Next Article in Journal
Biogasoline Obtained Using Catalytic Pyrolysis of Desmodesmus sp. Microalgae: Comparison between Dry Biomass and n-Hexane Extract
Next Article in Special Issue
Catalytic Etching and Oxidation of Platinum Group Metals: Morphology, Chemical Composition and Structure of Pt, Pd and Rh Foils in the O2 Atmosphere and during NH3 Oxidation with Air at 1133 K
Previous Article in Journal
Valorization of Recycled Honeycombs from Exhausted TWCs by Means of Their Use as a Support of MnOx Catalysts for Acetone Combustion
Previous Article in Special Issue
Influence of Components Deposition Order on Silver Species Formation in Bimetallic Ag-Fe System Supported on Mordenite
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Catalysts
Volume 12
Issue 12
10.3390/catal12121516
catalysts-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Synthesis of Polysubstituted 1,2-Dihydro-3H-pyrrolo[1,2-a]indol-3-ones through Domino Palladium-Catalyzed Reactions of Indol-2-ylmethyl Acetates with 1,3-Dicarbonyl Derivatives

by
Antonia Iazzetti
1,
Antonio Arcadi
2,
Stefano Dessalvi
3,
Giancarlo Fabrizi
3,
Antonella Goggiamani
3,*,
Federico Marrone
3,
Andrea Serraiocco
3,
Alessio Sferrazza
3,* and
Karim Ullah
3
1
Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of Sacred Heart, L.go F. Vito 1, 00168 Rome, Italy
2
Dipartimento di Ingegneria e Scienze dell’Informazione e Matematica, Università degli Studi di L’Aquila, Via Vetoio, 67100 L’Aquila, Italy
3
Department of Chemistry and Technologies of Drug, Sapienza, University of Rome, P.le A. Moro 5, 00185 Rome, Italy
*
Authors to whom correspondence should be addressed.
Catalysts 2022, 12(12), 1516; https://doi.org/10.3390/catal12121516
Submission received: 4 November 2022 / Revised: 18 November 2022 / Accepted: 22 November 2022 / Published: 25 November 2022
(This article belongs to the Special Issue Advances in Transition Metal Catalysis)
Browse Figures
Versions Notes

Abstract

:
A straightforward assembly of polysubstituted 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-ones through a domino palladium-catalyzed reaction of indol-2-ylmethyl acetates with 1,3-dicarbonyl derivatives is described. The key role of the features of the 1,3-dicarbonyls on the reaction outcome has been explored. The employment of 2-methylcyclohexan-1,3-dione as the dicarbonyl source could allow further challenging indole nucleus functionalizations.

Graphical Abstract

1. Introduction

The tricyclic 2,3-dihydro-1H-pyrrolo[1,2-a]-indole core and its oxidized derivatives represent an important structural motif found in many biologically active natural products and drug candidates [1,2,3]. For example, flinderole C exhibits excellent antimalarial activity against the Plasmodium falciparum parasite [4,5,6] and mitomycin C is an effective antitumor agent [7,8]. Moreover, the antiviral [9,10] as well as antinociceptive [11] and psychotropic [12] properties of these derivatives boosted the development of effective strategies for their rapid construction. In 1983, Danishefsky described the formation of the 2-methyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one through the palladium-catalyzed cyclization of the N-(2-allylphenyl)acrylamide; [13] subsequently, various cascade reactions have been used as powerful tools to construct the 2,3-dihydro-1H-pyrrolo[1,2-a]-indoles in a pot fashion, achieving also remarkable progress in the rapid construction of enantioenriched pyrroloindolones [14,15,16,17,18,19,20,21].
Indeed, because of the problems of chemical sustainability of resources, the application of efficient methods for the concise synthesis of valuable scaffolds by avoiding a step-by-step approach, which involves tedious isolation processes, has attracted a great deal of attention from the synthetic community [22].
During our studies in the field of the synthesis of heterocyclic compounds, great interest has been devoted to the formation/functionalization of indole/benzofuran rings and the construction of indole-fused polycyclic systems through simple domino processes [23,24,25,26]. Nevertheless, the diversity-oriented synthesis of polysubstituted 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-ones through straightforward one-pot approaches from easily available building blocks would be particularly significant considering the structural variety of the biologically active derivatives. From all possible retrosynthetic schemes of 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-ones, a simple one requires one C-C bond and one C-N disconnection. It was plausible to suppose that the reaction of 2-indolylmethyl acetates 1 with various common active methylene compounds 2 should achieve a general entry into the title target through the in situ generation of 2-methide-2H-indole intermediate I/nucleophile Michael addition/cyclization/decarboxylation cascade reaction (Scheme 1).
The sequential addition/annulation reaction of Meldrum’s acid, malononitrile, and 1,3-dicarbonyls with ortho-quinone methides generated in situ under basic conditions was previously reported to achieve the one-pot synthesis of 3,4-dihydrocoumarins, 4H-chromenes, and xanthenones [27]. Moreover, the in situ-generated aza-ortho-quinone methydes from o-aminobenzyl alcohol derivatives were reacted with Meldrum’s acid to afford dihydroquinolinones [28].
In the literature, methodologies are also reported to easily obtain indolo[1,2-a]indoles derivatives from 1H-indol-2-yl carbinols via the in situ generation of 2-methide-2H-indoles intermediates. Particularly, the enantioselective Brønsted acid catalyzed [3 + 2]-cycloaddition of cyclic enamides and organocatalyzed asymmetric (4 + 3) cycloaddition with dienolsilanes to bicyclo[3.2.2]cyclohepta[b]indoles have been described [29,30,31,32]. In addition, recently, we observed the formation of reactive indole-methides under basic conditions, starting from indolylmethyl acetates [33].
In the following, we describe the scope and limitations of this approach to the synthesis of the 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-ones 3.

2. Results and Discussions

We started our investigation by examining the reaction of (1H-indol-2-yl)methyl acetate 1a with (1H-indol-2-yl)methyl ethyl carbonate 1b with the 2,2,5-trimethyl-1,3-dioxane-4,6-dione 2a under basic conditions as the model system. Pleasingly, the desired 2-methyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one 3a was isolated in 55% yield by reacting 1a with 2a in DMSO at 100 °C in the presence of K2CO3 as the base (Table 1, entry 1).
A poorer result was observed by reacting 1b under the same reaction conditions in the presence of the stronger base NaH (Table 1, entry 2).
The advantages of the palladium catalysis in the reaction of benzofuran-2-ylmethyl acetates with nucleophiles [34] prompted us to explore the palladium-catalyzed version of the same reaction using different ligands and solvents, as shown in Table 1. The palladium-catalyzed reaction of indolemethyl acetates 1 with boronic acid to afford the corresponding indole-containing diarhylmethanes has been previously investigated [35]. The formation of the target 3a occurred in good-to-high yields in DMSO or MeCN, both in the presence of a palladium complex containing a monodentate phosphine ligand (Table 1, entries 3–6 and 9–10) or bidentate phosphine one (Table 1, entries 7–8, 11–12). The best result was obtained by carrying out the reaction in DMSO at 100 °C in the presence of Pd2(dba)3/dppf as the catalyst (Table 1, entry 11). In previous studies on palladium-catalyzed benzylic substitution reactions, it was shown that the yields of the benzylation products were strongly affected by the bite angle of the bidentate bisphosphine ligand on the palladium catalyst [36,37,38]. The ligands dppf and DPEPhos were preferred for the benzylation of stabilized carbanions and amines, respectively. A complex mixture was observed when the reaction was performed without 2a and the starting material 1a was not recovered.
The exploration of the substrate scope of the procedure under the optimized condition reaction (Table 2) showed that 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-ones 3 bearing a variety of useful functional groups can be prepared in moderate-to-good yields.
Several substituents, including methyl, nitro, fluoro, bromo, and tolyl, on the indole moiety of 3 were tolerated. A gram-scale experiment was also performed and showed the practicability of this methodology (Table 2, entry 14) Moreover, we tested the reactivity of the (1H-indol-2-yl)(phenyl)methyl acetate 4a and the 1-(1H-indol-2-yl)ethyl acetate 4b with some 5-substituted Meldrum’s acid derivatives (Table 3).
In all the tested cases, the reaction led to the formation of the corresponding 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one with good-to-excellent diastereoselectivity. Control experiments have shown that the observed diastereoselectivity depends on the relative stability of the trans 5 compared to the cis- diastereomer 5′. In fact, by heating the pure diastereomer 5a or 5a′ (R1 = Ph, R2 = Me) at 100 °C in DMSO for 1h in the presence of K2CO3, a rapid equilibrium occurred, leading to the formation of the mixture of the two diastereomers in equal ratio to that observed in the synthetic run (Table 3, entry 1). These data match with ΔG°calculated with Gaussian (HF, 3–21G*) (the trans stereoisomer is more stable than cis by 1.23 Kcal/mol, corresponding to the 88/12 5a/5a′ ratio) [39].
Regarding the reaction mechanism for the one-pot synthesis of 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one 3 from indol-2-ylmethyl acetates and Meldrum’s acid derivatives, we believe that the in situ generation of the indolyl methide intermediate I could be a common intermediate both for the base promoted and the palladium-catalyzed process (Scheme 2). Experiments to detect the key intermediate I under basic conditions have been previously described. [31] Regarding the palladium-catalyzed procedure, it is well known that the oxidative addition of the Pd(0) to the indol-2-ylmethyl acetate generates the η3 palladium complex III in equilibrium with the η1 palladium complex II. It may be supposed that an unusual 1,4- elimination from this later intermediate, involving cleavage of the N-H bond, [40] may afford the indolyl methide I with the regeneration of the Pd(0) catalyst. Although the formation of the intermediate derivative 6 via the palladium-catalyzed Tsuji–Trost-type reaction could not be ruled out, we failed to isolate any C3 functionalized indole derivative.
The subsequent sequential cyclization of 6, followed by the elimination of acetone and CO2, affords the target products (Scheme 3).
Accordingly, we continued our studies to address product selectivity control. For this purpose, we analyzed the reaction outcome when the indol-2-ylmethyl acetate 1a was reacted with unsubstituted Meldrum’s acid 7 in different stoichiometric ratios. Our result suggested that the competitive deprotonation of the Michael adduct 6a under the basic reaction conditions generates a new enolate species which is prone to undergo a second Michael addition over the indolyl methide intermediate to afford the 2-((1H-indol-2-yl)methyl)-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one 9 after cyclization. Conversely, the prevalence of the cyclization of 6a allowed the isolation of the 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one 8 when the reaction was carried out in the presence of a large excess of Meldrum’s acid (Scheme 4).
Next, we explored the reactivity of the building block 1a with other methylene active compounds. Both the ethyl malonate 10 and the ethyl-3-oxobutanoate 12 were compatible with the procedure, allowing to obtain, respectively, the title products 11 and 13 in moderate yields in the presence of 5 equiv. excess of the starting dicarbonyl (Scheme 5).
More intriguing results were observed when 1a was reacted with the ethyl 2-methyl-3-oxobutanoate 14a or the diethyl 2-methylmalonate 14b (Scheme 6). Surprisingly, both the palladium reaction of the ethyl 2-methyl-3-oxobutanoate 14a and its base-promoted one occurred with poor results, while a good yield of the corresponding product 3 was observed in the reaction of 1a with the ethyl 2-acetylpent-4-enoate 14c (Table 4, entries 3). Moreover, we isolated in satisfactory yield the ethyl 2-methyl-3-oxo-2,3-dihydro-1H-pirrolo[1,2-a]indole-2-carboxylate 15 in the palladium-catalyzed reaction of 1a with 14b.
Finally, we examined the reaction of 1a with the 2-methylcyclohexan-1,3-dione 16a or its potassium salt 16b. In both cases, the product of sequential Michael addition/retro Dieckmann reaction 7-(1H-indol-2-yl)-6-methyl-5-oxoheptanoic acid 17, together with its cyclized derivative 4-(2-methyl-1H-pyrrolo[1,2-a]indol-3-yl)butanoic acid 18 (16% yield), was isolated (Scheme 6).

3. Materials and Methods

3.1. General Information

All the commercially available reagents, catalysts, bases, and solvents were used as purchased, without further purification. Starting materials and reaction products were purified by flash chromatography using SiO2 as the stationary phase, eluting with n-hexane/ethyl acetate mixture. 1H NMR (400.13 MHz), 13C NMR (100.6 MHz), and 19F spectra (376.5 MHz) were recorded with an Avance 400 spectrometer (Bruker, Milan, Italy). Splitting patterns were designed as s (singlet), d (doublet), t (triplet), dt (doublets of triplets), td (triplet of doublets), triplets of triplets (tt), q (quartet), m (multiplet), or br s (broad singlet). IR spectra were recorded with a FT/IR-430 spectrometer (Jasco Europe, Milan, Italy) (compounds 1e-f, 2e, 3a-h, 3j-n, 5a-d, 5′a-d, 15a-b, 18) and FT/IR 6800, ATR (Jasco Europe, Milan, Italy) (compounds 1a, 1c-d, 1g-h, 2b-c, 3i, 4a-b, 8, 9, 11, 13, 17). HRMS were recorded on Orbitrap Elite Mass Spectrometer (Thermo Fisher, Monza, Italy) (3a-h, 3j-n, 5a-d, 11, 13, and 17), or on Orbitrap Exactive Mass Spectrometer (Thermo Fisher, Monza Italy) (1a, c-h, 2b-e, 3i, 4a-b, 8, 9, 15, 18). Melting points were determined with a Büchi B-545 apparatus (Büchi, Milan, Italy) and were uncorrected. To obtain suitable NMR spectra of diastereoisomers 5 and 5′, the isomeric mixtures were further purified by semi-preparative HPLC (Waters, Milan, Italy) under normal phase conditions using a Nucleodur 100-5 column (762007.100) and eluting with n-hexane/AcOEt mixtures (Merck Science Life, Milan, Italy).

3.2. Synthetic Procedures and Characterization Data

3.2.1. General Procedure for the Preparation of (1H-indol-2-yl)methyl Acetates

The (1H-indol-2-yl)methyl acetates (1a, 1c-h; 4a-b) were synthesized according to the procedures reported in the Supplementary Materials.

3.2.2. Characterization Data of (1H-indol-2-yl)methyl Acetates (1a, c-h; 4a-b)

(1H-indol-2-yl)methyl acetate (1a): known compound; 95% yield (7.47 mmol scale, 1.34 g); yellow solid; lit. [35] mp: 111–112 °C;. mp: 111–112 °C; Rf = 0.27 (n-hexane-EtOAc, 80:20); IR (neat): 3303, 1726, 1045, 1454, 1274, 805 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ = 8.51 (br s, 1 H), 7.52 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.13 (t, J = 7.6 Hz, 1 H), 7.00 (t, J1 = 7.6 Hz, 1 H), 6.46 (s, 1 H), 5.15 (s, 2 H), 2.03 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 172.3 (C), 136.6 (C), 133.0 (C), 127.5 (C), 122.8 (CH), 120.9 (CH), 120.1 (CH), 111.1 (CH), 103.9 (CH), 59.8 (CH2), 21.0 (CH3); HRMS: m/z [M + H]+ calcd. for C11H12NO2: 188.0717; found: 188.0705.
(5-methyl-1H-indol-2-yl)methyl acetate (1c): known compound; 98% yield (7.47 mmol scale, 1.49 g); brown solid; lit. [35] mp: 84–86 °C; mp: 84–86 °C; Rf = 0.24 (n-hexane-EtOAc, 75:25); IR (neat): 3427, 1718, 1361, 806 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.42 (br s, 1 H), 7.31 (q, J = 0.80 Hz, 1 H), 7.16 (d, J = 8.2 Hz, 1 H), 6.96 (dd, J1 = 8.2 Hz, J2 = 1.6 Hz, 1 H), 6.38 (d, J = 1.6 Hz, 1 H), 5.14 (s, 2 H), 2.36 (s, 3 H), 2.03 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 172.3 (C), 134.9 (C), 133.1 (C), 129.2 (C), 127.8 (C), 124.5 (CH), 120.5 (CH), 110.8 (CH), 103.4 (CH), 59.8 (CH2), 21.5 (CH3), 21.0 (CH3); HRMS: m/z [M + Na]+ calcd. for C12H15NO2Na: 226.0838; found: 226.0838.
(5-bromo-1H-indol-2-yl)methyl acetate (1d): 98% yield (7.47 mmol scale, 1.96 g); brown solid; mp: 69–71 °C; Rf = 0.21 (n-hexane-EtOAc, 87:13); IR (neat): 3323, 2916, 1714, 1383, 1211, 1133 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.87 (br s, 1 H), 7.71 (d, J = 1.2 Hz, 1 H), 7.28 (dd, J1 = 8.5 Hz, J2 = 1.7 Hz, 1 H), 7.21 (d, J = 8.5 Hz, 1 H), 6.47 (d, J = 1.2 Hz, 1 H), 5.20 (s, 2 H), 2.11 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 172.5 (C), 135.2 (C), 134.4 (C), 129.4 (C), 125.8 (CH), 123.5 (CH), 113.2 (C), 112.7 (CH), 103.5(CH), 59.6 (CH2), 21.1 (CH3); HRMS: m/z [M − H]− calcd. for C11H9BrNO2: 265.9822; found: 265.9818.
(5-(p-tolyl)-1H-indol-2-yl)methyl acetate (1e): 98% yield (4.35 mmol scale, 1.19 g); yellow solid; mp: 178–180 °C; Rf = 0.23 (n-hexane-EtOAc, 75:25); IR (KBr): 3399, 2919, 1728, 1385, 1235; 1H NMR (400.13 MHz) (CDCl3): δ = 8.62 (br s, 1 H), 7.79 (s, 1 H), 7.55–7.53 (m, 2 H), 7.45 (dd, J1 = 8.50 Hz, J2 = 1.62, 1 H), 7.39 (d, J = 8.50 Hz, 1 H), 7.25 (m, 2 H), 6.58 (d, J = 1.17 Hz, 1 H), 5.24 (s, 2 H), 2.40 (s, 3 H), 2.11 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ = 172.5 (C), 139.6 (C), 136.1 (C), 136.0 (C), 133.8 (C), 133.7 (C), 129.5 (CH), 128.2 (C), 127.3 (CH), 122.8 (CH), 119.2 (CH), 111.4 (CH), 104.3 (CH), 59.9 (CH2), 21.2 (CH3), 21.1 (CH3); HRMS: m/z [M + Na]+ calcd. for C18H17NO2Na: 302.1152; found: 302.1153.
(5-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)methyl acetate (1f): 97% yield (3.14 mmol scale, 0.90 g); yellow solid; mp: 98–100 °C; Rf = 0.26 (n-hexane-EtOAc, 80:20); IR (KBr): 3366, 2919, 1712, 1472, 1385, 1265; 1H NMR (400.13 MHz) (CDCl3): δ = 8.55 (s, 1 H), 7.73 (s, 1 H), 7.543–7.37 (m, 4 H), 7.51–7.34 (m, 3 H), 7.05 (t, J = 8.9 Hz, 1 H), 6.57 (d, J = 1.4 Hz, 1 H), 5.24 (s, 2 H), 2.34 (s, 3 H), 2.11 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ = 172.5 (C), 161.0 (d, J = 241.5 Hz) (C), 138.3 (d, J = 3.2 Hz) (C), 136.1 (C), 134.0 (C), 133.0 (C), 130.3 (d, J = 5.0 Hz), 128.2 (C), 126.2 (d, J = 7.0 Hz) (CH), 125.0 (d, J = 15.5 Hz) (C), 122.7 (CH), 119.3 (CH), 121.4, 118.6, 115.16 (d, J = 15.5 Hz) (C), 111.5 (CH), 104.3 (CH), 59.86 (CH2), 21.2 (CH3), 14.9 (d, J = 3.5 Hz); 1H-coupled 19F (376.5 MHz) (CDCl3): δ −121.6 (hept, J = 3.0 Hz); HRMS: m/z [M + Na]+ calcd. for C18H16FNO2Na: 320.1057; found: 320.1051.
(3-phenyl-1H-indol-2-yl)methyl acetate (1g): yield quantitative (5.15 mmol scale, 1.37 g); yellow solid; mp: 133–135 °C; Rf = 0.25 (n-hexane-EtOAc, 80:20); IR (neat): 3391, 2917, 1730, 1456, 1384, 1231 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.71 (br s, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.47 (d, J = 7.5 Hz, 2 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.30 (t, J = 8.3 Hz, 2 H), 7.17 (d, J = 7.0 Hz, 1 H), 7.06 (t, J = 7.5 Hz, 1 H), 5.19 (s, 2 H), 2.06 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 172.8 (C), 135.8 (C), 134.2 (C), 129.8 (CH), 129.4 (C), 128.8 (CH), 126.8 (CH), 126.7 (C) 123.5 (CH), 120.4 (CH), 120.2(CH), 118.8 (C), 111.4(CH), 58.5 (CH2), 21.2 (CH3); HRMS: m/z [M + Na]+ calcd. for C17H15NO2Na: 288.0995; found: 288.0997.
(3-(4-(trifluoromethyl)phenyl)-1H-indol-2-yl)methyl acetate (1h): 95% yield (5.39 mmol scale, 1.71 g); red solid; mp: 120–122 °C; Rf = 0.30 (n-hexane-EtOAc, 75:25); IR (neat): 3388, 3287, 2941, 1730, 1616, 1384, 1326 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.81 (br s, 1 H), 7.67 (d, J = 8.2 Hz, 2 H), 7.62–7.57 (m, 3 H), 7.33 (d, J = 8.1 Hz, 1 H), 7.21 (t, J = 7.4 Hz, 1 H), 7.09 (t, J = 7.4 Hz, 1 H), 5.17 (s, 2 H), 2.07 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 172.6 (C), 138.0 (C), 135.7 (C), 129.9 (C), 129.8 (CH), 128.7 (q, JCF = 33.2 Hz, C), 126.2 (C), 125.7 (q, JCF = 3.6 Hz, CH), 124.3 (q, JCF = 273.4 Hz, C), 123.7 (CH), 120.7 (CH), 119.6 (CH), 117.3 (C), 111.5 (CH), 58.1 (CH2), 21.0 (CH3); 19F NMR (376.5 MHz) (CDCl3): δ = −62.3; HRMS: m/z [M − H]− calcd. for C18H13F3NO2: 332.0904; found: 332.0894.
(1H-indol-2-yl)(phenyl)methyl acetate (4a): 95% yield (6.20 mmol scale, 1.56 g); yellow solid; mp: 93–95 °C; Rf = 0.25 (n-hexane-EtOAc, 85:15); IR (neat): 3362, 2919, 1445, 1383, 1238 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.45 (br s, 1 H), 7.53 (d, J = 8.3 Hz, 1 H), 7.50–7.48 (m, 2 H), 7.45–7.39 (m, 3 H), 7.34–7.32 (m, 1 H), 7.19 (td, J1 = 7.7 Hz, J2 = 1.1 Hz, 1 H), 7.01 (td, J1 = 7.7 Hz, J2 = 1.1 Hz, 1 H), 7.05 (s, 1 H), 6.22–6.21 (m, 1 H), 2.18 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ = 171.2 (C), 137.6 (C), 136.9 (C), 136.4 (C), 128.6 (CH), 128.5 (CH), 127.5 (C), 127.2 (CH), 122.7 (CH), 120.9 (CH), 120.0 (CH), 111.1 (CH), 103.4 (CH), 71.8 (CH), 21.3 (CH3);); HRMS: m/z [M + Na]+ calcd. for C17H15NO2Na: 288.0995; found: 288.0989.
1-(1H-indol-2-yl)ethyl acetate (4b): 96% yield (6.20 mmol scale, 1.18 g); brown solid; mp: 209–211 °C; Rf = 0.23 (n-hexane-EtOAc, 80:20); IR (neat): 3330, 2918, 1713, 1455, 1384 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.60 (br s, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.35 (dd, J1 = 8.2 Hz, J2 = 0.7 Hz, 1 H), 7.19 (td, J1 = 7.2 Hz, J2 = 1.1 Hz, 1 H), 7.10 (td, J1 = 7.2 Hz, J2 = 1.1 Hz, 1 H), 6.53–6.53 (m, 1 H), 6.07 (q, J = 6.4 Hz, 1 H), 2.09 (s, 3 H), 1.74 (d, J = 6.4 Hz, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 172.1 (C), 138.0 (C), 136.1 (C), 127.5 (CH), 122.7 (CH), 121.0 (CH), 120.1, 111.2 (CH), 100.7, 66.5 (CH), 21.4 (CH3), 18.7 (CH3); HRMS: m/z [M + Na]+ calcd. for C12H13NO2Na: 266.0838; found: 266.0838.

3.2.3. General Procedure for the Preparation of 5-(aryl-2-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-diones (2)

The 5-(aryl-2-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-diones (2a-c) were synthesized according to the one-pot procedure reported by Shibasaki et al.; [41] (2e) was synthesized according to the procedure reported by Chande et al. [42].

3.2.4. Characterization Data of 5-(aryl-2-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-diones (2)

5-(4-Methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2b): known compound; 98% yield (4.50 mmol scale, 1.17 g); yellow solid; lit. [41] mp: 82–85 °C; mp: 83–85 °C; Rf 0.24 (n-hexane-EtOAc, 75:25); IR (neat): 3036, 2920, 1784, 1743, 1514, 1243 cm−1; 1H NMR (400.13 MHz, CDCl3): δ 7.25 (d, J = 8.8 Hz, 2 H), 6.82 (d, J = 8.8 Hz, 2 H), 3.77 (s, 3 H), 3.72 (t, J = 4.9 Hz, 1 H), 3.44 (d, J = 4.9 Hz, 2 H), 1.72 (s, 3 H), 1.48 (d, 3 H); 13C NMR (100.6 MHz, CDCl3): δ 165.6 (C), 158.9 (C), 131.1 (CH), 129.2 (C), 114.1 (CH), 105.3 (C), 55.4 (CH3), 48.5 (CH), 31.7 (CH2), 28.6 (CH3), 27.5 (CH3); HRMS: m/z [M + H]+ calcd. for C14H15O5: 263.0925; found: 263.0922.
5-(Furan-2-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2c): known compound; 98% yield (4.50 mmol scale, 988.8 mg); grey solid; lit. [41] mp: 92–93 °C; mp: 92–93 °C; Rf 0.30 (Rf = 0.24 (n-hexane-EtOAc, 85:15); IR (neat): 3123, 2896, 1783, 1740, 1067, 907 cm−1; 1H NMR (400.13 MHz, CDCl3): δ 7.30 (dd, J1 = 1.8 Hz, J2 = 0.7 Hz, 1 H), 6.29 (dd, J1 = 3.2 Hz, J2 = 1.8 Hz, 1 H), 6.18 (dd, J1 = 3.2 Hz, J2 = 0.7 Hz, 1 H), 3.83 (t, J = 5.0 Hz, 1 H), 3.51 (d, J = 5.0 Hz, 2 H), 1.79 (s, 3 H), 1.67 (s, 3 H); 13C NMR (100.6 MHz, CDCl3): δ 164.9 (C), 150.7 (C), 141.7 (CH), 110.8 (CH), 107.9 (CH), 105.4 (C), 45.6 (CH), 28.5 (CH3), 27.2 (CH3), 25.1 (CH2); HRMS: m/z [M + Na]+ calcd. for C11H12O5Na: 247.0577; found: 247.0581.
Methyl 3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propanoate (2e): known compound; 78% yield (4.50 mmol scale, 1.10 g); white solid; lit. [42] mp: 75–76 °C; mp: 78–80 °C; Rf 0.21 (Rf = 0.24 (n-hexane-EtOAc, 75:25); IR (KBr): 2995, 2952, 2893, 1749 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ = 3.92 (t, J = 5.5 Hz, 1 H), 3.67 (s, 3 H), 2.64 (t, J = 7.2 Hz, 2 H), 2.40–2.35 (m, 2 H), 1.82 (s, 3 H), 1.77 (s, 3 H), 13C NMR (100.6 MHz) (CDCl3): δ = 173.4 (C), 165.2 (C), 105.2 (C), 51.8 (CH3), 44.8 (CH), 30.1 (CH2), 28.6 (CH3), 26.5 (CH3), 21.2 (CH2); HRMS: m/z [M + H]+ calcd. for C19H18NO2: 292.1332; found: 292.1321.

3.2.5. Typical Procedure for the Preparation of 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-ones (3a-m; 5a-d): Synthesis of 2-methyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (3a)

In a 50 mL Carousel Tube Reactor (Radely Discovery Technology) containing a magnetic stirring bar, Pd2dba3 (6.4 mg, 0.007 mmol, 0.025 equiv.) and dppf (7.8 mg, 0.014 mmol, 0.04 equiv.) were dissolved with 1.5 mL of anhydrous DMSO, at room temperature under Ar. Then, (1H-indol-2-il)methyl acetate (1a) (66.15 mg, 0.35 mmol, 1.0 equiv.), 2,2,5-trimethyl-1,3-dioxane-4,6-dione (5a) (138.6, 0.525 mmol, 1.5 equiv.) and K2CO3 (72.5 mg, 0.525 mmol, 1.5 equiv.) were added and the mixture reaction was stirred for 1h at 100 °C. After this time, the reaction mixture was cooled to room temperature, diluted with Et2O, and washed with a solution of KHSO4 (10% w/w) and with brine. The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (25–40 μm), eluting with a 80/20 (v/v) n-hexane/EtOAc mixture (Rf = 0.22) to obtain 102.4 mg (85% yield) of 2-methyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (3a): known compound 7; 85% yield (0.35 mmol scale, 102.4 mg); yellow solid; mp: 73–76 °C; Rf = 0.22 (n-hexane-EtOAc, 80:20); IR (KBr): 3052, 2969, 1729, 1589, 1384 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ = 8.00–7.97 (m, 1 H), 7.42–7.40 (m, 1 H), 7.20–7.15 (m, 2 H), 6.17 (s, 1 H), 3.31 (m, 1 H), 3.19–3.10 (m, 1 H), 2.68 (m, 1 H), 1.37 (d, J = 7.5 Hz, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ = 174.7 (C), 142.0 (C), 135.3 (C), 130.5 (C), 124.0 (C), 123.2 (CH), 120.5 (CH), 113.6 (CH), 100.3 (CH), 41.6 (CH), 28.4 (CH2), 17.0 (CH3); HRMS: m/z [M + H]+ calcd. for C12H12NO: 186.0913; found: 186.0902.

3.2.6. Characterization Data of of 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-ones (3b-3m; 5a-d)

2-(4-methoxybenzyl)-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (3b): known compound; [43] 78% yield (0.35 mmol scale, 79mg); yellow solid; mp: 109–110 °C; Rf = 0.23 (n-hexane-EtOAc, 85:15); IR (KBr): 3098, 2924, 1744, 1384 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ = 8.09–8.07 (m, 1 H), 7.48–7.45 (m, 1 H), 7.27–7.25 (m, 2 H), 7.16 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.6 Hz, 2 H), 6.20 (br s, 1 H), 3.77 (s, 3 H), 3.48–3.41 (m, 1 H), 3.32 (dd, J1 = 14.1 Hz, J2 = 4.5 Hz, 1 H), 3.17–3.10 (m, 1 H), 2.91–2.84 (m, 2 H); 13C NMR (100.6 MHz) (CDCl3): δ 173.4 (C), 158.6 (C), 142.2 (C), 135.4 (C), 130.5 (C), 130.2 (C), 130.1 (CH), 124.2 (CH), 123.4 (CH), 120.6 (CH), 114.2 (CH), 113.8 (CH), 100.5 (CH), 55.4 (CH3), 48.5 (CH), 36.3 (CH2), 25.4 (CH2); HRMS: m/z [M + H]+ calcd. for C19H18NO2: 292.1332; found: 292.1321.
2-(furan-2-ylmethyl)-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (3c): 63% yield (0.35 mmol scale, 55 mg); brown solid; mp: 95–97 °C; Rf = 0.25 (n-hexane-EtOAc, 85:15); IR (KBr): 3092, 2917, 1737, 1454, 1384 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.03–7.97 (m, 2 H), 7.42–7.38 (m, 2 H), 7.22–7.15 (m, 3 H), 6.19 (dd, J1 = 3.3 Hz, J2 = 1.9 Hz, 1 H), 6.15 (br s, 1 H), 6.02 (dd, J1 = 3.14 Hz, J2 = 0.6 Hz, 1 H), 3.46–3.39 (m, 1 H), 3.27 (dd, J1 = 15.3 Hz, J2 = 4.4 Hz 1 H), 3.23–3.17 (m, 1 H), 2.95 (dd, J1 = 15.3 Hz, J2 = 9.2 Hz 1 H), 2.90–2.85 (m, 1 H); 13C NMR (100.6 MHz) (CDCl3): δ 172.3 (C), 152.2 (C), 142.0 (C), 141.9 (CH), 135.3 (C), 130.5 (C), 124.1 (CH), 123.3 (CH), 120.6 (CH), 113.7 (CH), 110.3 (CH), 107.0 (CH), 100.5 (CH), 46.0 (CH), 29.6 (CH2), 25.8 (CH2); HRMS: m/z [M + H]+ calcd. for C16H14NO2: 252.1019; found: 252.1009.
methyl 3-(3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-2-yl)propanoate (3d): 74% yield (0.35 mmol scale, 67 mg); brown solid; mp: 41–43 °C; Rf = 0.25 (n-hexane-EtOAc, 80:20); IR (KBr): 3007, 2916, 1754, 1455, 1385 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ = 8.06–8.03 (m, 1 H), 7.50–7.48 (m, 1 H), 7.27–7.25 (m, 2 H), 6.27 (br s, 1 H), 3.70 (s, 3 H), 3.39–3.32 (m, 1 H), 3.26–3.19 (m, 1 H), 2.82 (dd, J1 = 15.3 Hz, J2 = 4.4 Hz, 1 H), 2.58 (m, 1 H), 2.34–2.26 (m, 1 H), 2.08–2.00 (m, 1 H); 13C NMR (100.6 MHz) (CDCl3): δ = 173.3 (C), 173.2 (C), 141.7 (C), 135.4 (C), 130.5 (C), 124.2 (CH), 123.4 (CH), 120.7 (CH), 113.8 (CH), 100.6 (CH), 52.0 (CH3), 45.8 (CH), 31.4 (CH2), 27.1 (CH2), 26.4 (CH2); HRMS: m/z [M + H]+ calcd. for C15H16NO3: 258.1114; found: 258.1124.
2,7-dimethyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (3e): 70% yield (0.35 mmol scale, 49 mg); brown wax; Rf = 0.20 (n-hexane-EtOAc, 90:10); IR (KBr): 3004, 2918, 1717, 1475, 1352 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ = 7.93 (d, J = 8.2 Hz, 1 H), 7.29 (br s, 1 H), 7.09 (dd, J1 = 1.1 Hz, J2 = 8.2 Hz, 1 H), 6.19–6.18 (m, 1 H), 3.42–3.34 (m, 1 H), 3.26–3.20 (m, 1 H), 2.78–2.72 (m, 1 H), 2.44 (br s, 3 H), 1.45 (d, J = 7.4 Hz, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ = 174.7 (C), 142.2 (C), 135.8 (C), 133.8 (C), 128.8 (CH), 124.6 (CH),120.6 (CH), 113.3 (CH), 100.2 (CH), 41.7 (CH3), 28.5 (CH3), 21.8 (CH2), 17.7 (CH); HRMS: m/z [M + H]+ calcd. for C13H14NO: 200.1070; found: 200.1062.
7-bromo-2-methyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (3f): 50% yield (0.35 mmol scale, 46 mg); yellow solid; mp: 96–99 °C; Rf = 0.21 (n-hexane-EtOAc, 90:10; IR (KBr): 3091.0, 2918.7, 1731.8, 1590.0, 1447.5, 1384.6 cm−1; 1H NMR (400.13 MHz) (DMSO-d6): δ = 7.85 (d, J = 8.3 Hz, 1 H), 7.79 (d, J = 1.6 Hz, 1 H), 7.40 (dd, J1 = 8.5 Hz, J2 = 1.9 Hz, 1 H), 6.39 (s, 1 H), 3.45–3.30 (m, 2 H), 2.82–2.77 (m, 1 H), 1.34 (d, J = 7.3 Hz, 3 H); 13C NMR (100.6 MHz) (DMSO-d6): δ 175.3 (C), 145.3 (C), 137.5 (C), 128.9 (C), 125.9 (CH) (CH), 123.6 (CH), 116.6 (C), 114.8 (CH), 99.5 (CH), 41.4 (CH), 28.4 (CH2), 16.9 (CH3); HRMS: m/z [M + H]+ calcd. for C12H11BrNO: 264.0019; found: 264.0008.
2-methyl-7-(p-tolyl)-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (3g): 70% yield (0.35 mmol scale, 67 mg); yellow solid; mp: 140–143 °C; Rf = 0.18 Rf = 0.24 (n-hexane-EtOAc, 75:25); IR (KBr): 3071, 2917, 1728, 1585, 1470, 1384 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.09 (d, J = 8.5 Hz, 1 H), 7.68 (d, J = 1.3 Hz, 1 H), 7.55–7.52 (m, 3 H), 7.50 (dd, J1 = 8.4 Hz; J2 = 1.7Hz, 1 H), 7.26 (d, J = 7.8 Hz, 2 H), 6.31 (s, 1 H), 3.46–3.39 (m, 1 H), 3.30–3.21 (m, 1 H), 2.82–2.77 (m, 1 H), 3.10 (s, 3 H); 1.48 (d, J = 7.4 Hz, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 174.7 (C), 142.7 (C), 139.0 (C), 137.5 (C), 136.8 (C), 136.0 (C), 129.8 (CH), 129.6 (CH), 127.4 (CH), 122.8 (CH), 118.9 (CH), 113.8 (CH), 100.7 (CH), 41.7 (CH), 28.5 (CH2), 21.1 (CH3), 17.1 (CH3); HRMS: m/z [M + H]+ calcd. for C19H18NO: 276.1383; found: 276.1372.
7-(4-fluoro-3-methylphenyl)-2-methyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (3h): 70% yield (0.35 mmol scale, 72 mg); pink solid; mp: 136–139 °C; Rf = 0.23 (n-hexane-EtOAc, 85:15); IR (KBr): 3102, 2972, 1743, 1586, 1467, 1384 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.09 (d, J = 8.5 Hz, 1 H), 7.68 (d, J = 1.3 Hz, 1 H), 7.46–7.37 (m, 3 H), 7.07 (t, J1 = 8.4 Hz, 1 H), 6.31 (s, 1 H), 3.46–3.39 (m, 1 H), 3.30–3.21 (m, 1 H), 2.82–2.77 (m, 1 H), 2.34 (s, 3 H); 1.48 (d, J = 7.4 Hz, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 174.7 (C), 161.0 (d, J = 249.3 Hz) (C), 142.8 (C), 137.8 (d, J = 3.5 Hz) (C), 136.8 (C), 136.0 (C), 130.6 (d, J = 5.12 Hz) (CH), 129.8 (C), 126.3 (d, J = 7.9 Hz) (CH), 125.2 (C)., 125.0 (C), 120.9 (d, J = 380.8 Hz) (CH), 115.4 (CH), 115.2 (CH), 107.2 (d, J = 1337.1 Hz), 41.8 (CH), 28.6 (CH2), 17.2 (CH3), 14.8 (d, J = 3.4 Hz) (CH3); 1H-coupled 19F (376.5 MHz) (CDCl3): δ −120.6 (hept, J = 2.9 Hz); HRMS: m/z [M + H]+ calcd. for C19H17FNO: 294.1289; found: 294.1275.
2-methyl-9-phenyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (3i): 58% yield (0.35 mmol scale, 53 mg); white solid; mp: 148–149 °C; Rf = 0.24(n-hexane-EtOAc, 85:15); IR (neat): 2973, 2924, 1720, 1603, 1079 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.16–8.13 (m, 1 H), 7.80–7.77(m, 1 H), 7.61 (d, J = 7.9 Hz 2 H), 7.49 (d, J = 7.9 Hz 2 H), 7.36–7.33 (m, 3 H), 3.60–3.54 (m, 1 H), 3.34–3.25 (m, 1 H), 2.97–2.92 (m, 1 H), 1.50 (d, J = 7.5 Hz, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 174.7 (C), 138.4 (C), 133.8 (C), 133.7 (C), 130.9 (C), 129.0 (CH), 128.5 (CH), 127.9 (CH), 126.8(CH), 124.4 (CH), 123.8 (CH), 119.8 (CH), 114.8 (C), 114.0 (CH), 41.5 (CH), 28.8 (CH2), 17.2 (CH3); HRMS: m/z [M + Na]+ calcd. for C18H15NONa: 284.1046; found: 284.1046.
2-(4-methoxybenzyl)-9-phenyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (3j): 64% yield (0.35 mmol scale, 82 mg); white solid; mp: 156–159 °C; Rf = 0.21 (n-hexane-EtOAc, 85:15); IR (KBr): 3093, 2917, 1742, 1582 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.09–8.04 (m, 1 H), 7.68–7.63 (m, 1 H), 7.46–7.43 (m, 2 H), 7.37–7.33 (m, 2 H), 7.27–7.20 (m, 3 H), 7.09–7.06 (m, 2 H), 6.77–6.73 (m, 2 H), 3.68 (s, 3 H), 3.44–3.37 (m, 1 H), 3.28 (dd, J1 = 14.2 Hz, J2 = 4.6 Hz, 1 H), 3.20 (dd, J1 = 17.8 Hz, J2 = 8.7 Hz, 1 H), 2.90 (dd, J1 = 17.5 Hz, J2 = 5.0 Hz, 1 H), 2.81 (dd, J1 = 14.2 Hz, J2 = 9.8 Hz, 1 H); 13C NMR (100.6 MHz) (CDCl3): δ 173.2 (C), 158.6 (C), 138.4 (C), 133.9 (C), 133.6 (C), 130.9 (C), 130.2 (C), 130.0 (CH), 129.0 (CH), 127.9 (CH), 126.9 (CH), 124.5 (CH), 123.9 (CH), 119.8 (CH), 114.9 (C), 114.3 (CH), 114.0 (CH), 55.4 (CH3), 48.3 (CH), 36.3 (CH2), 25.7 (CH2).); HRMS: m/z [M + H]+ calcd. for C25H22NO2: 368.1645; found: 368.1629.
2-(furan-2-ylmethyl)-9-phenyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (3k): 54% yield (0.35 mmol scale, 62 mg); white solid; mp: 162–165 °C; Rf = 0.23 (n-hexane-EtOAc, 85:15); IR (KBr): 3002, 2917, 1733, 1576, 1455 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.18–8.12 (m, 1 H), 7.79–7.76 (m, 1 H), 7.58–7.56 (m, 2 H), 7.49–7.45 (m, 2 H), 7.35–7.33 (m, 2 H), 7.31–7.30 (m, 1 H), 6.29 (dd, J1 = 3.3 Hz, J2 = 1.9 Hz, 1 H), 6.13 (dd, J1 = 3.3 Hz, J2 = 0.5 Hz, 1 H), 3.61–3.55 (m, 1 H), 3.49–3.38 (m, 2 H), 3.15–3.13 (m, 2 H); 13C NMR (100.6 MHz) (CDCl3): δ 172.7 (C), 152.2 (C), 142.0 (CH), 138.2 (C), 133.9 (C), 133.5 (C), 130.9 (C), 129.0 (CH), 128.0(CH), 126.9 (CH), 124.5 (CH), 123.9 (CH), 119.9 (CH), 115.0 (C), 114.1 (CH), 110.5 (CH), 107.2 (CH), 46.0 (CH), 29.8 (CH2), 26.2 (CH2); HRMS: m/z [M + H]+ calcd. for C22H18NO2: 328.1332; found: 328.1317.
methyl 3-(3-oxo-9-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-2-yl)propanoate (3l): 66% yield (0.35 mmol scale, 77 mg); brown solid; mp: 126–129 °C; Rf = 0.19 (n-hexane-EtOAc, 85:15); IR (KBr): 3004, 2918, 1737, 1454, 1383 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.15–8.10 (m, 1 H), 7.80–7.76 (m, 1 H), 7.61–7.59 (m, 2 H), 7.51–7.47 (m, 2 H), 7.37–7.32 (m, 3 H), 3.70 (s, 3 H), 3.53 (dd, J1 = 17.3 Hz, J2 = 8.8 Hz, 1 H), 3.33–3.26 (m, 1 H), 2.99 (dd, J1 = 17.3 Hz, J2 = 4.9 Hz, 1 H), 2.67–2.54 (m, 2 H), 2.40–2.31 (m, 1 H), 2.11–2.02 (m, 1 H); 13C NMR (100.6 MHz) (CDCl3): δ 173.2 (C), 173.1 (C), 138.0 (C), 133.9 (C), 133.5 (C), 130.8 (C), 129.1 (CH), 127.9 (CH), 127.0 (CH), 124.5 (CH), 124.0 (CH), 119.9 (CH), 115.0 (C), 114.1 (CH), 51.9 (CH3), 45.6 (CH), 31.4 (CH2), 27.2 (CH2), 26.8 (CH2); HRMS: m/z [M + H]+ calcd. for C21H20NO3: 334.1438; found: 334.1421.
2-methyl-9-(4-(trifluoromethyl)phenyl)-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (3m): 71% yield (0.35 mmol scale, 82 mg); white solid; mp: 128–130 °C; Rf = 0.19 (n-hexane-EtOAc, 85:15); IR (KBr): 3103, 2972, 1753, 1323, 1132 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.17–8.14 (m, 1 H), 7.76–7.69 (m, 5 H), 7.38–7.33 (m, 2 H), 3.56 (dd, J1 = 8.8 Hz, J2 = 8.7 Hz, 1 H), 3.35–3.27 (m, 1 H), 2.95 (dd, J1 = 17.4 Hz, J2 = 4.7 Hz, 1 H), 1.51 (d, J = 7.5 Hz, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 174.5 (C), 139.5 (C), 137.5 (C), 133.3 (C), 130.9 (C), 128.9 (q, J = 32.4 Hz) (CH), 128.0 (CH), 126.0 (q, J = 3.7 Hz) (CH), 124.8 (CH), 124.5 (q, J = 272.1 Hz) (CH), 124.2 (CH), 119.5 (CH), 114.2 (CH), 113.6 (C), 41.6 (CH), 29.09 (CH2), 17.0 (CH3); 19F (376.5 MHz) (CDCl3): δ −62.4; HRMS: m/z [M + H]+ calcd. for C19H15F3NO: 330.1100; found: 330.1084.
(trans)- 2-methyl-1-phenyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (5a): 62% yield (0.35 mmol scale, 57 mg); yellow wax; Rf = 0.24 (n-hexane-EtOAc, 85:15); IR (KBr): 3021, 2919, 1736, 1587, 1452, 1385 cm−1; 1H NMR (400.13 MHz) (DMSO-d6): δ = 7.98 (d, J = 7.42 Hz, 1 H), 7.58–7.56 (m, 1 H), 7.43–7.37 (m, 4 H), 7.35–7.26 (m, 3 H), 6.27 (s, 1 H), 4.37 (d, J = 6.5 Hz, 1 H), 3.28–3.21 (m, 1 H), 3.15 (d, J = 7.2, 3 H); 13C NMR (100.6 MHz) (DMSO-d6): δ 173.4, 146.4, 140.6, 135.3, 130.3, 129.3 (CH), 128.3 (CH), 127.8 (CH), 124.3 (CH), 123.8 (CH), 121.5 (CH), 113.4 (CH), 100.5 (CH), 51.5 (CH), 47.3 (CH), 14.5 (CH3); HRMS: m/z [M + H]+ calcd. for C18H16NO: 262.1226; found: 262.1215.
(cis)- 2-methyl-1-phenyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one+ (5′a): 12% yield (0.35 mmol scale, 11 mg); yellow wax; Rf = 0.24 (n-hexane-EtOAc, 85:15); IR (KBr): 3060, 2919, 1736, 1452, 1386 cm−1; 1H NMR (400.13 MHz) (DMSO-d6): δ 8.01–7.97 (m, 1 H), 7.61–7.56 (m, 1 H), 7.36–7.26 (m, 5 H), 7.13–7.10 (m, 2 H), 6.41 (m, 1 H), 4.94 (dd, J1 = 8.7 Hz, J2 = 0.83 Hz, 1 H), 3.78–3.70 (m, 1 H), 0.80 (d, J = 7.7, 3 H).
(trans)-2-(4-methoxybenzyl)-1-phenyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (5b): 48% yield (0.35 mmol scale, 62 mg); orange solid; mp: 111–113 °C; Rf = 0.19 (n-hexane-EtOAc, 85:15); IR (KBr): 3074, 2918, 1738, 1451, 1384 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.14 (d, J = 7.9 Hz, 1 H), 7.48 (d, J = 7.3 Hz, 1 H), 7.34–7.21 (m, 5 H), 7.19 (d, J = 8.6 Hz, 2 H), 7.02–6.99 (m, 2 H), 6.84–6.80 (m, 2 H), 6.13 (d, J = 0.9 Hz, 1 H), 4.30 (dd, J1 = 5.2 Hz, J2 = 1.1 Hz, 1 H), 3.78 (s, 3 H), 3.42–3.37 (m, 1 H), 3.25–3.15 (m, 2 H); 13C NMR (100.6 MHz) (CDCl3): δ 172.2 (C), 158.7 (C), 145.6 (C), 141.1 (C), 135.3 (C), 130.7 (CH), 130.5 (C), 129.5 (C), 128.9 (CH), 127.7 (CH), 127.4 (CH), 124.3 (CH), 123.8 (CH), 121.0 (CH), 114.3 (CH), 114.1 (CH), 101.5 (CH), 58.8 (CH3), 55.4 (CH), 43.6 (CH), 34.9 (CH2); HRMS: m/z [M + H]+ calcd. for C25H22NO2: 368.1645; found: 368.1627.
(cis)-2-(4-methoxybenzyl)-1-phenyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (5′b): 2% yield (0.35 mmol scale, 3 mg); yellow solid; mp: 135–138 °C; Rf = 0.19 (n-hexane-EtOAc, 85:15); IR (KBr): 3074, 2919, 1737, 1512, 1452, 1385 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.15 (d, J = 7.9 Hz, 1 H), 7.51 (d, J = 7.2 Hz, 1 H), 7.36–7.22 (m, 5 H), 6.91–6.89 (m, 2 H), 6.75–6.71 (m, 4 H), 6.24 (s, 1 H), 4.70 (d, J = 8.4 Hz, 1 H), 3.88–3.82 (m, 1 H), 3.78 (s, 3 H), 3.17 (dd, J1 = 15.0 Hz, J2 = 4.9 Hz, 1 H), 2.43 (dd, J1 = 15.0 Hz, J2 = 10.1 Hz, 1 H).
(trans)-2-(furan-2-ylmethyl)-1-phenyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (5c): 39% yield (0.35 mmol scale, 44.2 mg); red solid; mp: 101–103 °C; Rf = 0.19 (n-hexane-EtOAc, 90:10); IR (KBr): 3053, 2197, 1739, 1586, 1453 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.14 (d, J = 7.8 Hz, 1 H), 7.49 (d, J = 7.2 Hz, 1 H), 7.35–7.24 (m, 6 H), 7.12–7.10 (m, 2 H), 6.28–6.27 (m, 1 H), 6.18 (d, J = 0.9 Hz, 1 H), 6.16 (d, J = 2.8 Hz, 1 H), 4.35 (dd, J1 = 5.4 Hz, J2 = 1.3 Hz, 1 H), 3.43–3.39 (m, 1H), 3.33–3.22 (m, 2 H); 13C NMR (100.6 MHz) (CDCl3): δ 171.6 (C), 151.7 (C), 145.3 (C), 142.0 (CH), 140.8 (C), 135.3 (C), 130.6 (C), 129.0 (CH), 127.7 (CH), 127.6 (CH), 124.4 (CH), 123.8 (CH), 121.0 (CH), 114.1 (CH), 110.5 (CH), 108.0 (CH), 101.6 (CH), 56.7 (CH), 44.3 (CH), 28.3 (CH2); HRMS: m/z [M + H]+ calcd. for C22H18NO2: 328.1332; found: 328.1316.
(cis)-2-(furan-2-ylmethyl)-1-phenyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (5′c): 13% yield (0.35 mmol scale, 15.5 mg); a suitable characterization is not available.
(trans)- 1,2-dimethyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (5d): 64% yield (0.35 mmol scale, 45 mg); yellow solid; mp: 46–49 °C; Rf = 0.23 (n-hexane-EtOAc, 85:15); IR (KBr): 3058, 2918, 1741, 1453, 1384 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.05–8.03 (m, 1 H), 7.51–7.49 (m, 1 H), 7.29–7.23 (m, 2 H), 6.27 (d, J = 0.9 Hz, 1 H), 3.08–3.04 (m, 1 H), 2.78–2.71 (m, 1 H), 1.47 (d, J = 7.1 Hz, 3 H), 1.45 (d, J = 7.5 Hz, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 174.0 (C), 147.6 (C), 135.3 (C), 130.5 (C), 124.1 (CH), 123.5 (CH), 120.7 (CH), 113.9 (CH), 99.4 (CH), 50.4 (CH), 36.6 (CH), 18.7 (CH3), 15.2 (CH3); HRMS: m/z [M + H]+ calcd. for C13H14NO: 200.1070; found: 200.1061.
(cis)-1,2-dmethyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (5′d): 12% yield (0.35 mmol scale, 8 mg); yellow solid; mp: 58–61 °C; Rf = 0.23 (n-hexane-EtOAc, 85:15); IR (KBr): 3060, 2917, 1735, 1584, 1453 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.06–8.04 (m, 1 H), 7.52–7.50(m, 1 H), 7.30–7.24 (m, 2 H), 6.29 (s, 1 H), 3.63–3.55 (m, 1 H), 3.31 (quint, J = 7.8 Hz, 1 H), 1.34 (d, J = 5.7 Hz, 3 H), 1.32 (d, J = 5.4 Hz, 3 H).

3.2.7. Typical Procedure for the Preparation of 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (8), ethyl 3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate (11) and 2-acetyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (13)

The products 10 and 12 were synthesized according to the typical procedure described for the preparation of 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-ones using 5 equiv. of 9 and 11, respectively, as a nucleophile instead of 5.
1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (8): known compound of 52% yield (0.35 mmol scale, 31 mg); grey solid; lit. [44] mp: 150–151 °C, mp: 153–154; Rf = 0.20 (n-hexane-EtOAc, 85:15); IR (neat): 2973, 2937, 1722, 1387, 1168 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ = 8.11–8.08 (m, 1 H), 7.53–7.51 (m, 1 H), 7.30–7.28 (m, 2 H), 6.32 (s, 1 H), 3.20–3.17 (m, 2 H), 3.13–3.09 (m, 2 H); 13C NMR (100.6 MHz) (CDCl3): δ = 171.8 (C), 143.7 (C), 135.4 (C), 124.2 (CH), 123.4 (CH), 120.6 (CH), 113.7 (CH), 100.5 (CH), 35.0 (CH2), 19.7 (CH2); HRMS: m/z [M + Na]+ calcd. for C11H9NONa: 194.0576; found: 194.0578.
2-((1H-indol-2-yl)methyl)-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (9): 54% yield (0.35 mmol scale, 57 mg); purple solid; mp: 164–165 Rf = 0.24 (n-hexane-EtOAc, 85:15); IR (neat): 3404, 1715, 1593, 1544, 1173, 667 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.64 (br s, 1 H), 8.02–8.00 (m, 1 H), 7.45 (d, J = 7.8 Hz, 1 H), 7.41–7.39 (m, 1 H), 7.25 (d, J = 7.8 Hz, 2 H), 7.22–7.17 (m, 2 H), 7.05 (dd, J1 = 7.3 Hz, J2 = 1.1 Hz, 1 H), 6.99 (dd, J1 = 7.3 Hz, J2 = 1.1 Hz, 1 H), 6.24 (s, 1 H), 6.17 (s, 1 H), 3.52–3.48 (m, 1 H), 3.32–3.28 (m, 1 H), 3.25–3.22 (m, 2 H), 2.92 (dd, J1 = 16.9 Hz, J2 = 1.3 Hz, 1 H); 13C NMR (100.6 MHz) (CDCl3): δ 174.1, 141.7, 136.6, 135.5, 135.3, 130.5, 128.4, 124.5, 123.6, 121.7, 120.8, 120.1, 119.9, 113.8, 110.9, 101.8, 101.2, 47.1, 29.6, 26.1; HRMS: m/z [M + Na]+ calcd. for C20H16N2ONa: 323.1155; found: 323.1154.
ethyl 3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate (11): 58% yield (0.35 mmol scale, 49 mg); white solid; mp: 99–100; Rf = 0.23 (n-hexane-EtOAc, 80:20); IR (neat): 2991, 2919, 1726, 1596, 1187, 743 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.10–8.08 (m, 1 H), 7.55–7.53 (m, 1 H), 7.33–7.31 (m, 2 H), 6.34 (s, 1 H), 4.25 (dd, J1 = 7.3 Hz, J2 = 0.8 Hz, 1 H), 4.22 (dd, J1 = 7.3 Hz, J2 = 0.8 Hz, 1 H), 3.68 (dd, J1 = 17.4 Hz, J2 = 1.5 Hz, 1 H), 3.07 (dd, J1 = 17.4 Hz, J2 = 1.5 Hz, 1 H), 1.72 (s, 3 H), 1.26 (t, J = 7.3 Hz, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 168.2 (C), 166.1 (C), 141.1 (C), 135.6 (C), 130.6 (C), 124.6 (CH), 123.7 (CH), 120.8 (CH), 113.8 (CH), 101.2 (CH), 62.4 (CH2), 52.7 (CH), 24.3 (CH2), 14.2 (CH3); HRMS: m/z [M + H]+ calcd. for C14H14NO3: 244.0868; found: 244.0857.
2-acetyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (13): 55% yield (0.35 mmol scale, 40 mg); brown solid; mp: 96–97; Rf = 0.21 (n-hexane-EtOAc, 85:15); IR (neat): 2916, 2849, 1641, 1454, 1190, 772 cm−1. In a chloroform solution, this compound has as an equilibrium mixture of ketone and enol forms; both tautomers were observed by 1H NMR, and the peaks of enol form were reported as marked with an asterisk*; 1H NMR (400.13 MHz) (CDCl3) (ketone: enol = 75/25): δ 11.41* (br s, 1 H) 8.04–7.98 (m, 2 H, aromatic protons of both tautomers), 7.53–7.47 (m, 2 H, aromatic protons of both tautomers), 7.29–7.25 (m, 4 H aromatic protons of both tautomers), 6.32* (br s, 1 H), 6.30 (br s, 1 H), 4.26 (dd, J1 = 8.7 Hz, J2 = 4.3 Hz, 1 H), 3.76* (m, 1 H), 3.64* (s, 2 H), 3.17–3.10 (m, 1 H), 2.56 (s, 3 H), 2.06* (s, 3 H); 13C NMR (100.6 MHz) (CDCl3) (unselected signals): δ 200.2 (C), 169.5 (C), 167.7 (C), 166.5 (C), 141.4 (C), 139.7 (C), 135.6 (C), 134.6 (C), 130.6 (C), 124.7 (CH), 123.8 (CH), 123.7 (CH), 123.2 (CH), 120.9 (CH), 120.8 (CH), 113.7 (CH), 113.5 (CH), 102.7 (C), 101.3 (CH), 100.2 (CH), 60.5 (CH), 29.8 (CH2), 29.7 (CH3), 23.6 (CH2), 21.5 (CH2), 19.1 (CH3); HRMS: m/z [M + H]+ calcd. for C13H12NO2: 214.0862; found: 214.0887.
2-allyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (3n): 71% yield (0.35 mmol scale, 52 mg); brown oil; Rf = 0.25 (n-hexane-EtOAc, 85:15); IR (KBr): 3081, 2918, 1714, 1454, 1385 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.11–8.09 (m, 1 H), 7.53–7.50 (m, 1 H), 7.32–7.27 (m, 2 H), 6.29 (s, 1 H), 5.89–5.78 (m, 1 H), 5.23–5.11 (m, 2 H), 3.34–3.26 (m, 2 H), 2.96–2.88 (m, 1 H), 2.81–2.75 (m, 1 H), 2.53–2.46 (m, 1 H); 13C NMR (100.6 MHz) (CDCl3): δ 173.5 (C), 142.3 (C), 135.5 (C), 134.2 (CH), 130.5 (C), 124.2 (CH), 123.4 (CH), 120.6 (CH), 118.2 (CH2), 113.8 (CH), 100.5 (CH), 46.2 (CH), 35.8 (CH2), 25.5 (CH2); HRMS: m/z [M + H]+ calcd. for C14H14NO: 212.1070; found: 212.1057.
2-acetyl-2-methyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one (15a): 18% yield (0.35 mmol scale, 14 mg); brown oil; Rf = 0.23 (n-hexane-EtOAc, 85:15); IR (KBr): 3073, 2919, 1736, 1714, 1455, 1386 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.05–8.02 (m, 1 H), 7.52–7.50 (m, 1 H), 7.30–7.28 (m, 2 H), 6.32 (s, 1 H), 3.84 (dd, J1 = 17.6 Hz, J2 = 1.3 Hz, 1 H), 2.88 (dd, J1 = 17.6 Hz, J2 = 1.5 Hz, 1 H), 2.37 (s, 3 H), 1.70 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 203.5 (C), 170.8 (C), 140.0 (C), 135.5 (C), 130.6 (C), 124.6 (CH), 123.7 (CH), 120.8 (CH), 113.8 (CH), 101.4 (CH), 63.9 (C), 30.9 (CH2), 25.8 (CH3), 21.9 (CH3); HRMS: m/z [M + H]+ calcd. for C13H11NO2: 214.0862; found: 214.0887.
ethyl 2-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate (15b): 60% yield (0.35 mmol scale, 54 mg); yellow oil; Rf = 0.23 (n-hexane-EtOAc, 80:20); IR (KBr): 2984, 2934, 1710, 1602, 1127 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.10–8.08 (m, 1 H), 7.55–7.53 (m, 1 H), 7.33–7.31 (m, 2 H), 6.34 (s, 1 H), 4.25 (dd, J1 = 7.3 Hz, J2 = 0.8 Hz, 1 H), 4.22 (dd, J1 = 7.3 Hz, J2 = 0.8 Hz, 1 H), 3.68 (dd, J1 = 17.4 Hz, J2 = 1.5 Hz, 1 H), 3.07 (dd, J1 = 17.4 Hz, J2 = 1.5 Hz, 1 H), 1.72 (s, 3 H), 1.26 (t, J = 7.3 Hz, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ 168.2 (C), 166.1 (C), 141.1 (C), 135.6 (C), 130.6 (C), 124.6 (CH), 123.7 (CH), 120.8 (CH), 113.8 (CH), 101.2 (CH), 62.4 (CH2), 52.7 (CH), 24.3 (CH2), 14.2 (CH3); HRMS: m/z [M + Na]+ calcd. for C15H15NO3Na: 280.0944; found: 280.0943.
7-(1H-indol-2-yl)-6-methyl-5-oxoheptanoic acid (17): 47% yield (0.35 mmol scale, 45 mg); red solid; mp: 112–115 °C; Rf = 0.18 (n-hexane-EtOAc, 70:30, 10% MeCO2H); IR (neat): 3055, 2951, 1735, 1713, 1456 cm−1; 1H NMR (400.13 MHz) (DMSO-d6): δ 12.08 (br s, 1 H), 10.90 (s, 1 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.28 (d, J = 7.9 Hz, 1 H), 7.00 (td, J1 = 7.1 Hz, J2 = 1.1 Hz, 1 H), 6.92 (td, J1 = 7.1 Hz, J2 = 1.0 Hz, 1 H), 6.11 (d, J = 1.1 Hz, 1 H), 3.04–2.98 (m, 2 H), 2.68–2.56 (m, 2 H), 2.49–2.45 (m, 1 H), 2.17 (t, J = 7.3 Hz, 2 H), 1.66 (quint, J = 7.3 Hz, 2 H), 1.03 (d, J = 6.6 Hz, 3 H); 13C NMR (100.6 MHz) (DMSO-d6): δ 213.2 (C), 174.7 (C), 138.2 (C), 136.4 (C), 128.7 (C), 120.6 (CH), 119.6 (CH), 119.1 (CH), 111.1 (CH), 99.7 (CH), 45.8 (CH), 39.9 (CH2), 33.2 (CH2), 31.2 (CH2), 19.1 (CH2), 16.6. (CH3); HRMS: m/z [M + H]+ calcd. for C16H20NO3: 274.1438; found: 274.1425.
4-(2-methyl-1H-pyrrolo[1,2-a]indol-3-yl)butanoic acid (18): 22% yield (0.35 mmol scale, 20 mg); red solid; mp: 130–133 °C; Rf = 0.25 (n-hexane-EtOAc, 70:30, 10% MeCO2H); IR (KBr): 3102, 2918, 1699, 1485, 1452, 1384 cm−1; 1H NMR (400.13 MHz) (DMSO-d6): δ 12.18 (br s, 1 H), 7.48 (d, J = 7.5 Hz, 1 H), 7.43 (d, J = 7.5 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 1 H), 7.06 (t, J = 7.5 Hz, 1 H), 5.83 (s, 1 H), 3.77 (s, 2 H), 2.85 (t, J = 7.5 Hz, 2 H), 2.30 (t, J = 6.9 Hz, 2 H), 2.02 (s, 3 H), 1.76 (quint., J = 7.5 Hz, 2 H); 13C NMR (100.6 MHz) (DMSO-d6): δ 179.1 (C), 142.0 (C), 135.2 (C), 134.0 (C), 127.5 (CH), 125.9 (CH), 122.3 (CH), 122.2 (C), 120.8 (C), 110.3 (CH), 102.8 (CH), 32.8 (CH2), 28.7 (CH2), 24.9 (CH2), 23.9 (CH2), 11.6 (CH3); HRMS: m/z [M − H]− calcd. for C16H16NO2: 254.1187; found: 254.1179.

4. Conclusions

In summary, a viable approach to polysubstituted 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-ones through a domino palladium-catalyzed reaction of the readily available indol-2-ylmethyl acetates with 1,3-dicarbonyl derivatives has been developed. The employment of 5-substituted Meldrum’s as the dicarbonyl source in the palladium-catalyzed reaction with indol-2-ylmethyl acetates method allowed the synthesis of the 2-substituted-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one derivatives in moderate-to-high yields and tolerates a variety of useful functional groups both in the indole and in Meldrum’s acids, including bromo, fluoro, nitro, aryl, heteroaryl ether, and ester groups. The extension of the procedure to the highly diastereoselective synthesis of the trans- 1,2-disubstituted-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-ones from the (1H-indol-2-yl)phenyl acetate under the same reaction conditions has been explored. The product selectivity control of the outcome of the reaction of indol-2-ylmethyl acetate with various alicyclic 1,3-dicarbonyls was addressed by a suitable choice of the reagent ratio. A different cascade reaction of the indol-2-ylmethyl acetate with 2-methylcyclohexan-1,3-dione and the corresponding potassium salt involving Michael addition/retro Dieckmann or/and Michael addition/retro Dieckmann/cyclization sequences provides promise for further challenging the elaboration of the indole nucleus, and is under investigation in our laboratories.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal12121516/s1 [35,45,46,47,48].

Author Contributions

Conceptualization: G.F.; Data curation: A.I. and A.G.; Formal analysis: A.S. (Alessio Sferrazza); Funding acquisition: G.F.; Investigation: A.I., S.D., F.M., A.S. (Andrea Serraiocco) and K.U.; Methodology: A.I. and A.S. (Alessio Sferrazza); Project administration: G.F.; Supervision: A.G.; Writing—original draft: A.A.; Writing—review and editing: A.I., A.G. and A.S. (Alessio Sferrazza). All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Not applicable.

Acknowledgments

We gratefully acknowledge “Sapienza”, University of Rome, University of L’ Aquila, the Catholic University of Sacred Heart, and PRIN project 2017 “Targeting Hedgehog pathway: virtual screening identification and sustainable synthesis of novel Smo and Gli inhibitors and their pharmacological drug delivery strategies for improved therapeutic effects in tumors” (2017SXBSX4), for financial support.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Dethe, D.H.; Erande, R.D.; Ranjan, A. Biomimetic Total Syntheses of Borreverine and Flinderole Alkaloids. J. Org. Chem. 2013, 78, 10106–10120. [Google Scholar] [CrossRef] [PubMed]
  2. Vallakati, R.; May, J.A. Biomimetic Synthesis of the Antimalarial Flindersial Alkaloids. J. Am. Chem. Soc. 2012, 134, 6936–6939. [Google Scholar] [CrossRef] [PubMed]
  3. Lucas, S.; Negri, M.; Heim, R.; Zimmer, C.; Hartmann, R.W. Fine-tuning the selectivity of aldosterone synthase inhibitors: Structure-activity and structure-selectivity insights from studies of heteroaryl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one derivatives. J. Med. Chem. 2011, 54, 2307–2319. [Google Scholar] [CrossRef]
  4. Dethe, D.H.; Erande, R.D.; Ranjan, A. Biomimetic total syntheses of flinderoles B and C. J. Am. Chem. Soc. 2011, 133, 2864–2867. [Google Scholar] [CrossRef]
  5. Zeldin, R.M.; Toste, F.D. Synthesis of flinderoles B and C by a gold-catalyzed allene hydroarylation. Chem. Sci. 2011, 2, 1706–1709. [Google Scholar] [CrossRef] [Green Version]
  6. Fernandez, L.S.; Buchanan, M.S.; Carroll, A.R.; Feng, Y.J.; Quinn, R.J.; Avery, V.M. Flinderoles A-C: Antimalarial bis-indole alkaloids from Flindersia species. Org. Lett. 2009, 11, 329–332. [Google Scholar] [CrossRef]
  7. Galm, U.; Hager, M.H.; Van Lanen, S.G.; Ju, J.; Thorson, J.S.; Shen, B. Antitumor antibiotics: Bleomycin, enediynes, and mitomycin. Chem. Rev. 2005, 105, 739–758. [Google Scholar]
  8. Wolkenberg, S.E.; Boger, D.L. Mechanisms of in Situ Activation for DNA-Targeting Antitumor Agents. Chem. Rev. 2002, 102, 2477–2496. [Google Scholar] [CrossRef]
  9. Liu, J.-F.; Jiang, Z.-Y.; Wang, R.-R.; Zheng, Y.-T.; Chen, J.-J.; Zhang, X.-M.; Ma, Y.-B. Isatisine A, a Novel Alkaloid with an Unprecedented Skeleton from Leaves of Isatis indigotica. Org. Lett. 2007, 9, 4127–4129. [Google Scholar] [PubMed]
  10. Dorow, R.L.; Herrington, P.M.; Hohler, R.A.; Maloney, M.T.; Mauragis, M.A.; McGhee, W.E.; Moeslein, J.A.; Strohbach, J.W.; Veley, M.F. Development of an Efficient Synthesis of the Pyrrolquinolone PHA-529311. Org. Process. Res. Dev. 2006, 10, 493–499. [Google Scholar] [CrossRef]
  11. Elmegeed, G.A.; Baiuomy, A.R.; Abdel-Salam, O.M. Evaluation of the anti-inflammatory and anti-nociceptive activities of novel synthesized melatonin analogues. Eur. J. Med. Chem. 2007, 42, 1285–1292. [Google Scholar] [CrossRef] [PubMed]
  12. Protter, A.A.; Chakravarty, S. Compounds and Methods of Treating Hypertension. U.S. Patent WO2012/112961A1, 23 August 2012. [Google Scholar]
  13. Danishefsky, S.; Taniyama, E. Cyclizations of mercury and palladium substituted acyrylanilides. Tetrahedron Lett. 1983, 24, 15–18. [Google Scholar] [CrossRef]
  14. Duan, X.-Y.; Tian, Z.; Liu, B.; He, T.; Zhao, L.-L.; Dong, M.; Zhang, P.; Qi, J. Highly Enantioselective Synthesis of Pyrroloindolones and Pyrroloquinolinones via an N-Heterocyclic Carbene-Catalyzed Cascade Reaction. Org. Lett. 2021, 23, 3777–3781. [Google Scholar] [CrossRef]
  15. Yang, W.-L.; Sun, Z.-T.; Sun, H.; Deng, W.-P. Nickel(II)-Catalyzed Diastereo- and Enantioselective [3 + 2] Cycloaddition of α-Ketoesters with 2-Nitrovinylindoles and 2-Nitrovinylpyrroles. Chin. J. Chem. 2019, 37, 216–220. [Google Scholar] [CrossRef]
  16. Yang, Y.-J.; Ji, Y.; Qi, L.; Wang, G.; Hui, X.-P. Asymmetric Synthesis of Cyclopenta[3,4]pyrroloindolones via N-Heterocyclic Carbene-Catalyzed Michael/Aldol/Lactamization Cascade Reaction. Org. Lett. 2017, 19, 3271–3274. [Google Scholar] [CrossRef]
  17. Wang, C.; Wang, A.; Rueping, M. Manganese-Catalyzed C−H Functionalizations: Hydroarylations and Alkenylations Involving an Unexpected Heteroaryl Shift. Angew. Chem. Int. Ed. 2017, 56, 9935–9938. [Google Scholar] [CrossRef] [Green Version]
  18. Ghosh, A.; Bainbridge, D.T.; Stanley, L.M. Enantioselective Model Synthesis and Progress toward the Putative Structure of Yuremamine. J. Org. Chem. 2016, 81, 7945–7951. [Google Scholar] [CrossRef]
  19. Lu, H.; Lin, J.-B.; Liu, J.-Y.; Xu, P.-F. One-Pot Asymmetric Synthesis of Quaternary Pyrroloindolones through a Multicatalytic N-Allylation/Hydroacylation Sequence. Chem. Eur. J. 2014, 20, 11659–11663. [Google Scholar] [CrossRef]
  20. Ikemoto, H.; Yoshino, T.; Sakata, K.; Matsunaga, S.; Kanai, M. Pyrroloindolone Synthesis via a Cp*CoIII-Catalyzed Redox-Neutral Directed C–H Alkenylation/Annulation Sequence. J. Am. Chem. Soc. 2014, 136, 5424–5431. [Google Scholar] [CrossRef] [PubMed]
  21. Ni, Q.; Zhang, H.; Grossmann, A.; Loh, C.C.J.; Merkens, C.; Enders, D. Asymmetric Synthesis of Pyrroloindolones by N-Heterocyclic Carbene Catalyzed [2+3] Annulation of α-Chloroaldehydes with Nitrovinylindoles. Angew. Chem. Int. Ed. 2013, 52, 13562–13566. [Google Scholar] [CrossRef]
  22. Wang, Y.; Lu, H.; Xu, P.-F. Asymmetric Catalytic Cascade Reactions for Constructing Diverse Scaffolds and Complex Molecules. Acc. Chem. Res. 2015, 48, 1832–1844. [Google Scholar] [CrossRef]
  23. Arcadi, A.; Cacchi, S.; Fabrizi, G.; Ghirga, F.; Goggiamani, A.; Iazzetti, A.; Marinelli, F. Synthesis of indolo[1,2-c]quinazolines from 2-alkynylaniline derivatives through Pd-catalyzed indole formation/cyclization with N,N-dimethylformamide dimethyl acetal. Beilstein J. Org. Chem. 2018, 14, 2411–2417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Arcadi, A.; Blesi, F.; Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Marinelli, F. Multisubstituted benzo[b]furans through a copper- and/or palladium-catalyzed assembly and functionalization process. Tetrahedron 2013, 69, 1857–1871. [Google Scholar] [CrossRef]
  25. Arcadi, A.; Blesi, F.; Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Marinelli, F. Palladium-Catalyzed Cascade Reactions of 1-(3-Arylprop-2-ynyloxy)-2-bromo Benzene Derivatives with Organoboron Compounds. J. Org. Chem. 2013, 78, 4490–4498. [Google Scholar] [CrossRef] [PubMed]
  26. Cera, G.; Piscitelli, S.; Chiarucci, M.; Fabrizi, G.; Goggiamani, A.; Ramón, R.S.; Nolan, S.P.; Bandini, M. One-Pot Gold-Catalyzed Synthesis of Azepino[1,2-a]indoles. Angew. Chem. Int. Ed. 2012, 51, 9891–9895. [Google Scholar] [CrossRef]
  27. Caruana, L.; Mondatori, M.; Corti, V.; Morales, S.; Mazzanti, A.; Fochi, M.; Bernardi, L. Catalytic Asymmetric Addition of Meldrum’s Acid, Malononitrile, and 1,3-Dicarbonyls to ortho-Quinone Methides Generated In Situ Under Basic Conditions. Chem. Eur. J. 2015, 21, 6037–6041. [Google Scholar] [CrossRef] [PubMed]
  28. Arcadi, A.; Calcaterra, A.; Fabrizi, G.; Fochetti, A.; Goggiamani, A.; Iazzetti, A.; Marrone, F.; Mazzoccanti, G.; Serraiocco, A. One-pot synthesis of dihydroquinolones by sequential reactions of o-aminobenzyl alcohol derivatives with Meldrum’s acids. Org. Biomol. Chem. 2022, 20, 3160–3173. [Google Scholar] [CrossRef]
  29. Ouyang, J.; Maji, R.; Leutzsch, M.; Mitschke, B.; List, B. Design of an Organocatalytic Asymmetric (4 + 3) Cycloaddition of 2-Indolylalcohols with Dienolsilanes. J. Am. Chem. Soc. 2022, 144, 8460–8466. [Google Scholar] [CrossRef] [PubMed]
  30. Tan, W.; Shi, F. A breakthrough in 2-indolylmethanol-involved organocatalytic asymmetric reactions. Chem. Synth. 2022, 2, 11. [Google Scholar] [CrossRef]
  31. Bera, K.; Schneider, C. Brønsted Acid Catalyzed [3 + 2]-Cycloaddition of Cyclic Enamides with in Situ Generated 2-Methide-2H-indoles: Enantioselective Synthesis of Indolo[1,2-a]indoles. Org. Lett. 2016, 18, 5660–5663. [Google Scholar] [CrossRef] [PubMed]
  32. Bera, K.; Schneider, C. Brønsted Acid Catalyzed [3 + 2]-Cycloaddition of 2-Vinylindoles with In Situ Generated 2-Methide-2H-indoles: Highly Enantioselective Synthesis of Pyrrolo[1,2-a]indoles. Chem. Eur. J. 2016, 22, 7074–7078. [Google Scholar] [CrossRef]
  33. Arcadi, A.; Berden, G.; Ciogli, A.; Corinti, D.; Crestoni, M.E.; De Angelis, M.; Fabrizi, G.; Goggiamani, A.; Iazzetti, A.; Marrone, F.; et al. Reactivity of Indolylmethylacetates with N, O, and S Soft Nucleophiles: Evidence of 2-Alkylideneindolenines and 3-Alkylideneindoleninium Generation by ESI-MS and IRMPD Spectroscopy. Eur. J. Org. Chem. 2022, 2022, e202201166. [Google Scholar] [CrossRef]
  34. Arcadi, A.; Fabrizi, G.; Fochetti, A.; Ghirga, F.; Goggiamani, A.; Iazzetti, A.; Marrone, F.; Mazzoccanti, G.; Serraiocco, A. Palladium-catalyzed Tsuji–Trost-type reaction of benzofuran-2-ylmethyl acetates with nucleophiles. Rsc. Adv. 2021, 11, 909–917. [Google Scholar] [CrossRef] [PubMed]
  35. Arcadi, A.; Calcaterra, A.; Chiarini, M.; Fabrizi, G.; Fochetti, A.; Goggiamani, A.; Iazzetti, A.; Marrone, F.; Marsicano, V.; Serraiocco, A. Synthesis of Indole/Benzofuran-Containing Diarylmethanes through Palladium-Catalyzed Reaction of Indolylmethyl or Benzofuranylmethyl Acetates with Boronic Acids. Synthesis 2022, 54, 741–753. [Google Scholar]
  36. Kuwano, R.; Kondo, Y.; Shirahama, T. Transformation of Carbonates into Sulfones at the Benzylic Position via Palladium-Catalyzed Benzylic Substitution. Org. Lett. 2005, 7, 2973–2975. [Google Scholar] [CrossRef] [PubMed]
  37. Kuwano, R.; Kondo, Y. Palladium-catalyzed benzylation of active methine compounds without additional base: Remarkable effect of 1,5-cyclooctadiene. Org. Lett. 2004, 6, 3545–3547. [Google Scholar] [CrossRef]
  38. Kuwano, R.; Kondo, Y.; Matsuyama, Y. Palladium-Catalyzed Nucleophilic Benzylic Substitutions of Benzylic Esters. J. Am. Chem. Soc. 2003, 125, 12104–12105. [Google Scholar] [CrossRef] [PubMed]
  39. Calculated by HF, 3-21G* in Titan 1.0.1 2000; Wavefunction Inc.: Irvine, CA, USA, 2000.
  40. Rossi, E.; Arcadi, A.; Abbiati, G.; Attanasi, O.A.; De Crescentini, L. Sequential base-promoted annulation/ palladium-catalyzed domino 1,5-enyne arylation and vinylation of alpha-propargylaminohydrazones. Angew. Chem. Int. Ed. 2002, 41, 1400–1402. [Google Scholar] [CrossRef]
  41. Yu, J.-S.; Espinosa, M.; Noda, H.; Shibasaki, M. Traceless Electrophilic Amination for the Synthesis of Unprotected Cyclic β-Amino Acids. J. Am. Chem. Soc. 2019, 141, 10530–10537. [Google Scholar] [CrossRef] [PubMed]
  42. Chande, M.S.; Khanwelkar, R.R. Michael addition approach for the synthesis of novel spiro compounds and 2-substituted malonic acid derivatives from Meldrum’s acid. Tetrahedron Lett. 2005, 46, 7787–7792. [Google Scholar] [CrossRef]
  43. Chen, J.-P.; Xu, M.-H. Chiral diene-promoted room temperature conjugate arylation: Highly enantioselective synthesis of substituted chiral phenylalanine derivatives and α,α-di(arylmethyl)acetates. Org. Biomol. Chem. 2020, 18, 4569–4574. [Google Scholar] [CrossRef]
  44. Saget, T.; König, B. Photocatalytic Synthesis of Polycyclic Indolones. Chem. Eur. J. 2020, 26, 7004–7007. [Google Scholar] [CrossRef] [PubMed]
  45. Hammoud, S.; Anselmi, E.; Cherry, K.; Kizirian, J.-C.; Thibonnet, J. Synthesis and Reactivity of Oxazinoindolones via Regioselective 6-exo-dig Iodolactonization. Eur. J. Org. Chem. 2018, 45, 6314–6327. [Google Scholar] [CrossRef]
  46. Goriya, Y.; Ramana, C.V. 2-Aroylindoles from o-bromochalcones via Cu (i)-catalyzed SN Ar with an azide and intramolecular nitrene C–H insertion. Chem. Comm. 2014, 50, 7790–7792. [Google Scholar] [CrossRef]
  47. Collot, V.; Schmitt, M.; Marwah, P. Regiospecific functionalization of indole-2-carboxylates and diastereoselective preparation of the corresponding indolines. Heterocycles 1999, 51, 2823–2847. [Google Scholar] [CrossRef]
  48. Akunuri, R.; Veerareddy, V.; Kaul, G.; Akhir, A.; Unnissa, T.; Parupalli, R.; Nanduri, S. Synthesis and antibacterial evaluation of (E)-1-(1H-indol-3-yl) ethanone O-benzyl oxime derivatives against MRSA and VRSA strains. Bioorg. Chem. 2021, 116, 105288. [Google Scholar] [CrossRef]
Catalysts 12 01516 sch001 550
Scheme 1. Retrosynthetic approach to the 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one scaffold.
Scheme 1. Retrosynthetic approach to the 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one scaffold.
Catalysts 12 01516 sch001
Catalysts 12 01516 sch002 550
Scheme 2. The reaction of 1a with Meldrum’s acid 2.
Scheme 2. The reaction of 1a with Meldrum’s acid 2.
Catalysts 12 01516 sch002
Catalysts 12 01516 sch003 550
Scheme 3. Cyclization of 6.
Scheme 3. Cyclization of 6.
Catalysts 12 01516 sch003
Catalysts 12 01516 sch004 550
Scheme 4. The reaction of 1a with Meldrum’s acid 7.
Scheme 4. The reaction of 1a with Meldrum’s acid 7.
Catalysts 12 01516 sch004
Catalysts 12 01516 sch005 550
Scheme 5. Reaction of 1a with ethyl malonate 10 and the ethyl-3-oxobutanoate 12.
Scheme 5. Reaction of 1a with ethyl malonate 10 and the ethyl-3-oxobutanoate 12.
Catalysts 12 01516 sch005
Catalysts 12 01516 sch006 550
Scheme 6. Reaction of indol-2-ylmethyl acetate 1a with 2-methylciclohexan-1,3-dione 16a and its potassium salt 16b.
Scheme 6. Reaction of indol-2-ylmethyl acetate 1a with 2-methylciclohexan-1,3-dione 16a and its potassium salt 16b.
Catalysts 12 01516 sch006
Table
Table 1. Optimization studies for the reaction of 1 with methyl Meldrum’s acid 3a. a
Table 1. Optimization studies for the reaction of 1 with methyl Meldrum’s acid 3a. a
Catalysts 12 01516 i001
Entry1CatalystBaseSolventT (°C)t (h)Yield 3a (%) b
11a/K2CO3DMSO100755
21b/NaHDMSO1007242(17) c
31bPd2(dba)3/PPh3K2CO3MeCN705.568
41bPd2(dba)3/PPh3K2CO3MeCN80768
51bPd2(dba)3/PPh3K2CO3DMSO801.575
61bPd2(dba)3/P(2-furyl)3K2CO3DMSO80178
71bPd2(dba)3/dppfK2CO3DMSO801.585
81bPd2(dba)3/dppf/DMSO8024(30) c
91aPd2(dba)3/PPh3K2CO3MeCN1004067
101aPd2(dba)3/PPh3K2CO3DMSO1005.575
111aPd2(dba)3/dppfK2CO3DMSO100288
121aPd2(dba)3/dppfK2CO3DMSO1002/(/) c,d
a Unless otherwise stated, reactions were carried out on a 0.35 mmol scale under an argon atmosphere using 0.02 equiv. of Pd2(dba)3, 0.04 equiv. of dppf or 0.08 mmol of PPh3 or P(2-furyl)3, 1.5 equiv. of 2a, 1.5 equiv. of K2CO3 in 1.5 mL of DMSO. b Yields are given for isolated products. c Numbers in brackets refer to the percentage of the recovered 1. d The reaction was carried out without 2a.
Table
Table 2. Synthesis of 2-substituted 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one 3 from indol-2-ylmethyl acetates 1 and Meldrum’s acid derivatives 2. a
Table 2. Synthesis of 2-substituted 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one 3 from indol-2-ylmethyl acetates 1 and Meldrum’s acid derivatives 2. a
Catalysts 12 01516 i002
Entry1R1R22R3t (h)Yield 3 (%) b
11aHH2b-CH2(4-OMe-C6H4)13b (78)
21aHH2c-CH2(furyl)43c (63)
31aHH2d-Ph24(/)
41aHH2e-CH2CH2CO2Me33d (74)
51c5-MeH2a-Me33e (70)
61d5-BrH2a-Me53f (50)
71e5-(4-Me-C6H4)H2a-Me4.53g (70)
81f5-(4-F,3-Me-C6H3)H2a-Me53h (70)
91gHPh2a-Me33i (58)
101gH-Ph2b-CH2(4-OMe-C6H4)23j (64)
111gH-Ph2c-CH2(2-furyl)23k (54)
121gH-Ph2e-CH2CH2CO2Me2.53l (66)
131hH4-CF3-C6H42a-Me13m (71)
14 HH2a-Me33a (72) c
a Unless otherwise stated, reactions were carried out on a 0.35 mmol scale under an argon atmosphere using 0.02 equiv. of Pd2(dba)3, 0.04 equiv. of dppf, 1.5 equiv. of 2, 1.5 equiv. of K2CO3 in 1.5 mL of DMSO at 100 °C. b Yields are given for isolated products. c The reaction was carried out on a 5.28 mmol scale.
Table
Table 3. Synthesis of 1,2-disubstituted 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one 5/5′ from indol-2-ylmethyl acetates 4 and Meldrum’s acid derivatives 2. a
Table 3. Synthesis of 1,2-disubstituted 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one 5/5′ from indol-2-ylmethyl acetates 4 and Meldrum’s acid derivatives 2. a
Catalysts 12 01516 i003
Entry4R12R2t (h)Ratio 5/5′ bYield 5 + 5′ (%) c
14a-Ph2a-Me284/165a + 5′a (74)
24a-Ph2b-CH2(4-OMe-C6H4)394/65b + 5′b (50)
34a-Ph2c-CH2(furyl)274/265c + 5′c (52)
44b-Me2a-Me2484/165d + 5′d (76)
a Unless otherwise stated, reactions were carried out on a 0.35 mmol scale under an argon atmosphere at 100 °C using 0.02 equiv. of Pd2(dba)3, 0.04 equiv. of dppf, 1.5 equiv. of 2, 1.5 equiv. of K2CO3 in 1.5 mL of DMSO. b Diastereomeric ratios were calculated from the 1H NMR analyses. c Yields are given for isolated products.
Table
Table 4. Synthesis of 2-substituted 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one 3/15 from indol-2-ylmethyl acetates 1a and substituted methylene active compound 14. a
Table 4. Synthesis of 2-substituted 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one 3/15 from indol-2-ylmethyl acetates 1a and substituted methylene active compound 14. a
Catalysts 12 01516 i004
Entry14R1R2t (h)Yield 3 (%)Yield 15 (%) b
1 14a-Me-Me13a (45)15a (18) c
214a-Me-Me33a (46)traces
314b-OEt-Me24/15b (60)
414c-Me-CH2CH = CH43n (71)/
a Unless otherwise stated, reactions were carried out on a 0.35 mmol scale under an argon atmosphere at 100 °C using 0.02 equiv. of Pd2(dba)3, 0.04 equiv. of dppf, 1.5 equiv. of 14, 1.5 equiv. of K2CO3 in 1.5 mL of DMSO. b Yields are given for isolated products. c The reaction was carried out without a catalyst.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Iazzetti, A.; Arcadi, A.; Dessalvi, S.; Fabrizi, G.; Goggiamani, A.; Marrone, F.; Serraiocco, A.; Sferrazza, A.; Ullah, K. Synthesis of Polysubstituted 1,2-Dihydro-3H-pyrrolo[1,2-a]indol-3-ones through Domino Palladium-Catalyzed Reactions of Indol-2-ylmethyl Acetates with 1,3-Dicarbonyl Derivatives. Catalysts 2022, 12, 1516. https://doi.org/10.3390/catal12121516

AMA Style

Iazzetti A, Arcadi A, Dessalvi S, Fabrizi G, Goggiamani A, Marrone F, Serraiocco A, Sferrazza A, Ullah K. Synthesis of Polysubstituted 1,2-Dihydro-3H-pyrrolo[1,2-a]indol-3-ones through Domino Palladium-Catalyzed Reactions of Indol-2-ylmethyl Acetates with 1,3-Dicarbonyl Derivatives. Catalysts. 2022; 12(12):1516. https://doi.org/10.3390/catal12121516

Chicago/Turabian Style

Iazzetti, Antonia, Antonio Arcadi, Stefano Dessalvi, Giancarlo Fabrizi, Antonella Goggiamani, Federico Marrone, Andrea Serraiocco, Alessio Sferrazza, and Karim Ullah. 2022. "Synthesis of Polysubstituted 1,2-Dihydro-3H-pyrrolo[1,2-a]indol-3-ones through Domino Palladium-Catalyzed Reactions of Indol-2-ylmethyl Acetates with 1,3-Dicarbonyl Derivatives" Catalysts 12, no. 12: 1516. https://doi.org/10.3390/catal12121516

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop