitted: July 31, 2010

Published online: November 23, 2010

Supplementary Information

Publication Dates

• Publication in this collection
  14 Apr 2011
• Date of issue
  2011

History

• Received
  31 July 2010
• Accepted
  23 Nov 2010