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Article

2-Bromopyridines as Versatile Synthons for Heteroarylated 2-Pyridones via Ru(II)-Mediated Domino C–O/C–N/C–C Bond Formation Reactions

by
Miha Drev
,
Helena Brodnik
,
Uroš Grošelj
,
Franc Perdih
,
Jurij Svete
,
Bogdan Štefane
and
Franc Požgan
*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(18), 4418; https://doi.org/10.3390/molecules29184418
Submission received: 22 August 2024 / Revised: 9 September 2024 / Accepted: 11 September 2024 / Published: 17 September 2024
(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)
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Versions Notes

Abstract

:
A novel methodology for the synthesis of 2-pyridones bearing a 2-pyridyl group on nitrogen and carbon atoms, starting from 2-bromopyridines, was developed employing a simple Ru(II)–KOPiv–Na2CO3 catalytic system. Unsubstituted 2-bromopyridine was successfully converted to the penta-heteroarylated 2-pyridone product using this method. Preliminary mechanistic studies revealed a possible synthetic pathway leading to the multi-heteroarylated 2-pyridone products, involving consecutive oxygen incorporation, a Buchwald–Hartwig-type reaction, and C–H bond activation.

Graphical Abstract

1. Introduction

Pyridine derivatives and related azaheterocycles are widely found as a central structural motif in biologically active compounds, natural products [1,2,3,4,5], and functional materials [6]. Furthermore, pyridine-based ligands [7] are characterized by high stability and tolerance to fluctuating redox environments, and are frequently used for the construction of metallosupramolecular architectures [8,9], as well as in crucial catalytic transformations [10]. It has been demonstrated that the 2-pyridone ring is an important building block [11,12,13] for the construction of valuable nitrogen-containing heterocyclic systems [14]. In addition, 2-pyridone ligands substituted with electron-withdrawing groups have been identified to facilitate site-selective C(sp3)–H fluorination [15] and arylation [16,17]. Therefore, there is a strong interest in synthetic, and especially catalytic, methods for the preparation [18] and functionalization [19] of 2-pyridones. For example, 3,6-disubstituted 4-fluoro-2-pyridones were prepared by Rh-catalyzed C–H activation–Lossen rearrangement followed by a Wallach reaction starting from alkynyl triazenes and N-(pivaloyloxy)acrylamides in a one-pot procedure (Scheme 1a) [20]. Rh-catalyzed C–H activation and intramolecular heterocyclization of ω-alkynyl α-substituted hydroxamates led to macrocyclic 2-pyridones (Scheme 1b) [21]. A 1,3,6-trisubstituted 2-pyridone scaffold was obtained by C–H/C–H coupling of N-alkenyl acrylamides exposed to a Pd(II) catalyst together with an oxidizing agent (Scheme 1c) [22]. Ackermann’s group introduced the Ru(II)-catalyzed oxidative annulation reaction of alkynes by acrylamides to form substituted 2-pyridones by N–H/C–H activations (Scheme 1d) [23]. The incorporation of various functional groups directly into the 2-pyridone core was successfully achieved by applying catalytic C–H bond functionalization strategies [24,25]. In this context, the 2-pyridone moiety was extensively explored for selective C-3 [26,27,28,29], C-4 [30], and C-5 [31,32,33] direct functionalization under transition metal catalyzed conditions. On the other hand, the selective functionalization of the more electron-deficient C-6 position of N-heteroaryl-pyridin-2-ones was mainly controlled by the 2-pyridyl substituent [34,35,36,37]. Miura and co-workers reported Cu-catalyzed dehydrogenative heteroarylation at the C-6 position with 1,3-azoles [38]. Several groups reported rhodium- [39], nickel- [40], or manganese-catalyzed [41] C-6-alkylation of 2-pyridones [42]. Miura and co-workers investigated C-6-borylation [43] catalyzed by rhodium complexes, while Liu’s research group reported C-6-arylation of 2-pyridones [44]. Wang and co-workers described a synthetic method for C-6-acylmethylation of N-pyridyl-2-pyridones catalyzed by the Ru(II) complex [45]. However, the direct catalytic C-6-heteroarylation of 2-pyridone using stable Ru(II) catalysts remains practically unexplored.

2. Results and Discussion

Recently we attempted the synthesis of hexaheteroarylbenzenes by applying Ru(II)-catalyzed multiple C–H functionalization of benzene substrates with pyridyl, pyrimidyl, or pyrazolyl directing groups [46]. Interestingly, in the case of 2-pyridylbenzene as the substrate and 3-methyl-2-bromopyridine (1a) as the arylating agent, di-ortho-heteroarylated 2-pyridylbenzene P was isolated as the major product together with 2-pyridone by-products 2a and 3a (Scheme 2). While we could not conclusively distinguish the N-arylated from the also possible O-arylated product by NMR spectroscopy, X-ray analysis of the self-condensation product 3a unambiguously revealed that one pyridyl group is attached to the nitrogen atom of the 2-pyridone ring, while the second is bonded to the C-6 carbon atom (see ESI, Figure S1). To our best knowledge, there is only one report of the direct conversion of 2-halopyridines to N-(2-pyridyl)pyridin-2-ones, which was achieved by using a CuI-trans-N,N’-dimethylcyclohexane-1,2-diamine-K2CO3 catalyst system (Scheme 1e) [47]. The authors hypothesized that 2-bromopyridine hydrolyzes under the established reaction conditions and undergoes a coupling reaction with non-hydrolyzed 2-bromopyridine, but the reaction pathway was not examined.
In this article, we report the optimization process of the formation of 2-pyridone derivatives directly from 2-bromo-3-methylpyridine in the presence of a Ru(II) catalyst. Based on our preliminary study, a plausible mechanistic route for the formation of N-pyridyl-2-pyridone is also suggested.
We initiated optimization studies by subjecting 2-bromo-3-methylpyridine (1a) to similar reaction conditions as we previously described for multiple heteroarylaton of 2-phenylpyridine [46]. Pleasingly, after 3 days, pyridones 2a and 3a were obtained in 40% and 35% relative yields, respectively, together with 25% of the remaining 2-bromopyridine 1a, as revealed by NMR analysis of the crude reaction mixture (Table 1, entry 1). As expected, no conversion of pyridine 1a was observed without catalyst addition. Next, we investigated which additives are needed for the efficient formation of pyridone 3a, since heating 1a together with the catalyst [RuCl2(p-cymene)]2 alone also did not lead to product formation. When either KOPiv or Na2CO3 were used together with 1 mol% of [RuCl2(p-cymene)]2, only a small quantity of 2-pyridone products was formed (Table 1, entries 2 and 3). We hypothesized that both a base and ligand must cooperate for a smooth reaction to occur. Indeed, the addition of 4 mol% of KOPiv and 1.25 equivalents of Na2CO3 gave a quantitative 1a conversion with a ratio of 80/20 of the products 2a/3a (Table 1, entry 4). To our delight, increasing the amount of Ru(II) dimer (5 mol%) and KOPiv (20 mol%) resulted in a complete conversion of 1a to a mixture of 2a and 3a, with 2-pyridone 3a being the major product (Table 1, entry 5). We concluded that the interaction of the Ru(II) center with the Na2CO3–KOPiv system is crucial for the efficient formation of N-pyridylpyridin-2-one. With the optimal catalyst system in hand, we further focused on evaluating the solvent effect. A significant reduction in the formation of pyridone 3a was observed in N-methyl-2-pyrrolidone (NMP), 2-methyltetrahydrofuran (2-MeTHF), and diethyl carbonate (DEC) (Table 1, entries 6–8). A quantitative conversion with the highest relative amount of product 3a was achieved when the reaction was carried out in toluene (Table 1, entry 9). Interestingly, the reaction was completely inhibited in water, while the mixture of 1,4-dioxane/water allowed a 25% conversion of 1a (Table 1, entries 10 and 11).
The extent of catalytic transformation was investigated with a rather small group of 2-bromopyridines 1 under the optimized reaction conditions ([RuCl2(p-cymene)]2 (5 mmol%), KOPiv (20 mol%), Na2CO3 (1.25 equiv.), toluene, 150 °C, 72 h) (Scheme 3). From the reaction of 2-bromo-5-trifluoromethylpyridine, which contains an electron-withdrawing group at position C-5, we were only able to isolate the monopyridyl substituted 2-pyridone 2b in a 57% yield. Similarly, the reaction of 2-bromo-4-trifluoromethylpyridine containing a CF3 group at the C-4 position gave quantitatively only the pyridyl-disubstituted 2-pyridone 3c in an isolated yield of 38%, while 2-bromo-3-cyanopyridine bearing an electron-withdrawing group at the C-3 position formed exclusively pyridone 2d (42% isolated yield). In addition, 2-bromo-4-methylpyridine with an electron-donating methyl group at the C-4 position converted almost quantitatively into a mixture of the 2-pyridones 3e and 4e with 15% and 32% isolated yields, respectively. In contrast, 2-bromopyridines with an electron-donating group at the C-3 (2-bromo-3-methoxypyridine), C-5 (2-bromo-5-methoxypyridine and 2-bromo-5-methylpyridine) or C-6 position (2-bromo-6-methylpyridine) did not react under the given reaction conditions.
We were pleased to obtain the fully heteroarylated 2-pyridone 5 (64% isolated yield) directly from 2-bromopyridine by applying the optimized reaction conditions (Scheme 4).
A series of experiments was performed to gain insight into the mechanism of 2-pyridone formation (Scheme 5). First, we carried out the reaction of 2-bromo-3-methylpyridine (1a) with 10 mol% of Ru(OPiv)2(p-cymene) as the catalyst under optimized conditions in 1,4-dioxane and found that the reaction proceeded with 100% conversion and formation of the products 2a/3a in a molar ratio of 23/77, which is similar to the result obtained with the catalyst system [RuCl2(p-cymene)]2/KOPiv (see Table 1). The free p-cymene ligand was also detected by 1H NMR spectroscopy in the crude reaction mixture. These results indicate that [RuCl2(p-cymene)]2 likely forms the active catalytic species Ru(OPiv)2L3 (L = solvent or 1a) in situ. While the reaction of 2-bromo-3-methylpyridine (1a) with 5 mol% of [RuCl2(p-cymene)]2 in the presence of 1.25 equivalents of Na2CO3 resulted in only a 52% conversion at a molar ratio of 2a/3a = 2/7, the addition of a catalytic amount of pyridyl pivalate 6 (20 mol%) to the reaction mixture led to the quantitative formation of pyridone 3a (Scheme 5a). The abovementioned experiments suggest that pivalate is beneficial for successful conversion of 1a and can be regenerated during the catalytic cycle. We suspected that the pyridone oxygen atom originated from the carbonate base; therefore, the reaction was studied with 18O-labeled Na2CO3 (Scheme 5b). The reaction was carried out in 1,4-dioxane at 150 °C for 72 h with 0.176 mmol of 2-bromopyridine 1a, resulting in a 40% conversion to products 2a′ and 3a′, which showed ~23% 18O-incorporation as evidenced by HRMS analysis of the crude reaction mixture as well as the isolated products 2a′ and 3a′. Since 3-methylpyridin-2(1H)-one (7) could not be detected in the reaction mixture, we assumed that the pyridone 7 formed in situ reacted immediately to give N-pyridylpyridone 2. To prove this, the reaction of pyridone 7 with 2-bromo-3-methylpyridine (1a) was carried out under the optimized reaction conditions in 1,4-dioxane. Pleasingly, the pyridone 3a was formed quantitatively, indicating that the pyridone 7 can be N-arylated with 1a to give first 2a and then 3a via C–H functionalization under the given reaction conditions (Scheme 5c). In contrast, when the reaction between pyridone 7 and bromopyridine 1a was carried out without [RuCl2(p-cymene)]2, only the starting materials could be detected by 1H NMR analysis of the crude reaction mixture.
Furthermore, we investigated the possibility of the formation of a ruthenacycle as an intermediate in the plausible C–H heteroarylation of pyridylpyridones 2. Pleasingly, we were able to isolate metallacycle 8 in a 73% yield from the reaction of 2f with two equivalents of [RuCl2(p-cymene)]2 by applying the protocol reported by Dixneuf et al. for the synthesis of five-membered ruthenacycles from arenes with some N-containing functionalities (Scheme 6a) [48,49]. Ruthenacycle 8 successfully catalyzed the polyheteroarylation of pyridone 2f with 2-bromopyridine and provided an identical reaction outcome as the precatalyst [RuCl2(p-cymene)]2. NMR analysis showed that the desired product 5 arising from four consecutive C–H bond arylations of pyridone 2f was formed with quantitative conversion in both cases (Scheme 6b).
Based on the above experiments, a plausible pathway for the conversion of 2-bromopyridines 1 to 2-pyridones 2 was proposed (Scheme 7). First, [RuCl2(p-cymene)]2 together with the solvent and KOPiv most likely forms a p-cymene-free catalytic species A. The Ru(II) species A then coordinates to 2-bromopyridine, whereupon an intermediate C is formed by nucleophilic aromatic substitution of the bromine atom with carbonate. Then pivalate adds to the carbon atom of the carbonate in C, which leads to the formation of pyridone D and the elimination of the intermediate F. The intermediate F spontaneously decarboxylates to regenerate the pivalate anion for the next catalytic cycle. Complex D undergoes oxidative addition with 2-bromopyridine to form the Ru(IV) intermediate E, followed by reductive elimination of N-pyridylpyridone 2 and regeneration of the ruthenium catalyst. In the next step, the C–H bond functionalization of pyridone 2 directed by a 2-pyridyl group leads to the C-6-heteroarylated product 3.

3. Materials and Methods

3.1. General Information

All reagents were commercial-grade and used without further purification. Reactions were monitored by analytical thin-layer chromatography (TLC) on Fluka silica gel TLC. Column chromatography was performed on 230–400 mesh silica gel. Merck silica gel 60 (PF254 containing gypsum (Merck Group, Darmstadt, Germany) was used to prepare chromatotron plates. Radial chromatography was performed with a Harrison Research chromatotron, model 7924 T (Harrison Research, Palo Alto, CA, USA). Melting points were determined on a Kofler micro hot stage instrument and with an SRS OptiMelt MPA100-Automated Melting Point System (Stanford Research System, Sunnyvale, CA, USA) and were uncorrected. The NMR spectroscopy data were recorded at 296 K with a Bruker Avance III at 500 MHz for 1H NMR and 125 MHz for 13C NMR (Bruker, Billerica, MA, USA). All NMR data were recorded in a CDCl3 and are given in ppm (δ). Chemical shifts for 1H NMR were referenced to TMS as an internal standard. The 13C NMR data were referenced against the central line of the CHCl3 triplet at δ 77.16 ppm. The coupling constants are given in Hertz (Hz). For the multiplicity signification, the standard abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), sept (septet), m (multiplet), and br (broad). IR spectra were obtained with a Bruker ALPHA FT-IR spectrophotometer and reported in reciprocal centimeters (cm−1). High-resolution mass spectra were recorded with an Agilent 6224 Accurate Mass TOF LC/MS instrument (Agilent Technologies, Santa Clara, CA, USA). Elemental analyses (C, H, N) were performed with a Perkin-Elmer 2400 Series II CHNS/O Analyzer (PerkinElmer, Inc., Waltham, MA, USA).

3.2. General Procedure for Synthesis of Pyridones 2–5

A high-pressure tube was loaded with substituted 2-bromopyridine (1 mmol), [RuCl2(p-cymene)]2 (30 mg, 0.05 mmol), potassium pivalate (KOPiv) (28 mg, 0.20 mmol), and Na2CO3 (123 mg, 1.25 mmol). The mixture was suspended in 1 mL of toluene, bubbled with argon for 3 min, and heated at 150 °C for 72 h. The reaction mixture was then cooled to room temperature and diluted with 10 mL DCM and 10 mL H2O. The product was extracted with DCM (2 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The crude product was further purified by radial chromatography on silica gel using a mixture of DCM and MeOH.
The following compounds were prepared using this general procedure:
5,5′-Bis(trifluoromethyl)-2H-[1,2′-bipyridin]-2-one (2b). Prepared from 2-bromo-5-(trifluoromethyl)pyridine (226 mg, 1 mmol). Radial chromatography (DCM/MeOH: 100/1) yielded 2b (90 mg, 0.285 mmol 57%) as a white solid. Mp. 145–147 °C. 1H NMR (500 MHz, CDCl3): δ 8.90–8.82 (m, 1H), 8.47–8.46 (m, 1H), 8.23 (d, J = 8.6 Hz, 1H), 8.12 (dd, J = 8.6, 2.4 Hz, 1H), 7.54 (dd, J = 9.7, 2.7 Hz, 1H), 6.75 (d, J = 9.6 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 161.3, 153.2, 146.3 (q, J = 4.1 Hz), 136.0 (q, J = 2.3 Hz), 135.7 (q, J = 3.4 Hz), 135.4 (q, J = 5.6 Hz), 126.8 (q, J = 79.5 Hz), 123.3 (q, J = 270.2 Hz), 123.2, 123.1 (q, J = 272.5 Hz), 121.0, 111.1 (q, J = 35.2 Hz). HRMS (ESI) m/z: [M + H]+ calcd for C12H7F6N2O, 309.0457; found, 309.0461. FT-IR (ATR): νmax/cm−1 3068, 1686, 1637, 1600, 1550, 1323, 1276, 1231, 1116, 1081, 1061, 845, 721, 642, 626. Analytical data agree with the literature data [50].
2-Oxo-2H-[1,2′-bipyridine]-3,3′-dicarbonitrile (2d). Prepared from 2-bromonicotinonitrile (183 mg, 1 mmol). Radial chromatography (DCM/MeOH: 100/1 to 25/1) yielded 2d (50 mg, 0.21 mmol, 42%) as a white solid. Mp. 200–202 °C (dec.). 1H NMR (500 MHz, CDCl3): δ 8.83 (dd, J = 4.9, 1.8 Hz, 1H), 8.22 (dd, J = 7.8, 1.8 Hz, 1H), 7.98 (dd, J = 7.0, 2.1 Hz, 1H), 7.77 (dd, J = 7.0, 2.1 Hz, 1H), 7.62 (dd, J = 7.8, 4.9 Hz, 1H), 6.48 (t, J = 7.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 158.2, 153.0, 152.1, 149.0, 142.6, 141.0, 124.7, 114.7, 113.9, 109.3, 107.6, 106.3. HRMS (ESI) m/z: [M + H]+ calcd for C12H7N4O, 223.0614; found, 223.0613. FT-IR (ATR): νmax/cm−1 3123, 3061, 2239, 226, 1656, 1600, 1586, 1540, 0430, 1360, 1276, 1076, 759. Analytical data agree with the literature data [51].
3,3″,5′-Trimethyl-6′H-[2,1′:2′,2″-terpyridin]-6′-one (3a). Prepared from 2-bromo-3-methylpyridine (123 µL, 1 mmol). Radial chromatography (DCM/MeOH: 100/1 to 50/1) yielded 3a (80 mg, 0.277 mmol, 83%) as a pale-brown solid. Mp. 145–150 °C. 1H NMR (500 MHz, CDCl3): δ 8.08 (dd, J = 4.7, 1.6 Hz, 1H), 8.03 (dd, J = 4.8, 1.7 Hz, 1H), 7.42 (dd, J = 7.6, 1.7 Hz, 1H), 7.40–7.30 (m, 2H), 6.97 (dd, J = 7.6, 4.8 Hz, 1H), 6.93 (dd, J = 7.7, 4.7 Hz, 1H), 6.14 (d, J = 6.8 Hz, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 162.8, 152.8, 151.6, 146.0, 145.9, 144.1, 138.8, 137.8, 136.8, 133.3, 133.1, 129.9, 123.7, 123.2, 106.6, 19.4, 17.7, 17.2. HRMS (ESI) m/z: [M + H]+ calcd for C18H18N3O, 292.1444; found, 292.1446. FT-IR (ATR): νmax/cm−1 3051, 2974, 2922, 1651, 1601, 1574, 1418, 1267, 1116, 807, 791, 796.
4,4′,4″-Tris(trifluoromethyl)-6′H-[2,1′:2′,2″-terpyridin]-6′-one (3c). Prepared from 2-bromo-4-(trifluoromethyl)pyridine (123 µL, 1 mmol). Radial chromatography (DCM/MeOH: 100/1) yielded 3c (57 mg, 0.127 mmol, 38%) as a red-brown oil. 1H NMR (500 MHz, CDCl3): δ 8.38 (d, J = 5.0 Hz, 1H), 8.32 (d, J = 5.1 Hz, 1H), 7.93 (s, 1H), 7.40 (d, J = 4.9 Hz, 1H), 7.37 (d, J = 4.7 Hz, 2H), 7.06 (s, 1H), 6.64 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 161.7, 153.9, 152.0, 150.0, 149.5, 147.5, 141.5 (q, J = 34.3 Hz), 139.9 (q, J = 34.8 Hz), 139.6 (q, J = 34.7 Hz), 122.3 (q, J = 273.4 Hz), 122.2 (q, J = 273.6 Hz), 121.9 (q, J = 274.4 Hz), 121.8 (q, J = 3.7 Hz), 120.2 (q, J = 4.3 Hz), 119.6 (q, J = 3.6 Hz), 119.2 (q, J = 3.3 Hz), 119.0 (q, J = 3.4 Hz), 104.4 (q, J = 2.7 Hz). HRMS (ESI) m/z: [M + H]+ calcd for C9H9F9N3O, 454.0596; found, 454.0591. FT-IR (ATR): νmax/cm−1 3079, 2017, 1685, 1405, 1327, 1135, 902, 838, 666.
4,4′,4″-Trimethyl-6′H-[2,1′:2′,2″-terpyridin]-6′-one (3e) and 4,4′,4″-trimethyl-3′-(4-methylpyridin-2-yl)-6′H-[2,1′:2′,2″-terpyridin]-6′-one (4e). Prepared from 2-bromo-4-methylpyridine (111 µL, 1 mmol). Radial chromatography (DCM/MeOH: 100/1 to 25/1) yielded 3e (15 mg, 0.075 mmol, 15%) as a pale-brown oil and 4e (30 mg, 0.107 mmol, 32%) as a brown oil. Data for 3e: 1H NMR (500 MHz, CDCl3): δ 8.12 (d, J = 5.0 Hz, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.38 (s, 1H), 7.22 (s, 1H), 6.93 (d, J = 5.1 Hz, 1H), 6.89 (d, J = 5.0 Hz, 1H), 6.53 (s, 1H), 6.29 (s, 1H), 2.36 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 163.2, 153.7, 152.0, 151.3, 148.8, 148.4, 148.0, 147.8, 146.4, 125.9, 125.1, 124.1, 123.7, 119.8, 111.4, 27.3, 21.6, 21.1. HRMS (ESI) m/z: [M + H]+ calcd for C18H18N3O, 292.1444; found, 292.1442. FT-IR (ATR): νmax/cm−1 3049, 2921, 1659, 1611, 1597, 1544, 1429, 1276, 994, 822, 729. Data for 4e: 1H NMR (500 MHz, CDCl3): δ 8.40 (d, J = 5.0 Hz, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.99 (d, J = 5.0 Hz, 1H), 7.28–7.22 (m, 1H), 6.92–6.84 (m, 3H), 6.77 (s, 1H), 6.67 (d, J = 1.2 Hz, 1H), 6.64 (dd, J = 5.1, 1.2 Hz, 1H), 2.30 (s, 3H), 2.10 (s, 3H), 2.08 (s, 3H), 2.02 (s, 3H).13C{1H} NMR (126 MHz, CDCl3): δ 162.3, 155.4, 152.4, 151.8, 151.5, 148.8, 148.7, 148.2, 147.7, 147.2, 146.6, 144.6, 127.9, 127.4, 125.8, 124.1, 123.1, 122.8, 121.7, 120.5, 20.93, 20.90, 20.77, 20.76. HRMS (ESI) m/z: [M + H]+ calcd for C22H21N4O, 383.1866; found, 383.1859. FT-IR (ATR): νmax/cm−1 3049, 2921, 1657, 1599, 1556, 1527, 1404, 994, 828, 730.
3′,4′,5′-Tri(pyridin-2-yl)-6′H-[2,1′:2′,2″-terpyridin]-6′-one (5). Prepared from 2-bromopyridine (90 µL, 1 mmol). Radial chromatography (DCM/MeOH: 50/1 to 10/1) yielded 5 (51 mg, 0.107 mmol, 64%) as a brown solid. Mp. > 300 °C (dec.). 1H NMR (500 MHz, CDCl3): δ 8.33 (dt, J = 4.9, 1.4 Hz, 1H), 8.22 (dd, J = 5.0, 1.8 Hz, 1H), 8.20–8.14 (m, 2H), 8.16–8.09 (m, 1H), 7.67 (td, J = 7.7, 1.9 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.54–7.52 (m, 2H), 7.30–7.26 (m, 1H), 7.26–7.22 (m, 1H), 7.19 (td, J = 7.7, 1.8 Hz, 1H), 7.07 (d, J = 7.6 Hz, 2H), 7.03–6.97 (m, 2H), 6.92 (d, J = 7.9 Hz, 1H), 6.84 (dd, J = 7.5, 4.9 Hz, 2H), 6.78 (ddd, J = 7.6, 5.0, 1.2 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 161.9, 156.4, 155.5, 154.4, 152.8, 152.0, 151.0, 148.8, 148.7, 148.5, 148.4, 148.3, 145.5, 137.2, 135.3, 135.2, 135.0, 134.9, 131.1, 127.3, 127.1, 126.8, 125.7, 125.6, 123.0, 122.2, 121.8, 121.4, 121.1, 121.0. HRMS (ESI) m/z: [M + 2H]2+ calcd for C30H22N6O, 241.092; found, 241.0919. FT-IR (ATR): νmax/cm−1 3050, 1650, 1582, 1564, 1527, 1463, 1430, 992, 762, 745. Elemental analysis calcd (%) for C30H20N6O x H2O: C 72.28, H 4.45, N 16.86; found: C 72.56, H 4.05, N 16.84.
Synthesis of 3,3′-Dimethyl-2H-[1,2′-bipyridin]-2-one (2a). A high-pressure tube was loaded with 2-bromo-3-methylpyridine (123 µL, 1 mmol), [RuCl2(p-cymene)]2 (30 mg, 0.05 mmol), potassium pivalate (KOPiv) (28 mg, 0.20 mmol), and Na2CO3 (123 mg, 1.25 mmol). The mixture was suspended in 1 mL of 1,4-dioxane, bubbled with Ar for 3 min and heated at 150 °C for 72 h. The reaction mixture was then cooled to room temperature and diluted with 10 mL DCM and 10 mL H2O. The product was extracted with DCM (2 × 10 mL). The combined organic phases were dried over anh. Na2SO4, filtered and evaporated in vacuo. The crude product (a mixture of 2a:3a 20/80) was further purified by radial chromatography on silica gel using a mixture of DCM and MeOH (100/1 to 25/1) to obtain pyridone 2a (12 mg, 0.06 mmol, 12%) as pale-yellow oil and pyridone 3a (59 mg, 0.207 mmol, 62%) as pale brown solid. Data for 2a: 1H NMR (500 MHz, CDCl3): δ 8.42 (dd, J = 4.8, 1.7 Hz, 1H), 7.68 (dd, J = 7.6, 1.8 Hz, 1H), 7.33 − 7.27 (m, 2H), 7.22 (dd, J = 6.9, 2.0 Hz, 1H), 6.20 (t, J = 6.8 Hz, 1H), 2.21 (s, 3H), 2.19 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 162.0, 152.6, 147.0, 139.8, 137.4, 134.1, 131.0, 130.6, 124.3, 105.8, 17.4, 17.1. HRMS (ESI) m/z: [M + H]+ calcd for C12H13N2O, 201.1022; found, 201.1023. FT-IR (ATR): νmax/cm−1 2923, 1652, 1603, 1553, 1451, 1419, 1274, 759. Analytical data agree with the literature data [52].
Synthesis of 3-Methylpyridin-2-yl pivalate (6). Compound 6 was prepared by following the literature procedure for a similar compound [53]. In a high-pressure tube, pyridone 7 (109 mg, 1 mmol) and pivaloyl chloride (134 µL, 1.1 mmol) were mixed in dry toluene (1 mL). After DMAP × HCl (7.9 mg, 0.05 mmol, 5 mol%) was added and the reaction mixture was stirred at 110 °C for 30 min under an Ar atmosphere. After that, the mixture was allowed to cool to room temperature, and then hexane (5 mL) was added. DMAP·HCl was precipitated and removed by filtration. The filtrate was extracted with saturated Na2HCO3 solution (2 × 5 mL). The organic phase was dried over anhydrous Na2SO2, filtrated, and evaporated in vacuo to obtain the pure product 6 (144 mg, 0.75 mmol, 75%) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 8.24 (dd, J = 5.0, 1.9 Hz, 1H), 7.59 (dd, J = 7.4, 1.7 Hz, 1H), 7.14 (dd, J = 7.4, 4.8 Hz, 1H), 2.19 (s, 3H), 1.41 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 176.4, 157.2, 146.1, 140.6, 125.6, 122.4, 27.2, 26.6, 16.0. HRMS (ESI) m/z: [M + H]+ calcd for C11H16NO2, 194.1181; found, 194.1177. FT-IR (ATR): νmax/cm−1 2908, 1666, 1635, 1605, 1475, 126, 971, 915, 772, 737.
Synthesis of 2H-[1,2′-bipyridin]-2-one (2f). An oven-dried high-pressure tube was charged with 2-hydroxypyridine (95 mg, 1 mmol), CuI (38 mg, 0.2 mmol, 20 mol%), and K2CO3 (2 mmol, 2 equiv.). The flask was purged with nitrogen. A solution of 2-bromopyridine (90 µL, 1 mmol) in toluene (1 mL) and TMEDA (42 µL, 0.2 mmol, 20 mol%) were added to the reaction mixture, which was stirred and heated 110 °C for 16 h. The resulting mixture was cooled to room temperature, diluted with dichloromethane, and filtered. The filtrate was washed with water. The organic phase was collected, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography to obtain product 2f (86 mg, 0.50 mmol, 50%) as a white solid. Mp. 50–54 °C. 1H NMR (500 MHz, CDCl3): δ 8.57 (dd, J = 5.0, 2.7 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.88 (dd, J = 7.2, 2.1 Hz, 1H), 7.84 (td, J = 7.8, 1.9 Hz, 1H), 7.40 (ddd, J = 9.0, 6.5, 2.1 Hz, 1H), 7.33 (ddd, J = 7.4, 4.9, 1.1 Hz, 1H), 6.65 (d, J = 9.2 Hz, 1H), 6.30 (td, J = 6.8, 1.3 Hz, 1H). HRMS (ESI) m/z: [M + H]+ calcd for C10H9N2O, 173.0715; found, 173.0711. FT-IR (ATR): νmax/cm−1 3058, 2991, 1673, 1612, 1540, 1175, 1130, 999, 785. Analytical data agree with the literature data [47].
Synthesis of ruthenacycle 8. Ruthenacycle was prepared by following slightly modified literature procedure [48]. A mixture of pyridone 2f (8.6 mg, 0.05 mmol), [RuCl2(p-cymene)]2 (61.4 mg, 0.1 mmol), and KOPiv (28 mg, 0.2 mmol) was dissolved in MeOH (1 mL) and then mixed at room temperature for 24 h. A solvent was then evaporated in vacuo and the crude product was further purified by radial chromatography on silica gel using ethyl acetate to give ruthenacycle 8 (32 mg, 0.037 mmol, 73%) as an orange semisolid. 1H NMR (500 MHz, CDCl3): δ 9.38 (dd, J = 8.6, 1.5 Hz, 1H), 9.10 (dd, J = 5.7, 1.8 Hz, 1H), 7.81 (ddd, J = 9.0, 7.3, 1.8 Hz, 1H), 7.16 (ddd, J = 7.2, 5.8, 1.3 Hz, 1H), 7.09 (dd, J = 9.0, 6.8 Hz, 1H), 6.94 (dd, J = 6.9, 1.4 Hz, 1H), 6.14 (dd, J = 8.9, 1.3 Hz, 1H), 5.68 − 5.55 (m, 2H), 5.28 (dd, J = 6.1, 1.3 Hz, 1H), 5.08 (dd, J = 6.1, 1.3 Hz, 1H), 2.52 (sept, J = 6.9 Hz, 1H), 2.12 (s, 3H), 1.05 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 186.8, 166.6, 158.8, 153.9, 139.2, 138.5, 121.7, 119.0, 118.0, 113.7, 103.8, 103.2, 92.0, 91.3, 86.0, 84.4, 30.8, 22.6, 22.1, 18.8. HRMS (ESI) m/z: [M + H]+ calcd for C20H22ClN2ORu, 437.0491; found, 437.0495. FT-IR (ATR): νmax/cm−1 2958, 1634, 1498, 1464, 1434, 1277, 1186, 1135, 1000, 785.
Reaction with 18O-labeled Na2CO3. A high-pressure tube was loaded with substituted 2-bromopyridine 1a (20 µL, 0.176 mmol), [RuCl2(p-cymene)]2 (5 mg, 0.0088 mmol), KOPiv (5 mg, 0.035 mmol), and Na2CO3 (25 mg, 0.22 mmol). The mixture was suspended in 200 µL of 1,4-dioxane, bubbled with Ar for 3 min, and heated at 150 °C for 72 h. The reaction mixture was then cooled to room temperature and diluted with 3 mL DCM and 3 mL H2O. The product was extracted with DCM (2 × 3 mL). The combined organic phases were dried over anh. Na2SO4, filtered and evaporated in vacuo. The crude product was further purified by radial chromatography on silica gel using a mixture of DCM and MeOH (100/1 to 25/1) to obtain pyridone 2a′ (3 mg, 0.015 mmol, 17%) and 3a′ (4 mg, 0.013 mmol, 23%). Data for 2a′: HRMS (ESI) m/z: [M + H]+ calcd for C12H13N218O, 203.1065; found, 203.1107. Data for 3a′: HRMS (ESI) m/z: [M + H]+ calcd for C18H18N318O, 294.1487; found, 294.1534. The 1H NMR data agree with those of pyridones 2a and 3a.

4. Conclusions

In summary, we have developed a novel synthetic route to polyheteroarylated 2-pyridones from various substituted 2-bromopyridines. As a result, 2-pyridones with different degrees of 2-pyridyl substitution and, in particular, pyridone with one (2-pyridyl) C–N bond and with 2-, 4- ,5-, and 6-(2-pyridyl) C–C bonds, can now be readily prepared. The small scope of the various 2-bromopyridine starting compounds indicates that electron-withdrawing groups have an advantage over electron-donating groups in pyridone formation. The preliminary mechanistic study suggests that the oxygen required for 2-pyridone formation is derived from carbonate. Although the yields of 2-pyridone products were only moderate, the catalytic method represents an interesting synthetic route to construct complex molecular scaffolds from simple precursors. The prepared 2-pyridone derivatives can be used as ligands in coordination with transition metals for supramolecular architectures or for the preparation of multimetallic catalytically active species.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules29184418/s1: Table of crystallographic details, and the 1H and 13C NMR spectra. CCDC 2345218 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif (accessed on 22 August 2024) or by emailing [email protected] or by contacting The Cambridge Crystallography Data Centre, 12 Unior Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. References [54,55,56,57].

Author Contributions

Conceptualization, F.P. (Franc Požgan); Methodology, H.B., M.D. and F.P. (Franc Požgan); Validation, H.B., M.D., U.G., J.S. and B.Š.; Investigation, H.B., M.D., F.P. (Franc Perdih) and F.P. (Franc Požgan); Writing—Original Draft Preparation, F.P. (Franc Požgan); Writing—Review and Editing, H.B., M.D., U.G., F.P., J.S., B.Š. and F.P. (Franc Požgan); Supervision, F.P. (Franc Požgan); Project Administration, F.P. (Franc Požgan). All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Slovenian Research Agency through grant P1-0179.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Acknowledgments

We thank Pierre H. Dixneuf (Institut des Sciences Chimiques, Université de Rennes, France) for discussions on our chemistry.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 04418 sch001
Scheme 1. Content status: selected syntheses of 2-pyridones (a–e) and C–C bond-forming reactions through C6–H functionalization of a 2-pyridone ring (f) [34,37,38,39,40,41,42,45].
Scheme 1. Content status: selected syntheses of 2-pyridones (a–e) and C–C bond-forming reactions through C6–H functionalization of a 2-pyridone ring (f) [34,37,38,39,40,41,42,45].
Molecules 29 04418 sch001
Molecules 29 04418 sch002
Scheme 2. The formation of pyridone by-products 2a + 3a in C–H-heteroarylation of 2-pyridylbenzene (our previous work [46]).
Scheme 2. The formation of pyridone by-products 2a + 3a in C–H-heteroarylation of 2-pyridylbenzene (our previous work [46]).
Molecules 29 04418 sch002
Molecules 29 04418 sch003
Scheme 3. The scope of the N-pyridyl-pyridin-2-ones formation.
Scheme 3. The scope of the N-pyridyl-pyridin-2-ones formation.
Molecules 29 04418 sch003
Molecules 29 04418 sch004
Scheme 4. The synthesis of polypyridyl-2-pyridone 5.
Scheme 4. The synthesis of polypyridyl-2-pyridone 5.
Molecules 29 04418 sch004
Molecules 29 04418 sch005
Scheme 5. Control experiments.
Scheme 5. Control experiments.
Molecules 29 04418 sch005
Molecules 29 04418 sch006
Scheme 6. Synthesis of and catalysis with cyclometallated complex 8.
Scheme 6. Synthesis of and catalysis with cyclometallated complex 8.
Molecules 29 04418 sch006
Molecules 29 04418 sch007
Scheme 7. Plausible mechanism for 2-pyridone formation.
Scheme 7. Plausible mechanism for 2-pyridone formation.
Molecules 29 04418 sch007
Table 1. Optimization study of pyridone 3a formation 1.
Table 1. Optimization study of pyridone 3a formation 1.
Molecules 29 04418 i001
Entry[Ru] (mol%)Additive (mol%)Solvent1a/2a/3a 2
1(1.25)KOPiv (20)/PPh3 (2.5)/Na2CO3 (125)1,4-dioxane25/40/35
2(1)KOPiv (4)1,4-dioxane95/5/0
3(1)Na2CO3 (125)1,4-dioxane85/7/8
4(1)KOPiv (4)/Na2CO3 (125)1,4-dioxane0/80/20
5(5)KOPiv (20)/Na2CO3 (125)1,4-dioxane0/20 (12%) 3/80 (62%) 3
6(5)KOPiv (20)/Na2CO3 (125)NMP15/20/65
7(5)KOPiv (20)/Na2CO3 (125)2-MeTHF0/50/50
8(5)KOPiv (20)/Na2CO3 (125)DEC0/25/75
9(5)KOPiv (20)/Na2CO3 (125)toluene0/5/95 (83) 3
10(5)KOPiv (20)/Na2CO3 (125)H2O100/0/0
11(1)KOPiv (4)/Na2CO3 (125)1,4-dioxane/H2O (4:1)75/20/5
1 Reagents and conditions: 2-bromo-3-methylpyridine (1a) (1 mmol), solvent (1 mL), 150 °C argon. 2 Molar ratio determined by 1H NMR analysis. 3 Isolated yield. [Ru] = [RuCl2(p-cymene)]2.
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Drev, M.; Brodnik, H.; Grošelj, U.; Perdih, F.; Svete, J.; Štefane, B.; Požgan, F. 2-Bromopyridines as Versatile Synthons for Heteroarylated 2-Pyridones via Ru(II)-Mediated Domino C–O/C–N/C–C Bond Formation Reactions. Molecules 2024, 29, 4418. https://doi.org/10.3390/molecules29184418

AMA Style

Drev M, Brodnik H, Grošelj U, Perdih F, Svete J, Štefane B, Požgan F. 2-Bromopyridines as Versatile Synthons for Heteroarylated 2-Pyridones via Ru(II)-Mediated Domino C–O/C–N/C–C Bond Formation Reactions. Molecules. 2024; 29(18):4418. https://doi.org/10.3390/molecules29184418

Chicago/Turabian Style

Drev, Miha, Helena Brodnik, Uroš Grošelj, Franc Perdih, Jurij Svete, Bogdan Štefane, and Franc Požgan. 2024. "2-Bromopyridines as Versatile Synthons for Heteroarylated 2-Pyridones via Ru(II)-Mediated Domino C–O/C–N/C–C Bond Formation Reactions" Molecules 29, no. 18: 4418. https://doi.org/10.3390/molecules29184418

APA Style

Drev, M., Brodnik, H., Grošelj, U., Perdih, F., Svete, J., Štefane, B., & Požgan, F. (2024). 2-Bromopyridines as Versatile Synthons for Heteroarylated 2-Pyridones via Ru(II)-Mediated Domino C–O/C–N/C–C Bond Formation Reactions. Molecules, 29(18), 4418. https://doi.org/10.3390/molecules29184418

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