Next Article in Journal
Reconversion of Parahydrogen Gas in Surfactant-Coated Glass NMR Tubes
Next Article in Special Issue
New 6′-Amino-5′-cyano-2-oxo-1,2-dihydro-1′H-spiro[indole-3,4′-pyridine]-3′-carboxamides: Synthesis, Reactions, Molecular Docking Studies and Biological Activity
Previous Article in Journal
Computational Procedure for Analysis of Crystallites in Polycrystalline Solids of Quasilinear Molecules
Previous Article in Special Issue
Dess–Martin Periodinane-Mediated Oxidative Coupling Reaction of Isoquinoline with Benzyl Bromide
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 28
Issue 5
10.3390/molecules28052324
molecules-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

An Effective Synthesis of Previously Unknown 7-Aryl Substituted Paullones

by
Dmitrii A. Aksenov
,
Alesia S. Akulova
,
Elena A. Aleksandrova
,
Nicolai A. Aksenov
,
Alexander V. Leontiev
and
Alexander V. Aksenov
*
Department of Chemistry, North Caucasus Federal University, 1a Pushkin St., 355009 Stavropol, Russia
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(5), 2324; https://doi.org/10.3390/molecules28052324
Submission received: 16 February 2023 / Revised: 28 February 2023 / Accepted: 28 February 2023 / Published: 2 March 2023
(This article belongs to the Special Issue Chemistry of Indoles)
Browse Figures
Versions Notes

Abstract

:
A straightforward three-step procedure affording a wide range of novel 7-aryl substituted paullone derivatives was developed. This scaffold is structurally similar to 2-(1H-indol-3-yl)acetamides—promising antitumor agents—hence, could be useful for the development of a new class of anticancer drugs.

Graphical Abstract

1. Introduction

Paullones are an important class of biologically active compounds that were found to be, for instance, efficient inhibitors of various kinases [1,2,3,4,5], including diazepam-binding sites [6] and agonists of GABA-A receptors [6]. Other types of activities shown by this kind of molecules are antitumor [3,7,8], anti-inflammatory [9], anti-parasitic [10], and antiviral [11] ones. Thus, recently, several members of the paullone family (Figure 1) were subjects of studies evaluating their applicability to treat some common illnesses and conditions, such as Alzheimer’s disease [2], osteoporosis [12], and leishmaniasis [13].
Although a large number of paullone derivatives are known, including 7-alkylidene [14] and 7-trifluoromethyl [15] ones, compounds possessing an aryl substituent at C-7 (7, Scheme 1) are somewhat underrepresented and, therefore, understudied. At the same time, in our opinion, such molecules should be of great interest, since they are structurally similar to indolyl-3-arylacetylhydroxamic acids 3, which demonstrated very promising in vitro activity against cancer cells resistant to apoptosis, as well as against multi-drug resistant cell lines [16,17,18]. However, according to the initial in vivo tests, those hydroxamic acids 3, while being readily accessible from indoles 1 and nitroalkanes 2 in polyphosphoric acid (PPA) (Scheme 1a) [16,19], have shown inefficiency in the remediation of cancer tumor in mice, supposedly, because of a highly unfavorable pharmacokinetic profile.
As it was found, the concentration of 3 in plasma goes below the activity threshold level within one hour, most likely due to the facile glucuronidation of hydroxamic acid functionality [17]. This result prompted us to search for the structural analogs of 3 that would be more resilient towards such metabolic degradation. Our first attempt involving protection of the hydroxamic acid moiety with the methoxy group proved to be unsuccessful because the obtained derivatives 4 demonstrated only marginal antitumor activity (Scheme 1b) [18]. Another approach relied upon the replacement of hydroxamic acid with primary amide function to obtain compounds 5. To do so, two alternative synthetic pathways, both based on reactions of indoles 1 with nitrostyrenes 2, were developed. According to the first one, the reaction takes place in a mixture of PPA (both as a solvent and reagent) and PCl3 (as a reductant) (Scheme 1c) [20]. The second method is a stepwise sequence where the intermediate spirane 6 (Scheme 1d) [21,22] formed in H3PO3 (a reaction media); then, it was reduced to the corresponding amide 5 with sodium borohydride (Scheme 1e) [23]. To our satisfaction, either approach works well and the obtained 2-(1H-indol-3-yl)acetamides 5 demonstrated in vitro submicromolar antitumor activity significantly exceeding the performance of hydroxamic acid analogs 3. Supposedly, the structurally related cyclic amides, i.e., paullones 7 bearing aryl substituents R3 at C-7, would also possess the desired activity as well as required metabolic stability. Herein, we disclose the method for preparation of such compounds.

2. Results and Discussion

Presently, there are many studies dedicated to the synthesis of various members of the paullone family. Most of them employ a rather standard approach of assembling the indole subunit via Fischer reaction [5,7,24,25,26,27,28,29] of arylhydrazines with a ketone 10 which, in turn, are accessed by the intramolecular condensation of anthranilic acids 8 following the decarboxylation of the resulting β-keto-acids 9 (Scheme 2). Several examples utilizing the lactonization of 2-(o-aminophenyl)indole-3-acetic esters 11 have also been reported [30,31,32,33,34].
We speculated that paullone derivatives 7 could be easily accessed as well via synthetic methodologies previously developed in our laboratories, such as the acetamidation of electron-rich arenes with nitroalkenes [35]. It was shown, however, that the reaction of the corresponding 2-arylindoles with nitrostyrenes 2 leads to the formation of 2-quinolones 12 instead of desired paullones 7 [19] (Scheme 3a). An attempt to introduce an ortho-amine function into the aryl substituent did not afford the paullones either, resulting in indoloquinolines 13 related to the isocryptolepine alkaloid as the only isolable products (Scheme 3b) [36]. This prompted us to explore alternative approaches based on the classical Fischer indolization reaction.
To explore this venue, however, one would need an efficient route to suitable keto-lactam precursors 16. Originally, we assumed that this could be achieved through the direct cyclization of readily available cyanoketones 14 [37] to keto-lactams 16; however, none of the attempts to carry out this transformation were successful affording only black tar-like residue. Therefore, a two-step protocol, involving initial acid-mediated hydrolysis of the nitrile function, was implemented (Scheme 4) to give the expected acids 15 with yields ranging from 51 to 78%.
The next step, a cyclization of the obtained acid 15 to the corresponding lactam 16 was carried out in the presence of 1,1′-carbonyldiimidazole (CDI) in acetonitrile (Scheme 5).
Having access to a variety of keto-lactams 16, we were ready to run the Fisher indolization only to find out, disappointingly, that this reaction does not proceed under the commonly used conditions. Therefore, screening studies of the reaction between keto-lactam 16a and phenylhydrazine 17 under various conditions were undertaken (Table 1).
Thus, it was found that reaction in PPA containing 80% P2O5 produces only trace amounts of targeted paullone 7aa (entries 1,2) and PPA with an increased concentration of P2O5 gives even worse results (entries 3,4). Similarly, an unsatisfactory outcome was observed with methanesulfonic acid (MsOH) (entry 5). Marginal improvement was achieved when a reaction in the presence of 80% PPA was carried out in organic solvent (EtOAc or EtOH), as the yields were increased to almost 30% (entries 6,7). At this point, it seemed evident that the root of the problem lies in the formation of the key intermediate—corresponding hydrazone—which is problematic in PPA for some reasons. This issue was addressed by carrying out the indolization reaction in two steps (entry 8). First, 3-phenyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dion (16a) and phenylhydrazine (17) were allowed to react in ethanol at room temperature for 30 min in the presence of acetic acid (entry 8.1). Then PPA containing 80% P2O5 was added to the reaction mixture, which was then heated for another 30 min at 70 °C (entry 8.2). Under these conditions, the desired product 7aa was obtained in 79% yield. Therefore, with the optimized conditions in hand, we proceeded with the synthesis of a series of paullones 7 (Scheme 6). As could be seen, the reaction is rather tolerant to the nature of the aryl substituent both in hydrazine and keto-lactam 16 as the yields stays in the range between 67 and 86%.

3. Experimental

3.1. General Information

NMR spectra (1H, 13C and 19F) were recorded on a Bruker AVANCE-III HD spectrometer (400, 101, and 376 MHz, respectively) equipped with a BBO probe in CDCl3 or DMSO-d6 using residual solvent signals as the internal standard. Spectral data are provided in the Supplementary Materials (Figures S1–S75). High-resolution mass spectra were registered in MeCN solutions on a Bruker maXis impact (electrospray ionization, using HCO2 Na–HCO2H for calibration). IR spectra were measured on a FT-IR spectrometer Shimadzu IRAffinity-1 S equipped with an ATR sampling module. Reaction progress, the purity of isolated compounds, and Rf values were assessed by TLC on Silufol UV-254 plates. Column chromatography was performed on silica gel (32–63 μm, 60 Å pore size). Melting points were measured on Stuart SMP30 apparatus. Cyanoketones 14a–d,f,h,j,k [37] and 14e [38] were synthesized according to the previously reported procedures and were identical to those described. All the reagents and solvents were purchased from commercial vendors and used as received.

3.2. General Procedure for Preparation of 4-(2-Aminophenyl)-2-aryl-4-oxo-butanenitriles 14g,i

These compounds were prepared in analogy to the method described in [37]. A 25 mL round-bottom flask was charged with 3-aryl-2′-aminochalcone (2.00 mmol), acetic acid (120 mg, 0.114 mL, 2.00 mmol), and DMSO (6 mL). The mixture was vigorously stirred, and a solution of KCN (260 mg, 4.00 mmol) in water (0.5 mL) was added dropwise. Then, the reaction vessel was equipped with a reflux condenser, and the mixture was stirred at 50 °C for 1 h, while the reaction progress was monitored by TLC. Upon complete conversion, the mixture was diluted with water (30 mL) and extracted with dichloromethane (4 × 15 mL). Combined organic extracts were washed with water (4 × 15 mL), concentrated in vacuum, and purified by preparative column chromatography on silica gel eluting with 1:4 EtOAc/hexane.
4-(2-Aminophenyl)-2-(3-methoxyphenyl)-4-oxobutanenitrile (14g). Orange solid, mp (EtOH) 94.9–96.5 °C, Rf 0.63 (EtOAc/Hex, 1:2). Yield: 376 mg (1.40 mmol, 70%). 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.2 Hz, 1H), 7.37–7.31 (m, 2H), 7.30–7.24 (m, 1H), 6.95–6.86 (m, 2H), 6.70–6.57 (m, 2H), 6.31 (s, 2H), 4.47 (dd, J = 8.4, 5.7 Hz, 1H), 3.81 (s, 3H), 3.66 (dd, J = 17.5, 8.4 Hz, 1H), 3.44 (dd, J = 17.5, 5.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 196.4, 159.6, 150.8, 135.1, 130.6, 128.8 (2C), 127.5, 121.4, 117.6, 116.9, 116.0, 114.7 (2C), 55.5, 45.1, 31.4. IR, vmax/cm−1: 2939, 2255, 1676, 1646, 1238, 1539, 1622, 1236, 974. HRMS (ES TOF) calculated for [M + Na]+ C17H16 N2NaO2 303.1104, found 303.1098 (−2.0 ppm).
4-(2-Aminophenyl)-2-(3,4-dimethylphenyl)-4-oxobutanenitrile (14i). Yellow solid, mp (EtOH) 137.3–139.7 °C, Rf 0.39 (EtOAc/Hex, 1:2). Yield: 423 mg (1.52 mmol, 76%). 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 8.3, 1.5 Hz, 1H), 7.31–7.23 (m, 1H), 6.96 (dd, J = 8.2, 2.2 Hz, 1H), 6.91 (d, J = 2.2 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.66 (dd, J = 8.3, 1.1 Hz, 1H), 6.64–6.59 (m, 1H), 6.32 (s, 2H), 4.47 (dd, J = 8.4, 5.7 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.67 (dd, J = 17.6, 8.4 Hz, 1H), 3.45 (dd, J = 17.5, 5.7 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 196.4, 150.8, 149.5, 149.0, 135.1, 130.6, 127.9, 121.3, 119.8, 117.6, 116.8, 116.0, 111.6, 110.6, 56.10, 56.08, 45.1, 31.8. IR, vmax/cm−1: 2931, 2247, 1684, 1507, 1254, 1248, 1018. HRMS (ES TOF) calculated for [M + Na]+ C18H18N2NaO 301.1311, found 301.1319 (2.7 ppm).

3.3. General Procedure for Preparation of 4-(2-Aminophenyl)-4-oxo-2-arylbutanoic Acids 15a–k

A 5 mL round-bottom flask equipped with a magnetic stirring bar was charged with the corresponding 4-(2-aminophenyl)-4-oxo-2-arylbutanenitrile 14a–k (2.00 mmol), concentrated aqueous HCl solution (2 mL), and refluxed for 2 h (TLC control). After the consumption of the starting material, the reaction mixture was cooled to room temperature, carefully neutralized with 10% solution of NaHCO3, and then washed with EtOAc (5 × 20 mL). The combined organic layer was concentrated and purified by column chromatography (EtOAc:Hex), followed by recrystallization from EtOAc.
4-(2-Aminophenyl)-4-oxo-2-phenylbutanoic acid (15a). Yellow solid, mp (EtOAc) 138.0–139.1 °C, Rf 0.40 (EtOAc/Hex, 1:1). Yield: 376 mg (1.40 mmol, 70%). 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 7.84–7.81 (m, 1H), 7.39–7.32 (m, 4H), 7.29–7.21 (m, 2H), 7.18 (s, 2H), 6.77–6.72 (m, 1H), 6.55–6.48 (m, 1H), 4.06 (dd, J = 10.8, 3.7 Hz, 1H), 3.80 (dd, J = 17.9, 10.8 Hz, 1H), 3.20 (dd, J = 17.7, 3.8 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 199.5, 174.5, 151.1, 139.2, 134.2, 131.3, 128.6 (2C), 128.0 (2C), 127.1, 116.9, 116.2, 114.4, 46.2, 42.5. IR, vmax/cm−1: 3507, 3380, 2915, 2362, 1646, 1622, 1539, 1236, 974. HRMS (ES TOF) calculated for [M + Na]+ C16H15NNaO3 292.0944, found 292.0950 (2.1 ppm).
4-(2-Aminophenyl)-2-(4-methoxyphenyl)-4-oxobutanoic acid (15b). Yellow solid, mp (EtOAc) 192.3–194.3 °C, Rf 0.27 (EtOAc/Hex, 1:1). Yield: 304 mg (1.02 mmol, 51%). 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.18 (s, 2H), 6.90 (d, J = 8.2 Hz, 2H), 6.74 (d, J = 8.3 Hz, 1H), 6.56–6.47 (m, 1H), 4.00 (dd, J = 10.5, 3.7 Hz, 1H), 3.78 (dd, J = 17.7 Hz, 1H), 3.73 (s, 3H), 3.15 (dd, J = 17.7, 3.9 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 199.6, 174.8, 158.3, 151.1, 134.2, 131.3, 131.1, 129.0 (2C), 116.9, 116.3, 114.4, 114.0 (2C), 55.1, 45.3, 42.5. IR, vmax/cm−1: 3507, 3384, 2990, 2366, 1769, 1238, 827, 743. HRMS (ES TOF) calculated for [M + Na]+ C17H17NNaO4 322.1050, found 322.1059 (2.8 ppm).
4-(2-Aminophenyl)-2-(4-fluorophenyl)-4-oxobutanoic acid (15c). Yellow solid, mp (EtOAc) 157.8–158.9 °C, Rf 0.31 (EtOAc/Hex, 1:1). Yield: 315 mg (1.10 mmol, 55%). 1H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.45–7.40 (m, 2H), 7.25–7.16 (m, 4H), 7.15 (s, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.52 (t, J = 7.5 Hz, 1H), 4.08 (dd, J = 10.6, 3.9 Hz, 1H), 3.80 (dd, J = 17.8, 10.6 Hz, 1H), 3.20 (dd, J = 17.8, 4.0 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 199.4, 174.4, 161.3 (d, J = 242.8 Hz), 151.1, 135.4 (d, J = 2.9 Hz), 134.3, 131.3, 129.9 (d, J = 8.1 Hz, 2C), 116.9, 116.2, 115.3 (d, J = 21.3 Hz, 2C), 114.4, 45.4, 42.4. 19F NMR (376 MHz, DMSO-d6) δ −115.9. IR, vmax/cm−1: 3460, 2919, 2358, 1765, 1507, 1236, 978, 739. HRMS (ES TOF) calculated for [M + Na]+ C16H14FNNaO3 310.0850, found 310.0842 (2.6 ppm).
4-(2-Aminophenyl)-2-(4-chlorophenyl)-4-oxobutanoic acid (15d). Yellow solid, mp (EtOAc) 191.1–192.4 °C, Rf 0.37 (EtOAc/Hex, 1:1). Yield: 315 mg (1.04 mmol, 52%). 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.40 (s, 4H), 7.26–7.22 (m, 1H), 7.18 (s, 2H), 6.74 (d, J = 8.2 Hz, 1H), 6.52 (t, J = 7.5 Hz, 1H), 4.08 (dd, J = 10.5, 4.0 Hz, 1H), 3.78 (dd, J = 17.9, 10.5 Hz, 1H), 3.22 (dd, J = 17.8, 4.1 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 199.3, 174.2, 151.1, 138.3, 134.3, 131.7, 131.3, 129.9 (2C), 128.5 (2C), 116.9, 116.2, 114.4, 45.6, 42.2. IR, vmax/cm−1: 3519, 3376, 3002, 2358, 1773, 1244, 820, 749. HRMS (ES TOF) calculated for [M + Na]+ C16H14ClNNaO3 326.0554, found 326.0562 (2.6 ppm).
4-(2-Aminophenyl)-2-(4-bromophenyl)-4-oxobutanoic acid (15e). Yellow solid, mp (EtOAc) 196.5–197.8 °C, Rf 0.33 (EtOAc/Hex, 1:1). Yield: 298 mg (0.86 mmol, 43%). 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 7.83–7.81 (m, 1H), 7.56–7.52 (m, 2H), 7.36–7.33 (m, 2H), 7.26–7.22 (m, 1H), 7.18 (s, 2H), 6.75–6.73 (m, 1H), 6.54–6.50 (m, 1H), 4.06 (dd, J = 10.5, 4.0 Hz, 1H), 3.78 (dd, J = 17.8, 10.5 Hz, 1H), 3.22 (dd, J = 17.7, 4.0 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 199.3, 174.1, 151.1, 139.0, 134.2, 131.4 (2C), 131.3, 130.3 (2C), 120.1, 116.9, 116.2, 114.4, 45.9, 42.2. IR, vmax/cm−1: 3360, 2994, 2358, 1771, 1244, 1053, 819, 751. HRMS (ES TOF) calculated for [M + Na]+ C16H14BrNNaO3 370.0049, found 370.0038 (−3.0 ppm).
4-(2-Aminophenyl)-4-oxo-2-(p-tolyl)butanoic acid (15f). Colorless solid, mp (EtOAc) 153.7–155.2 °C, Rf 0.34 (EtOAc/Hex, 1:1). Yield: 350 mg (1.24 mmol, 62%). 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.1 Hz, 1H), 7.30–7.20 (m, 4H), 7.15 (d, J = 8.1 Hz, 2H), 6.66–6.57 (m, 2H), 4.21 (dd, J = 10.4, 3.9 Hz, 1H), 3.88 (dd, J = 17.8, 10.5 Hz, 1H), 3.27 (dd, J = 17.8, 4.0 Hz, 1H), 2.33 (s, 3H).13C NMR (101 MHz, CDCl3) δ 199.4, 178.8, 150.5, 137.6, 134.9, 134.7, 131.0, 129.7 (2C), 128.0 (2C), 117.5, 115.9, 46.1, 43.1, 21.2. IR, vmax/cm−1: 3380, 2994, 1773, 1684, 1656, 1507, 1475, 1437, 1240. HRMS (ES TOF) calculated for [M + Na]+ C17H17NNaO3 306.1101, found 306.1088 (4.3 ppm).
4-(2-Aminophenyl)-2-(3-methoxyphenyl)-4-oxobutanoic acid (15g). Colorless solid, mp (EtOAc) 163.9–165.1 °C, Rf 0.26 (EtOAc/Hex, 1:1). Yield: 316 mg (1.06 mmol, 53%). 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 7.82 (dd, J = 8.3, 1.5 Hz, 1H), 7.32–7.25 (m, 2H), 7.28–7.19 (m, 1H), 7.16 (d, J = 13.6 Hz, 2H), 6.94–6.86 (m, 2H), 6.74 (dd, J = 8.4, 1.2 Hz, 1H), 6.52 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 4.00 (dd, J = 10.8, 3.9 Hz, 1H), 3.81–3.74 (m, 1H), 3.73 (s, 3H), 3.15 (dd, J = 17.8, 3.8 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 199.6, 174.7, 158.3, 151.1, 134.2, 131.3, 131.1, 129.0 (2C), 116.9, 116.2, 114.4, 114.0 (2C), 55.1, 45.3, 42.5. IR, vmax/cm−1: 3392, 2994, 1775, 1735, 1698, 1654, 1558, 1453, 1244. HRMS (ES TOF) calculated for [M + Na]+ C17H17NNaO4 322.1050, found 322.1055 (1.6 ppm).
4-(2-Aminophenyl)-2-(4-isopropylphenyl)-4-oxobutanoic acid (15h). Colorless solid, mp (EtOAc) 121.1–122.9 °C, Rf 0.6 (EtOAc/Hex, 1:1). Yield: 348 mg (1.12 mmol, 56%). 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 6.7 Hz, 1H), 7.29 (s, 2H), 7.24–7.16 (m, 5 H), 6.74 (d, J = 7.2 Hz, 1H), 6.51 (t, J = 7.6 Hz, 1H), 4.01 (dd, J = 10.8, 3.7 Hz, 1H), 3.78 (dd, J = 17.8, 10.8 Hz, 1H), 3.17 (dd, J = 17.8, 3.7 Hz, 1H), 2.86 (p, J = 6.9 Hz, 1H), 1.19 (d, J = 7.0 Hz, 6 H). 13C NMR (101 MHz, DMSO-d6) δ 199.6, 174.6, 151.06, 147.2, 136.6, 134.2, 131.3, 127.9 (2C), 126.5 (2C), 116.9, 116.2, 114.4, 45.8, 42.5, 33.1, 24.0 (2C). IR, vmax/cm−1: 3280, 2954, 1712, 1668, 1556, 1514, 1442, 1427, 1251, 1062. HRMS (ES TOF) calculated for [M + Na]+ C19H21NNaO3 334.1414, found 334.1422 (4.1 ppm).
4-(2-Aminophenyl)-2-(3,4-dimethylphenyl)-4-oxobutanoic acid (15i). Yellowish solid, mp (EtOAc) 138.0–139.8 °C, Rf 0.42 (EtOAc/Hex, 1:1). Yield: 439 mg (1.48 mmol, 74%). 1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 7.82 (dd, J = 8.2, 1.6 Hz, 1H), 7.30–7.25 (m, 2H), 7.24–7.21 (m, 1H), 7.20–7.15 (m, 3H), 6.74 (dd, J = 8.5, 1.2 Hz, 1H), 6.51 (t, J = 7.5 Hz, 1H), 4.02 (dd, J = 10.7, 3.6 Hz, 1H), 3.78 (dd, J = 17.8, 10.8 Hz, 1H), 3.17 (dd, J = 17.8, 3.8 Hz, 1H), 2.57 (q, J = 7.6 Hz, 2H), 1.20–1.14 (m, 3H). 13C NMR (101 MHz, DMSO-d6) δ 199.5, 174.6, 151.1, 142.6, 136.4, 134.2, 131.3, 128.0 (2C), 127.9 (2C), 116.9, 116.2, 114.4, 45.8, 42.5, 27.8, 15.7. IR, vmax/cm−1: 3380, 2974, 1702, 1688, 1650, 1558, 1503, 1455, 1234, 1189. HRMS (ES TOF) calculated for [M + Na]+ C18H19NNaO3 320.1257, found 320.1248 (−2.8 ppm).
4-(2-Aminophenyl)-2-(3-chlorophenyl)-4-oxobutanoic acid (15j). Colorless solid, mp (EtOAc) 164.0–165.3 °C, Rf 0.42 (EtOAc/Hex, 1:1). Yield: 339 mg (1.12 mmol, 56%). 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.1 Hz, 1H), 7.40 (s, 1H), 7.29 (d, J = 6.7 Hz, H), 6.65 (d, J = 7.4 Hz, 2H), 4.25 (dd, J = 10.4, 4.0 Hz, 1H), 3.89 (dd, J = 17.8, 10.3 Hz, 1H), 3.32 (dd, J = 17.7, 4.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) 198.8, 177.4, 150.6, 139.8, 134.9, 134.8, 131.0, 130.3, 128.3, 128.2, 126.5, 117.5, 117.3, 116.0, 46.1, 42.9. IR, vmax/cm−1: 3002, 1775, 1759, 1708, 1618, 1562, 1435, 1240, 1053. HRMS (ES TOF) calculated for [M + Na]+ C17H14ClNNaO3 326.0554, found 306.0541 (4.1 ppm).
4-(2-Aminophenyl)-2-(4-ethylphenyl)-4-oxobutanoic acid (15k). Yellowish solid, mp (EtOAc) 138.0–139.8 °C, Rf 0.42 (EtOAc/Hex, 1:1). Yield: 439 mg (1.48 mmol, 74%). 1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 7.82 (dd, J = 8.2, 1.6 Hz, 1H), 7.30–7.25 (m, 2H), 7.24–7.21 (m, 1H), 7.20–7.15 (m, 3H), 6.74 (dd, J = 8.5, 1.2 Hz, 1H), 6.51 (t, J = 7.5 Hz, 1H), 4.02 (dd, J = 10.7, 3.6 Hz, 1H), 3.78 (dd, J = 17.8, 10.8 Hz, 1H), 3.17 (dd, J = 17.8, 3.8 Hz, 1H), 2.57 (q, J = 7.6 Hz, 2H), 1.20–1.14 (m, 3H). 13C NMR (101 MHz, DMSO-d6) δ 199.5, 174.6, 151.1, 142.6, 136.4, 134.2, 131.3, 128.0 (2C), 127.9 (2C), 116.9, 116.2, 114.4, 45.8, 42.5, 27.8, 15.7. IR, vmax/cm−1: 3380, 2974, 1702, 1688, 1650, 1558, 1503, 1455, 1234, 1189. HRMS (ES TOF) calculated for [M + Na]+ C18H19NNaO3 320.1257, found 320.1248 (−2.8 ppm).

3.4. General Procedure for Preparation of 3-Aryl-3,4-dihydro-1H-benzo[b]azepine-2,5-diones 16a–k

A 5 mL round-bottom flask equipped with a magnetic stirring bar was charged with the corresponding 4-(2-aminophenyl)-4-oxo-2-arylbutanoic acid 15a–k (1.00 mmol), 1,1′-carbonyldiimidazole (162 mg, 1.00 mmol), and acetonitrile (0.1 mL). The reaction mixture was left stirring at room temperature for 4 h. After this period of time, 20 mL of water was poured into the reaction mixture and then, extracted with EtOAc (5 × 20 mL). The organic phase was concentrated on a rotary evaporator and residue was purified by column chromatography using mixture EtOAc/Hex.
3-Phenyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (16a). Colorless solid, mp (EtOAc) 180.3–181.4 °C, Rf 0.48 (EtOAc/Hex, 1:1). Yield: 190 mg (0.76 mmol, 76%). 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.82–7.80 (m, 1H), 7.59–7.55 (m, 1H), 7.31–7.27 (m, 2H), 7.24–7.16 (m, 5 H), 4.29–4.25 (m, 1H), 3.60 (dd, J = 18.0, 12.0 Hz, 1H), 3.02–2.97 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 197.8, 173.5, 139.0, 138.3, 134.4, 130.0, 128.7 (2C), 128.1 (2C), 126.9, 126.7, 123.6, 121.9, 45.8, 43.2. IR, vmax/cm−1: 3312, 2919, 2366, 1670, 1485, 1250. HRMS (ES TOF) calculated for [M + Na]+ C16H13NNaO2 274.0838, found 274.0843 (1.8 ppm).
3-(4-Methoxyphenyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (16b). Colorless solid, mp (EtOAc) 174.8–176.2 °C, Rf 0.32 (EtOAc/Hex, 1:1). Yield: 166 mg (0.59 mmol, 59%). 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 2H), 4.16 (d, J = 11.5 Hz, 1H), 3.79 (s, 3H), 3.53–3.45 (m, 1H), 3.20 (d, J = 18.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 197.8, 174.7, 159.0, 137.7, 134.8, 131.1, 129.5 (2C), 128.7, 127.5, 125.0, 121.7, 114.2 (2C), 55.4, 46.6, 43.4. IR, vmax/cm−1: 2923, 2374, 1771, 1662, 1514, 1248, 1027, 843, 767. HRMS (ES TOF) calculated for [M + Na]+ C17H15NNaO3 304.0944, found 304.0944 (−1.6 ppm).
3-(4-Fluorophenyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (16c). Colorless solid, mp (EtOAc) 212.5–214.6 °C, Rf 0.34 (EtOAc/Hex, 1:1). Yield: 258 mg (0.96 mmol, 96%). 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.83–7.80 (m, 1H), 7.60–7.56 (m, 1H), 7.30–7.25 (m, 2H), 7.22–7.19 (m, 2H), 7.16–7.10 (m, 2H), 4.34–4.30 (m, 1H), 3.61 (dd, J = 18.2, 12.4 Hz, 1H), 2.96–2.91 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 197.9, 173.3, 161.2 (d, J = 242.5 Hz), 138.9, 134.7 (d, J = 3.3 Hz), 134.4, 130.8 (d, J = 8.4 Hz, 2C), 130.1, 126.8, 123.7, 121.9, 114.8 (d, J = 21.3 Hz, 2C), 46.1, 42.2. 19F NMR (376 MHz, DMSO-d6) δ −116.1. IR, vmax/cm−1: 3285, 2915, 2334, 1779, 1652, 1376, 1246. HRMS (ES TOF) calculated for [M + Na]+ C16H12FNNaO2 292.0744, found 292.0747 (−1.1 ppm).
3-(4-Chlorophenyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (16d). Colorless solid, mp (EtOAc) 191.8–193.4 °C, Rf 0.33 (EtOAc/Hex, 1:1). Yield: 167 mg (0.62 mmol, 62%). 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.83–7.80 (m, 1H), 7.60–7.56 (m, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 7.22–7.19 (m, 2H), 4.33 (d, J = 11.7 Hz, 1H), 3.62 (dd, J = 18.1, 12.5 Hz, 1H), 2.94 (d, J = 17.8 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 197.8, 173.1, 138.8, 137.6, 134.4, 131.6, 130.8 (2C), 130.1, 128.0 (2C), 126.8, 123.7, 121.9, 45.8, 42.3. IR, vmax/cm−1: 3297, 2994, 2370, 1771, 1383, 1242, 1057. HRMS (ES TOF) calculated for [M + Na]+ C16H12ClNNaO2 308.0449, found 308.0440 (−2.9 ppm).
3-(4-Bromophenyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (16e). Colorless solid, mp (EtOAc) 191.8–193.4 °C, Rf 0.46 (EtOAc/Hex, 1:1). Yield: 214 mg (0.65 mmol, 65%). 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.83–7.80 (m, 1H), 7.60–7.56 (m, 1H), 7.51–7.48 (m, 2H), 7.22–7.19 (m, 4H), 4.32 (dd, J = 12.5, 1.9 Hz, 1H), 3.61 (dd, J = 18.0, 12.5 Hz, 1H), 2.93 (dd, J = 18.1, 2.0 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 197.8, 173.1, 138.8, 138.0, 134.4, 131.2 (2C), 130.9 (2C), 130.1, 126.8, 123.8, 121.9, 120.1, 45.8, 42.4. IR, vmax/cm−1: 2927, 2386, 1773, 1664, 1244, 1043, 769. HRMS (ES TOF) calculated for [M + Na]+ C16H12BrNNaO2 351.9944, found 351.9951 (2.0 ppm).
3-(p-Tolyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (16f). Colorless solid, mp (EtOAc) 158.3–160.37 °C, Rf 0.34 (EtOAc/Hex, 1:2). Yield: 193 mg (0.73 mmol, 73%). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 8.2 Hz, 1H), 3.50 (dd, J = 18.1, 11.8 Hz, 1H), 3.21 (dd, J = 18.1, 2.0 Hz, 1H), 2.32 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 197.8, 174.9, 137.8, 137.4, 134.7, 133.6, 131.0, 129.5 (2C), 128.3 (2C), 127.4, 124.8, 121.8, 46.4, 43.8, 21.2. IR, vmax/cm−1: 3233, 2994, 1737, 1688, 1562, 1509, 1473, 1385, 1250, 1169. HRMS (ES TOF) calculated for [M + Na]+ C17H17NNaO4 288.0995, found 288.0985 (3.5 ppm).
3-(3-Methoxyphenyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (16g). Colorless solid, mp (EtOAc) 169.7–170.2 °C, Rf 0.47 (EtOAc/Hex, 1:1). Yield: 163 mg (0.58 mmol, 58%). 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 8.2 Hz, 2H), 4.19–4.11 (m, 1H), 3.78 (s, 3H), 3.48 (dd, J = 18.1, 11.7 Hz, 1H), 3.24–3.14 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 197.8, 175.1, 159.0, 137.8, 134.7, 131.0, 129.5 (2C), 128.7, 127.5, 124.9, 121.8, 114.2 (2C), 55.3, 46.6, 43.4. IR, vmax/cm−1: 3209, 2990, 1733, 1686, 1558, 1505, 1475, 1433, 1244. HRMS (ES TOF) calculated for [M + Na]+ C17H15NNaO3 304.0944, found 304.0939 (1.8 ppm).
3-(4-Isopropylphenyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (16h). Colorless solid, mp (EtOAc) 139.2–140.1 °C, Rf 0.44 (EtOAc/Hex, 1:2). Yield: 217 mg (0.74 mmol, 74%). 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.81 (dd, J = 7.9, 1.7 Hz, 1H), 7.57 (ddd, J = 8.2, 7.2, 1.7 Hz, 1H), 7.24–7.17 (m, 2H), 7.16–7.09 (m, 4H), 4.22 (dd, J = 12.0, 1.9 Hz, 1H), 3.56 (dd, J = 17.9, 12.1 Hz, 1H), 2.98 (dd, J = 18.0, 1.9 Hz, 1H), 2.85 (hept, J = 6.9 Hz, 1H), 1.18 (d, J = 7.3 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 197.9, 173.6, 146.80, 139.0, 135.7, 134.3, 130.0, 128.6 (2C), 126.7, 126.0 (2C), 123.6, 121.8, 45.9, 42.8, 33.1, 24.0, 23.9. IR, vmax/cm−1: 3209, 2990, 1733, 1686, 1558, 1519, 1505, 1457, 1433, 1393, 1244. HRMS (ES TOF) calculated for [M + Na]+ C19H19NNaO2 316.1308, found 316.1316 (2.5 ppm).
3-(3,4-Dimethylphenyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (16i). Colorless solid, mp (EtOAc) 194.6–195.9 °C, Rf 0.28 (EtOAc/Hex, 1:1). Yield: 200 mg (0.72 mmol, 72%). 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 8.0, 1.7 Hz, 1H), 7.90 (s, 1H), 7.55–7.50 (m, 1H), 7.25–7.20 (m, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.76–6.70 (m, 2H), 4.17 (dd, J = 11.8, 2.0 Hz, 1H), 3.85 (d, J = 6.5 Hz, 6 H), 3.50 (dd, J = 18.1, 11.8 Hz, 1H), 3.23 (dd, J = 18.1, 2.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 197.7, 174.4, 149.0, 148.6, 137.6, 134.8, 131.2, 129.0, 127.6, 125.1, 121.6, 120.6, 111.6, 111.3, 56.0 (2C), 46.6, 43.7. IR, vmax/cm−1: 3193, 2939, 1775, 1737, 1668, 1521, 1504, 1473, 1455, 1242, 1151. HRMS (ES TOF) calculated for [M + Na]+ C18H17NNaO2 302.1151, found 302.1143 (−2.6 ppm).
3-(3-Chlorophenyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (16j). Colorless solid, mp (EtOAc) 221.7–222.7 °C, Rf 0.4 (EtOAc/Hex, 1:2). Yield: 160 mg (0.56 mmol, 56%). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.9 Hz, 1H), 7.89 (s, 1H), 7.59–7.50 (m, 1H), 7.33–7.25 (m, 3H), 7.21 (s, 1H), 7.10 (ddd, J = 5.7, 3.2, 1.9 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 4.17 (dd, J = 12.3, 2.0 Hz, 1H), 3.49 (dd, J = 18.2, 12.3 Hz, 1H), 3.18 (dd, J = 18.2, 2.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 197.3, 173.5, 138.7, 137.3, 134.9, 131.3, 130.1, 128.9, 128.1, 127.6, 126.8, 125.4, 121.8, 46.4, 43.7, 29.9. IR, vmax/cm−1: 3293, 2990, 1773, 1684, 1560, 1477, 1437, 1244. HRMS (ES TOF) calculated for [M + Na]+ C16H12ClNNaO2 308.0449, found 308.0456 (2.3 ppm).
3-(4-Ethylphenyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (16k). Colorless solid, mp (EtOAc) 159.8–162.1 °C, Rf 0.28 (EtOAc/Hex, 1:1). Yield: 176 mg (0.63 mmol, 63%). 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.80 (dd, J = 7.9, 1.7 Hz, 1H), 7.56 (ddd, J = 8.1, 7.2, 1.7 Hz, 1H), 7.22–7.16 (m, 2H), 7.12 (s, 4H), 4.21 (dd, J = 11.9, 1.9 Hz, 1H), 3.56 (dd, J = 17.9, 11.9 Hz, 1H), 2.99 (dd, J = 17.9, 1.9 Hz, 1H), 2.56 (d, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 197.8, 173.6, 142.2, 139.0, 135.4, 134.4, 130.0, 128.6 (2C), 127.5 (2C), 126.6, 123.6, 121.8, 45.8, 42.9, 27.8, 15.6. IR, vmax/cm−1: 3225, 2990, 1769, 1700, 1654, 1612, 1522, 1511, 1417, 1240. HRMS (ES TOF) calculated for [M + Na]+ C18H17NNaO2 302.1151, found 302.1160 (3.0 ppm).

3.5. General Procedure for Preparation of 7-Arylpaullones (7aa–ak,ba,ca)

A 5 mL round-bottom flask equipped with magnetic stirring bar was charged with the corresponding keto-lactam 16a–k (0.50 mmol), phenylhydrazine (0.50 mmol), ethanol (0.25 mL), and AcOH (30 mg, 0.029 mL, 0.50 mmol). The reaction mixture was left stirring at room temperature for 30 min. After this, 0.5 g of 80% PPA was added and stirring continued at 70 °C for another 30 min. The reaction mixture was then poured into water (20 mL) and carefully neutralized with concentrated aqueous ammonia solution. The formed precipitate was filtered off, open-air dried, and purified by column chromatography using mixture EtOAc/Hex, followed by recrystallization from EtOAc.
7-Phenyl-7,12-dihydrobenzo [2,3]azepino[4,5-b]indol-6(5H)-one (7aa). Colorless solid, mp (EtOAc) 224.9–226.1 °C, Rf 0.67 (EtOAc/Hex, 1:1). Yield: 128 mg (0.40 mmol, 79%). 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 10.34 (s, 1H), 7.77–7.69 (m, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.25–7.17 (m, 3H), 7.15 (d, J = 7.4 Hz, 1H), 7.11–7.02 (m, 4H), 6.91 (d, J = 7.4 Hz, 2H), 5.52 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 171.6, 137.5, 137.4, 134.7, 132.6, 128.2 (2C), 128.1, 128.0, 127.6, 126.6, 126.4 (2C), 123.4, 122.6, 122.5, 121.3, 119.5, 117.8, 111.6, 110.1, 48.8. IR, vmax/cm−1: 3229, 2994, 1757, 1652, 1558, 1487, 1459, 1248, 1063. HRMS (ES TOF) calculated for [M + Na]+ C22H16N2NaO 347.1155, found 347.1149 (−1.7 ppm).
7-(4-Methoxyphenyl)-7,12-dihydrobenzo[2,3]azepino[4,5-b]indol-6(5H)-one (7ab). Colorless solid, mp (EtOAc) 284.2–287.2 °C, Rf 0.38 (EtOAc/Hex, 1:1). Yield: 145 mg (0.41 mmol, 82%) 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 10.31 (s, 1H), 7.72 (t, J = 6.6 Hz, 2H), 7.49 (d, J = 8.2 Hz, 1H), 7.23–7.13 (m, 3H), 7.08 (t, J = 7.5 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 5.45 (s, 1H), 3.58 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 171.8, 157.9, 137.5, 134.8, 132.5, 129.2, 128.0, 127.53, 127.50 (2C), 126.4, 123.4, 122.6, 122.5, 121.3, 119.4, 117.8, 113.6 (2C), 111.5, 110.4, 54.9, 48.1. IR, vmax/cm−1: 3297, 2978, 2366, 1773, 1638, 1240, 1039. HRMS (ES TOF) calculated for [M + Na]+ C23H18N2NaO2 377.1260, found 377.1251 (−2.4 ppm).
7-(4-Fluorophenyl)-7,12-dihydrobenzo[2,3]azepino[4,5-b]indol-6(5H)-one (7ac). Colorless solid, mp (EtOAc) 298.8–303.1 °C, Rf 0.36 (EtOAc/Hex, 1:1). Yield: 147 mg (0.43 mmol, 86%). 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 10.37 (s, 1H), 7.76–7.71 (m, 2H), 7.50 (d, J = 8.2 Hz, 1H), 7.24–7.19 (m, 2H), 7.17–7.13 (m, 1H), 7.11–7.05 (m, 2H), 6.92 (d, J = 7.2 Hz, 4H), 5.51 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 171.4, 160.8 (d, J = 242.8 Hz), 137.5, 134.6, 133.5 (d, J = 2.9 Hz), 132.6, 128.3 (d, J = 8.4 Hz, 2C), 128.1, 127.4, 126.4, 123.5, 122.6, 122.5, 121.4, 119.5, 117.8, 115.0 (d, J = 21.3 Hz, 2C), 111.6, 110.1, 48.0. 19F NMR (376 MHz, DMSO-d6) δ -116.3. IR, vmax/cm−1: 3297, 2919, 1726, 1640, 1499, 1220, 1029. HRMS (ES TOF) calculated for [M + Na]+ C22H15FN2NaO 365.1061, found 365.1072 (3.0 ppm).
7-(4-Chlorophenyl)-7,12-dihydrobenzo[2,3]azepino[4,5-b]indol-6(5H)-one (7ad). Colorless solid, mp (EtOAc) 291.0–293.0 °C, Rf 0.33 (EtOAc/Hex, 1:1). Yield: 143 mg (0.40 mmol, 80%). 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 10.40 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.72–7.70 (m, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.25–7.19 (m, 2H), 7.17–7.13 (m, 3H), 7.11–7.05 (m, 2H), 6.90–6.88 (m, 2H), 5.52 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 171.2, 137.5, 136.4, 134.5, 132.6, 131.2, 128.24 (2C), 128.23 (2C), 128.1, 127.5, 126.4, 123.6, 122.7, 122.4, 121.4, 119.6, 117.9, 111.6, 109.8, 48.1. IR, vmax/cm−1: 3281, 3010, 2362, 1771, 1238, 1051. HRMS (ES TOF) calculated for [M + Na]+ C22H15ClN2NaO 381.0765, found 381.0770 (1.3 ppm).
7-(4-Bromophenyl)-7,12-dihydrobenzo[2,3]azepino[4,5-b]indol-6(5H)-one (7ae). Colorless solid, mp (EtOAc) 273.2–274.5 °C, Rf 0.47 (EtOAc/Hex, 1:1). Yield: 155 mg (0.39 mmol, 77%). 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.40 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 6.5 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.25–7.19 (m, 2H), 7.17–7.13 (m, 1H), 7.11–7.06 (m, 2H), 6.83 (d, J = 8.6 Hz, 2H), 5.50 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 171.1, 137.5, 136.9, 134.5, 132.6, 131.1 (2C), 128.6 (2C), 128.2, 127.5, 126.5, 123.6, 122.7, 122.4, 121.4, 119.8, 119.6, 117.9, 111.6, 109.7, 48.1. IR, vmax/cm−1: 2994, 2362, 1773, 1248, 1053. HRMS (ES TOF) calculated for [M + Na]+ C22H15BrN2NaO 425.0260, found 425.0272 (2.8 ppm).
7-(p-Tolyl)-7,12-dihydrobenzo[2,3]azepino[4,5-b]indol-6(5H)-one (7af). Yellowish solid, mp (EtOAc) 252.3–255.1 °C, Rf 0.55 (EtOAc/Hex, 1:1). Yield: 125 mg (0.36 mmol, 71%). 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 10.31 (s, 1H), 7.75–7.67 (m, 2H), 7.49 (d, J = 8.2 Hz, 1H), 7.24–7.17 (m, 2H), 7.16–7.11 (m, 1H), 7.10–7.03 (m, 2H), 6.88 (d, J = 7.9 Hz, 2H), 6.78 (d, J = 8.3 Hz, 2H), 5.46 (s, 1H), 2.10 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 171.7, 137.5, 135.7, 134.7, 134.4, 132.5, 128.8 (2C), 128.0, 127.6, 126.4, 126.3 (2C), 123.4, 122.6, 122.5, 121.3, 119.4, 117.8, 111.5, 110.2, 48.4, 20.5. IR, vmax/cm−1: 3225, 2991, 1749, 1655, 1555, 1482, 1452, 1248. HRMS (ES TOF) calculated for [M + Na]+ C23H18N2NaO 361.1311, found 361.1305 (−1.7 ppm).
7-(3-Methoxyphenyl-7,12-dihydrobenzo [2,3]azepino [4,5-b]indol-6(5H)-one (7ag). Colorless solid, mp (EtOAc) 268.6–270.9 °C, Rf 0.45 (EtOAc/Hex, 1:1). Yield: 135 mg (0.38 mmol, 76%). 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 10.30 (s, 1H), 7.72 (t, J = 6.9 Hz, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.18 (dt, J = 24.3, 7.2 Hz, 3H), 7.07 (d, J = 7.8 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 6.64 (d, J = 8.6 Hz, 2H), 5.44 (s, 1H), 3.58 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 171.8, 157.9, 137.5, 134.7, 132.5, 129.2, 128.0, 127.52, 127.50 (2C), 126.4, 123.4, 122.6, 122.5, 121.3, 119.4, 117.8, 113.6 (2C), 111.6, 110.4, 54.9, 48.1. IR, vmax/cm−1: 3015, 2895, 1773, 1759, 1654, 1556, 1506, 1451, 1363, 1159. HRMS (ES TOF) calculated for [M + Na]+ C23H18N2NaO2 377.1260, found 377.1256 (−1.1 ppm).
7-(4-Isopropylphenyl)-7,12-dihydrobenzo [2,3]azepino [4,5-b]indol-6(5H)-one (7ah). Colorless solid, mp (EtOAc) 234.6–235.9 °C, Rf 0.51 (EtOAc/Hex, 1:1). Yield: 148 mg (0.40 mmol, 81%). 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.33 (d, J = 1.7 Hz, 1H), 7.78–7.68 (m, 2H), 7.48 (d, J = 8.1 Hz, 1H), 7.24–7.18 (m, 2H), 7.18–7.13 (m, 1H), 7.11–7.06 (m, 2H), 6.96 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8.1 Hz, 2H), 5.47 (s, 1H), 2.69 (p, J = 6.9 Hz, 1H), 1.04 (dd, J = 6.9, 3.3 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 171.7, 146.7, 137.5, 134.9, 134.7, 132.4, 128.1, 127.5, 126.4 (3 C), 126.2 (2C), 123.4, 122.6, 122.3, 121.3, 119.4, 117.8, 111.5, 110.1, 48.63, 32.8, 23.8, 23.7. IR, vmax/cm−1: 2986, 2891, 1777, 1700, 1638, 1521, 1457, 1419, 1244, 1049. HRMS (ES TOF) calculated for [M + Na]+ C25H22N2NaO 389.1624, found 389.1630 (1.5 ppm).
7-(3,4-Dimethylphenyl)-7,12-dihydrobenzo[2,3]azepino[4,5-b]indol-6(5H)-one (7ai). Colorless solid, mp (EtOAc) 192.8–195.4 °C, Rf 0.55 (EtOAc). Yield: 134 mg (0.38 mmol, 76%). 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 10.26 (s, 1H), 7.74 (dd, J = 18.3, 7.8 Hz, 2H), 7.52–7.45 (m, 1H), 7.28–7.15 (m, 3H), 7.08 (t, J = 7.1 Hz, 2H), 6.69–6.63 (m, 1H), 6.51–6.45 (m, 2H), 5.45 (s, 1H), 3.58 (d, J = 2.3 Hz, 3H), 3.38 (d, J = 2.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 171.8, 148.1, 147.5, 137.5, 134.9, 132.5, 129.6, 128.1, 127.4, 126.4, 123.5, 122.7, 122.6, 121.3, 119.4, 119.0, 117.8, 111.6, 111.5, 110.3, 110.2, 55.3, 55.0, 48.6. IR, vmax/cm−1: 2990, 1773, 1759, 1634, 1560, 1507, 1457, 1378, 1246, 1135, 1055. HRMS (ES TOF) calculated for [M + Na]+ C24H20N2NaO 375.1468, found 375.1475 (1.8 ppm).
7-(3-Chlorophenyl)-7,12-dihydrobenzo[2,3]azepino[4,5-b]indol-6(5H)-one (7aj). Colorless solid, mp (EtOAc) 243.9–245.9 °C, Rf 0.5 (EtOAc/Hex, 1:1). Yield: 120 mg (0.34 mmol, 67%). 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.41 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.73 (dd, J = 7.7, 1.7 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.25–7.20 (m, 3H), 7.18 (dd, J = 7.5, 1.4 Hz, 1H), 7.15–7.11 (m, 2H), 7.11–7.04 (m, 1H), 6.90–6.86 (m, 1H), 6.85 (d, J = 1.7 Hz, 1H), 5.57 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 171.0, 139.9, 137.5, 134.5, 132.8, 132.7, 130.2, 128.2, 127.4, 126.7, 126.5, 126.2, 125.2, 123.7, 122.7, 122.4, 121.4, 119.6, 117.9, 111.6, 109.5, 48.3. IR, vmax/cm−1: 3002, 1773, 1759, 1638, 1556, 1509, 1451, 1378, 1242, 1053. HRMS (ES TOF) calculated for [M + Na]+ C22H15ClN2NaO 381.0765, found 381.0773 (2.1 ppm).
7-(4-Ethylphenyl)-7,12-dihydrobenzo[2,3]azepino[4,5-b]indol-6(5H)-one (7ak). Colorless solid, mp (EtOAc) 241.0–243.2 °C, Rf 0.49 (EtOAc). Yield: 139 mg (0.4 mmol, 79%). 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 10.32 (d, J = 1.7 Hz, 1H), 7.76–7.69 (m, 2H), 7.49 (d, J = 8.2 Hz, 1H), 7.25–7.17 (m, 2H), 7.17–7.12 (m, 1H), 7.11–7.05 (m, 2H), 6.92 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 5.47 (s, 1H), 2.40 (q, J = 7.5 Hz, 2H), 1.02 (t, J = 7.6 Hz, 3H).13C NMR (101 MHz, DMSO-d6) δ 171.7, 142.0, 137.5, 134.7 (2C), 132.5, 128.0, 127.7 (2C), 127.6, 126.4, 126.3 (2C), 123.4, 122.5, 122.4, 121.3, 119.4, 117.8, 111.5, 110.2, 48.5, 27.6, 15.4. IR, vmax/cm−1: 3283, 3007, 2365, 1773, 1652, 1555, 1481, 1229, 1055. HRMS (ES TOF) calculated for [M + Na]+ C24H20N2NaO 375.1468, found 375.1457 (−2.9 ppm).
9-Bromo-7-phenyl-7,12-dihydrobenzo[2,3]azepino[4,5-b]indol-6(5H)-one (7ba). Yellowish solid, mp (EtOAc) 295.2–297.4 °C, Rf 0.39 (EtOAc/Hex, 1:1). Yield: 165 mg (0.41 mmol, 82%). 1H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 10.36 (s, 1H), 8.03 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.33 (t, J = 9.7 Hz, 1H), 7.22 (t, J = 7.6 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 7.11–6.99 (m, 3H), 6.89 (d, J = 7.4 Hz, 2H), 5.58 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 171.5, 137.2, 136.1, 134.9, 134.1, 129.4, 128.5, 128.2 (2C), 126.7, 126.5, 126.4 (2C), 125.0, 123.5, 122.0, 121.4, 120.4, 113.5, 112.1, 109.8, 48.4. IR, vmax/cm−1: 3277, 2994, 1769, 1757, 1638, 1558, 1455, 1401, 1240, 1045. HRMS (ES TOF) calculated for [M + Na]+ C22H15BrN2NaO 425.0260, found 425.0271 (2.6 ppm).
9,10-Dimethyl-7-phenyl-7,12-dihydrobenzo[2,3]azepino[4,5-b]indol-6(5H)-one (7ca). Yellowish solid, mp (EtOAc) 252.3–255.1 °C, Rf 0.55 (EtOAc/Hex, 1:1). Yield: 125 mg (0.36 mmol, 71%). 1H NMR (400 MHz, DMSO-d6) δ (s, 1H), 10.29 (s, 1H), 7.68 (d, J = 9.5 Hz, 1H), 7.48 (s, 1H), 7.26 (s, 1H), 7.17–7.11 (m, 2H), 7.10–7.02 (m, 4H), 6.89 (d, J = 7.3 Hz, 2H), 5.44 (s, 1H), 2.35 (s, 3H), 2.30 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 171.5, 137.5, 136.5, 134.4, 131.6, 131.3, 128.2 (2C), 127.7, 127.6, 126.6, 126.4 (2C), 126.2, 126.1, 123.4, 122.7, 121.3, 117.8, 111.8, 109.7, 48.9, 20.3, 19.9. IR, vmax/cm−1: 2986, 2893, 1777, 1710, 1635, 1522, 1505, 1451, 1363, 1149. HRMS (ES TOF) calculated for [M + Na]+ C24H20N2NaO 375.1468, found 375.1472 (−1.6 ppm).

4. Conclusions

In conclusion, a novel approach towards previously unknown paullone analogs bearing aryl substituent at C-7 was developed. Such paullones could be promising candidates for anticancer drug development as they are structurally similar to 2-(1H-indol-3-yl)acetamides known for their submicromolar antitumor activity. The reported synthetic approach is based on the reaction of readily available cyanoketones 14 and involves three steps: (1) acid-mediated hydrolysis of nitrile function; (2) assembly of a seven-membered lactam ring; and (3) Fischer indolization. Evaluation of the bioactivity of the synthesized paullones 7 is currently under way.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28052324/s1, Figures S1–S4: 1H and 13C NMR spectral charts for starting cyanoketones 14g,i; Figures S5–S30: 1H and 13C NMR spectral charts for 7-arylpaullones 7aa-ak,ba,ca; Figures S31–S52: 1H and 13C NMR spectral charts for 4-(2-aminophenyl)-4-oxo-2-arylbutanoic acids 15a-k; Figures S53–S74: 1H and 13C NMR spectral charts for 3-aryl-3,4-dihydro-1H-benzo[b]azepine-2,5-diones 16a-k.

Author Contributions

D.A.A.—investigation, data analysis, and funding acquisition; A.S.A.—investigation; E.A.A.—investigation; N.A.A.—investigation, conceptualization, supervision, and data analysis; A.V.L.—original draft, review, and editing; A.V.A.—supervision and data analysis. All authors have read and agreed to the published version of the manuscript.

Funding

Synthetic studies performed in the frame of this project were supported by grants from the Russian Science Foundation (Grant No. 21-73-00044). This work was supported by the Russian Science Foundation No. 21-73-00044, https://rscf.ru/project/21-73-00044/ (last accessed 27 February 2023).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Supporting data including NMR spectral charts are available from the authors.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not available.

References

  1. Power, D.P.; Lozach, O.; Meijer, L.; Grayson, D.H.; Connon, S.J. Concise Synthesis and CDK/GSK Inhibitory Activity of the Missing 9-Azapaullones. Bioorg. Med. Chem. Lett. 2010, 20, 4940–4944. [Google Scholar] [CrossRef]
  2. Leost, M.; Schultz, C.; Link, A.; Wu, Y.-Z.; Biernat, J.; Mandelkow, E.-M.; Bibb, J.A.; Snyder, G.L.; Greengard, P.; Zaharevitz, D.W.; et al. Paullones Are Potent Inhibitors of Glycogen Synthase Kinase-3β and Cyclin-Dependent Kinase 5/P25. Eur. J. Biochem. 2000, 267, 5983–5994. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Fischer, P.; Lane, D. Inhibitors of Cyclin-Dependent Kinases as Anti-Cancer Therapeutics. Curr. Med. Chem. 2000, 7, 1213–1245. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Sielecki, T.M.; Boylan, J.F.; Benfield, P.A.; Trainor, G.L. Cyclin-Dependent Kinase Inhibitors: Useful Targets in Cell Cycle Regulation. J. Med. Chem. 2000, 43, 1–18. [Google Scholar] [CrossRef] [PubMed]
  5. Becker, A.; Kohfeld, S.; Lader, A.; Preu, L.; Pies, T.; Wieking, K.; Ferandin, Y.; Knockaert, M.; Meijer, L.; Kunick, C. Development of 5-Benzylpaullones and Paullone-9-Carboxylic Acid Alkyl Esters as Selective Inhibitors of Mitochondrial Malate Dehydrogenase (MMDH). Eur. J. Med. Chem. 2010, 45, 335–342. [Google Scholar] [CrossRef]
  6. Kozikowski, A.P.; Ma, D.; Brewer, J.; Sun, S.; Costa, E.; Romeo, E.; Guidotti, A. Chemistry, Binding Affinities, and Behavioral Properties of a New Class of “Antineophobic” Mitochondrial DBI Receptor Complex (MDRC) Ligands. J. Med. Chem. 1993, 36, 2908–2920. [Google Scholar] [CrossRef]
  7. Schultz, C.; Link, A.; Leost, M.; Zaharevitz, D.W.; Gussio, R.; Sausville, E.A.; Meijer, L.; Kunick, C. Paullones, a Series of Cyclin-Dependent Kinase Inhibitors: Synthesis, Evaluation of CDK1/Cyclin B Inhibition, and in Vitro Antitumor Activity. J. Med. Chem. 1999, 42, 2909–2919. [Google Scholar] [CrossRef]
  8. Zaharevitz, D.W.; Gussio, R.; Leost, M.; Senderowicz, A.M.; Lahusen, T.; Kunick, C.; Meijer, L.; Sausville, E.A. Discovery and Initial Characterization of the Paullones, a Novel Class of Small-Molecule Inhibitors of Cyclin-Dependent Kinases. Cancer Res. 1999, 59, 2566–2569. [Google Scholar]
  9. Yuskaitis, C.J.; Jope, R.S. Glycogen Synthase Kinase-3 Regulates Microglial Migration, Inflammation, and Inflammation-Induced Neurotoxicity. Cell. Signal. 2009, 21, 264–273. [Google Scholar] [CrossRef] [Green Version]
  10. Donald, R.G.K.; Zhong, T.; Meijer, L.; Liberator, P.A. Characterization of Two T. Gondii CK1 Isoforms. Mol. Biochem. Parasitol. 2005, 141, 15–27. [Google Scholar] [CrossRef]
  11. Guendel, I.; Agbottah, E.T.; Kehn-Hall, K.; Kashanchi, F. Inhibition of Human Immunodeficiency Virus Type-1 by Cdk Inhibitors. AIDS Res. Ther. 2010, 7, 7. [Google Scholar] [CrossRef] [Green Version]
  12. Gong, L.; Hirschfeld, D.; Tan, Y.-C.; Heather Hogg, J.; Peltz, G.; Avnur, Z.; Dunten, P. Discovery of Potent and Bioavailable GSK-3β Inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 1693–1696. [Google Scholar] [CrossRef] [PubMed]
  13. Knockaert, M.; Wieking, K.; Schmitt, S.; Leost, M.; Grant, K.M.; Mottram, J.C.; Kunick, C.; Meijer, L. Intracellular Targets of Paullones. J. Biol. Chem. 2002, 277, 25493–25501. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Denis, J.G.; Franci, G.; Altucci, L.; Aurrecoechea, J.M.; de Lera, Á.R.; Álvarez, R. Synthesis of 7-Alkylidene-7,12-Dihydroindolo[3,2-d]Benzazepine-6-(5H)-Ones (7-Alkylidene-Paullones) by N-Cyclization–Oxidative Heck Cascade and Characterization as Sirtuin Modulators. Org. Biomol. Chem. 2015, 13, 2800–2810. [Google Scholar] [CrossRef] [Green Version]
  15. Tsyshchuk, I.E.; Vorobyeva, D.V.; Peregudov, A.S.; Osipov, S.N. Cu-Catalyzed Carbenoid Functionalization of Indoles by Methyl 3,3,3-Trifluoro-2-Diazopropionate. Eur. J. Org. Chem. 2014, 2014, 2480–2486. [Google Scholar] [CrossRef]
  16. Aksenov, A.V.; Smirnov, A.N.; Magedov, I.V.; Reisenauer, M.R.; Aksenov, N.A.; Aksenova, I.V.; Pendleton, A.L.; Nguyen, G.; Johnston, R.K.; Rubin, M.; et al. Activity of 2-Aryl-2-(3-Indolyl)Acetohydroxamates against Drug-Resistant Cancer Cells. J. Med. Chem. 2015, 58, 2206–2220. [Google Scholar] [CrossRef] [Green Version]
  17. Segat, G.C.; Moreira, C.G.; Santos, E.C.; Heller, M.; Schwanke, R.C.; Aksenov, A.V.; Aksenov, N.A.; Aksenov, D.A.; Kornienko, A.; Marcon, R.; et al. A New Series of Acetohydroxamates Shows in Vitro and in Vivo Anticancer Activity against Melanoma. Investig. New Drugs 2020, 38, 977–989. [Google Scholar] [CrossRef]
  18. Aksenov, D.A.; Aksenov, A.V.; Prityko, L.A.; Aksenov, N.A.; Frolova, L.V.; Rubin, M. Methylation of 2-Aryl-2-(3-Indolyl)Acetohydroxamic Acids and Evaluation of Cytotoxic Activity of the Products. Molbank 2021, 2022, M1307. [Google Scholar] [CrossRef]
  19. Aksenov, A.V.; Smirnov, A.N.; Aksenov, N.A.; Aksenova, I.V.; Frolova, L.V.; Kornienko, A.; Magedov, I.V.; Rubin, M. Metal-Free Transannulation Reaction of Indoles with Nitrostyrenes: A Simple Practical Synthesis of 3-Substituted 2-Quinolones. Chem. Commun. 2013, 49, 9305. [Google Scholar] [CrossRef]
  20. Aksenov, A.V.; Aksenov, N.A.; Dzhandigova, Z.V.; Aksenov, D.A.; Voskressensky, L.G.; Nenajdenko, V.G.; Rubin, M. Direct Reductive Coupling of Indoles to Nitrostyrenes En Route to (Indol-3-Yl)Acetamides. RSC Adv. 2016, 6, 93881–93886. [Google Scholar] [CrossRef] [Green Version]
  21. Aksenov, A.V.; Aksenov, N.A.; Aksenov, D.A.; Khamraev, V.F.; Rubin, M. Nitrostyrenes as 1,4- CCNO -Dipoles: Diastereoselective Formal [4+1] Cycloaddition of Indoles. Chem. Commun. 2018, 54, 13260–13263. [Google Scholar] [CrossRef] [PubMed]
  22. Aksenov, A.V.; Aksenov, D.A.; Arutiunov, N.A.; Aksenov, N.A.; Aleksandrova, E.V.; Zhao, Z.; Du, L.; Kornienko, A.; Rubin, M. Synthesis of Spiro[Indole-3,5′-Isoxazoles] with Anticancer Activity via a Formal [4 + 1]-Spirocyclization of Nitroalkenes to Indoles. J. Org. Chem. 2019, 84, 7123–7137. [Google Scholar] [CrossRef] [PubMed]
  23. Aksenov, A.V.; Kirilov, N.K.; Arutiunov, N.A.; Aksenov, D.A.; Kuzminov, I.K.; Aksenov, N.A.; Turner, D.N.; Rogelj, S.; Kornienko, A.; Rubin, M. Reductive Cleavage of 4′ H -Spiro[Indole-3,5′-Isoxazoles] En Route to 2-(1 H -Indol-3-Yl)Acetamides with Anticancer Activities. J. Org. Chem. 2022, 87, 13955–13964. [Google Scholar] [CrossRef] [PubMed]
  24. Falke, H.; Chaikuad, A.; Becker, A.; Loaëc, N.; Lozach, O.; Abu Jhaisha, S.; Becker, W.; Jones, P.G.; Preu, L.; Baumann, K.; et al. 10-Iodo-11 H -Indolo[3,2- c ]Quinoline-6-Carboxylic Acids Are Selective Inhibitors of DYRK1A. J. Med. Chem. 2015, 58, 3131–3143. [Google Scholar] [CrossRef] [PubMed]
  25. Lee, S.-Y.; Lee, S.; Choi, E.; Ham, O.; Lee, C.Y.; Lee, J.; Seo, H.-H.; Cha, M.-J.; Mun, B.; Lee, Y.; et al. Small Molecule-Mediated up-Regulation of MicroRNA Targeting a Key Cell Death Modulator BNIP3 Improves Cardiac Function Following Ischemic Injury. Sci. Rep. 2016, 6, 23472. [Google Scholar] [CrossRef] [Green Version]
  26. Reichwald, C.; Shimony, O.; Dunkel, U.; Sacerdoti-Sierra, N.; Jaffe, C.L.; Kunick, C. 2-(3-Aryl-3-Oxopropen-1-Yl)-9- Tert -Butyl-Paullones: A New Antileishmanial Chemotype. J. Med. Chem. 2008, 51, 659–665. [Google Scholar] [CrossRef]
  27. Kunick, C.; Lauenroth, K.; Wieking, K.; Xie, X.; Schultz, C.; Gussio, R.; Zaharevitz, D.; Leost, M.; Meijer, L.; Weber, A.; et al. Evaluation and Comparison of 3D-QSAR CoMSIA Models for CDK1, CDK5, and GSK-3 Inhibition by Paullones. J. Med. Chem. 2004, 47, 22–36. [Google Scholar] [CrossRef]
  28. Orban, O.; Korn, R.; Unger, L.; Yildiz, A.; Kunick, C. 3-Chlorokenpaullone. Molbank 2015, 2015, M856. [Google Scholar] [CrossRef] [Green Version]
  29. Orban, O.C.F.; Korn, R.S.; Benítez, D.; Medeiros, A.; Preu, L.; Loaëc, N.; Meijer, L.; Koch, O.; Comini, M.A.; Kunick, C. 5-Substituted 3-Chlorokenpaullone Derivatives Are Potent Inhibitors of Trypanosoma Brucei Bloodstream Forms. Bioorg. Med. Chem. 2016, 24, 3790–3800. [Google Scholar] [CrossRef]
  30. Lee, S.; Lee, S.; Cheon, C.-H. Concise Total Syntheses of Paullone and Kenpaullone via Cyanide-Catalyzed Intramolecular Imino-Stetter Reaction. Synthesis 2017, 49, 4247–4253. [Google Scholar] [CrossRef] [Green Version]
  31. Soto, S.; Vaz, E.; Dell’Aversana, C.; Álvarez, R.; Altucci, L.; de Lera, Á.R. New Synthetic Approach to Paullones and Characterization of Their SIRT1 Inhibitory Activity. Org. Biomol. Chem. 2012, 10, 2101. [Google Scholar] [CrossRef]
  32. Chen, Z.; Wang, X. A Pd-Catalyzed, Boron Ester-Mediated, Reductive Cross-Coupling of Two Aryl Halides to Synthesize Tricyclic Biaryls. Org. Biomol. Chem. 2017, 15, 5790–5796. [Google Scholar] [CrossRef]
  33. Harish, B.; Subbireddy, M.; Suresh, S. N-Heterocyclic Carbene (NHC)-Catalysed Atom Economical Construction of 2,3-Disubstituted Indoles. Chem. Commun. 2017, 53, 3338–3341. [Google Scholar] [CrossRef]
  34. Arun, V.; Pilania, M.; Kumar, D. Access to 2-Arylindoles via Decarboxylative C−C Coupling in Aqueous Medium and to Heteroaryl Carboxylates under Base-Free Conditions Using Diaryliodonium Salts. Chem. An Asian J. 2016, 11, 3345–3349. [Google Scholar] [CrossRef] [PubMed]
  35. Aksenov, A.; Aksenov, N.; Nadein, O.; Aksenova, I. Nitroethane in Polyphosphoric Acid: A New Reagent for Acetamidation and Amination of Aromatic Compounds. Synlett 2010, 2010, 2628–2630. [Google Scholar] [CrossRef]
  36. Aksenov, A.V.; Aksenov, D.A.; Griaznov, G.D.; Aksenov, N.A.; Voskressensky, L.G.; Rubin, M. Unexpected Cyclization of 2-(2-Aminophenyl)Indoles with Nitroalkenes to Furnish Indolo[3,2-c]Quinolines. Org. Biomol. Chem. 2018, 16, 4325–4332. [Google Scholar] [CrossRef] [PubMed]
  37. Aksenov, N.A.; Aksenov, D.A.; Skomorokhov, A.A.; Prityko, L.A.; Aksenov, A.V.; Griaznov, G.D.; Rubin, M. Synthesis of 2-(1 H -Indol-2-Yl)Acetamides via Brønsted Acid-Assisted Cyclization Cascade. J. Org. Chem. 2020, 85, 12128–12146. [Google Scholar] [CrossRef] [PubMed]
  38. Aksenov, N.A.; Aksenov, A.V.; Prityko, L.A.; Aksenov, D.A.; Aksenova, D.S.; Nobi, M.A.; Rubin, M. Oxidative Cyclization of 4-(2-Aminophenyl)-4-oxo-2-phenylbutanenitriles into 2-(3-Oxoindolin-2-ylidene)acetonitriles. ACS Omega 2022, 7, 14345–14356. [Google Scholar] [CrossRef]
Molecules 28 02324 g001 550
Figure 1. Some biologically active paullones.
Figure 1. Some biologically active paullones.
Molecules 28 02324 g001
Molecules 28 02324 sch001 550
Scheme 1. Indole hydroxamic acids 3 and indole amides 5 as structural analogs of 7-aryl substituted paullones 7.
Scheme 1. Indole hydroxamic acids 3 and indole amides 5 as structural analogs of 7-aryl substituted paullones 7.
Molecules 28 02324 sch001
Molecules 28 02324 sch002 550
Scheme 2. Common approaches to synthesis of the paullone derivatives.
Scheme 2. Common approaches to synthesis of the paullone derivatives.
Molecules 28 02324 sch002
Molecules 28 02324 sch003 550
Scheme 3. Overview of speculative approaches to paullones 7 based on the previously reported reactions of indoles with nitrostyrenes 2.
Scheme 3. Overview of speculative approaches to paullones 7 based on the previously reported reactions of indoles with nitrostyrenes 2.
Molecules 28 02324 sch003
Molecules 28 02324 sch004 550
Scheme 4. Preparation of the starting acids 15.
Scheme 4. Preparation of the starting acids 15.
Molecules 28 02324 sch004
Molecules 28 02324 sch005 550
Scheme 5. Intramolecular cyclization of acids 15 to keto-lactams 16.
Scheme 5. Intramolecular cyclization of acids 15 to keto-lactams 16.
Molecules 28 02324 sch005
Molecules 28 02324 sch006 550
Scheme 6. Library of 7-aryl paullones (7) synthesized by the procedure developed herein.
Scheme 6. Library of 7-aryl paullones (7) synthesized by the procedure developed herein.
Molecules 28 02324 sch006
Table
Table 1. Screening of the reaction conditions for Fisher indolization of keto-lactam 16a to 7-phenyl paullone 7aa.
Table 1. Screening of the reaction conditions for Fisher indolization of keto-lactam 16a to 7-phenyl paullone 7aa.
Molecules 28 02324 i001
No.Acid 1 g/mmolSolventTemp. (°C)Time (h)Yield (%)
1PPA 80%-1000.53
2PPA 80%-8016
3PPA 87%-801-
4PPA 87% (0.5 g)/H3PO3 (0.5 g)-801-
5MsOH-901-
6PPA 80%EtOAc70129
7PPA 80%EtOH70124
8.1
8.2		EtOH/AcOH (1 mmol)
Then, PPA 80% (0.5 g)		EtOH
EtOH		r.t.
70		0.5
0.5		-
79
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Aksenov, D.A.; Akulova, A.S.; Aleksandrova, E.A.; Aksenov, N.A.; Leontiev, A.V.; Aksenov, A.V. An Effective Synthesis of Previously Unknown 7-Aryl Substituted Paullones. Molecules 2023, 28, 2324. https://doi.org/10.3390/molecules28052324

AMA Style

Aksenov DA, Akulova AS, Aleksandrova EA, Aksenov NA, Leontiev AV, Aksenov AV. An Effective Synthesis of Previously Unknown 7-Aryl Substituted Paullones. Molecules. 2023; 28(5):2324. https://doi.org/10.3390/molecules28052324

Chicago/Turabian Style

Aksenov, Dmitrii A., Alesia S. Akulova, Elena A. Aleksandrova, Nicolai A. Aksenov, Alexander V. Leontiev, and Alexander V. Aksenov. 2023. "An Effective Synthesis of Previously Unknown 7-Aryl Substituted Paullones" Molecules 28, no. 5: 2324. https://doi.org/10.3390/molecules28052324

APA Style

Aksenov, D. A., Akulova, A. S., Aleksandrova, E. A., Aksenov, N. A., Leontiev, A. V., & Aksenov, A. V. (2023). An Effective Synthesis of Previously Unknown 7-Aryl Substituted Paullones. Molecules, 28(5), 2324. https://doi.org/10.3390/molecules28052324

Article Metrics

Back to TopTop