pubs.acs.org/joc Article Chemoselective Ru-Catalyzed Oxidative Lactamization vs Hydroamination of Alkynylamines: Insights from Experimental and Density Functional Theory Studies Andrés M. Á lvarez-Constantino, Andrea Á lvarez-Pérez, Jesús A. Varela, Giuseppe Sciortino,* Gregori Ujaque,* and Carlos Saá* Cite This: J. Org. Chem. 2023, 88, 1185−1193 Read Online ACCESS Metrics & More Article Recommendations * sı Supporting Information ABSTRACT: The Ru-catalyzed intramolecular oxidative amida- tion (lactamization) of aromatic alkynylamines with 4-picoline N- oxide as an external oxidant has been developed. This chemo- selective process is very efficient to achieve medium-sized ε- and ζ- lactams (seven- and eight-membered rings) but not for the formation of common δ-lactams (six-membered rings). DFT studies unveiled the capital role of the chain length between the amine and the alkyne functionalities: the longer the connector, the more favored the lactamization process vs hydroamination. ■ INTRODUCTION Amines and their derivatives are present in a myriad of Scheme 1. (a) Metal-Catalyzed Oxidative Amidation of Alkynes and (b) Ru-Catalyzed Oxidative Lactamization of Alkynylamines bioactive natural products and pharmaceuticals.1 Among all the synthetic strategies to these compounds,2 transition metal- catalyzed addition of amines (hydroamination) and amides (hydroamidation) to unsaturated C−C bonds have emerged as powerful sustainable tools to access such functionalities.3 In the particular case of alkynes, their electrophilic activation by π-coordination to transition metals make them prone to receive nucleophilic attacks, generating enamines or enam- ides.4 Apart from chemoselectivity, efficient strategies to control the regioselectivity of terminal alkynes have been developed to produce Markovnikov-type products.3d On the contrary, generation of catalytic metal-vinylidenes from the initially coordinated metal-alkyne allows the polarization of the unsaturated bond in such a way that the carbon α to the metal center is now electrophilic affording exclusively the anti- Markovnikov addition products.5 In cases where an oxidizing nucleophile is present, the oxygen atom is transferred to the carbon-metal bond of the vinylidene complex, entailing a very reactive ketene intermediate, which could be subsequently trapped by other nucleophiles (e.g., amine) present in the media (Scheme 1a).6 A pioneer work by Kim and Lee and Zhang et al. showed that ketenes generated from Rh- and Ru- Received: November 16, 2022 vinylidenes in the presence of oxidants could be intermolec- Published: December 29, 2022 ularly trapped with heteronucleophiles (e.g., amines, alcohols) or be involved in [2 + 2] cycloadditions, respectively.7 Recently, our group has successfully developed a general Ru- catalyzed intermolecular oxidative amidation of alkynes8 with © 2022 The Authors. Published by American Chemical Society https://doi.org/10.1021/acs.joc.2c02770 1185 J. Org. Chem. 2023, 88, 1185−1193 The Journal of Organic Chemistry pubs.acs.org/joc Article all types of aliphatic and aromatic amines, which allowed for substrate.18 Interestingly, the amount of oxidant employed had the synthesis of a variety of primary and secondary amides in a significant effect in the efficiency of the reaction (Table S1e). good to excellent yields. Thus, when the amount of N-oxide was reduced to 1.1 equiv More challenging would be the intramolecular processes (entry 6) an excellent 90% yield of 3-benzazepin-4-one 2a was since the desired intramolecular oxidative amidation (oxidative obtained.19 To our delight, excellent yields of 2a were also lactamization) would have to compete with the intramolecular obtained when loadings of 3% of catalyst were used even at 60 hydroamination reaction (capture of the electrophilic vinyl- °C (entry 7 and Table S1f).20 idene).9 Thus, the ammonium salts of (o-propynylphenyl)- Herein, we describe the chemoselective Ru-catalyzed methanamines 3a·HCl (R = Me) and 3b·HCl (R = Bn) oxidative lactamization10 of aromatic 1,5- and 1,6-alkynyl- smoothly underwent the oxidative lactamization to give the amines, which provides efficient access to valuable seven- corresponding 2-benzazepin-3-ones 4a and 4b in reasonable membered 1-, 2-, and 3-benzazepin-2-, 3-, and 4-ones,11 good yields (Scheme 2). As in the case of intermolecular privileged scaffolds in natural products and pharmaceuticals,12 and eight-membered 4-benzazocin-5-ones, respectively13 Scheme 2. 1- and 2-Benzazepin-2- and -3-ones by Ru- (Scheme 1b). Catalyzed Oxidative Lactamization of Aromatic 1,5- ■ RESULTS AND DISCUSSION We started our investigation by testing the oxidative Alkynylamines lactamization of N-(2-ethynylphenethyl)propan-1-amine 1a (a 1,5-alkynylamine) under our previously optimized inter- molecular oxidative amidation conditions for secondary amines (Table 1).8 Table 1. Optimization of the Reaction Conditionsa entry substrate cat (%) N-oxide (equiv) KPF6 (equiv) 2a (% yield) a Ammonium salt 3a·HCl, 0.3 equiv K2CO3. bAmmonium salt 3b· 1b 1a 5 2 1 dec HCl, 0.3 equiv K2CO3. 2bc 1a 5 2 dec 3 1a·HCl 10 2 30 4 1a·HCl 10 2 0.3 50 5 1a·HCl 10 2 1 58 oxidative amidation of anilines,8 the free primary and 6 1a·HCl 10 1.1 1 92 (90)d secondary o-butynylanilines 5a and 5b (R = H and Me, X = 7 1a·HCl 3 1.1 1 (97)def CH2) were readily converted into the corresponding 1- a benzazepin-2-ones 6a and 6b in fairly good yields. The Typical conditions: 0.2 mmol of substrate, 2 mL of DCE, sealed presence of a heteroatom in the linker is well tolerated. Thus, tube, NMR yields. bWithout K2CO3. cSimilar results were obtained at 70 and 50 °C. At rt, the starting material was recovered. dIsolated the free primary and secondary (o-propynyloxy)anilines 5c (R yield. e100 °C, 30 min. f60 °C, 1 h. dec: decomposition. = H, X = O), 5d (R = Me, X = O), and 5e (R = Bn, X = O) smoothly cyclized to give the corresponding 1,4-benzoxazepi- nones 6c−e in moderate to good yields. In the case of the free To our initial surprise, heating a solution of 1a in DCE at primary (o-propynylthio)aniline 5f (R = H, X = S), a slow 100 °C for 4 h in the presence of 5 mol % CpRuCl(PPh3)2 and conversion was observed to give the 1,4-benzothiazepinone 6f 2 equiv of 4-picoline N-oxide with or without 1 equiv of KPF6 in a moderate 43% yield. (entries 1 and 2) led to decomposition. Variation of Pleasingly, oxidative lactamization seems a very reliable temperature conditions from 100 °C to rt resulted again in process for the construction of medium-sized lactams since the decomposition14 or starting material recovery (entry 2 and higher homolog 1,6-alkynylamine, as ammonium salt 1c·HCl, Table S1a).15 Interestingly, using the ammonium salt 1a·HCl, smoothly afforded the corresponding eight-membered 3- to favor a controlled release of the amine during the reaction, benzazocinone 7 in an excellent 90% yield (Scheme 3). allowed us to obtain the desired seven-membered 3- Unfortunately, the next homolog member 4-(2-ethynylphen- benzazepin-4-one 2a albeit in a low yield (entry 3 and Table yl)-N-propylbutan-1-amine failed to react due probably to an S1b).16 We then analyzed the use of salt additives in the course unfavorable Thorpe−Ingold effect. Conversely, the ammonium of the reaction (Table S1b).8 Thus, addition of KPF6 (0.3 salt of the lower homolog 1,4-alkynylamine 1b·HCl slowly equiv) gave a moderate yield of 2a (entry 4), which could be decomposed under the same conditions (Scheme 3). This last slightly increased to 58% yield when 1 equiv of KPF6 was unexpected result led us to examine the competitive intra- added (entry 5).17 These results would suggest that KPF6 molecular hydroamination reaction of alkynylamines 1a·HCl might be involved not only in the formation of a cationic and 1b·HCl (Scheme 3). Thus, while the 1,5-alkynylamine 1a· ruthenium catalyst but also as a counterion of the ammonium HCl gave the desired 3-benzazepine 8a but in a low 14% yield, 1186 https://doi.org/10.1021/acs.joc.2c02770 J. Org. Chem. 2023, 88, 1185−1193 The Journal of Organic Chemistry pubs.acs.org/joc Article Scheme 3. Ru-Catalyzed Oxidative Lactamization of The novelty of the transformation prompted us to undertake Aromatic 1,4- and 1,6-Alkynylamines 1b·HCl and 1c·HCl a DFT mechanistic analysis to unveil the origin of the and Hydroamination of Aromatic 1,5- and 1,4- chemoselectivity observed toward oxidative lactamization vs Alkynylamines 1a·HCl and 1b·HCl intramolecular hydroamination of alkynylamines.22 For this study, both 1,5-alkynylamine 1a and its lower homolog 1,4- alkynylamine 1b have been used as model substrates. Following our previous mechanistic proposal,8 the catalytic cycle for the oxidative lactamization can be divided in three main steps (Scheme 5, blue): (i) Ru(II)-catalyzed vinylidene Scheme 5. Competitive Mechanisms for the Ru(II)- Catalyzed Oxidative Lactamization (blue) and Ru(II)- Catalyzed Alkyne Intramolecular Hydroamination (Green) of 1,5- and 1,4-Alkynylamines a Same result without 4-Pic-N-oxide. the lower homolog 1,4-alkynylamine 1b·HCl gave, as some- what expected, decomposition.9a We speculate that the benzylamine derivatives could undergo competitive intramolecular C−H activation processes that lead to complex mixtures or decomposition. For this reason, we turned our attention to the evaluation of alkynylamide derivatives in the cyclization processes (Scheme formation, (ii) Ru(II)-vinylidene oxidation by external 4- 4). Thus, the 1,5-alkynylamide 9a underwent an oxidative picoline N-oxide, and (iii) metal-free lactamization of the generated ketene. On the other hand, the competitive Ru(II)- Scheme 4. Ru-Catalyzed Oxidative Lactamization and hydroamination processes toward the formation of dihydro-3- Intramolecular Hydroamination of 1,5-Alkynylamide 9a and benzazepine 8a and dihydroisoquinoline 8b (not experimen- 1,4-Alkynylamide 9b tally observed) would proceed through trapping of the initially formed Ru-vinylidenes by intramolecular hydroamination (Scheme 5, green). The computed Gibbs energy profile for the formation of Ru- vinylidenes from 1a (black color) and 1b (red color) is depicted in Figure 1. The DFT computed mechanism starts with the chloride release forming the active catalyst [CpRu(PPh3)2]+, I, entailing the formation of the η2-alkyne intermediate IIa and IIb at −2.4 and −0.2 kcal·mol−1, respectively. The activation of the substrates goes through the well-established 1,2-hydrogen a In the absence of 4-Pic-N-oxide. migration favored by the agostic interaction with the methylidyne C−H bond in intermediates III.23,24 The energy barrier, TSII−III, is quite affordable requiring 6.6 and 6.7 kcal· lactamization to afford the imide 10 (benzazepine-2,4(3H)- mol−1 for the formation of the agostic intermediates IIIa and dione) in a quite good yield, and the lower homolog 1,4- IIIb falling at 2.9 and 5.3 kcal·mol−1, respectively. Inter- alkynylamide 9b gave the hydroamination product 11 mediates III evolve through a 1,2-hydrogen migration (isoquinolin-1-one) in a moderate 48% yield under the same overcoming energy barriers of 11.3 and 13.1 kcal·mol−1 to oxidative conditions or a 83% yield in the absence of 4-Pic-N- the Ru(II)-vinylidene intermediates IVa and IVb at −13.4 and oxide (Scheme 4).21 By contrast, the reaction of 1,5- −12.7 kcal mol−1, respectively. Experimentally, in a deuteration alkynylamide 9a in the absence of 4-Pic-N-oxide gave a study of the Ru-catalyzed heterocyclization of aromatic bis- complex mixture. homopropargyl alcohols, we had already shown results that 1187 https://doi.org/10.1021/acs.joc.2c02770 J. Org. Chem. 2023, 88, 1185−1193 The Journal of Organic Chemistry pubs.acs.org/joc Article indicate the formation of ruthenium vinylidene species as key intermediates.25 In addition, other competitive cyclization experiments also showed the involvement of vinylidene intermediates. Thus, heterocyclization of 1,4-alkynylanilide with catalytic CpRuCl(PPh3)2 gave rise to the corresponding 1,4-dihydroquinolinone, a product derived from hydroamina- tion through a Ru-vinylidene intermediate, while with catalytic RuCl2(p-cymene)2/PBu3 gave the indol derivative, most likely through a typical alkyne activation/aromatization.9a We next turned our attention to the Ru(II)-catalyzed vinylidene oxidation from IVa and IVb. The Gibbs energy profiles for IVa (black pathway) and IVb (red pathway) are depicted in Figure 2 (right side of the profile). The nucleophilic attack of picoline N-oxide to the Cα of the Ru-vinylidene (ΔG‡ = 22.2 and 20.0 kcal mol−1 for TSIVa−Va and TSIVb−Vb, respectively) takes place in a coplanar approach to the Ru-vinylidene (Figure 2, inset drawing), affording intermediate Va and Vb at −0.5 and −1.8 kcal mol−1, respectively. Then, release of 4-picoline occurs (ΔG‡ = 6.7 and 7.3 kcal mol−1 for both TSVa−VIa and TSVb−VIb, respectively) to Figure 1. Gibbs energy profiles (DLPNO-CCSD(T)/def2-TZVP// afford η2-coordinated ruthenium ketene complexes VIa and B3LYP-D3/6-31G(d,p)-SDD(Ru)DCE(SMD) 373 K) for the Ru(II)- VIb,26 which further evolve to the more stable free ketenes vinylidenes IVa and IVb. Energies are relative to [CpRu(PPh3)2]+ I VIIa and VIIb with the recovery of the catalytic species I in a and alkynylamines 1a and 1b, respectively, and are mass balanced. global exergonic process. Competitive hydroamination pathways for both Ru(II)- vinylidenes IVa and IVb (Figure 2, left) were then analyzed. Figure 2. Gibbs energy profiles (DLPNO-CCSD(T)/def2-TZVP//B3LYP-D3/6-31G(d,p)-SDD(Ru)DCE(SMD) 373 K) for the Ru(II)-catalyzed oxidation with picoline N-oxide (right) and for the intramolecular Ru(II)-catalyzed hydroamination of Ru(II)-vinylidenes IVa and IVb (left). Truncated structure of TSIVa−Va (inset draw). Energies are relative to [CpRu(PPh3)2]+ I and alkynylamines 1a and 1b, respectively, and are mass balanced. 1188 https://doi.org/10.1021/acs.joc.2c02770 J. Org. Chem. 2023, 88, 1185−1193 The Journal of Organic Chemistry pubs.acs.org/joc Article The initial step is the intramolecular nucleophilic attack of the amine to the Cα of the Ru(II)-vinylidenes IV to yield the cationic alkenylruthenium complexes VIIIa and VIIIb. The transition state of this step resulted in being significantly more favorable for vinylidene IVb (ΔΔG‡ = (27.3 − 14.6) = 12.7 kcal·mol−1) presumably due to the less entropic penalty caused by the closer proximity of the reactive centers and the formation of a more stable six-membered ring intermediate. Similarly, from the formed cationic heterocycles VIII, the subsequent bicarbonate assisted deprotonation followed by protonolysis of the Ru−C bonds and Ru-decoordination displays a lower energy barrier (ΔΔG‡ = (13.2 − 11.2) = 2.0 kcal mol−1, TSVIIIa−8a vs TSVIIIb−8b) for the formation of the dihydroisoquinoline 8b rather than dihydrobenzazepine 8a.27 Although from vinylidene IVb the intramolecular hydro- amination to 8b is more energetically favored than oxidative amidation with overall Gibbs energy barriers of 14.6 and 20.0 kcal mol−1, respectively, the cyclization of benzylamine 1b·HCl gave decomposition products through other non-analyzed competitive pathways.9a By contrast, from vinylidene IVa, oxidative lactamization to 2a is more favorable than hydro- amination with overall barriers of 22.2 and 27.3 kcal mol−1, respectively.28 Figure 4. Gibbs energy profiles (DLPNO-CCSD(T)/def2-TZVP// Finally, to have a complete picture of the oxidative B3LYP-D3/6-31G(d,p)-SDD(Ru)DCE(SMD) 373 K) for the Ru(II)- lactamization process, pathways involving metal-bound ketenes catalyzed nucleophilic addition of picoline N-oxide (right) and the VI and metal-free ketenes VII as intermediates were intramolecular nucleophilic addition of nitrogen to vinylidene (left) of evaluated.29 It was found that the most favorable pathways Ru(II)-vinylidenes species XVIa and XVIb derived from alkynyla- involve the metal-free ketenes VII with a water molecule acting mides 9a and 9b, respectively. Energies are relative to [CpRu- as a proton carrier (Figure 3),30 whereas that of metal-bound (PPh3)2]+ I and alkynylamines 9a and 9b, respectively, and are mass balanced. Starting from vinylidene XVIa, oxidative lactamization to 10 (Scheme 4) is more favorable than hydroamination with overall barriers of 22.5 and 33.0 kcal mol−1, respectively. Conversely, from vinylidene XVIb, the intramolecular hydro- amination to 11 (Scheme 4) is more favorable than oxidative amidation with overall Gibbs energy barriers of 23.2 and 28.8 kcal mol−1, respectively. According to these results, the chain length between the alkyne and amide functionalities is crucial for the chemoselectivity found. The effects caused by the longer carbon-tethered in 9a (1,5-alkynylamide) vs 9b (1,4- alkynylamide) slows down the intramolecular direct nucleo- philic attack of the nitrogen to the vinylidene making the intermolecular addition of the picoline N-oxide a competitive process. Figure 3. Gibbs energy profile (DLPNO-CCSD(T)/def2-TZVP// ■ CONCLUSIONS Medium-sized benzofused seven-membered lactams (1-, 2-, 3- B3LYP-D3/6-31G(d,p)-SDD(Ru)DCE(SMD) 373 K) for the lactamiza- benzazepin-2-, -3-, and -4-ones) and eight-membered lactams tion of metal-free ketene VIIa with water acting as a proton carrier. (3-benzazocinone) could be efficiently assembled by chemo- Energies are relative to [CpRu(PPh3)2]+ I and alkynylamine 1a and selective Ru-catalyzed oxidative lactamization of aromatic 1,5- are mass balanced. alkynylamines and 1,6-alkynylamines with 4-picoline N-oxide as an external oxidant. DFT mechanistic studies revealed that ketene is higher in energy (Figures S2−S5, Supporting the oxidation of the catalytic Ru-vinylidene intermediate Information).27 Thus, intramolecular nucleophilic attack of occurs via a coplanar intermolecular nucleophilic attack of the amine to the central carbon in ketene VIIa (ΔG‡ = 12.2 the 4-picoline N-oxide to the electrophilic α carbon. The chain kcal mol−1) affords enol−water complex IXa-H2O (ΔG° = 3.5 length between the alkyne and the amine functionalities (1,5- kcal mol−1),31 which after keto-enol tautomerization (ΔG‡ = and 1,6-alkynylamines) proved to be crucial for the chemo- 17.8 kcal mol−1) and water release gives rise to the ε-lactam 2a selective oxidation since only ε- and ζ-lactams could be (ΔG° = −34.4 kcal mol−1). obtained but not δ-lactams. In the case of 1,4-alkynylamides, Once the complete cyclization energetic profiles of alkynyl- the hydroamination product was obtained on being more amines were analyzed, we calculate the cyclization rate- favorable the intramolecular nucleophilic attack to the Ru- determining steps of alkynylamides 9a and 9b (Figure 4). vinylidene. 1189 https://doi.org/10.1021/acs.joc.2c02770 J. Org. Chem. 2023, 88, 1185−1193 The Journal of Organic Chemistry pubs.acs.org/joc Article ■ EXPERIMENTAL SECTION All reactions were performed under an argon atmosphere, and the (CH), 128.1 (CH), 125.9 (CH), 54.4 (CH2), 35.2 (CH3), 33.5 (CH2), 28.7 (CH2). 2-Benzyl-1,2,4,5-tetrahydro-3H-benzo[c]azepin-3-one (4b). Pro- glassware was oven dried at 80 °C or flame dried unless otherwise cedure B. The product was purified by silica gel chromatography stated. All dry solvents were stored under an argon atmosphere and (EtOAc/Hex 3:7). Compound 4b, 0.027 g (53%), colorless oil. 1H over 4 Å molecular sieves. All chemicals were purchased from Acros NMR (300 MHz, CDCl3): δ 7.63−7.53 (m, 4H), 7.21−7.13 (m, 3H), Organics, TCI Chemicals, Sigma-Aldrich, Alfa Aesar, or Strem 7.06−7.04 (m, 1H), 6.85−6.82 (m, 1H), 4.66 (s, 2H), 4.40 (s, 2H), Chemicals chemical companies and used without further purification. 3.22 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 6.8 Hz, 2H). 13C{1H} NMR, The catalyst for Sonogashira coupling, PdCl2(PPh3)2, was prepared DEPT (75 MHz, CDCl3): δ 173.1 (CO), 140.4 (C), 138.2 (C), 136.5 according to previously published procedure. (C), 129.5 (CH), 129.3 (CH), 128.4 (2× CH), 127.9 (2× CH), For the catalytic reactions, the CpRuCl(PPh3)2 catalyst used was 127.8 (2× CH), 127.7 (CH), 50.0 (CH2), 49.1 (CH2), 34.4 (CH2), purchased from Strem; the 4-picoline-N-oxide was purchased from 28.8 (CH2). HRMS (EI-TOF) m/z: [M]+ calcd for C17H17NO: Aldrich, and the DCE anhydrous was purchased from Acros Organics. 251.1310; found: 251.1316. Analytical thin-layer chromatography was carried out on silica- 1,3,4,5-Tetrahydro-2H-benzo[b]azepin-2-one (6a). Known com- coated aluminum plates (silica gel 60 F254 Merck) using UV light as pound.33 Procedure A. The product was purified by silica gel a visualizing agent (254 nm) and KMnO4 (solution of 1.5 g of chromatography (EtOAc/Hex 3:7). Compound 6a, 0.017 (53%), potassium permanganate, 10 g of potassium bicarbonate and 1.25 mL yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.70 (bs, 1H), 7.27−7.19 of 10% sodium hydroxide in 200 mL of water) or p-anisaldehyde (m, 2H), 7.13 (td, J = 7.3, 1.3 Hz, 1H), 7.01−6.93 (m, 1H), 2.81 (t, J (solution of 3.7 mL of p-anisaldehyde, 1.5 mL of glacial acetic acid, 5 = 7.2 Hz, 2H), 2.36 (t, J = 7.2 Hz, 2H), 2.29−2.17 (m, 2H). 13C{1H} mL of conc. sulfuric acid in 135 mL of absolute ethanol) with heat as NMR, DEPT (101 MHz, CDCl3): δ 175.2 (CO), 137.9 (C), 134.5 developing agents. Flash column chromatography was performed on (C), 130.0 (CH), 127.6 (CH), 125.9 (CH), 121.9 (CH), 32.9 (CH2), silica gel 60 (Merck, 230−400 mesh) with the indicated eluent. 30.5 (CH2), 28.6 (CH2). MS (CI), m/z (%): 162 (M + 1, 100). 1 H and 13C nuclear magnetic resonance experiments were carried 1-Methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (6b). out using a Varian Inova 400 MHz or a Varian Mercury 300 MHz. Known compound.34 Procedure A. The product was purified by Coupling constants J are given in Hertz (Hz). Multiplicities are silica gel chromatography (EtOAc/Hex 3:7). Compound 6b, 0.022 g reported as follows: s = singlet, bs = broad singlet, d = doublet, t = (62%), yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.29 (ddd, J = 7.9, triplet, q = quartet, sxt = sextet, m = multiplet, or as a combination of 7.0, 1.8 Hz, 1H), 7.21−7.13 (m, 3H), 3.35 (s, 3H), 2.72 (t, J = 7.2 Hz, them. Multiplicities of 13C NMR signals were determined by DEPT 2H), 2.30 (t, J = 7.2 Hz, 2H), 2.19−2.14 (m, 2H). 13C{1H} NMR, experiments. Yields refer to isolated compounds estimated to be DEPT (126 MHz, CDCl3): δ 173.5 (CO), 143.9 (C), 135.3 (C), >95% pure as determined by 1H NMR. 129.4 (CH), 127.6 (CH), 126.2 (CH), 122.4 (CH), 35.3 (CH3), 33.3 Ru-Catalyzed Oxidative Lactamizations. General Procedure (CH2), 30.2 (CH2), 29.0 (CH2). MS (CI), m/z (%): 176 (M + 1, A. A suspension of the corresponding alkynylamine (1 equiv), 100). HRMS (CI-TOF) m/z: [M + H]+ calcd for C11H14NO: CpRuCl(PPh3)2 (0.03 equiv), 4-Pic-N-oxide (1.1 equiv), and KPF6 (1 176.1070; found: 176.1064. equiv) in DCE was heated in a screw-cap vial until complete 2,3-Dihydrobenzo[b][1,4]oxazepin-4(5H)-one (6c). Known com- disappearance of a starting material (TLC monitoring). The resulting pound.35 Procedure A. The product was purified by silica gel mixture was washed with saturated solution of CuSO4 and extracted chromatography (EtOAc/Hex 1:1 to EtOAc). Compound 6c, 0.017 g with DCM (3 × 10 mL). The combined organic layers were dried (53%), yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.28 (bs, 1H), (Na2SO4) and concentrated in vacuo. The residue was purified by 7.08−7.00 (m, 3H), 6.99−6.94 (m, 1H), 4.46 (t, J = 5.7 Hz, 2H), silica gel flash column chromatography to yield the corresponding 2.86 (t, J = 5.7 Hz, 2H). 13C{1H} NMR, DEPT (101 MHz, CDCl3): lactam. δ 172.9 (CO) 148.6 (C), 128.9 (C), 125.5 (CH), 123.8 (CH), 122.2 General Procedure B. A suspension of the corresponding (CH), 121.7 (CH), 68.8 (CH2), 36.9 (CH2). MS (CI), m/z (%): 164 alkynylamine hydrochloride (1 equiv), CpRuCl(PPh3)2 (0.03 (M + 1, 100). equiv), K2CO3 (0.3 equiv), 4-Pic-N-oxide (1.1 equiv), and KPF6 (1 5-Methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (6d). Pro- equiv) in DCE was heated in a screw-cap vial until complete cedure A. The product was purified by silica gel chromatography (EtOAc/Hex 1:1 to EtOAc). Compound 6d, 0.021 g (58%), yellow disappearance of the starting material (TLC monitoring). The oil. 1H NMR (400 MHz, CDCl3): δ 7.21−7.07 (m, 4H), 4.57 (t, J = resulting mixture was washed with saturated solution of CuSO4 and 6.6 Hz, 2H), 3.35 (s, 3H), 2.64 (t, J = 6.6 Hz, 2H). 13C{1H} NMR, extracted with DCM (3 × 10 mL). The combined organic layers were DEPT (101 MHz, CDCl3): δ 171.0 (CO), 149.5 (C), 138.3 (C), dried (Na2SO4) and concentrated in vacuo. The residue was purified 127.0 (CH), 125.2 (CH), 123.1 (CH), 122.9 (CH), 74.5 (CH2), 35.2 by silica gel flash column chromatography to yield the corresponding (CH2), 35.0 (CH3). MS (CI), m/z (%): 178 (M + 1, 100). HRMS lactam. (CI-TOF) m/z: [M + H]+ calcd for C10H12NO2: 178.0863; found: 3-Propyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (2a). Pro- 178.0860. cedure B. The product was purified by silica gel chromatography 5-Benzyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (6e). Pro- (EtOAc/Hex 1:1). Compound 2a, 0.04 g (97%), yellow oil. 1H NMR cedure A. The product was purified by silica gel chromatography (500 MHz, CDCl3): δ 7.18−7.14 (m, 1H), 7.13−7.10 (m, 1H), (EtOAc/Hex 3:7). Compound 6e, 0.035 g (70%), yellow oil. 1H 7.10−7.06 (m, 2H), 3.89 (s, 2H), 3.77−3.61 (m, 2H), 3.44−3.30 (m, NMR (500 MHz, CDCl3): δ 7.30−7.07 (m, 9H), 5.07 (s, 2H), 4.62 2H), 3.15−3.09 (m, 2H), 1.58 (sxt, J = 7.4 Hz, 2H), 0.89 (t, J = 7.4 (t, J = 6.6 Hz, 2H), 2.74 (t, J = 6.6 Hz, 2H). 13C{1H} NMR (126 Hz, 3H). 13C{1H} NMR, DEPT (126 MHz, CDCl3): δ 171.8 (CO), MHz, CDCl3): δ 171.2 (CO), 149.9 (C), 137.5 (C), 137.3 (C), 128.7 135.9(C), 131.8(C), 131,1 (CH), 130.3 (CH), 127.1 (CH), 126.6 (2× CH), 127.30 (CH), 127.26 (CH), 127.1 (2× CH), 125.2 (CH), (CH), 48.7 (CH2), 46.5 (CH2), 43.4 (CH2), 32.9 (CH2), 21.6 123.2 (CH), 123.0 (CH), 74.6 (CH2), 51.0 (CH2), 35.3 (CH2). MS (CH2), 11.4 (CH3). MS (CI), m/z (%): 204 (M + 1, 100). HRMS (CI), m/z (%): 254 (M + 1, 100). HRMS (CI-TOF) m/z: [M + H]+ (EI-TOF) m/z: [M]+ calcd for C13H17NO: 203.1310; found: calcd for C16H16NO2: 254.1176; found: 254.1176. 203.1315. 2,3-Dihydrobenzo[b][1,4]thiazepin-4(5H)-one (6f). Known com- 2-Methyl-1,2,4,5-tetrahydro-3H-benzo[c]azepin-3-one (4a). pound.36 Procedure A. The product was purified by silica gel Known compound.32 Procedure B. The product was purified by chromatography (EtOAc/Hex 4:6). Compound 6f, 0.031 g (43%), silica gel chromatography (EtOAc/Hex 7:3). Compound 4a, 0.024 g brown semisolid. 1H NMR (500 MHz, CDCl3): δ 8.41 (bs, 1H), 7.60 (69%), yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.25−7.22 (m, (dd, J = 7.7, 1.5 Hz, 1H), 7.35 (td, J = 7.7, 1.5 Hz, 1H), 7.16 (td, J = 1H), 7.15−7.06 (m, 3H), 4.48 (s, 2H), 3.16 (t, J = 6.8 Hz, 2H), 3.04 7.7, 1.5 Hz, 1H), 7.11 (dd, J = 7.7, 1.5 Hz, 1H), 3.48−3.41 (m, 2H), (s, 3H), 2.91 (t, J = 6.8 Hz, 2H). 13C{1H} NMR, DEPT (126 MHz, 2.63 (t, J = 6.9 Hz, 2H). 13C{1H} NMR, DEPT (126 MHz, CDCl3): CDCl3): δ 173.6 (CO), 137.7 (C), 134.2 (C), 130.5 (CH), 128.8 δ 174.0 (CO), 141.6 (C), 135.6 (CH), 129.9 (CH), 127.0 (C), 126.6 1190 https://doi.org/10.1021/acs.joc.2c02770 J. Org. Chem. 2023, 88, 1185−1193 The Journal of Organic Chemistry pubs.acs.org/joc Article (CH), 123.4 (CH), 34.5 (CH2), 33.7 (CH2). MS (CI), m/z (%): 180 de Santiago de Compostela, 15782 Santiago de Compostela, (M + 1, 100). Spain; orcid.org/0000-0001-8948-1258 3-Propyl-3,4,5,6-tetrahydrobenzo[d]azocin-2(1H)-one (7). Andrea Á lvarez-Pérez − Centro Singular de Investigación en Known compound.37 Procedure B. The product was purified by Química Biolóxica e Materiais Moleculares (CiQUS), silica gel chromatography (EtOAc/Hex 3:7 to 1:1). Compound 7, 0.039 g (90%), yellow oil. 1H NMR (500 MHz, CDCl3): δ (243 K): Departamento de Química Orgánica, Universidade de 7.41 (dd, J = 6.9, 2.0 Hz, 1H), 7.21−7.08 (m, 3H), 4.07 (d, J = 11.7 Santiago de Compostela, 15782 Santiago de Compostela, Hz, 1H), 3.87 (dd, J = 15.8, 11.3 Hz, 1H), 3.46−3.24 (m, 3H), 3.07− Spain 2.83 (m, 3H), 2.16−2.08 (m, 1H), 1.64−1.53 (m, 1H), 1.53−1.33 Jesús A. Varela − Centro Singular de Investigación en Química (m, 2H), 0.75 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (126 MHz, Biolóxica e Materiais Moleculares (CiQUS), Departamento CDCl3): δ (243 K): 173.0 (CO), 139.9 (C), 136.0 (C), 130.0 (CH), de Química Orgánica, Universidade de Santiago de 129.8 (CH), 127.2 (CH), 127.2 (CH), 51.4 (CH2), 49.5 (CH), 40.2 Compostela, 15782 Santiago de Compostela, Spain; (CH), 36.7 (CH), 30.2 (CH), 20.9 (CH), 11.3 (CH3). MS (CI), m/z orcid.org/0000-0001-8499-4257 (%): 218 (M + 1, 100). HRMS (EI-TOF) m/z: [M]+ calcd for C14H19NO: 217.1467; found: 217.1469. Complete contact information is available at: 3-Methyl-1,5-dihydro-2H-benzo[d]azepine-2,4(3H)-dione (10). https://pubs.acs.org/10.1021/acs.joc.2c02770 Procedure A. The product was purified by silica gel chromatography (EtOAc/Hex 3:7). Compound 10, 0.028 g (73%), orange needles. 1H Notes NMR (500 MHz, CDCl3): δ 7.30−7.27 (m, 4H), 4.11 (s, 4H), 3.13 The authors declare no competing financial interest. (s, 3H). 13C{1H} NMR, DEPT (126 MHz, CDCl3): δ 171.0 (CO), 131.9 (2× C), 128.6 (2× CH), 128.5 (2× CH), 45.0 (CH2), 29.8 (CH3). MS (CI), m/z (%): 190 (M + 1, 100), 163 (3), 162 (28). HRMS (CI-TOF) m/z: [M + H]+ calcd for C11H12NO2: 190.0863; ■ ACKNOWLEDGMENTS This work has received financial support from MICINN found: 190.0862. (projects PID2020-118048GB-I00, PID2020-116861GB-I00, Isoquinolin-1(2H)-one (11). Procedure A in the absence of and ORFEO-CINQA network RED2018-102387-T), the oxidant. Known compound.9a The product was purified by silica gel Xunta de Galicia (project ED431C 2022/27, Centro singular chromatography (EtOAc/Hex 1:1). Compound 11, 0.042 g (83%), de investigación de Galicia accreditation 2019-2022, ED431G brown solid. 1H NMR (300 MHz, CDCl3): δ 11.49 (s, 1H), 8.43 (d, J 2019/03), and the European Union (European Regional = 8.00 Hz, 1H), 7.68 (t, J = 6.9 Hz, 1H), 7.59−7.51 (m, 2H), 7.20 (d, Development Fund). We are also grateful to the CESGA J = 7.1 Hz, 1H), 6.58 (d, J = 7.1 Hz, 1H). 13C{1H} NMR, DEPT (75 MHz, CDCl3): δ 164.4 (C�O), 138.1(C), 132.5 (CH), 127.6 (CH), (Xunta de Galicia) for computational time. 127.3 (CH), 126.8 (CH), 126.2 (CH), 126.1(C), 106.7 (CH). MS (EI) (m/z, %): 145 (M+, 100), 118 (36), 90 (29). HRMS (EI-TOF) m/z: [M]+ calcd for C9H7NO: 145.0528; found: 145.0528. ■ REFERENCES (1) (a) Hager, A.; Vrielink, N.; Hager, D.; Lefranc, J.; Trauner, D. Synthetic approaches towards alkaloids bearing α-tertiary amines. Nat. ■ * ASSOCIATED CONTENT sı Supporting Information Prod. Rep. 2016, 33, 491−522. (b) Afanasyev, O. I.; Kuchuk, E.; Usanov, D. L.; Chusov, D. Reductive Amination in the Synthesis of Pharmaceuticals. Chem. Rev. 2019, 119, 11857−11911. The Supporting Information is available free of charge at (2) (a) de Figueiredo, R. M.; Suppo, J.-S.; Campagne, J.-M. https://pubs.acs.org/doi/10.1021/acs.joc.2c02770. Nonclassical Routes for Amide Bond Formation. Chem. 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