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Article

Using Quinolin-4-Ones as Convenient Common Precursors for a Metal-Free Total Synthesis of Both Dubamine and Graveoline Alkaloids and Diverse Structural Analogues

by
Rodrigo Abonia
1,*,
Lorena Cabrera
1,
Diana Arteaga
1,
Daniel Insuasty
1,2,*,
Jairo Quiroga
1,
Paola Cuervo
1,3 and
Henry Insuasty
4
1
Research Group of Heterocyclic Compounds, Department of Chemistry, Universidad del Valle, Cali A.A. 25360, Colombia
2
Grupo de Investigación en Química y Biología, Departamento de Química y Biología, Universidad del Norte, Barranquilla A.A. 081007, Colombia
3
Grupo de Estudios en Síntesis y Aplicaciones de Compuestos Heterocíclicos, Facultad de Ciencias, Departamento de Química, Universidad Nacional de Colombia, Bogotá A.A. 14490, Colombia
4
Departamento de Química, Universidad de Nariño, Calle 18 No. 50-02 Torobajo, Pasto 520001, Colombia
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(9), 1959; https://doi.org/10.3390/molecules29091959
Submission received: 18 February 2024 / Revised: 12 March 2024 / Accepted: 14 March 2024 / Published: 25 April 2024
(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)
Browse Figures
Figure 1
<p>Structures of alkaloids Graveoline <b>1</b> and Dubamine <b>2</b> and the antibacterial compounds <b>3</b> and <b>4</b>.</p> "> Scheme 1
<p>Some representative synthetic approaches for obtaining Graveoline <b>1</b>.</p> "> Scheme 2
<p>Some representative synthetic approaches for obtaining Dubamine <b>2</b> and its derivatives.</p> "> Scheme 3
<p>Proposed synthetic sketch of the synthesis of alkaloids Graveoline <b>1</b> and Dubamine <b>2</b> and their structural analogues <b>23</b> and <b>24</b>, respectively.</p> "> Scheme 4
<p>Total synthesis of Graveoline <b>1</b>, Dubamine <b>2</b> and their corresponding quinolinic-analogues (<b>23</b>,<b>24</b>)<b>h</b> from dihydroquinolin-4-ones <b>22h</b>,<b>i</b> through the two-step synthetic approaches developed in this research work.</p> ">
Versions Notes

Abstract

:
The Rutaceae family is one of the most studied plant families due to the large number of alkaloids isolated from them with outstanding biological properties, among them the quinoline-based alkaloids Graveoline 1 and Dubamine 2. The most common methods for the synthesis of alkaloids 1 and 2 and their derivatives involves cycloaddition reactions or metal-catalyzed coupling processes but with some limitations in scope and functionalization of the quinoline moiety. As a continuation of our current studies on the synthesis and chemical transformation of 2-aminochalcones, we are reporting here an efficient metal-free approach for the total synthesis of alkaloids 1 and 2 along with their analogues with structural diversity, through a two-step sequence involving intramolecular cyclization, oxidation/aromatization, N-methylation and oxidative C-C bond processes, starting from dihydroquinolin-4-ones as common precursors for the construction of the structures of both classes of alkaloids.

1. Introduction

Heterocyclic compounds containing quinoline nuclei have a special place in medicinal chemistry. They are substructures of more complex systems usually related to biologically active synthetic or naturally occurring products (mainly alkaloids) [1,2,3,4,5]. These nuclei have been considered as good starting materials for the synthesis of new compounds with a wide spectrum of biological activities such as antimycobacterial, antiparasitic, antibacterial, cytotoxic, antineoplastic, antimalarial, antiviral, antitumor, immunomodulatory, antiangiogenic, antileishmanial, antiarrhythmic, local anesthetic and anti-inflammatory activities [6,7,8,9,10].
Plants of the family Rutaceae are among the most studied, due to the large number of alkaloids that they provide and their pharmacological importance [11]. In particular, various studies on the Haplopylum dubium species have reported the existence of a series of quinoline-type alkaloids, among them Graveoline 1 and Dubamine 2, as seen in Figure 1 [12].
Both compounds have displayed remarkable antimicrobial activity associated with their structural similarity to the quinolinic antifungal and molluscicidal agents 3 and 4, respectively [13,14]. Additionally, Graveoline 1 has been identified as a stimulant of the CNS [15,16] and as phytotoxic [17], while Dubamine 2 has displayed antitumor activity, as shown in some previous studies [18].
Some synthetic approaches have previously been reported to construct the structures of alkaloids 1 [18,19,20,21,22,23,24,25,26] and 2 [11,27,28,29,30,31,32,33,34,35,36]. Thus, Graveoline 1 and its derivatives were obtained through different strategies like the treatment of Dubamine 2 with a methylating agent and subsequent oxidation (Scheme 1a) [18]. Treatment of o-iodoanilines 5 with terminal acetylenic carbinols 6, catalyzed by palladium, afforded acetylenic derivative 7, which after several steps was converted into Graveoline 1 and its derivatives in moderate yields (Scheme 1b) [11]. The Pd-catalyzed reductive carbonylation of 2-nitrochalcones 8 under a CO atmosphere and toluene as a solvent afforded the alkaloid Norgraveoline 9 in a 78% yield; its subsequent treatment with CH3I led to the obtainment of the expected Graveoline 1 (Scheme 1c) [20].
On the other hand, the most common methods for the synthesis of Dubamine 2 involve the coupling reaction of organic electrophiles with diverse organometallic complexes. Thus, the reaction of the triflate 10 with the tin derivative 11 led to the obtainment of alkaloid 2 in a 79% yield (Scheme 2a) [27]. Similarly, Dubamine 2 was obtained in a 44% yield from a Pd-catalyzed reaction of the o-iodoaniline 12 (Scheme 2b) [11]. A BF3-catalyzed reaction was also proposed for the synthesis of 2 starting from aniline 14. Although this process proceeded via an imino Diels–Alder reaction between the imine 16 and vinyl ether, the authors could recover the expected alkaloid 2 in only a 1% yield (Scheme 2c) [28]. As an alternative to the previous inefficient process, Kouznetsov et al. proposed the synthesis of a series of quinolines 18 (including Dubamine 2, when R = R1 = R2 = R3 = H) using the tetrahydroquinoline intermediates 17, obtained from a Bi-catalyzed tri-component reaction, and their subsequent aromatization with sulfur at a high temperature, obtaining the target products in 40–62% overall yields (Scheme 2d) [29].
Although the usefulness of the metal-catalyzed coupling reactions described above for the synthesis of Graveoline 1 and Dubamine 2 is evident, it is also known that these strategies do not allow a diverse functionalization of the benzene ring of the quinoline moiety, which is a fundamental aspect for programs routed toward discovering and developing lead bioactive molecules inspired by quinoline-based drugs. Therefore, proposals of more efficient procedures of broader scope for the synthesis of these kinds of alkaloids and their derivatives are highly desired.
Thus, we are reporting here a metal-free alternative method for the total synthesis of Graveoline 1 and Dubamine 2 alkaloids and a series of their analogues starting from substituted dihydroquinolin-4-ones as common precursors for both kinds of alkaloidal frameworks.

2. Results and Discussion

As a continuation of our current studies directed toward the synthesis and chemical transformations of 2-aminochalcones [37,38,39,40], we planned to obtain a series of 2-aminochalcones 21, along with their intramolecular cyclization products (i.e., the corresponding dihydroquinolin-4-ones 22), as target intermediates to be evaluated as the key starting materials for developing of an alternative and short-step approach for the synthesis of Graveoline 1 and Dubamine 2 alkaloids, as well as a series of their structural analogues 23 and 24, respectively.
Before beginning the experiments, the synthesis of the target compounds 1, 2, 23 and 24 was visualized according to the following synthetic sketch shown in Scheme 3.
The present study was initiated with the synthesis of the starting 2-aminochalcones 21a–g which were readily obtained in 60–97% yields by heating alcoholic solutions of equimolar amounts of o-aminoacetophenones 19a (R = H) and the corresponding aryl aldehydes 20a–g (see R1 in Table 1) in the presence of 20% aq NaOH (see Section 3 Materials and Methods) [37,38]. Subsequently, the intramolecular cyclization of chalcones 21, catalyzed by Amberlyst®-15 [38], afforded the corresponding dihydroquinolin-4-ones 22a–h in 65–94% yields (see Table 1 and Section 3 Materials and Methods).
All the starting chalcones 21 were yellow-to-orange solids, whereas their corresponding dihydroquinolin-4-ones 22 were pale yellow-colored compounds exhibiting strong fluorescence under exposure to long-wavelength UV irradiation in both solid-state and solution forms, in agreement with previous studies on these kinds of systems [41,42,43]. This characteristic easily permitted us to follow the reaction progress by TLC, as well as to check the purity of the key compounds 22. The main spectroscopic features for compounds 22 corresponded to the presence of N-H and C=O absorption bands in the ranges of 3302–3336 cm−1 and 1606–1660 cm−1, respectively, in the IR spectra, in addition to two double-doublets for C-3(Ha)/C-3(Hb) protons [carbon] (in the ranges of 2.54–2.72/2.72–2.91 ppm and [45.2–46.0] ppm) and a double-doublet for the H-2 [C-2] proton [carbon] (in the ranges of 4.60–4.82 ppm and [56.0–57.3] ppm) in the 1H and 13C NMR spectra, respectively.
Once our key dihydroquinolin-4-ones 22 were synthesized, we turned our attention toward the Graveoline 1 and its analogues 23 as described in Scheme 3. For this purpose, we planned a sequential strategy consisting in an N-methylation of 22 followed by an oxidative C-C process to afford 23. Thus, as a model reaction, a mixture of the dihydroquinolin-4-one 22a (R = H, R1 = 4-Br) (0.5 g, 1.0 equiv), anhydrous Na2CO3 (1.5 equiv), CH3I (5.0 equiv) and p-dioxane (3 mL) was subjected to heating at 100 °C. After 72 h of heating, the total consumption of the starting material 22a was not achieved and a complex mixture of products was detected by TLC. In a new experiment, the same reaction was repeated but p-dioxane was switched with DMF. After heating at 190 °C for 2 h, the starting compound 22a was consumed (TLC control), the solvent was removed under reduced pressure, water (3 mL) was added to the residue and the product formed was extracted with ethyl acetate, affording the corresponding N-methyl derivative 25a as a greenish fluorescent solid in a 68% yield. (Complete characterization data for compound 25a are supplied in the Section 3 Materials and Methods). Subsequently, several attempts to oxidize compound 25a were performed in order to obtain our target product 23a. The results are summarized in Table 2. Initially, compound 25a (0.3 g, 1.0 equiv) was treated with NBS (1.0 equiv) in MeOH in the presence of silica gel for 1 h to try and induce the α-bromination reaction [44,45]. After consumption of the starting compound 25a (TLC control), the silica gel was filtered and the resulting solution was subjected to heating at 50 °C for two additional hours, in the presence of KOH, with the purpose of inducing a dehydrohalogenation process. However, a complex mixture of products was obtained after the signaled heating time (entry 1, Table 2). In a second experiment, a mixture of compound 25a (1.0 equiv) and p-chloranil [46,47] (1.2 equiv) was subjected to reflux in DCM (3 mL) for 24 h (entry 2). Afterwards, the desired product 23a was isolated, but at 8% only. In an attempt to improve the yield of product 23a, the above reaction was repeated, switching DCM with DMF and heating for 2 h (entry 3). After removing the solvent under reduced pressure and purifying the resulting residue, the expected oxidized product 23a was obtained as a yellow solid in a 61% yield.
Once this two-step sequence (i.e., N-methylation followed by the C-C oxidative process) was optimized for the synthesis of compound 23a, this approach was extended to the remaining dihydroquinolin-4-ones 22b–g. Reactions proceeded in a similar way and the products 23a–g were obtained in 61–94% yields; see Table 3 and the Section 3 Materials and Methods.
The main spectroscopic features for compounds 23 corresponded to the absence of the N-H bands and the presence of C=O absorption bands in the range of 1606–1660 cm−1 in the IR spectra, as well as two singlets for N-CH3 and 3- =CH protons [carbons] (in the ranges of 3.61–3.98 [37.2–39.5] ppm and 6.26–6.91 [110.2–112.8] ppm) in the 1H and 13C NMR spectra, respectively.
Continuing with our purposes depicted in Scheme 3, the synthesis of Dubamine 2 and analogues 24 was planned in a three-step reduction/dehydration/oxidation sequence from the same key dihydroquinolin-4-ones 22, as shown in Scheme 3 and Table 4. Thus, as a model reaction, a solution of dihydroquinolin-4-one 22a (R = H, R1 = 4-Br) (0.5 g, 1.0 equiv) in MeOH (3 mL) was treated with NaBH4 (2.0 equiv) at room temperature in order to reduce the carbonyl group. Upon consumption of compound 22a (TLC control), the solvent was removed under reduced pressure and the product was extracted with DCM to afford the expected 4-hydroxytetrahydroquinoline 26a in a 90% yield and good purity. (Complete characterization data for compound 26a are supplied in the Section 3 Materials and Methods). Subsequently, a sample of the derivative 26a (0.3 g, 1.0 equiv) was subjected to a dehydration reaction with the aim of obtaining the dehydrated intermediate 27a. Several attempts were performed, as shown in Table 4.
Initially, an open-vessel alkaline methanolic solution containing the previously obtained 4-hydroxyl-derivative 26a was subjected to reflux (entry 1, Table 4). After 3 h of heating (TLC control), we noticed that the starting compound 26a was not consumed; hence, the dehydration reaction did not proceed. In a second attempt, compound 26a was similarly subjected to reflux in MeOH (3 mL) in the presence of p-toluenesulfonic acid (PTSA) (2.0 equiv) as a catalyst (entry 2, Table 4). After 2 h of heating (TLC control), the formation of a complex and inseparable mixture of products was observed. Then, the same reaction was repeated but MeOH was switched with dry toluene at reflux (entry 3, Table 4). After 3 h of heating, several products were formed and the main component of the mixture was isolated and purified by column chromatography. To our surprise and satisfaction, this product corresponded to our target aromatized compound 24a, although in a 20% yield only. This finding indicated that the dehydration and oxidation processes proceeded sequentially in only one step. In this approach, the oxidant agent [O] should be the oxygen in the air (open-vessel conditions), potentialized by the stability gained by the molecule through the aromatization process of the dihydropyridine moiety of the intermediate 27a. Pursuing an improvement in the reaction yield of compound 24a, the above experiment was repeated using p-dioxane at room temperature instead of toluene (entry 4, Table 4). Interestingly, this variation afforded product 24a in an 80% yield upon 2 h of stirring. It is worth mentioning that in neither of the cases of entries 3 and 4 could the dehydrated intermediate 27a be detected (by TLC) or isolated, suggesting a very fast conversion of 27a into the thermodynamic product 24a.
With the optimized reaction conditions in hand, this two-step (i.e., reduction followed by a sequential dehydration/oxidation) procedure was extended to the remaining dihydroquinolin-4-ones 22b–g. The reactions proceeded in a similar way and quinolines 24a–g were obtained in 70–87% yields (Table 5 and Section 3 Materials and Methods).
The main spectroscopic features for compounds 24 corresponded to the absence of N-H, O-H and C=O absorption bands (signals) in their corresponding IR and NMR spectra. Complete (NMR, mass and elemental analysis) characterization data for compounds 24 are supplied in the Section 3 Materials and Methods.
In order to evaluate the practical synthetic usefulness of the above two developed approaches, we planned the synthesis of the dihydroquinolin-4-ones 22h,i (R = OCH2O and H, respectively) and their subsequent transformation into Graveoline 1, Dubamine 2 and their bis-dioxolo-derivatives 23h and 24h, respectively, as shown in Scheme 4.
The reactions proceeded in a similar way to that described in Table 3 and Table 5. Initially, dihydroquinolin-4-ones 22h,i were obtained in 97% and 87% yields, respectively, from the intramolecular cyclization of their corresponding 2-aminochalcones 21h,i (see Section 3 Materials and Methods). Subsequently, treatment of 22h,i with CH3I followed by the oxidation process with p-chloranil afforded the expected Graveoline alkaloid 1 along with its bis-dioxolo-derivative 23h in 65% and 90% yields, respectively. Alternatively, treatment of 22h, i with NaBH4 followed by the PTSA-catalyzed dehydration/oxidation process in the presence of air afforded the expected Dubamine alkaloid 2 along with its bis-dioxolo-derivative 24h in 81% and 75% yields, respectively. These findings demonstrate the synthetic usefulness of our established protocols.
It is very interesting that both dehydration/oxidation processes performed on compounds 22 occurred in only one step, simplifying the synthesis of Dubamine 1 and its analogues 24. It is also remarkable that all products, Graveoline 1, Dubamine 2 and their analogues 23 and 24, respectively, were obtained in just a two-step sequence starting with dihydroquinolin-4-ones 22. This fact became the main advantage of our metal-free approach in comparison to previous synthetic routes, which require more than two-step sequences and/or mediation of transition metal complexes.

3. Materials and Methods

Melting points were measured on a Büchi melting point apparatus (Flawil, Switzerland) and are uncorrected. All reactions were monitored by TLC with silica gel aluminum plates (Merck 60 F254, Hong Kong, China). Column chromatography was performed with Merck 230–400 mesh silica gel. IR spectra (KBr disks) were recorded on a Shimadzu FTIR 8400 spectrophotometer (Carlsbad, CA, USA). 1H and 13C NMR spectra were run on a Bruker Avance 400 spectrophotometer (Mannheim, Germany) operating at 400 and 100 MHz, respectively, using CDCl3 and (CD3)2SO as solvents and TMS as an internal standard. Mass spectra were obtained on a Shimadzu GCMS 2010-DI-2010 spectrometer (equipped with a direct inlet probe) operating at 70 eV (Carlsbad, CA, USA). Microanalyses were performed on an Agilent CHNS elemental analyzer (Santa Clara, CA, USA), and the values are within ±0.4% of the theoretical values. The starting reagents and solvents were purchased from Aldrich (St. Louis, MO, USA), Sigma (Kanagawa, Japan), Fluka (Buchs, Switzerland) and Merck (analytical reagent grades) and were used without further purification. Regarding the synthesis of the 2-aminochalcones 21, these compounds were obtained from o-aminoacetophenones 19 and benzaldehydes 20 via a Claisen–Schmidt condensation reaction by following the procedure described in references [37,38].
  • (E)-1-(2-Aminophenyl)-3-(4-bromophenyl)prop-2-en-1-one 21a: Yellow solid, 89% yield. M.p. 84–86 °C. FTIR (KBr): ν = [3398, 3300] (NH2), 3037, 2902, 1649 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 6.54 (td, J = 7.9, J = 0.8 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 7.30 (td, J = 8.2, J = 1.2 Hz, 1H), 7.42 (bs, 2H, NH2), 7.59–7.69 (m, 3H, Ar-H × 2 and =CH), 7.83 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 15.5 Hz, 1H, =CH), 8.09 (d, J = 7.5 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 115.0, 117.4, 117.9 (Cq), 123.9 (Cq), 124.7, 130.7 (Cq), 131.0, 132.0, 132.3, 135.0, 141.0, 152.6 (Cq), 190.8 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 303/301 (10.0/10.3) [M+], 302/300 (15.9/15.22), 146 (100).
  • (E)-1-(2-Aminophenyl)-3-(4-chlorophenyl)prop-2-en-1-one 21b: Yellow solid, 97% yield. M.p. 94–96 °C. FTIR (KBr): ν = [3324, 3328] (NH2), 2990, 2882, 1646 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 6.61 (td, J = 8.4, J = 1.0 Hz, 1H), 6.82 (dd, J = 8.4, J = 1.2 Hz, 1H), 7.30 (td, J = 8.4, J = 1.4 Hz, 1H), 7.42 (bs, 2H, NH2), 7.54 (d, J = 8.4, 2H), 7.63 (d, J = 15.5 Hz, 1H, =CH), 7.91 (d, J = 8.5 Hz, 2H), 7.99 (d, J = 15.5 Hz, 1H, =CH), 8.10 (dd, J = 8.4, J = 1.2 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 114.9, 117.4, 117.9 (Cq), 124.7, 129.4, 130.8, 132.0, 134.5 (Cq), 134.9, 135.0 (Cq), 140.9, 152.6 (Cq), 190.8 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 259/257 (6.8/20.4) [M+], 258/256 (12.9/31.4), 146 (100).
  • (E)-1-(2-Aminophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one 21c: Yellow solid, 60% yield. M.p. 70–72 °C. FTIR (KBr): ν = [3327, 3340] (NH2), 2989, 2982, 1649 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 3.83 (s, 3H, OCH3), 6.60 (t, J = 7.7 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.2 Hz, 2H), 7.29 (t, J = 8.0 Hz, 1H), 7.34 (bs, 2H, NH2), 7.58 (d, J = 15.5 Hz, 1H, =CH), 7.82–7.85 (m, 3H, Ar-H × 2 and =CH), 8.08 (d, J = 8.2 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 55.8 (OCH3), 114.5 114.9, 117.4, 118.2, 121.3 (Cq), 128.2, 130.9 (Cq), 131.7, 134.5, 142.4, 152.4 (Cq), 161.4 (Cq), 191.0 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 253 (32) [M+], 252 (69), 146 (100).
  • (E)-1-(2-Aminophenyl)-3-(p-tolyl)prop-2-en-1-one 21d: Yellow solid, 82% yield. M.p. 96–97 °C. FTIR (KBr): ν = [3327, 3330] (NH2), 2989, 2982, 1649 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.35 (s, 3H, CH3), 6.60 (td, J = 8.1, J = 1.0 Hz, 1H), 6.81 (dd, J = 8.4, J = 0.8 Hz, 1H), 7.24–7.32 (m, 3H), 7.39 (bs, 2H, NH2), 7.63 (d, J = 15.5 Hz, 1H, =CH), 7.77 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 15.5 Hz, 1H, =CH), 8.08 (dd, J = 8.2, J = 1.2 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 21.6 (CH3), 114.9, 117.4, 118.1 (Cq), 122.8, 129.1, 130.0 (Cq), 131.8, 132.8, 134.7, 140.5 (Cq), 142.5, 152.5 (Cq), 190.1 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 237 (28) [M+], 237 (47),146 (100).
  • (E)-1-(2-Aminophenyl)-3-phenylprop-2-en-1-one 21e: Yellow solid, 64% yield. M.p. 174–177 °C. FTIR (KBr): ν = [3290, 3220] (NH2), 2989, 2982, 1649 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 6.63 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.38–7.50 (m, 5H, Ar-H × 3 and NH2), 7.66 (d, J = 15.5 Hz, 1H, =CH), 7.86 (d, J = 6.8 Hz, 2H), 7.96 (d, J = 15.5 Hz, 1H, =CH), 8.10 (d, J = 8.0 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 115.0, 117.4, 118.0 (Cq), 123.9, 129.1, 129.4, 130.6, 131.9, 134.8, 135.5 (Cq), 142.4, 152.5 (Cq), 191.1 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 223 (24) [M+], 222 (35), 146 (100).
  • (E)-1-(2-Aminophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 21f: Yellow solid, 86% yield. M.p. 120–122 °C. FTIR (KBr): ν = [3327, 3340] (NH2), 2989, 2982, 1649 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 3.73 (s, 3H, OCH3), 3.88 (s, 6H, OCH3), 6.62 (t, J = 7.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 7.20 (s, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.40 (bs, 2H, NH2), 7.61 (d, J = 15.5 Hz, 1H, =CH), 7.92 (d, J = 15.5 Hz, 1H, =CH), 8.13 (d, J = 8.1 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 56.6 (OCH3), 60.6 (OCH3), 106.7, 114.9, 117.4, 118.1 (Cq), 123.1 (Cq), 131.1 (Cq), 132.0, 134.7, 139.8 (Cq), 142.9, 152.5 (Cq), 153.6 (Cq), 191.0 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 313 (84) [M+], 312 (100), 146 (88).
  • (E)-1-(2-Aminophenyl)-3-(3,4-dichlorophenyl)prop-2-en-1-one 21g: Yellow solid, 98% yield. M.p. 126–128 °C. FTIR (KBr): ν = [3327, 3345] (NH2), 2990, 2995, 1657 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 6.63 (t, J = 7.9 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 7.31 (t, J = 8.2 Hz, 1H), 7.44 (bs, 2H, NH2), 7.60 (d, J = 15.4 Hz, 1H, =CH), 7.71 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.4, J = 1.9 Hz, 1H), 8.08 (d, J = 15.5 Hz, 1H, =CH), 8.14 (d, J = 8.1 Hz, 1H), 8.27 (d, J = 1.8 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 114.9, 117.4, 117.8 (Cq), 126.1, 129.4, 130.4, 131.4, 132.1, 132.6 (Cq), 135.0, 136.4 (Cq), 136.5 (Cq), 139.6, 152.6 (Cq), 190.1 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 295/293/291 (1.4/7.9/12) [M+], 294/292/290 (2.8/11/15), 146 (100).
  • (E)-1-(6-Aminobenzo[d][1,3]dioxol-5-yl)-3-(benzo[d][1,3]dioxol-5-yl)prop-2-en-1-one 21h: Yellow solid, 70% yield. M.p. 148–151 °C. FTIR (KBr): ν = [3327, 3330] (NH2), 2989, 2982, 1649 (C=O), 1604 (C=C) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 5.95 (s, 2H, OCH2O), 5.99 (s, 2H, OCH2O), 6.32 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.25 (dd, J = 8.1, J = 1.3 Hz, 1H), 7.36 (bs, 2H, NH2), 7.52 (d, J = 15.5 Hz, 1H, =CH), 7.69 (s, 1H), 7.74 (d, J = 15.5 Hz, 1H, =CH) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 101.6 (OCH2O), 102.0 (OCH2O), 107.3, 108.6, 108.9, 109.3, 110.5 (Cq), 122.2, 125.6, 130.4 (Cq), 138.3 (Cq), 141.9, 148.5 (Cq), 149.3 (Cq), 152.1 (Cq), 153.3 (Cq), 188.2 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 311 (4.5) [M+], 310 (4.7), 164 (100).
  • (E)-1-(2-Aminophenyl)-3-(benzo[d][1,3]dioxol-5-yl)prop-2-en-1-one 21i: Yellow solid, 80% yield. M.p. 117–118 °C. FTIR (KBr): ν = [3425, 3309] (NH2), 3070, 2904, 1633 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 6.11 (s, OCH2O, 2H), 6.60 (td, J = 8.0, J = 1.0 Hz, 1H), 6.81 (dd, J = 8.4, J = 1.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 7.26–7.30 (m, 2H), 7.38 (bs, 2H, NH2), 7.59 (d, J = 15.4 Hz, 1H, =CH), 7.63 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 15.0 Hz, 1H, =CH), 8.11 (dd, J = 8.2, J = 1.1 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 102.0 (OCH2O), 107.4, 108.9, 114.9, 117.3, 118.2 (Cq), 121.8, 125.8, 130.1 (Cq), 131.9, 134.6, 142.5, 148.6 (Cq), 149.6 (Cq), 152.5 (Cq), 191.0 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 267 (31) [M+], 266 (51), 146 (100).
Synthesis of the dihydroquinolin-4-ones 22: These compounds were obtained by the intramolecular cyclization of the 2-aminochalcones 21 in the presence of Amberlyst®-15 by following the procedure described in ref. [38].
  • 2-(4-Bromophenyl)-2,3-dihydroquinolin-4(1H)-one 22a: Yellow solid, 94% yield. M.p. 165–167 °C. FTIR (KBr): ν = 3306 (NH), 1647 (C=O), 1600 (C=C) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.70 (dd, J = 16.1, J = 4.0 Hz, 1H, Ha-3), 2.81 (dd, J = 16.1, J = 11.7 Hz, 1H, Hb-3), 4.78 (dd, J = 11.6, J = 4.4 Hz, 1H, H-2), 6.66 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 7.14 (bs, 1H, NH), 7.34 (td, J = 7.7, J = 4.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.59–7.62 (m, 3H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 45.5 (C-3), 56.0 (C-2), 116.8, 117.2, 118.2 (Cq), 121.2 (Cq), 126.8, 129.6, 131.9, 135.7, 141.6 (Cq), 152.7 (Cq), 192.7 (C=O) ppm. MS (70 eV): m/z (%) = 303/301 (41.4/41.6) [M+], 302/300 (22.5/16.2), 146 (100), 119 (37).
  • 2-(4-Chlorophenyl)-2,3-dihydroquinolin-4(1H)-one 22b: Yellow solid, 92% yield. M.p. 179–181 °C. FTIR (KBr): ν = 3302 (NH), 1647 (C=O), 1600 (C=C) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.69 (dd, J = 16.1, J = 4.3 Hz, 1H, Ha-3), 2.83 (dd, J = 16.1, J = 11.8 Hz, 1H, Hb-3), 4.79 (dd, J = 11.8, J = 4.4 Hz, 1H, H-2), 6.66 (td, J = 7.5, J = 4.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 7.15 (bs, 1H, NH), 7.34 (td, J = 7.7, J = 4.0 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 7.9 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 45.6 (C-3), 56.0 (C-2), 116.8, 117.1, 118.2 (Cq), 126.8, 129.0, 129.2, 132.7 (Cq), 135.6, 141.2 (Cq), 152.8 (Cq), 192.7 (C=O) ppm. MS (70 eV): m/z (%) = 259/257 (28.2/83) [M+], 258/256 (26/39), 146 (100), 119 (41).
  • 2-(4-Methoxyphenyl)-2,3-dihydroquinolin-4(1H)-one 22c: Yellow solid, 67% yield. M.p. 131–132 °C. FTIR (KBr): ν = 3329 (NH), 1606 (C=O, C=C), 1242 (C-O-C) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.63 (dd, J = 16.0, J = 4.0 Hz, 1H, Ha-3), 2.82 (dd, J = 16.0, J = 12.3 Hz, 1H, Hb-3), 3.77 (s, 3H, OCH3), 4.75 (dd, J = 12.2, J = 3.80 Hz, 1H, H-2), 6.65 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H), 7.06 (bs, 1H, NH), 7.32 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 7.8 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 45.9 (C-3), 55.6 (OCH3), 56.2 (C-2), 114.4, 116.8, 116.9, 118.2 (Cq), 126.8, 128.5, 134.1 (Cq), 135.5, 153.0 (Cq), 159.3 (Cq), 193.1 (C=O) ppm. MS (70 eV): m/z (%) = 253 (95) [M+], 252 (78), 146 (100), 119 (31).
  • 2-(p-Tolyl)-2,3-dihydroquinolin-4(1H)-one 22d: Yellow solid, 65% yield. M.p. 153–155 °C. FTIR (KBr): ν = 3309 (NH), 1649 (C=O), 1600 (C=C) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.63 (dd, J = 16.0, J = 3.5 Hz, 1H, Ha-3), 2.82 (dd, J = 16.0, J = 12.3 Hz, 1H, Hb-3), 3.39 (s, 3H, CH3), 4.72 (dd, J = 12.1, J = 3.7 Hz, 1H, H-2), 6.64 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 7.13 (bs, 1H, NH), 7.20 (d, J = 7.8 Hz, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.61 (d, J = 7.6 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 21.2 (CH3), 45.9 (C-3), 56.5 (C-2), 116.8, 116.9, 118.1 (Cq), 126.8, 127.2, 129.6, 135.6, 137.4 (Cq), 139.1 (Cq), 153.0 (Cq), 193.0 (C=O) ppm. MS (70 eV): m/z (%) = 237 (100) [M+], 236 (55), 146 (83), 119 (33).
  • 2-Phenyl-2,3-dihydroquinolin-4(1H)-one 22e: Yellow solid, 72% yield. M.p. 156–158 °C. FTIR (KBr): ν = 3334 (NH), 1654 (C=O), 1600 (C=C) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.67 (d, J = 15.9 Hz, 1H, Ha-3), 2.85 (t, J = 14.1 Hz, 1H, Hb-3), 4.77 (d, J = 12.0 Hz, 1H, H-2), 6.65 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 7.18 (bs, 1H, NH), 7.28–7.44 (m, 4H), 7.51 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 7.7 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 45.8 (C-3), 56.8 (C-2), 116.8, 117.0, 118.2 (Cq), 126.8, 127.4, 128.2, 129.0, 135.6, 142.2 (Cq), 152.9 (Cq), 192.9 (C=O) ppm. MS (70 eV): m/z (%) = 223 (100) [M+], 222 (43), 146 (95), 119 (29).
  • 2-(3,4,5-Trimethoxyphenyl)-2,3-dihydroquinolin-4(1H)-one 22f: Yellow solid, 90% yield. M.p. 142–144 °C. FTIR (KBr): ν = 3336 (NH), 1660 (C=O), 1595 (C=C), 1236 (C-O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.63 (d, J = 16.0 Hz, 1H, Ha-3), 2.91 (bt, J = 14.7 Hz, 1H, Hb-3), 3.67 (s, 3H, OCH3), 3.80 (s, 6H, OCH3), 4.68 (dd, J = 13.1, J = 3.2 Hz, 1H, H-2), 6.66 (t, J = 7.4 Hz, 1H), 6.85 (s, 2H), 6.91 (d, J = 8.2 Hz, 1H), 7.06 (bs, 1H, NH), 7.33 (td, J = 7.7, J = 4.0 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 46.0 (C-3), 56.4 (OCH3), 57.3 (C-2), 60.5 (OCH3), 104.8, 116.8, 117.1, 118.2 (Cq), 126.8, 135.5, 137.4 (Cq), 137.7 (Cq), 153.0 (Cq), 153.3 (Cq), 193.1 (C=O) ppm. MS (70 eV): m/z (%) = 313 (31) [M+], 312 (14), 146 (29), 83 (100), 119 (6).
  • 2-(3,4-Dichlorophenyl)-2,3-dihydroquinolin-4(1H)-one 22g: Yellow solid, 92% yield. M.p. 122–123 °C. FTIR (KBr): ν = 3334 (NH), 1654 (C=O), 1600 (C=C) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.72 (dd, J = 16.1, J = 3.9 Hz, 1H, Ha-3), 2.86 (dd, J = 16.1, J = 11.8 Hz, 1H, Hb-3), 4.82 (dd, J = 11.7, J = 4.3 Hz, 1H, H-2), 6.68 (td, J = 7.5, J = 4.0 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 7.17 (bs, 1H, NH), 7.35 (td, J = 7.7, J = 4.0 Hz, 1H), 7.49 (dd, J = 8.4, J = 1.9 Hz, 1H), 7.61 (dd, J = 7.9, J = 1.3 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 45.2 (C-3), 55.6 (C-2), 116.8, 117.3, 118.3 (Cq), 126.8, 127.8, 129.5, 130.6 (Cq), 131.2, 131.6 (Cq), 135.7, 143.4 (Cq), 152.6 (Cq), 192.5 (C=O) ppm. MS (70 eV): m/z (%) = 295/293/291 (14.2/84.1/100) [M+], 294/292/290 (19/51/45), 146 (98), 119 (36).
  • 6-(Benzo[d][1,3]dioxol-5-yl)-6,7-dihydro-[1,3]dioxolo [4,5-g]quinolin-8(5H)-one 22h: Yellow solid, 97% yield. M.p. >300 °C. FTIR (KBr): ν = 3327 (NH), 1649 (C=O), 1604 (C=C), 1236 (C-O-C) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.54 (dd, J = 16.0, J = 3.2 Hz, 1H, Ha-3), 2.72 (dd, J = 16.1, J = 12.7 Hz, 1H, Hb-3), 4.60 (dd, J = 12.7, J = 4.1 Hz, 1H, H-2), 5.97 (d, J = 6.0 Hz, 2H, OCH2O), 6.01 (bd, J = 1.0 Hz, 2H, OCH2O), 6.44 (s, 1H), 6.87–6.96 (m, 3H), 7.0 (s, 1H), 7.08 (bs, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 45.5 (C-3), 57.1 (C-2), 96.1, 101.5 (OCH2O), 101.7 (OCH2O), 103.7, 107.8, 108.6, 111.4 (Cq), 120.6, 136.0 (Cq), 140.6 (Cq), 147.2 (Cq), 147.8 (Cq), 151.4 (Cq), 154.1 (Cq), 190.7 (C=O) ppm. MS (70 eV): m/z (%) = 311 (99) [M+], 310 (70), 190 (100), 163 (33).
  • 2-(Benzo[d][1,3]dioxol-5-yl)-2,3-dihydroquinolin-4(1H)-one 22i: Yellow solid, 87% yield. M.p. 125–127 °C. FTIR (KBr): ν = 3327 (NH), 1649 (C=O), 1604 (C=C), 1236 (C-O-C) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.62 (ddd, J = 16.0, J = 4.1, J = 1.1 Hz, 1H, Ha-3), 2.83 (dd, J = 16.0, J = 12.3 Hz, 1H, Hb-3), 4.68 (dd, J = 12.3, J = 4.1 Hz, 1H, H-2), 6.01 (bd, J = 1.6 Hz, 2H, OCH2O), 6.65 (td, J = 7.9, J = 0.9 Hz, 1H), 6.58–6.97 (m, 3H), 7.05 (bs, 1H, NH), 7.09 (d, J = 1.5 Hz, 1H), 7.32 (td, J = 8.5, J = 1.6 Hz, 1H), 7.60 (dd, J = 7.9, J = 1.50 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 45.9 (C-3), 56.5 (C-2), 101.5 (OCH2O), 107.8, 108.6, 116.7, 117.0, 118.2 (Cq), 120.6, 126.8, 135.5, 136.0 (Cq), 147.2 (Cq), 147.8 (Cq), 152.9 (Cq), 193.0 (C=O). MS (70 eV): m/z (%) = 267 (80) [M+], 266 (54), 146 (77), 83 (100), 119 (18).
General procedure for the synthesis Graveoline 1 and analogues 23: (a) Methylation reaction: A mixture of dihydroquinolin-4-one 22 (1.0 equiv), anhydrous Na2CO3 (1.5 equiv), CH3I (5.0 equiv) and DMF (3 mL) was heated at 190 °C for 1–2 h. After the reaction was complete (TLC control), the solvent was removed under reduced pressure, water (3 mL) was added to the residue and product 25 was extracted with ethyl acetate. (b) Oxidation reaction: A mixture of N-methyl dihydroquinolin-4-one 25 (1.0 equiv), p-chloranil (1.2 equiv) and DMF was subjected to reflux for 2–3 h until complete consumption of the starting material 25 (TLC control). The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate/hexane (10:2) as an eluent to afford products 23.
  • 2-(4-Bromophenyl)-1-methyl-2,3-dihydroquinolin-4(1H)-one 25a: Greenish solid, 68% yield. M.p. 98 °C. FTIR (KBr): ν = 1655 (C=O), 1604 (C=C) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.90 (dd, J = 16.1, J = 6.0 Hz, 1H, Ha-3), 2.97 (s, 3H, N-CH3), 3.19 (dd, J = 16.1, J = 6.2 Hz, 1H, Hb-3), 4.67 (bt, J = 6.0 Hz, 1H, H-2), 6.78–6.81 (m, 2H), 7.07 (d, J = 8.4 Hz, 2H), 7.43–7.57 (m, 3H), 7.89 (dd, J = 8.0, J = 1.4 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 38.0 (N-CH3), 45.3 (C-3), 64.2 (C-2), 113.0, 117.0, 119.8 (Cq), 121.8 (Cq), 127.7, 128.3, 132.2, 136.2, 139.0 (Cq), 151.5 (Cq), 192.0 (C=O) ppm. MS (70 eV): m/z (%) = 317/315 (86.8/88.5) [M+], 160 (100).
  • 2-(4-Bromophenyl)-1-methylquinolin-4(1H)-one 23a: Yellow solid, 61% yield. M.p. 97–98 °C. FTIR (KBr): ν = 3120, 2918, 2849, 1618 (C=O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.70 (s, 3H, N-CH3), 6.46 (s, 1H, H-3), 7.35 (d, J = 8.2, 2H), 7.51 (t, J = 7.6, 1H), 7.63 (d, J = 8.6, 1H), 7.70 (d, J = 8.2, 2H), 7.80 (t, J = 7.8, 1H), 8.52 (d, J = 7.9, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 37.6 (N-CH3), 112.3 (C-3), 116.1, 124.4, 124.5 (Cq), 126.8, 130.2, 132.3, 132.9, 134.4 (Cq), 136.5 (Cq), 141.8 (Cq), 154.0 (Cq), 176.9 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 315/313 (2.4/2.6) [M+], 86 (58), 84 (100). Anal. Calcd for C16H12BrNO: C, 61.17; H, 3.85; N, 4.46. Found: C, 60.98; H, 3.90; N, 4.62.
  • 2-(4-Chlorophenyl)-1-methylquinolin-4(1H)-one 23b: Yellow solid, 62% yield. M.p. 83–84 °C. FTIR (KBr): ν = 3072, 2938, 2837, 1599 (C=O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.65 (s, 3H, N-CH3), 6.32 (s, 1H, H-3), 7.39 (d, J = 8.4, 2H), 7.47 (t, J = 7.5, 1H), 7.53 (d, J = 8.4, 2H), 7.63 (d, J = 8.6, 1H), 7.77 (t, J = 7.1, 1H), 8.54 (d, J = 8.0, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 37.4 (N-CH3), 112.6 (C-3), 116.0, 124.1, 126.7 (Cq), 126.8, 129.2, 130.0, 132.7, 134.1 (Cq), 136.1 (Cq), 141.9 (Cq), 153.8 (Cq), 177.6 (C=O) ppm. MS (EI, 70 eV): m/z (%): = 271/269 (37/100) [M+], 241 (61). Anal. Calcd for C16H12ClNO: C, 71.25; H, 4.48; N, 5.19. Found: C, 71.12; H, 4.54; N, 5.30.
  • 2-(4-Methoxyphenyl)-1-methylquinolin-4(1H)-one 23c: Yellow solid, 75% yield. M.p. 193–194 °C. FTIR (KBr): ν = 3080, 2974, 2943, 1598 (C=O), [1249, 1078] C-O cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.67 (s, 3H, N-CH3), 3.91 (s, 3H, OCH3), 6.34 (s, 1H, H-3), 7.04 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.45 (td, J = 8.0, J = 1.0 Hz, 1H), 7.59 (d, J = 8.6, 1H), 7.75 (td, J = 8.6, J = 3.2 Hz, 1H), 8.51 (dd, J = 8.1, J = 1.4 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 37.5 (N-CH3), 55.5 (OCH3), 112.6 (C-3), 114.3, 116.1, 123.8, 126.7, 128.0 (Cq), 130.0 (x 2, Cq and CH), 132.4, 142.0 (Cq), 155.0 (Cq), 160.7 (Cq), 177.6 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 265 (23) [M+], 237 (17), 222 (14), 85 (69), 83 (100). Anal. Calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C, 77.09; H, 5.92; N, 5.17.
  • 1-Methyl-2-(p-tolyl)quinolin-4(1H)-one 23d: Yellow solid, 94% yield. M.p. 86–87 °C. FTIR (KBr): ν = 3070, 2924, 2857, 1627 (C=O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3H, CH3), 3.77 (s, 3H, N-CH3), 6.52 (s, 1H, H-3), 7.28–7.36 (m, 4H), 7.48 (t, J = 8.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.85 (t, J = 8.0 Hz, 1H), 8.54 (d, J = 8.2 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 38.1 (N-CH3), 111.4 (C-3), 116.4, 124.7, 126.6, 128.4, 129.6, 130.2 (Cq), 133.5, 136.4 (Cq), 137.5 (Cq), 139.3 (Cq), 140.6 (Cq), 187.4 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 249 (45) [M+], 221 (44), 85 (71), 83 (100). Anal. Calcd for C17H15NO: C, 81.90; H, 6.06; N, 5.62. Found: C, 82.03; H, 6.23; N, 5.79.
  • 1-Methyl-2-phenylquinolin-4(1H)-one 23e: Yellow solid, 93% yield. M.p. 82–83 °C. FTIR (KBr): ν = 3110, 2925, 2859, 1650 (C=O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.98 (s, 3H, N-CH3), 6.91 (s, 1H, H-3), 7.55 (d, J = 8.9, 2H), 7.62–7.64 (bd, 3H), 7.70 (t, J = 8.6, 1H), 7.93 (d, J = 7.8, 1H), 8.01 (t, J = 7.8, 1H), 8.62 (d, J = 7.9, 1H) ppm. NMR 13C (100 MHz, CDCl3): δ = 39.5 (N-CH3), 110.2 (C-3), 117.6, 126.3, 126.4 (×2, Cq and CH), 128.8, 129.4, 130.9, 133.7 (Cq), 134.8, 140.6 (Cq), 150.3 (Cq), 177.3 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 235 (2.4) [M+], 149 (28), 57 (100). Anal. Calcd for C16H13NO: C, 81.68; H, 5.57; N, 5.95. Found: C, 81.53; H, 5.66; N, 6.04.
  • 1-Methyl-2-(3,4,5-trimethoxyphenyl)quinolin-4(1H)-one 23f: Yellow solid, 64% yield. M.p. 146–145 °C. FTIR (KBr): ν = 3070, 2934, 2836, 1676 (C=O), [1242, 1126] C-O cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3H, N-CH3), 3.92 (s, 6H, OCH3), 3.97 (s, 3H, OCH3), 6.71 (s, 1H, H-3), 7.57 (t, J = 7.4, 1H), 7.77 (d, J = 8.7, 1H), 7.89 (t, J = 8.7, 1H), 8.05 (s, 2H), 8.57 (d, J = 7.9, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 38.7 (N-CH3), 56.8 (OCH3), 61.1 (OCH3), 106.2, 111.0 (C-3), 116.9, 125.3, 126.4, 130.2 (Cq), 133.7, 136.4 (Cq), 139.2 (Cq), 141.5 (Cq), 153.6 (Cq), 156.5 (Cq), 176.7 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 325 (2.5) [M+], 167 (20), 149 (100). Anal. Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C, 70.02; H, 5.96; N, 4.15.
  • 2-(3,4-Dichlorophenyl)-1-methylquinolin-4(1H)-one 23g: Yellow solid, 93% yield. M.p. 82–83 °C. FTIR (KBr): ν = 3102, 2940, 1626 (C=O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.64 (s, 3H, N-CH3), 6.26 (s, 1H, H-3), 7.29 (dd, J = 7.2, J = 1.2 Hz, 1H), 7.47 (t, J = 7.5, 1H), 7.54–7.60 (m, 2H), 7.63 (d, J = 8.2, 1H), 7.76 (td, J = 7.3, J = 1.1 Hz, 1H), 8.50 (dd, J = 8.0, J = 1.3 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 37.3 (N-CH3), 112.8 (C-3), 116.0, 124.0, 126.8, 126.9 (Cq), 127.9, 130.6, 131.0, 132.7, 133.4 (Cq), 134.4 (Cq), 135.6 (Cq), 141.9 (Cq), 152.1 (Cq), 177.5 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 307/305/303 (0.5/2.1/3.3) [M+], 149 (21), 85 (77), 83 (100). Anal. Calcd for C16H11Cl2NO: C, 63.18; H, 3.65; N, 4.60. Found: C, 63.32; H, 3.74; N, 4.48.
  • 6-(Benzo[d][1,3]dioxol-5-yl)-5-methyl-[1,3]dioxolo[4,5-g]quinolin-8(5H)-one 23h: Yellow solid, 90% yield. M.p. 185–186 °C. FTIR (KBr): ν = 3040, 2989, 1658 (C=O), [1238, 1120] C-O cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.61 (s, 3H, N-CH3), 6.09 (s, 2H, OCH2O), 6.13 (s, 2H, OCH2O), 6.26 (s, 1H, H-3), 6.88 (d, J = 1.3 Hz, 1H), 6.90 (dd, J = 7.8, J = 1.6 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.98 (s, 1H), 7.85 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 38.0 (N-CH3), 95.5, 101.7 (OCH2O), 102.1 (OCH2O), 103.9, 108.6, 109.1, 112.0 (C-3), 122.6 (Cq), 122.8, 129.4 (Cq), 139.2 (Cq), 145.5 (Cq), 148.0 (Cq), 148.7 (Cq), 152.4 (Cq), 153.2(Cq), 176.3 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 323 (0.8) [M+], 279 (31), 167 (99), 149 (100). Anal. Calcd for C18H13NO5: C, 66.87; H, 4.05; N, 4.33. Found: C, 66.91; H, 3.96; N, 4.52.
  • 2-(Benzo[d][1,3]dioxol-5-yl)-1-methylquinolin-4(1H)-one (Graveoline 1): Yellow solid, 65% yield. M.p. 193–194 °C. FTIR (KBr): ν = 3160, 2919, 2854, 1623 (C=O), [1264, 1164] C-O cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.68 (s, 3H, N-CH3), 6.11 (s, 2H, OCH2O), 6.35 (s, 1H, H-3), 6.91 (s, 1H), 6.92–6.98 (m, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.76 (td, J = 11.4, J = 4.2 Hz, 1H), 8.53 (d, J = 7.1 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 37.2 (N-CH3), 101.6 (OCH2O), 108.7, 109.3, 112.6 (C-3), 115.9, 122.7, 123.9, 126.6 (Cq), 126.8, 129.5 (Cq), 132.5, 142.0 (Cq), 148.0 (Cq), 148.8 (Cq), 154.4 (Cq), 177.1 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 279 (80) [M+], 149 (100). Anal. Calcd for C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found: C, 72.98; H, 4.55; N, 5.00.
General procedure for the synthesis of Dubamine 2 and analogues 24: Dihydroquinolin-4-one 22 (1.0 equiv) dissolved in methanol (3 mL) was subjected to reduction by treatment with NaBH4 (2.0 equiv), added portion-wise, for 1–2 h at room temperature. Then, the methanol was removed under reduced pressure and the crude was extracted with DCM (3 mL). After the DCM was removed under reduced pressure, the corresponding 4-hydroxyquinoline 26 was obtained in a quantitative yield. Subsequently, a mixture of 4-hydroxyquinoline 26 (1.0 equiv), p-dioxane (3 mL) and PTSA (2.0 equiv) was stirred for 2–3 h at room temperature. After the reaction was complete (TLC control), the solvent was removed under reduced pressure and the solid formed was purified by column chromatography on silica gel using a mixture of DCM/hexane (10:2) as an eluent to afford the desired compound 24.
  • 2-(4-Bromophenyl)-1,2,3,4-tetrahydroquinolin-4-ol 26a: Pale yellow solid, 90% yield. M.p. 114–115 °C. FTIR (KBr): ν = 3420br (OH), 1602 (C=C), 1070 (C-O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.74 (d, J = 8.3 Hz, 1H, OH), 2.02–2.08 (m, 1H, Ha-3), 2.36–2.41 (m, 1H, Hb-3), 3.97 (bs, 1H, NH), 4.55 (dd, J = 11.2, J = 2.6 Hz, 1H, H-2), 5.02–5.08 (m, 1H, H-4), 6.56 (d, J = 8.0 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 7.32 (d, J = 8.4, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 41.4 (C-3), 55.2 (C-2), 67.2 (C-4), 114.3, 118.3, 121.5 (Cq), 124.4 (Cq), 127.0, 128.3, 128.7, 131.9, 142.4 (Cq), 144.0 (Cq) ppm. MS (70 eV): m/z (%) = 305/303 (73.9/75.4) [M+], 287/285 (98.0/100.0) [M-H2O], 148 (87).
  • 2-(4-Bromophenyl)quinoline 24a: Yellow solid, 80% yield. M.p. 120–121 °C. FTIR (KBr): ν = 1539 (C=C), 1475 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 7.54 (t, J = 7.4 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.74 (td, J = 7.7, J = 1.2 Hz, 1H), 7.80–7.85 (bd, 2H), 8.06 (d, J = 8.5 Hz, 2H), 8.18–8.25 (bt, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 118.7, 124.2 (Cq), 126.7, 127.4 (Cq), 127.6, 129.3, 129.7, 130.1, 132.1, 137.3, 138.4 (Cq), 148.2 (Cq), 156.1 (Cq) ppm. MS (70 eV): m/z (%) = 285/283 (86/90) [M+], 204 (100). Anal. Calcd for C15H10BrN: C, 63.40; H, 3.55; N, 4.93. Found: C, 63.23; H, 3.41; N, 5.05.
  • 2-(4-Chlorophenyl)quinoline 24b: Beige solid, 75% yield. M.p. 115–116 °C. FTIR (KBr): ν = 1591 (C=C), 1485 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 7.50 (d, J = 8.6 Hz, 2H), 7.54 (td, J = 7.5, J = 1.0 Hz, 1H), 7.75 (td, J = 7.7, J = 1.0 Hz, 1H), 7.80–7.85 (bd, 2H), 8.12 (d, J = 8.6 Hz, 2H), 8.17 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 8.6 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 118.6, 126.5, 127.3 (Cq), 127.5, 128.9, 129.0, 129.7, 129.9, 135.6 (Cq), 137.0, 138.1 (Cq), 148.3 (Cq), 156.0 (Cq) ppm. MS (70 eV): m/z (%) = 241/239 (32/100) [M+], 204 (67). Anal. Calcd for C15H10ClN: C, 75.16; H, 4.21; N, 5.84. Found: C, 75.23; H, 4.29; N, 5.75.
  • 2-(4-Methoxyphenyl)quinoline 24c: Beige solid, 73% yield. M.p. 122–123 °C. FTIR (KBr): ν = 1597 (C=C), 1492 (C=N),1246 (C-O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 3.89 (s, 3H, OCH3), 7.06 (d, J = 8.8 Hz, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.72 (td, J = 7.7, J = 1.0 Hz, 1H), 7.78–7.86 (bt, 2H), 8.12–8.21 (m, 4H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 55.4 (OCH3), 114.3, 118,6, 126.0, 127.0 (Cq), 127.5, 129.0, 129.5, 129.7, 132.2 (Cq), 136.8, 148.2 (Cq), 156.9 (Cq), 160.9 (Cq) ppm. MS (70 eV): m/z (%) = 235 (100) [M+], 220 (31), 192 (34), 191 (35). Anal. Calcd for C16H13NO: C, 81.68; H, 5.57; N, 5.95. Found: C, 81.57; H, 5.36; N, 6.03.
  • 2-(p-Tolyl)quinoline 24d: Yellow solid, 85% yield. M.p. 83–84 °C. FTIR (KBr): ν = 1595 (C=C), 1494 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.45 (s, 3H, CH3), 7.35 (d, J = 8.1 Hz, 2H), 7.53 (t, J = 7.5 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 8.1 Hz, 2H), 8.20–8.27 (bt, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 21.4 (CH3), 119.0, 126.3, 127.1 (Cq), 127.5, 127.6, 129.4, 129.6, 129.8, 136.5 (Cq), 137.0, 139.7 (Cq), 148.0 (Cq), 157.3 (Cq) ppm. MS (70 eV): m/z (%) = 219 (100) [M+], 204 (39). Anal. Calcd for C16H13N: C, 87.64; H, 5.98; N, 6.39. Found: C, 87.57; H, 6.05; N, 6.44.
  • 2-Phenylquinoline 24e: Beige solid, 70% yield. M.p. 82–83 °C. FTIR (KBr): ν = 1595 (C=C), 1489 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 7.48 (t, J = 7.1 Hz, 1H), 7.52–7.58 (m, 3H), 7.75 (t, J = 7.6 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 8.16–8.25 (m, 4H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 119.1, 126.3, 127.2 (Cq), 127.5, 127.6, 128.9, 129.4, 129.7, 129.8, 136.8, 139.7 (Cq), 148.3 (Cq), 157.4 (Cq) ppm. MS (70 eV): m/z (%) = 205 (100) [M+], 204 (94). Anal. Calcd for C15H11N: C, 87.77; H, 5.40; N, 6.82. Found: C, 87.50; H, 5.28; N, 6.86.
  • (3,4,5-Trimethoxyphenyl)quinoline 24f: Yellow solid, 80% yield. M.p. 90–93 °C. FTIR (KBr): ν = 1593 (C=C), 1496 (C=N), 1244 (C-O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 3.93 (s, 3H, OCH3), 4.01 (s, 6H, OCH3), 7.42 (s, 2H), 7.53 (t, J = 7.5 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.81–7.85 (m, 2H), 8.20–8.24 (bd, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 56.4 (OCH3), 61.0 (OCH3), 105.0, 118.9, 126.4, 127.2 (Cq), 127.5, 129.5, 129.9, 135.0 (Cq), 137.0, 139.6 (Cq), 147.9 (Cq), 153.6 (Cq), 156.9 (Cq) ppm. MS (70 eV): m/z (%) = 295 (100) [M+], 280 (49), 222 (38). Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.48; H, 5.65; N, 4.82.
  • 2-(3,4-Dichlorophenyl)quinoline 24g: Yellow solid, 87% yield. M.p. 107–108 °C. FTIR (KBr): ν = 1593 (C=C), 1543 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 7.53–7.60 (m, 2H), 7.76 (t, J = 7.7 Hz, 1H), 7.79–7.86 (bt, 2H), 8.00 (dd, J = 8.4, J = 1.8 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 8.6 Hz, 1H), 8.32 (d, J = 1.7 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 118.3, 126.6, 126.8, 127.4 (Cq), 127.5, 129.4, 129.8, 130.0, 130.7, 133.2 (Cq), 133.6 (Cq), 137.2, 139.5 (Cq), 148.2 (Cq), 154.6 (Cq) ppm. MS (70 eV): m/z (%) = 277/275/273 (12/66/100) [M+], 238 (67), 203 (29). Anal. Calcd for C15H9Cl2N: C, 65.72; H, 3.31; N, 5.11. Found: C, 65.82; H, 3.13; N, 4.98.
  • 6-(Benzo[d][1,3]dioxol-5-yl)-[1,3]dioxolo[4,5-g]quinoline 24h: Pink solid, 75% yield. M.p. 195–196 °C. FTIR (KBr): ν = 1581 (C=C), 1481 (C=N), 1253 (C-O-C) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 6.03 (s, 2H, OCH2O), 6.10 (s, 2H, OCH2O), 6.93 (d, J = 8.1 Hz, 1H), 7.04 (s, 1H), 7.41 (s, 1H), 7.58–7.64 (m, 2H), 7.67 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 101.3 (OCH2O), 101.7 (OCH2O), 102.6, 106.1, 107.7, 108.5, 116.8, 121.3, 123.9 (Cq), 134.3 (Cq), 135.5, 146.5 (Cq), 147.6 (Cq), 148.3 (Cq), 148.5 (Cq), 150.8 (Cq), 154.7 (Cq) ppm. MS (70 eV): m/z (%) = 293 (100) [M+], 177 (19). Anal. Calcd for C17H11NO4: C, 69.62; H, 3.78; N, 4.78. Found: C, 69.78; H, 3.86; N, 4.81.
  • 2-(Benzo[d][1,3]dioxol-5-yl)quinoline (Dubamine 2): Pink solid, 81% yield. M.p. 93–94 °C. FTIR (KBr): ν = 1593 (C=C), 1485 (C=N), 1250 (C-O-C) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 6.05 (s, 2H, OCH2O), 6.96 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.67 (dd, J = 8.1, J = 1.7 Hz, 1H), 7.72 (td, J = 7.7, J = 1.7 Hz, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.77–7.82 (m, 2H), 8.10–8.20 (bt, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 101.4 (OCH2O), 108.0, 108.5, 118.6, 121.8, 126.1, 127.0 (Cq), 127.4, 129,6, 129.7, 134.2 (Cq), 136.7, 148.2 (Cq), 148.4 (Cq), 148.9 (Cq), 156.7 (Cq) ppm. MS (70 eV): m/z (%) = 249 (100) [M+], 191 (52). Anal. Calcd for C16H11NO2: C, 77.10; H, 4.45; N, 5.62. Found: C, 77.22; H, 4.36; N, 5.80.

4. Conclusions

We have successfully developed a useful and metal-free alternative method for the total synthesis of Graveoline 1 and Dubamine 2 alkaloids along with their analogue products 23 and 24, respectively. In both cases, the synthesis was efficiently achieved in just a two-step sequence starting from the dihydroquinolin-4-ones 22 as common precursors for both classes of alkaloidal structures.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules29091959/s1. Copies of 1H, 13C and DEPT-135 NMR spectra for compounds 22a–i, 23a–h, 24a–h, 26a, Graveoline (1) and Dubamine (2).

Author Contributions

Conceptualization, R.A.; methodology, L.C., D.A. and D.I.; formal analysis, R.A., L.C., D.A., D.I., J.Q., P.C. and H.I.; writing—original draft preparation, R.A., D.I., L.C., D.A., J.Q., P.C. and H.I.; writing—review and editing, R.A., D.I., L.C., D.A., J.Q., P.C. and H.I. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in article and Supplementary Materials.

Acknowledgments

Authors: R.A. and D.I. thank MINCIENCIAS, Universidad del Valle-Project Number CI-7907 and Universidad del Norte for financial support. P.C. and H.I. specially thank the Universidad Nacional de Colombia and Universidad de Nariño, respectively, for their support.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 01959 g001
Figure 1. Structures of alkaloids Graveoline 1 and Dubamine 2 and the antibacterial compounds 3 and 4.
Figure 1. Structures of alkaloids Graveoline 1 and Dubamine 2 and the antibacterial compounds 3 and 4.
Molecules 29 01959 g001
Molecules 29 01959 sch001
Scheme 1. Some representative synthetic approaches for obtaining Graveoline 1.
Scheme 1. Some representative synthetic approaches for obtaining Graveoline 1.
Molecules 29 01959 sch001
Molecules 29 01959 sch002
Scheme 2. Some representative synthetic approaches for obtaining Dubamine 2 and its derivatives.
Scheme 2. Some representative synthetic approaches for obtaining Dubamine 2 and its derivatives.
Molecules 29 01959 sch002
Molecules 29 01959 sch003
Scheme 3. Proposed synthetic sketch of the synthesis of alkaloids Graveoline 1 and Dubamine 2 and their structural analogues 23 and 24, respectively.
Scheme 3. Proposed synthetic sketch of the synthesis of alkaloids Graveoline 1 and Dubamine 2 and their structural analogues 23 and 24, respectively.
Molecules 29 01959 sch003
Molecules 29 01959 sch004
Scheme 4. Total synthesis of Graveoline 1, Dubamine 2 and their corresponding quinolinic-analogues (23,24)h from dihydroquinolin-4-ones 22h,i through the two-step synthetic approaches developed in this research work.
Scheme 4. Total synthesis of Graveoline 1, Dubamine 2 and their corresponding quinolinic-analogues (23,24)h from dihydroquinolin-4-ones 22h,i through the two-step synthetic approaches developed in this research work.
Molecules 29 01959 sch004
Table 1. Synthesis of 2-aminochalcones 21 and the key dihydroquinolin-4-ones 22.
Table 1. Synthesis of 2-aminochalcones 21 and the key dihydroquinolin-4-ones 22.
Molecules 29 01959 i001
Molecules 29 01959 i002
Table 2. Optimization of the C-C oxidative process performed on compound 25a for the synthesis of product 23a.
Table 2. Optimization of the C-C oxidative process performed on compound 25a for the synthesis of product 23a.
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EntryConditionsReaction Time (h)Yield (%)
1(1) NBS/MeOH/silica gel
(2) KOH/MeOH/50 °C		3Complex mixture
2p-chloranil/DCM/reflux248
3p-chloranil/DMF/reflux261
Table 3. Synthesis of Graveoline-analogues 23 via a two-step N-methylation/C-C oxidation sequence from dihydroquinolin-4-ones 22.
Table 3. Synthesis of Graveoline-analogues 23 via a two-step N-methylation/C-C oxidation sequence from dihydroquinolin-4-ones 22.
Molecules 29 01959 i004
Molecules 29 01959 i005
Table 4. Optimization of the dehydration/oxidation process for the synthesis of quinoline-derivative 24a from the 4-hydroxytetrahydroquinoline 26a.
Table 4. Optimization of the dehydration/oxidation process for the synthesis of quinoline-derivative 24a from the 4-hydroxytetrahydroquinoline 26a.
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EntryConditionsReaction Time (h)Yield (%) a of 27a/24a
1MeOH/B(OH)3/reflux3NR
2MeOH/PTSA/reflux2Complex mixture
3Toluene/PTSA/reflux/air3ND/20
4p-dioxane/PTSA/air/rt2ND/80
a NR = no reaction; ND = not detected.
Table 5. Synthesis of Dubamine-analogues 24 from dihydroquinolin-4-ones 22 via a two-step reduction followed by a dehydration/oxidation sequence.
Table 5. Synthesis of Dubamine-analogues 24 from dihydroquinolin-4-ones 22 via a two-step reduction followed by a dehydration/oxidation sequence.
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Molecules 29 01959 i008
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Abonia, R.; Cabrera, L.; Arteaga, D.; Insuasty, D.; Quiroga, J.; Cuervo, P.; Insuasty, H. Using Quinolin-4-Ones as Convenient Common Precursors for a Metal-Free Total Synthesis of Both Dubamine and Graveoline Alkaloids and Diverse Structural Analogues. Molecules 2024, 29, 1959. https://doi.org/10.3390/molecules29091959

AMA Style

Abonia R, Cabrera L, Arteaga D, Insuasty D, Quiroga J, Cuervo P, Insuasty H. Using Quinolin-4-Ones as Convenient Common Precursors for a Metal-Free Total Synthesis of Both Dubamine and Graveoline Alkaloids and Diverse Structural Analogues. Molecules. 2024; 29(9):1959. https://doi.org/10.3390/molecules29091959

Chicago/Turabian Style

Abonia, Rodrigo, Lorena Cabrera, Diana Arteaga, Daniel Insuasty, Jairo Quiroga, Paola Cuervo, and Henry Insuasty. 2024. "Using Quinolin-4-Ones as Convenient Common Precursors for a Metal-Free Total Synthesis of Both Dubamine and Graveoline Alkaloids and Diverse Structural Analogues" Molecules 29, no. 9: 1959. https://doi.org/10.3390/molecules29091959

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