Rh(III)‐Catalyzed C‐2 Alkylation of Indoles followed by a Post‐Synthetic Modification via the Ugi Reaction

Abstract

Indole derivatives substituted at the C‐2 position have shown important biological activities. Due to these properties, several methods have been described for the preparation of structurally diverse indoles. In this work, we have synthesized highly functionalized indole derivatives via Rh(III)‐catalyzed C‐2 alkylation with nitroolefins. Under the optimized condition, 23 examples were prepared with 39–80 % yield. Moreover, the nitro compounds were reduced and submitted to the Ugi four‐component reaction, furnishing a series of new indole‐peptidomimetics in moderate to good overall yields.

An efficient C−H activation protocol for nitroalkylation of indoles at the C‐2 position using easily available nitroolefins is described. This method gives access to nitroalkylindoles, strategic frameworks for the preparation of primary 2‐nitroindoleamines, which were employed in the synthesis of new Ugi peptidomimetics, compounds of recognized pharmacological interest.

Introduction

Among various heterocyclic compounds, the indoles have been extensively investigated as they constitute the core structures of numerous biologically relevant molecules and have been found to be active against different types of diseases. ^[1] In this sense, indoles are considered a highly privileged motif for the design and development of, for example, anticancer, ^[2] anti‐tubercular, ^[3] antihypertensive, ^[4] and anti‐HIV agents. ^[5] Accordingly, the indole scaffold is found in several commercially available drugs, such as Delavirdine, a non‐nucleoside reverse transcriptase inhibitor used to treat HIV infections, ^[6] Indomethacin, a non‐steroidal anti‐inflammatory drug with anti‐inflammatory, analgesic, and antipyretic properties, ^[7] and Fluvastatin, an HMG‐CoA reductase inhibitor used to lower lipid levels and reduce the risk of cardiovascular disease including myocardial infarction and stroke (Figure 1). ^[8] Moreover, indoles have been used as a synthon for the preparation of large number of bioactive heterocycles and paved a way to develop effective targets. ^[9] Due to these properties, several methods have been described for the preparation of structurally diverse indoles via C−H activation.[ ¹⁰ , ¹¹ ]

Figure 1.

Examples of active pharmaceutical ingredients containing C2‐substitued indoles.

Compared with conventional synthetic strategies, direct functionalization of indoles provides straightforward access to construct diverse scaffolds. ^[12] Nevertheless, highly efficient greener methods for the synthesis and functionalization of indole derivatives are still needed, ^[13] since harsh reaction conditions have been still used, especially for the C2 alkylation. ^[14]

In general, the C2 vs. C3 selectivity to overcome the inherent C3 preference of electrophilic indole reactivity has been achieved by positional blocking, development of new catalyst systems, directing groups, reaction conditions and properties of the metal used for the functionalization. ^[15]

The use of nitroolefins as partner is very attractive in indole chemistry, since the nitro groups of the products allow subsequent versatile transformations, such as the synthesis of tryptamine and carboline derivatives. Along these lines, C5‐alkylated indoles have been synthesized in two steps from N‐benzylindolines with nitroolefins. ^[16]

A plethora of reaction conditions may be employed in the synthesis of 3‐(2‐nitroalkyl) indoles (Scheme 1a), ^[17] including chiral Brønsted and Lewis acids as catalysts under homogeneous or heterogeneous phases. On the other hand, Ellman and coworkers described the addition of aryl and alkenyl derivatives to nitroalkenes via Csp²−H activation catalyzed by Rh(III), including two examples of C4 alkylation of indoles (Scheme 1b). ^[18] Only very recently, Liu et al. reported the first Rh(III)‐catalyzed synthesis of 2‐(2‐nitroalkyl)indoles (Scheme 1c). ^[19] Herein, we report the C2 alkylation of indoles with β‐nitroolefins, followed by reduction of the nitro group and the Ugi reaction, furnishing highly functionalized indole derivatives (Scheme 1d).

Scheme 1.

Examples of alkylation of indoles with nitroolefins.

Results and Discussion

Guided by the success of the pyridinyl and pyrimidyl directing groups in C−H activation of indoles at the C‐2 position,[ ²⁰ , ²¹ , ²² , ²³ , ²⁴ ] we initially examined the reaction of N‐pyridinylindole 1 a with β‐nitrostyrene (2 a) (Scheme 2) in dry TFE, catalyzed by Cp*Co(CO)I₂ (catalyst I) (2.5 mol %) in the absence of base (Table 1, entry 1), however no product was obtained. Keeping the amount of catalyst I at 2.5 mol %, we evaluated the reaction using 10 mol of AgSbF₆ and 1 equiv. of KOPiv (entry 2), also with 2 equiv. of this base (entry 2) and again we were not successful in obtaining 3 a, and only the C‐3 alkylated indole derivative 4 was isolated. Increasing the amount of catalyst I to 10 mol %, the reaction was carried out in the presence of 1 and 2 equiv. of KOPiv (entries 4 and 5), but again, only compound 4 was obtained. The product of interest 3 a was not obtained, even when we used the Ru catalyst II (entry 8).

Scheme 2.

Catalysts and directing groups explored in the C−H activation of indole at the C‐2 position with β‐nitrostyrene.

Table 1.

Screening of catalysts for the alkylation of indole with β‐nitrostyrene.

Entry[a]	Catalyst [mol %]	AgSbF6 [mol %]	4, Yield [%][b]
1	I, 2.5	–	–
2[c]	I, 2.5	10	16
3[d]	I, 2.5	10	29
4[c]	I, 10	20	37
5[d]	I, 10	20	43
6	I, 5.0	20	–
7[c]	I, 5.0	20	–
8[e]	II, 10	20	–

[a] 0.1 mmol 1 a and 0.2 mmol 2 a, Schlenk tube, 50 °C, N₂ atm, dry TFE (0.5 mL); [b] isolated yield; [c] KOPiv, 1 equiv.; [d] KOPiv, 2 equiv.; [e] dry DCE (0.5 mL).

Based on previous reports,[ ¹⁸ , ²⁵ , ²⁶ , ²⁷ ] we then evaluated the reaction between N‐pyrrolidinylindolecarboxamide 1 c and with β‐nitrostyrene 2 a at 50 °C in the presence of 5 mol % of Co catalyst I (Table 2, entry 1) as well as of Ru catalyst II (entry 2) under the same conditions, without success. However, employing [Cp*RhCl₂]₂ (10 mol %) and AgSbF₆ (20 mol %) in dry DCE at 85 °C over four days, ^[18] 3 c was obtained with 27 % yield (entry 3), together with the other C−H activation product 5 at the C‐7 position of indole. The structure of 3 c was fully established by 1D and 2D NMR experiments, in addition to X‐ray crystallography (Scheme 3).

Table 2.

Rh(III)‐catalyzed alkylation of indole with β‐nitrostyrene.

Entry[a]	Base [mol %]	T [°C]	t [h]	Yield [%][b] 3 c	Yield [%][b] 5
1[c]	–	50	96	0	0
2[d]	–	50	96	0	0
3	–	85	96	27	19
4	Cu(OAc)2 10	85	96	51	10
5	Cu(OAc)2 10	85	48	47	12
6[e]	Cu(OAc)2 10	85	48	28	traces
7[f]	Cu(OAc)2 10	85	48	42	12
8	Cu(OAc)2 5	85	48	38	9
9	Cu(OAc)2 5	85	96	49	7
10	Cu(OAc)2 30	85	48	44	4
11	Cu(OAc)2 50	85	48	48	8
12	Cu(OAc)2 100	85	48	49	traces
13[g]	Cu(OAc)2 10	85	96	0	0
14	Cu(OAc)2 10	100	48	37	traces
15	AgOAc, 20	85	48	56	18
16	CF3CO2Ag, 20	85	48	40	22
17	NaOAc, 20	85	48	0	0
18	KOAc, 20	85	48	0	0
19	KOPiv, 20	85	48	0	0
20[h]	AgOAc 10	85	48	9	16
21[h]	AgOAc 30	85	48	65	22
22[h]	AgOAc 40	85	48	68	18
23[h]	AgOAc 50	85	48	44	11
24[h]	AgOAc 50	85	72	71	10
25 [h]	AgOAc 30	85	72	74	18
26[h]	AgOAc 40	85	72	80	15
27[h]	AgOAc 40	100	72	69	13
28[h]	AgOAc 40	60	72	47	5
29[h]	AgOAc 50	85	72	73	16
30[h]	AgOAc 100	85	72	51	11
31[g,h,]	AgOAc 40	85	96	0	0
32[i]	AgOAc 40	85	72	52	13

[a] Reactions were carried out using 1 c (0.15 mmol), 2 a (0.1 mmol), [Cp*RhCl₂]₂ (10 mol %)/AgSbF₆ (20 mol %), N₂ atm., dry DCE (1.5 mL); [b] Yields of isolated compounds; [c] Cp*Co(CO)I₂ 5 mol % was employed; [d] [RuCl₂(p‐cymene)₂] 5 mol % was employed; [e] [Cp*RhCl₂]₂ (5 mol %)/AgSbF₆ (20 mol %); [f] 0.3 mmol 1 c, 0.1 mmol 2 a; [g] Reaction carried out in the absence of [Cp*RhCl₂]₂ and AgSbF₆; [h] 0.1 mmol 1 c, 0.3 mmol 2 a; [i] Reaction carried out in the absence of AgSbF₆.

Scheme 3.

C−H activation of indole 1 c at the C‐2 position with β‐nitrostyrene.

In the context of C−H activation, organic bases with adequate steric and electronic characteristics usually accelerate the deprotonation step, since the anions from the dissociation of these compounds in solution can function as ligands, entering the organometallic coordination sphere and facilitating hydrogen abstraction.[ ²⁸ , ²⁹ , ³⁰ ]

Thus, continuing with the optimization, we examined the presence of 10 mol % of Cu(OAc)₂, 1.5 equiv. of 1 c, 1 equiv. of 2 a, 10 mol % of [Cp*RhCl₂]₂, 20 mol % of AgSbF₆, at 85 °C for 96 h, and in this case, the isolated yield of 3 c has increased to 51 % (Table 2, entry 4).

Hence, the reaction was carried out for 2 days, and the yield of 3 c practically did not change (47 %, entry 5), and for this reason, the following experiments were conducted over 48 h. Using the reaction criteria of entry 3, the employment of 3 equiv. of 1 c to 1 equiv. of 2 a (entry 7) was examined and there was a decrease in the yield of 3 c (42 %). In the following entries, the use of a smaller amount of Cu(OAc)₂ (5 mol %) was tested in 48 h (Table 2, entry 8), and 96 h of reaction (entry 9), and the yields remained low (38 and 49 %, respectively).

The use of 30, 50 and 100 mol % (entries 10, 11 and 12, respectively) of Cu(OAc)₂ also caused small variation in the yield of 3 c, as well as the repetition of the reaction in the presence of 10 mol % of Cu(OAc)₂ at a higher temperature of 100 °C (37 %, entry 14).

In the face of our misfortune to increase the yield of 3 c with Cu(OAc)₂, other bases such as NaOAc, KOAc and KOPiv (Table 2, entries 17, 18 and 19, respectively), were used, but without success. On the other hand, when using 20 mol % of AgOAc (entry 15) in a reaction time of 48 h, the yield of 3 c increased to 56 %. At this point, the stoichiometric proportion between 1 c and 2 a was inverted (1 : 3 equiv., in that order), and the reaction was performed in the presence of 40 mol % of AgOAc, as the same reaction parameters as entry 15; in this case, the yield of 3 c increased to 68 % (entry 22).

In view of this result, the reaction was carried out under the same conditions, but over a longer time, 72 h, and the isolated yield of 3 c reached 80 % (entry 26). Increasing the amount of AgOAc to 50 and 100 mol % caused an attenuation in the yield of 3 c (73 and 51 %, in that order, entries 29 and 30), while reducing the loading of this base to 30 and 10 mol % also led to a considerable decline in the yield of 3 c, especially in the second case (65 and 39 %, entries 21 and 20, subsequently). The use of silver trifluoroacetate – a base with a strong electron‐withdrawing group – proved to be inadequate, as the yield of 3 c dropped significantly (40 %, entry 16). Increasing or decreasing the temperature to 100 and 60 °C, respectively, lowered the yield from 3 c to 69 and 47 % (entries 27 and 28, in that order).

It was also demonstrated that AgSbF₆ is fundamental for the methodology, since in the absence of this salt (Table 2, entry 31), no product was obtained. With the reduction of the catalytic loading to 5 mol % (entry 32), 3 c was obtained with a moderate yield of 52 %.

In view of all the implications that are associated with the use of DCE,[ ³¹ , ³² ] other solvents such as DMSO, DMF, ACN, 1,4‐dioxane, THF, EtOH, MeOH, EtOAc, toluene and anisole were evaluated (see Supporting Information). Using the optimized conditions (Table 2, entry 24), the reaction occurred only in THF and EtOAc, leading to 3 c being obtained in low yields (21 and 10 %, respectively). Thus, we continued the study of the scope and limitations with DCE by exploring different indoles and β‐nitroolefins (Scheme 4).

Scheme 4.

Study of the scope and limitations of C‐2 alkylation of indoles 1 c.

For our delight, the protocol well tolerates β‐nitrostyrenes substituted with electron‐donating groups (EDG), since the corresponding products containing methyl (3 d, 3 e), phenyl (3 f), protected hydroxyl groups (3 g, 3 h, 3 i, 3 j) and halogens in the para position (3 k, 3 l, 3 m) were obtained in moderate to good yields (45–78 %). Probably, due to the steric factor, the o‐methylated product (3 e) was obtained in a lower yield (54 %) than 3 d (69 %). Furthermore, the heteroaromatic β‐nitroolefins containing thiophene and the furfuryl moiety afforded the products 3 n and 3 o in 39 % and 48 % yields, respectively.

Here, a possible cause for the decrease in the yield would be the fact that the heteroatom has the ability to function as a ligand, donating the electron pair that is not involved in the aromaticity of these structures to the metallic center of the catalyst. Moreover, products 3 p and 3 q, bearing aliphatic β‐nitroolefins, were obtained in good yields (75–79 %), while product 3 v with a β‐nitroolefin derived from cinnamaldehyde was obtained in low yields (<5 %). In this case, probably, there was a competition between the double bonds of the nitroolefin 2 u for the metallic center of the catalyst in the complexation step of the mechanism, leading to an unsatisfactory product yield. However, this would only be a conjecture, since the 1,4‐addition product (3 w) – that would be formed as a result of this competition – was not identified.

Nevertheless, this method was not effective for β‐nitrostyrenes containing electron‐withdrawing groups, since the products containing p‐nitro (3 s), p‐trifluoromethyl (3 t) and p‐cyano groups (3 u) were obtained in very low yields (<5 %, 3 s) or in trace amounts only (3 t and 3 u).

A plausible hypothesis for this limitation could lie in the inefficient complexation of the corresponding β‐nitroolefins with the catalyst in the step prior to the migratory insertion (Scheme 5), due to the highly electron‐deficient double bond of this structures. Furthermore, in the case of β‐nitrostyrene 2 p, it is possible that there is a complexation that might occur between the nitrogen of the cyano group and the metallic center of the catalyst, which would contribute to the observed result.

Scheme 5.

Proposed mechanism for C−H activation of indoles at C‐2 with nitroolefins.

The study of the reaction with the p‐dimethylamine group have pointed out another limitation of the methodology, given that the product 3 r was not formed, which may be related to the fact that nitrogen is an efficient Lewis base, complexing with the Rh and making catalysis unfeasible.

To conclude the study of the scope of the aromatic β‐nitroolefins, we investigated the reaction of N‐pyrrolidinilindolecarboxamide 1 c with β‐nitrostyrene 2 l under standard conditions and, as we already suspected, there was no product formation. Our hypothesis for this result is that the methyl group alpha to the nitro group causes a steric hindrance that makes the complexation of Rh with the double bond impracticable before migratory insertion (Scheme 5).

Regarding the scope of substituted indole substrates, the products 3 y and 3 z containing an EDG in the indole portion were obtained with good yields (65 and 72 %).

In contrast, product 3 aa, brominated at C‐5 position, was isolated with a modest yield of 42 %. In this turn, product 3 ab containing the indole ring substituted by the p‐cyano group at the C‐4 position was not obtained, while the compound 3 ac bearing the nitro substituent at the C‐5 position was isolated in only 3 % yield. A justification for these results is the strong electron‐withdrawing effect of these groups, causing, by resonance effect, a lower electronic density in the oxygen of the directing group, impairing its complexation with Rh in the concerted metalation‐deprotonation step of the mechanism (Scheme 5). Furthermore, as already discussed, the cyano group is able to complex Rh, one more reason for the failure of the synthetic protocol in the case of product 3 ab.

Based on the results of the scope study and the literature,[ ¹⁸ , ¹⁹ ] we propose the following mechanism for the reaction: in the presence of AgSbF₆ and AgOAc, [Cp*RhCl₂]₂ gives rise to the catalytically active species A. Then, through a concerted deprotonation‐metalation process (CMD), the reactive intermediates D and D′ are formed. With the entry of nitroolefin E into the catalytic cycle, the species F is formed, which generates G after the migratory insertion. Then, after one more step consisting of a concerted protonation‐demetallation process, H product 3 a is produced.

Aiming to show the applicability of this method in producing highly functionalized indole derivatives, compounds 3 were reduced to the respective amines 6 and employed in the Ugi multicomponent reaction. Initially, we investigate different protocols to reduce nitroalkanes, such as Pd/C in the presence of H₂ generated in situ from ammonium formate ^[33] or a mixture of NaH₂PO₂/H₃PO₂, ^[34] without success. The procedure that proved to be the most efficient to our substrate was that of use an excess of NaBH₄ in presence of NiCl₂⋅6H₂O and MeOH at 0 °C. ^[35] After extraction, the amines 6 were employed in the Ugi reaction without further purification.

An expeditious optimization of the Ugi reaction was also performed starting by carrying out the reaction in the tube containing the amine 6 in MeOH, consecutive addition of paraformaldehyde, benzoic acid and t‐butylisonitrile at 55 °C for 72 h. ^[36] In this case, the Ugi adduct 7 a was obtained in 67 % yield. By using the same parameters, the yield of 7 a decreased when the reaction was carried out in 48 h (59 %) as well as at 45 °C (51 %). The imine pre‐formation strategy by reacting amine 6 with paraformaldehyde in MeOH at r.t. for 40 min and then adding the other components, proved to be inadequate, since many side products were identified in the TLC, along with 7 a with only 33 % yield. Moreover, changing the solvent to TFE was not effective, given that 7 a was formed only in the traces amount. When the order of addition of the components was modified, that is, addition of paraformaldehyde and benzoic acid to the tube containing the amine 6 and after 10 min addition of t‐butyl isocyanide, the yield of 7 a finally increased to 71 %, which identified these as the best conditions.

After this optimization, a series of new peptidomimetics were synthesized with reasonable yields (Scheme 6), taking into account the two transformations, that is, reduction and the Ugi reaction.

Scheme 6.

Reduction of nitro group followed by Ugi reaction.

In general, compounds not substituted on the indole or on the benzene ring of the amine moiety – with the exception of 7 i – were obtained in yields greater than 60 %. More specifically, the adducts 7 b and 7 c, containing cyclohexyl and n‐butylisocyanide were obtained with 68 and 69 % yield, respectively, while the use of aliphatic and substituted aromatic carboxylic acids afforded the corresponding compounds 7 d and 7 e, with 62 and 31 % yield, in this order. In contrast, the Ugi adducts bearing a methoxy (7 f) and methyl (7 g) group at C5 position of indole, as well as the one methylated (7 h) on the phenyl portion of the functionalized indole (7 h), were obtained with moderate yields (40–45 %).

Interestingly, the other aliphatic aldehydes as the aromatic ones – more reactive than paraformaldehyde – did not work in the Ugi reaction with our amine substrate, which is possibly related to the high nucleophilicity of C‐3 of indole, enough to carry out an intramolecular attack on the activated imine intermediate, leading, probably, to cyclization products.

The NMR analysis of Ugi adducts 7 showed some duplicated signals due the presence of rotamers. In one of the most representative cases, for instance (see Supporting Information), the ¹H NMR spectrum for compound 7 c at 25 °C showed four signals for the most unshielded hydrogen atoms of indole H‐7 (δ=7.92, 7.81, 7.63 and 7.54 ppm, the first two being broad singlets and the last two doublets with respective coupling constants J in range of 7.5 Hz), besides three singlets for the methine group of at C3 position (δ=6.87, 6.78, 6.46 ppm). In order of eliminating interference from these conformational isomers, a temperature‐resolved ¹H NMR experiment was carried out, showing that the increase in temperature caused a coalescence of the mentioned H signals, allowing to observe the already broadened singlets at 65 °C and, at 115 °C, as a unique doublet and singlet at 7.58 and 6.64 ppm, respectively, as expected, with good resolution.

Conclusion

This work describes a protocol for nitroalkylation of indoles at the C‐2 position via a C−H activation, using easily accessible nitroolefins. We also show the applicability of this method through the reduction of some selected 2‐(2‐nitroalkyl)indoles to the respective amines, which were subsequently employed in the Ugi reaction, furnishing highly functionalized indole derivatives.

Experimental Section

All commercially available reagents were purchased from Sigma‐Aldrich. β‐Nitroolefins were synthesized according to the reported procedures. ^[37] The known compounds 1 a–b ^[38] and 1 c, ^[39] as well the new derivatives 1 d–h[ ³⁹ , ⁴⁰ ] were prepared according to protocols available in the literature. The synthesized products were purified by column chromatography or preparative thin layer chromatography using silica gel 60, 230–400 mesh. TLC were performed on silica gel 60 F254 supported in aluminum sheets. The ¹H and ¹³C NMR spectra were recorded on a Bruker DRX 400 MHz spectrometer. The chemical shifts (δ) are given in ppm units and the coupling constants (J) in Hertz (Hz). The multiplicity of signs is expressed by the following abbreviations: s (singlet), brs (broad singlet), d (double), t (triplet), q (quartet), m (multiplet). Melting points were determined using a Büchi M‐560 Basic Melting Point Apparatus. The HRMS data were acquired using a Shimadzu Nexera LC‐30AD UHPLC equipped with QqTOF Brucker Daltonics Impact HD or in an Ultra‐High Performance Liquid Chromatography‐Electrospray Ionization Tandem Mass Spectrometry (UHPLC‐ESI‐MS/MS) using an Agilent 6545 LC/Q‐TOF MS system.

Crystal data were measured using graphite‐monochromated Mo−Kα radiation (λ=71.073 pm) on a four‐circle Kappa Apex‐II diffractometer Bruker, equipped with a CCD detector. Data reduction and a semi‐empirical (multi‐scan) ^[41] absorption correction were carried out using the APEX3 suite. ^[42] The structure was solved using SIR2014, ^[43] and subsequently refined against Fo² with SHELXL‐2014/6. ^[44] Deposition Number2251653 (for 3 c) contains the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service.

General procedure for the synthesis of indoles (3 c–3 ac): In a 10 mL Schlenk tube purged with N₂, consecutively, N‐pyrrolidinylindolecarboxamide (1 c) (0.1 mmol, 1.0 equiv., 0.021 g), β‐nitrostyrenes (2 a–u) (0.3 mmol, 3 equiv.), [Cp*Rh(Cl)₂]₂ (0.0062 g, 20 mol %), AgSbF₆ (0.0062 g, 20 mol %), AgOAc (0.0067 g, 40 mol %) and dry DCE (1.5 mL) were added. The reaction mixture was stirred at 85 °C for 72 h, being cooled to room temperature after this time, filtered through celite with EtOAc, concentrated and purified by preparative thin layer chromatography or column chromatography, as appropriate to give the 2‐nitrofunctionalizated indole derivatives.

(2‐(2‐nitro‐1‐phenylethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 c): obtained in 80 % yield as a pale greenish yellow solid.

(2‐(2‐nitro‐1‐(p–tolyl)ethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 d): obtained with 69 % yield as a light‐yellow solid.

(2‐(2‐nitro‐1‐(o–tolyl)ethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 e): obtained with 54 % yield as a greenish yellow solid.

(2‐(1‐([1,1′‐biphenyl]‐4‐yl)‐2‐nitroethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 f): obtained with 57 % yield as a yellowish brown solid.

(2‐(1‐(4‐methoxyphenyl)‐2‐nitroethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 g): obtained with 78 % yield as yellow solid.

(2‐(1‐(3‐methoxyphenyl)‐2‐nitroethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 h): obtained with 72 % yield as a yellow solid.

(2‐(2‐nitro‐1‐(3,4,5‐trimethoxyphenyl)ethyl)‐1H‐indol‐1 yl)(pyrrolidin1yl)methanone (3 i): obtained with 51 % yield as a yellowish solid.

(2‐(1‐(2,4‐bis(benzyloxy)phenyl)‐2‐nitroethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 j): obtained with 45 % yield as a sticky yellowish oil.

(2‐(1‐(4‐fluorophenyl)‐2‐nitroethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 k): obtained with 68 % yield as a sticky brown oil.

(2‐(1‐(4‐chlorophenyl)‐2‐nitroethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 l): obtained with 61 % yield as a yellowish brown solid.

(2‐(1‐(4‐bromophenyl)‐2‐nitroethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 m): obtained with 49 % yield as a yellowish solid.

(2‐(2‐nitro‐1‐(thiophen‐2‐yl)ethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 n): obtained with 39 % yield as a yellowish brown solid.

(2‐(1‐(5‐methylfuran‐2‐yl)‐2‐nitroethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 o): obtained with 48 % yield as a sticky brown oil.

(2‐(1‐cyclohexyl‐2‐nitroethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 p): obtained with 75 % yield as a ligth oil.

(2‐(1‐nitrononan‐2‐yl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 q): obtained with 79 % yield as a ligth oil.

(5‐methoxy‐2‐(2‐nitro‐1‐phenylethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 y): obtained with 72 % yield as a brown solid.

(5‐methyl‐2‐(2‐nitro‐1‐phenylethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 z): obtained with 65 % yield as a pale yellow solid.

(5‐bromo‐2‐(2‐nitro‐1‐phenylethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (3 aa): obtained with 42 % yield as a brown solid.

3‐(2‐nitro‐1‐phenylethyl)‐1‐(pyridin‐2‐yl)‐1H‐indole (4): obtained as yellowish oil (16–43 % yield).

(7‐(2‐nitro‐1‐phenylethyl)‐1H‐indol‐1‐yl)(pyrrolidin‐1‐yl)methanone (5): obtained as a yellowish solid with 26 % yield.

General procedure for reduction of compounds 3: To a suspension of compound 3 (0.1 mmol) and NiCl₂⋅6H₂O (0.071 g, 0.3 mmol) in methanol (1 mL), NaBH₄ (0.023 g, 0.6 mmol) was added at 0 °C and the mixture was stirred at this temperature for 1 h. Then, the reaction mixture was quenched by the addition of saturated NH₄Cl (3×10 mL) at 0 °C and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness in vacuo. The crude product was used in the next step without further purification.

General procedure for the Ugi reaction: To a tube containing amine 6 a (0.033 g) or 6 b–6 d, consecutively, paraformaldehyde (0.0033 g, 0.1 mmol), benzoic acid (0.012 g, 0.1 mmol), 4‐iodobenzoic acid or octanoic acid (0.1 mmol) and MeOH (0.5 mL) were added. After stirring for 10 min at r.t., the t‐butylisocyanide (0.011μL, 0.1 mmol), cyclohexylisocyanide (0.1 mmol) or n‐butylisocyanide 0.1 mmol) were added. The reaction mixture was heated to 55 °C and left stirring for 72 h, then cooled to r. t. and purified by preparative chromatography to give the Ugi adducts 7.

N ‐(2‐(tert‐butylamino)‐2‐oxoethyl)‐N‐(2‐phenyl‐2‐(1‐(pyrrolidine‐1‐carbonyl)‐1H‐indol‐2‐yl)ethyl)benzamide (7 a): obtained with 71 % yield as a white solid.

N ‐(2‐(cyclohexylamino)‐2‐oxoethyl)‐N‐(2‐phenyl‐2‐(1‐(pyrrolidine‐1‐carbonyl)‐1H‐indol‐2‐yl)ethyl)benzamide (7 b): obtained with 68 % yield as a white solid.

N ‐(2‐(butylamino)‐2‐oxoethyl)‐N‐(2‐phenyl‐2‐(1‐(pyrrolidine‐1‐carbonyl)‐1H‐indol‐2‐yl)ethyl)benzamide (7 c): obtained with 69 % yield as a white solid.

N ‐(2‐(tert‐butylamino)‐2‐oxoethyl)‐N‐(2‐phenyl‐2‐(1‐(pyrrolidine‐1‐carbonyl)‐1H‐indol‐2‐yl)ethyl)octanamide (7 d): obtained with 62 % yield as a stick ligth yellow solid.

N ‐(2‐(tert‐butylamino)‐2‐oxoethyl)‐4‐iodo‐N‐(2‐phenyl‐2‐(1‐(pyrrolidine‐1‐carbonyl)‐1H‐indol‐2‐yl)ethyl)benzamide (7 e): obtained with 31 % yield as a white solid.

N ‐(2‐(tert‐butylamino)‐2‐oxoethyl)‐N‐(2‐(5‐methyl‐1‐(pyrrolidine‐1‐carbonyl)‐1H‐indol‐2‐yl)‐2‐phenylethyl)benzamide (7 f): obtained with 45 % yield as a white solid.

N ‐(2‐(tert‐butylamino)‐2‐oxoethyl)‐N‐(2‐(5‐methoxy‐1‐(pyrrolidine‐1‐carbonyl)‐1H‐indol‐2‐yl)‐2‐phenylethyl)benzamide (7 g): obtained with 41 % yield as a yellow solid.

N ‐(2‐(tert‐butylamino)‐2‐oxoethyl)‐N‐(2‐(4‐methyphenyl)‐2‐(1‐(pyrrolidine‐1‐carbonyl)‐1H‐indol‐2‐yl)ethyl)benzamide (7 h): obtained with 40 % yield as a yellow solid.

Supporting Information Summary

The Supporting Information contains the experimental details for synthesis and fully analytical characterization of the compounds such as melting point, NMR and HRMS spectra.

Conflict of interest

The authors declare no conflict of interest.

Supporting information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

Supporting Information

Januário M. A. P., de Souza D. P., Zukerman-Schpector J., Corrêa A. G., ChemistryOpen 2023, 12, e202300070.

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.