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Communication

Efficient Metal-Free Oxidative C–H Amination for Accessing Dibenzoxazepinones via μ-Oxo Hypervalent Iodine Catalysis

by
Hirotaka Sasa
1,†,
Syotaro Hamatani
2,
Mayu Hirashima
3,
Naoko Takenaga
4,
Tomonori Hanasaki
3,* and
Toshifumi Dohi
2,*
1
Ritsumeikan Global Innovation Research Organization, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu 525-8577, Shiga, Japan
2
Graduate School of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu 525-8577, Shiga, Japan
3
Graduate School of Life Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu 525-8577, Shiga, Japan
4
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Aichi, Japan
*
Authors to whom correspondence should be addressed.
†
Current address: School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien Kyuban-cho, Nishinomiya 663-8179, Hyogo, Japan.
Chemistry 2023, 5(4), 2155-2165; https://doi.org/10.3390/chemistry5040145
Submission received: 4 September 2023 / Revised: 29 September 2023 / Accepted: 10 October 2023 / Published: 12 October 2023
(This article belongs to the Special Issue Catalytic Organic Synthesis—a Special Issue in Honor of Professor Masahiro Miura)
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Versions Notes

Abstract

:
Dibenzoxazepinones exhibit unique biological activities and serve as building blocks for synthesizing pharmaceutical compounds. Despite remarkable advancements in organic chemistry and recent developments in synthetic approaches to dibenzoxazepinone motifs, there is a strong demand for more streamlined synthesis methods. The application of the catalytic C–H amination strategy, which enables the direct transformation of inert aromatic C–H bonds into C–N bonds, offers a rapid route to access dibenzoxazepinone frameworks. Hypervalent-iodine-catalyzed oxidative C–H amination has the potential to become an effective approach for synthesizing dibenzoxazepinones. In this study, we present our method of employing μ-oxo hypervalent iodine catalysis for intramolecular oxidative C–H amination of O-aryl salicylamides, facilitating the synthesis of target dibenzoxazepinone derivatives bearing various functional groups in a highly efficient manner.

1. Introduction

Dibenzoxazepinones, a class of heterocyclic compounds comprising two benzene rings fused to a central oxazepinone ring, play an important role in the quest for pharmaceutically active compounds. A series of dibenzoxazepinones have been synthesized and evaluated for their biological activities thus far (Figure 1, top). Consequently, certain dibenzoxazepinones have exhibited unique biological activities, including the inhibition of HIV-1 reverse transcriptase (RT) [1], suppression of angiogenesis and vascular permeability [2], and antigiardial activity [3]. Furthermore, dibenzoxazepinones have been employed as synthetic intermediates for preparing structurally diverse heterocyclic compounds that demonstrate potent pharmacological attributes (Figure 1, bottom), such as the activation of transient receptor potential ankyrin 1 (TRPA1) [4], antitrypanosomal activity [5], and antibacterial efficacy [6]. Dibenzoxazepinones have thus proven useful in investigating drug candidates.
Several synthetic methods have been developed to access dibenzoxazepinones. Among them, a widely employed approach involves a nucleophilic aromatic substitution reaction (Scheme 1, path a) [7,8,9]. According to previous reports, subjecting salicylamides and substituted benzenes to basic conditions triggers intermolecular nucleophilic aromatic substitution and sequential Smiles rearrangement, resulting in the formation of dibenzoxazepinones (Scheme 1, path b) [10,11,12,13]. Another strategy for synthesizing dibenzoxazepinones relies on intramolecular aniline–carboxylic acid or –ester coupling, facilitating the creation of an amide bond and the desired tricyclic structure (Scheme 1, path c) [14,15,16,17]. Dibenzoxazepinones have also been synthesized through transition-metal-catalyzed cyclization reactions, including cyclocarbonylation (Scheme 1, path d) [18,19,20,21,22] and intramolecular cross-coupling (Scheme 1, path e) [23,24,25]. In addition, one specific dibenzoxazepinone was prepared from an aryl isocyanate via treatment with methyl trifluoromethanesulfonate (Scheme 1, path f) [26,27].
Oxidative C–H amination should offer an alternative route for accessing dibenzoxazepinones. Traditionally, the synthesis of dibenzoxazepinones necessitates the presence of two functional groups to induce ring-closing reactions. In contrast, oxidative C–H amination reactions can occur without any pre-functionalization of the starting materials, allowing the direct transformation of aromatic C–H bonds into C–N bonds [28,29,30,31,32,33,34]. We propose that an alternative synthetic approach to dibenzoxazepinones can be developed by applying the oxidative C–H amination technique.
Hypervalent iodine reagents are safe, low-toxic, and environmentally benign oxidants. They have served as an oxidative C–H amination tool in synthesizing dibenzoxazepinones. Notably, in 2015, Du et al. synthesized dibenzoxazepinones from N-methoxy-2-(aryloxy)benzamides (Scheme 2) using stoichiometric amounts of hypervalent iodine reagents, including phenyliodine diacetate (PhI(OAc)2) and iodosobenzene [35]. In the reaction devised by Du et al., the starting materials underwent oxidative C–H amination to assemble the corresponding dibenzoxazepinones in yields of 33–96%. Although the procedure successfully produced the desired compounds, more than one equivalent of iodobenzene was produced as a side product, leading to challenges in the purification process.
To realize the efficient and practical synthesis of dibenzoxazepinones, it is desirable to develop hypervalent iodine catalysis, which can operate with low catalyst loading and promote oxidative C–H amination with a broad substrate scope. In 2017, Xue et al. developed a hypervalent iodine-catalyzed C–H amination to obtain dibenzoxazepinone [36]. However, their method required a relatively large catalyst loading (10 mol%) and a limited substrate scope (1 example). The development of a more efficient catalytic C–H amination reaction would improve the existing methods for synthesizing dibenzoxazepinones. Recently, our group developed μ-oxo hypervalent iodine-mediated catalytic system, achieving efficient oxidative C–H amination reactions to yield aromatic amides [37,38]. Motivated by the goal of advancing an efficient catalytic C–H amination reaction and extending μ-oxo hypervalent iodine catalysis, this study investigated a diiodobiaryl-catalyzed intramolecular oxidative C–H amination reaction for the synthesis of dibenzoxazepinones from O-aryl salicylamides (Scheme 3).

2. Materials and Methods

2.1. General Information

All the commercially available reagents were used as received. For reactions requiring heating, an oil bath was used as the heating source. 1H and 13C NMR spectra were recorded with a JEOL JMN-400 spectrometer operating at 400 and 100 MHz in CDCl3 at 25 °C. The data are reported as follows: chemical shift in ppm (d), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet), coupling constant (Hz), and integration. Chemical shift values are given in ppm and referred to as the internal standard for TMS:0.00 ppm. Flash column chromatography and analytical TLC were performed on Merck Silica gel 60 (230–400 mesh) and Merck Silica gel F254 plates (0.25 mm), respectively. The spots and bands were detected by UV irradiation (254 and 365 nm) or staining with 5% phosphomolybdic acid, followed by heating.

2.2. Synthesis of Amides 1

2.2.1. General Procedures for the Synthesis of 2-Phenoxybenzoic Acids

According to the literature procedure [35], the substituted methyl 2-iodobenzoate (10 mmol, 1.0 eq.) and the substituted phenol (12 mmol, 1.2 eq.) were dissolved in dry toluene. Then, Cs2CO3 (15 mmol, 1.5 eq.) and CuI (10 mmol, 1.0 eq.) were added, and the flask was purged with N2. After stirring at room temperature for 5 min, the mixture was stirred at 125 °C for 15 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through Celite, and washed with AcOEt. The filtrate was concentrated under reduced pressure, followed by the addition of KOH (50 mmol, 5.0 eq.) and methanol (40 mL). Then, the mixture was stirred at 45 °C for 3 h. After the reaction, the mixture was acidified with 2M HCl and transferred to a separate funnel. The organic layer was separated, and the residual aqueous layer was extracted with AcOEt (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressures. The crude product can be used in the next step without further purification.

2.2.2. General Procedures for the Synthesis of Amides 1

The substituted 2-phenoxybenzoic acid was dissolved in dry dichloromethane (14 mL), and the flask was purged with N2. After cooling to 0 °C, a catalytic amount of dry DMF (2 drops) and oxalyl chloride (12 mmol, 1.2 eq.) was added slowly to the mixture, which was stirred at room temperature for 4 h. Upon completion of the reaction (monitored by TLC), the solvent was removed under reduced pressure. The residue was dissolved in AcOEt (5 mL) and slowly added dropwise to a solution of O-methylhydroxylamine hydrochloride (11 mmol, 1.1 eq.) and K2CO3 (20 mmol, 2.0 eq.) using an AcOEt/H2O ratio of 2:1 (30 mL). The mixture was stirred overnight at room temperature and monitored using TLC. Then, sat. NaHCO3 aq. (30 mL) was added to the reaction mixture, transferred to a separatory funnel, and extracted with AcOEt (3 × 50 mL). The combined organic phases were washed with sat. NH4Cl aq. and brine. After drying the organic layer with Na2SO4, the solution was concentrated under reduced pressure and purified via flash column chromatography (silica gel, AcOEt/hexane) to afford the desired amide 1.

2.3. Hypervalent Iodine-Catalyzed Oxidative C–H Amination Reaction

2.3.1. General Procedure A for the Synthesis of Dibenzoxazepinones 2

m-Chloroperoxybenzoic acid (abt. 30% water) (149.7 mg, 0.60 mmol, 1.0 eq.) was added to a solution of amide 1 (0.60 mmol, 1.0 eq.), precatalyst 3a (1.2 mg, 0.003 mmol, 0.5 mol%), and trifluoroacetic acid (91.8 μL, 1.2 mmol, 2.0 eq.) in HFIP (3 mL). The resulting mixture was then stirred at room temperature for 2 h. The mixture was then diluted with AcOEt and transferred to a separate funnel. The organic layer was washed with a sat. NaHCO3 (aq), Na2S2O3 (aq), brine, and dried over Na2SO4. The solution was concentrated under reduced pressure and purified using flash column chromatography (silica gel, AcOEt/hexane) to obtain the desired dibenzoxazepinone 2. 1H and 13C NMR data (See Supplementary Materials) are consistent with those reported in the literature [35].

2.3.2. General Procedure B for the Synthesis of Dibenzoxazepinones 2

First, 9% peracetic acid (0.38 mL, 0.45 mmol, 1.5 eq.) was added to a solution of amide 1 (0.30 mmol, 1.0 eq.), precatalyst 3a (2.4 mg, 0.006 mmol, 2.0 mol%), and trifluoroacetic acid (45.9 μL, 0.60 mmol, 2.0 eq.) in HFIP (1.5 mL). The resulting mixture was then stirred at 30 °C for 2 h. The mixture was then diluted with AcOEt and transferred to a separate funnel. The organic layer was washed with a sat. NaHCO3 (aq), Na2S2O3 (aq), brine, and dried over Na2SO4. The solution was concentrated under reduced pressure and purified via column chromatography (silica gel, AcOEt/hexane) to obtain the desired dibenzoxazepinone 2.

2.3.3. 10-Methoxy-dibenz[b,f][1,4]oxazepin-11(10H)-one (2a)

The title compound was synthesized using the general procedure A using N-methoxy-2-phenoxybenzamide 1a (149.6 mg, 0.61 mmol, 1.0 eq.) in 96% yield (142.5 mg, 0.59 mmol) as a light yellow oil. 1H NMR (400 MHz, CDCl3, δ/ppm): 7.98 (dd, J = 7.8, 1.5 Hz, 1H), 7.54 (dd, J = 8.0, 1.7 Hz, 1H), 7.50 (dt, J = 7.8, 1.8 Hz, 1H), 7.29–7.17 (m, 5H), 3.93 (s, 3H). 13C NMR (100 MHz, CDCl3, δ/ppm): 162.6, 159.7, 151.4, 134.1, 132.6, 132.1, 127.0, 126.0, 125.4, 124.4, 121.1, 120.5, 120.4, 62.6.

2.3.4. 10-Methoxy-2-methyl-dibenz[b,f][1,4]oxazepin-11(10H)-one (2b)

The title compound was synthesized via the general procedure B using N-methoxy-5-methyl-2-phenoxybenzamide 1b (79.3 mg, 0.31 mmol, 1.0 eq.) in 97% yield (76.8 mg, 0.30 mmol) as a light yellow oil. 1H NMR (400 MHz, CDCl3, δ/ppm): 7.76 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 7.8, 1.5 Hz, 1H), 7.29–7.24 (m, 2H), 7.23–7.16 (m, 2H), 7.11 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3, δ/ppm): 162.7, 157.7, 151.6, 135.1, 134.8, 132.6, 132.0, 126.9, 125.8, 123.8, 121.0, 120.5, 120.1, 62.6, 20.5.

2.3.5. 3-Chloro-10-methoxy-dibenz[b,f][1,4]oxazepin-11(10H)-one (2c)

The title compound was synthesized via the general procedure B using 4-chloro-N-methoxy-2-phenoxybenzamide 1c (82.5 mg, 0.30 mmol, 1.0 eq.) in 92% yield (76.1 mg, 0.28 mmol) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ/ppm): 7.93 (d, J = 8.3 Hz, 1H), 7.55 (dd, J = 8.5, 1.7 Hz, 1H), 7.29–7.26 (m, 2H), 7.25 (t, J = 2.0 Hz, 1H), 7.23–7.19 (m, 2H), 3.93 (s, 3H). 13C NMR (100 MHz, CDCl3, δ/ppm): 161.8, 159.8, 150.8, 139.7, 133.1, 132.4, 127.1, 126.3, 125.8, 122.9, 121.1, 120.9, 120.5, 62.7.

2.3.6. 10-Methoxy-8-methyl-dibenz[b,f][1,4]oxazepin-11(10H)-one (2d)

The title compound was synthesized via the general procedure A using N-methoxy-2-(p-tolyloxy)benzamide 1e (154.8 mg, 0.60 mmol, 1.0 eq.) in 97% yield (149.5 mg, 0.58 mmol) as a light yellow oil. 1H NMR (400 MHz, CDCl3, δ/ppm): 7.96 (dd, J = 7.8, 1.5 Hz, 1H), 7.48 (dt, J = 7.7, 1.6 Hz, 1H), 7.33 (d, J = 1.5 Hz, 1H), 7.25–7.19 (m, 2H), 7.15 (d, J = 8.3 Hz, 1H), 6.98 (dd, J = 8.3, 2.0 Hz, 1H), 3.93 (s, 3H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3, δ/ppm): 162.6, 159.8, 149.3, 135.9, 134.0, 132.0 132.0, 127.5, 125.2, 124.5, 120.7, 120.2, 62.6, 20.9 (one carbon peak was missing due to overlapping).

2.3.7. 8-Bromo-10-methoxy-dibenz[b,f][1,4]oxazepin-11(10H)-one (2e)

The title compound was synthesized via the general procedure A using 2-(4-Bromophenoxy)-N-methoxybenzamide 1f (193.3 mg, 0.60 mmol, 1.0 eq.) in 90% yield (172.0 mg, 0.54 mmol) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ/ppm): 7.98 (dd, J = 7.8, 1.5 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.30–7.25 (m, 2H), 7.21 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 3.95 (s, 3H). 13C NMR (100 MHz, CDCl3, δ/ppm): 162.2, 159.1, 150.0, 134.3, 134.0, 132.1, 129.6, 125.5, 123.8, 123.0, 122.5, 120.2, 118.5, 62.9.

2.3.8. 8-Chloro-10-methoxy-dibenz[b,f][1,4]oxazepin-11(10H)-one (2f)

The title compound was synthesized via the general procedure A using 2-(4-chlorophenoxy)-N-methoxybenzamide 1g (167.0 mg, 0.60 mmol, 1.0 eq.) in 94% yield (155.2 mg, 0.56 mmol) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ/ppm): 7.98 (dd, J = 7.8, 1.5 Hz, 1H), 7.53–7.49 (m, 2H), 7.29–7.18 (m, 3H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 3.95 (s, 3H). 13C NMR (100 MHz, CDCl3, δ/ppm): 162.3, 159.2, 149.4, 134.3, 133.7, 132.1, 131.2, 126.6, 125.5, 123.9, 122.2, 120.2, 120.2, 62.9.

2.3.9. 10-Methoxy-6,7-dimethyl-dibenz[b,f][1,4]oxazepin-11(10H)-one (2h)

The title compound was synthesized via the general procedure A using 2-(2,3-dimethylphenoxy)-N-methoxybenzamide 1i (165.9 mg, 0.61 mmol, 1.0 eq.) in 53% yield (87.2 mg, 0.32 mmol) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ/ppm): 7.98 (dd, J = 7.8, 1.5 Hz, 1H), 7.53–7.49 (t, J = 7.8 Hz, 1H), 7.28–7.22 (m, 3H), 7.01 (d, J = 8.3 Hz, 1H), 3.90 (s, 3H), 2.43 (s, 3H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3, δ/ppm): 162.6, 159.8, 149.9, 136.1, 133.8, 132.1, 130.4, 129.0, 126.6, 125.2, 125.1, 120.6, 117.5, 62.4, 19.8, 12.6.

2.3.10. 2-(11-Oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)isoindoline-1,3-dione (2i)

m-Chloroperoxybenzoic acid (abt. 30% water) (136.2 mg, 0.55 mmol, 1.1 eq.) was added to a solution of N-(1,3-dioxoisoindolin-2-yl)-2-phenoxybenzamide 1i (0.50 mmol, 1.0 eq.), precatalyst 3a (10.5 mg, 0.0025 mmol, 5 mol%), and trifluoroacetic acid (76.5 μL, 1.0 mmol, 2.0 eq.) in HFIP/CH2Cl2 (1:1, 3 mL). The resulting mixture was then stirred at room temperature for 24 h. The mixture was then diluted with AcOEt and transferred to a separate funnel. The organic layer was washed with a sat. NaHCO3 (aq), Na2S2O3 (aq), brine, and dried over Na2SO4. The solution was concentrated under reduced pressure and purified using flash column chromatography (silica gel, AcOEt/hexane) to obtain title compound 2i in 81% yield (143.9 mg, 0.40 mmol) as a white solid. 1H NMR (400 MHz, CDCl3, δ/ppm): 8.02–7.98 (m, 2H), 7.90 (d, J = 7.8 Hz, 1H), 7.87–7.83 (m, 2H), 7.55 (dt, J = 7.8, 2.0 Hz, 1H), 7.36–7.19 (m, 5H), 7.14 (t, J = 7.8 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ/ppm): 165.1, 163.9, 160.5, 152.5, 135.0, 134.8, 133.5, 132.7, 130.1, 127.7, 126.0, 125.5, 124.4, 123.9, 121.8, 120.7. HRMS (DART) m/z: ([M + H]+). Calcd for C21H13N2O4+ 357.0870; found 357.0868.

3. Results and Discussion

Our research group has been dedicated to advancing μ-oxo hypervalent iodine-mediated oxidation reactions. Previously, we demonstrated the efficient occurrence of hypervalent iodine-catalyzed aromatic C–N bond formation reaction utilizing biaryl-based diiodoarene precatalysts [39]. It was subsequently revealed that one of the diiodoarenes was converted into the corresponding μ-oxo hypervalent iodine species in the presence of a co-oxidant (such as peracetic acid) and that μ-oxo iodine served as a more effective reagent than conventional hypervalent iodine reagents such as PhI(OAc)2 [40]. Additionally, X-ray crystallographic analysis further highlighted that the μ-oxo species [39] had a longer I–OAc bond than PhI(OAc)2 [41]. This implies a more polarized I–OAc bond and an enhanced positive character of the iodine center, suggesting higher electrophilicity of μ-oxo iodine than that of PhI(OAc)2. Based on these experimental results and consideration of the analysis, it was anticipated that utilizing μ-oxo species as a catalyst would contribute to the realization of an efficient catalytic C–H amination reaction.
With the objective of establishing an efficient hypervalent-iodine-catalyzed oxidative C–H amination reaction for synthesizing dibenzoxazepinones, the reaction conditions were optimized (Table 1). Treatment of salicylamide derivatives 1a with 1.0 mol% of biaryl-type diiodoarene precatalyst 3a, m-chloroperbenzoic acid (mCPBA), and trifluoroacetic acid in dichloromethane at room temperature yielded 25% dibenzoxazepinone 2a (Entry 1). No formation of the desired product 2a was observed in ethanol, even though a small amount of 1a was consumed (Entry 2). The use of 2,2,2-trifluoroethanol as a solvent resulted in a 35% yield of 2a and 63% recovery of the starting material 1a (Entry 3). Notably, the yield of 2a increased when the reaction was performed in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) (Entry 4). Most of 1a remained unreacted in the absence of trifluoroacetic acid (Entry 5). The catalytic reaction satisfactorily furnished the desired product, even at a 0.1–0.5 mol% catalyst loading of 3a (Entries 6–9). In contrast, biaryl-based precatalysts 3b and 3c were not as effective in promoting the synthesis of dibenzoxazepinone as 3a (Entries 9–11). Thus, these findings indicate that 3a holds promise as an appropriate precatalyst for catalytic amination.
Compared to 3a, iodobenzene and its derivatives were less-efficient precatalysts for the catalytic C–H amination reactions. Using 3d–f instead of 3a under the optimal reaction conditions, we assessed the catalytic performance of the hypervalent iodine species derived from 3d–f (Table 2). Consequently, the desired product 2a was generated in lower yields with every precatalyst 3d–f, with 32–85% of starting material 1a detected after the reaction work-up. These experiments indicated that 3a was the optimal precatalyst among the iodoarenes tested for catalytic C–H amination.
Next, we explored the substrate scope of the catalytic C–H amination reaction with a 0.5 mol% loading of precatalyst 3a (Scheme 4). Starting material 1 was prepared via a copper-catalyzed cross-coupling reaction between methyl o-iodobenzoates and phenols, followed by the hydrolysis and condensation of N-methoxyamine [35]. Moreover, it was accessible via a metal-free coupling method using our iodonium salt-mediated-O-arylation protocol for salicylamide derivatives [42]. In μ-oxo hypervalent iodine catalysis, salicylamide derivatives 1b–c were transformed into dibenzoxazepinones 2b–c at 91% and 90% yields, respectively. The catalytic C–H amination was applied to substrates 1d–f, which carried a methyl or halogen group on one of the two aromatic rings, providing the corresponding dibenzoxazepinones 2d–f in yields ranging from 90% to 97%. Compared to stoichiometric reactions [35], our μ-oxo hypervalent iodine catalytic system showed efficient reaction progress for substrates bearing aryloxy groups. Salicylamides with a strong electron-withdrawing group, such as a nitro group on the aromatic ring, were not reactive under catalytic conditions. While Du et al.’s stoichiometric C–H amination reaction afforded dibenzoxazepinone 2h in 43% yield [35], our catalytic system afforded 2h in higher yield (53%), even with lower stoichiometric amounts of the catalyst. The yield of 2h was improved by the increased amount of precatalyst 3a. N-phthalimide salicylamide derivative 1i was compatible with the catalytic reaction conditions and transformed into corresponding dibenzoxazepinone 2i in 81%. In the catalytic synthesis of dibenzoxazepinones 2a–i, the maximum turnover number (TON) reached 194.
Peracetic acid, which is an environmentally benign oxidant, promotes catalytic C–H amination reactions (Scheme 5). Notably, substrates 1a–f and 1i underwent catalytic C–N bond formation to give 66–97% dibenzoxazepinones 2a–f and 2i in the presence of 2 mol% of the precatalyst 3a, trifluoroacetic acid, and peracetic acid in HFIP at 30 °C. The yields of the desired products 2a–f in this catalytic C–H amination reaction were comparable to or higher than those in the stoichiometric reaction [35]. It was demonstrated that mCPBA can be replaced by peracetic acid, which eventually decomposes into non-toxic acetic acid during the reaction. This alternative green catalytic system can reproduce reactions with high TONs of 37.5–48.5.

4. Conclusions

In summary, we have successfully developed an efficient intramolecular oxidative aromatic C–H amination reaction mediated by an μ-oxo hypervalent iodine catalyst to afford dibenzoxazepinones. Our hypervalent iodine catalyst was operable at only 0.1 mol% loading and recorded a turnover number of 870. This methodology was applicable to the synthesis of various dibenzoxazepines. The yields of the dibenzoxazepinones were comparable to or even higher than those observed in stoichiometric reactions. Regarding the substrate scope, our μ-oxo hypervalent iodine catalytic system developed reactions for salicylamides bearing substituted aryloxy groups more efficiently than stoichiometric reactions.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/chemistry5040145/s1, Figure S1–S16: 1H and 13C NMR spectroscopic charts for all compounds 2a–i.

Author Contributions

Conceptualization, T.D.; methodology, H.S. and T.D.; formal analysis, S.H.; investigation, S.H.; resources, H.S., S.H. and M.H.; data curation, S.H. and M.H.; writing—original draft preparation, H.S. and T.D.; writing—review and editing, N.T. and T.H.; visualization, H.S. and T.D.; supervision, T.D.; project administration, T.D.; funding acquisition, T.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by JSPS KAKENHI grant number 19K05466 (T.D.) and JST CREST grant number JPMJCR20R1. T.D. and H.S. also acknowledge support from the Ritsumeikan Global Innovation Research Organization (R-GIRO) project. M.H. thanks support from the Sasakawa Scientific Research Grant.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Chemistry 05 00145 g001
Figure 1. Biologically active dibenzoxazepinone derivatives.
Figure 1. Biologically active dibenzoxazepinone derivatives.
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Scheme 1. Synthetic routes to dibenzoxazepinones.
Scheme 1. Synthetic routes to dibenzoxazepinones.
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Scheme 2. Hypervalent iodine-reagent-mediated oxidative C–H amination (stoichiometric).
Scheme 2. Hypervalent iodine-reagent-mediated oxidative C–H amination (stoichiometric).
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Scheme 3. μ-Oxo hypervalent iodine-catalyzed oxidative C–H amination reaction for the synthesis of dibenzoxazepinones.
Scheme 3. μ-Oxo hypervalent iodine-catalyzed oxidative C–H amination reaction for the synthesis of dibenzoxazepinones.
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Scheme 4. Substrate scope. Reaction conditions: 1 (0.60 mmol), 3a (0.003 mmol, 0.5 mol%), mCPBA (0.60 mmol, 1.0 eq.), and CF3COOH (1.2 mmol, 2.0 eq.) in HFIP (3.0 mL, 0.2 M) at room temperature for 2 h; isolated yield. a 1H NMR yield using 1,1,2,2-tetrachloroethane as internal standard. b 1.0 mol% of 3a was used. c 1i (0.50 mmol), 5 mol% of 3a, mCPBA (1.1 eq.) in HFIP (1.5 mL), and dichloromethane (1.5 mL) at room temperature for 24 h; isolated yield. Phth = phtalimide group.
Scheme 4. Substrate scope. Reaction conditions: 1 (0.60 mmol), 3a (0.003 mmol, 0.5 mol%), mCPBA (0.60 mmol, 1.0 eq.), and CF3COOH (1.2 mmol, 2.0 eq.) in HFIP (3.0 mL, 0.2 M) at room temperature for 2 h; isolated yield. a 1H NMR yield using 1,1,2,2-tetrachloroethane as internal standard. b 1.0 mol% of 3a was used. c 1i (0.50 mmol), 5 mol% of 3a, mCPBA (1.1 eq.) in HFIP (1.5 mL), and dichloromethane (1.5 mL) at room temperature for 24 h; isolated yield. Phth = phtalimide group.
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Scheme 5. Catalytic C–H amination mediated by peracetic acid as a co-oxidant. Substrate: 1a (X = OMe, R1 = R2 = R3 = H), 1b (X = OMe, R1 = Me, R2 = R3 = H), 1c (X = OMe, R1 = R3 = H, R2 = Cl), 1d (X = OMe, R1 = R2 = H, R3 = Me), 1e (X = OMe, R1 = R2 = H, R3 = Br), 1f (X = OMe, R1 = R2 = H, R3 = Cl), and 1i (X = Phth, R1 = R2 = R3 = H). Reaction conditions: 1 (0.30 mmol) in HFIP (1.5 mL, 0.2 M); isolated yield. a HFIP (1.5 mL) and dichloromethane (1.5 mL), 24 h; isolated yield.
Scheme 5. Catalytic C–H amination mediated by peracetic acid as a co-oxidant. Substrate: 1a (X = OMe, R1 = R2 = R3 = H), 1b (X = OMe, R1 = Me, R2 = R3 = H), 1c (X = OMe, R1 = R3 = H, R2 = Cl), 1d (X = OMe, R1 = R2 = H, R3 = Me), 1e (X = OMe, R1 = R2 = H, R3 = Br), 1f (X = OMe, R1 = R2 = H, R3 = Cl), and 1i (X = Phth, R1 = R2 = R3 = H). Reaction conditions: 1 (0.30 mmol) in HFIP (1.5 mL, 0.2 M); isolated yield. a HFIP (1.5 mL) and dichloromethane (1.5 mL), 24 h; isolated yield.
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Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
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EntryPrecatalystSolventYield of 2a bRecovery of 1a b
13a (1.0 mol%)CH2Cl225%72%
23a (1.0 mol%)EtOHN.D.77%
33a (1.0 mol%)CF3CH2OH35%63%
43a (1.0 mol%)HFIP>99% (98%) cN.D.
5 d3a (1.0 mol%)HFIP5%94%
63a (0.5 mol%)HFIP64%33%
7 e3a (0.5 mol%)HFIP97%N.D.
8 f3a (0.25 mol%)HFIP82%15%
9 g3a (0.1 mol%)HFIP87%6%
103b (0.5 mol%)HFIP10%86%
113c (0.5 mol%)HFIP11%88%
a Reaction conditions: 1a (0.60 mmol) in solvent (3.0 mL, 0.2 M). b Nuclear magnetic resonance (NMR) yield using 1,1,2,2-tetrachloroethane as internal standard. c Isolated yield. d Without using CF3COOH. e 2 h. f 4 h. g 16 h. N.D. = not detected.
Table 2. Catalytic C–H amination mediated by iodobenzene derivatives as the precatalysts.
Table 2. Catalytic C–H amination mediated by iodobenzene derivatives as the precatalysts.
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PrecatalystYield of 2a aRecovery of 1a a
3d60%32%
3e25%72%
3f5%85%
a NMR yield using 1,1,2,2-tetrachloroethane as an internal standard.
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Sasa, H.; Hamatani, S.; Hirashima, M.; Takenaga, N.; Hanasaki, T.; Dohi, T. Efficient Metal-Free Oxidative C–H Amination for Accessing Dibenzoxazepinones via μ-Oxo Hypervalent Iodine Catalysis. Chemistry 2023, 5, 2155-2165. https://doi.org/10.3390/chemistry5040145

AMA Style

Sasa H, Hamatani S, Hirashima M, Takenaga N, Hanasaki T, Dohi T. Efficient Metal-Free Oxidative C–H Amination for Accessing Dibenzoxazepinones via μ-Oxo Hypervalent Iodine Catalysis. Chemistry. 2023; 5(4):2155-2165. https://doi.org/10.3390/chemistry5040145

Chicago/Turabian Style

Sasa, Hirotaka, Syotaro Hamatani, Mayu Hirashima, Naoko Takenaga, Tomonori Hanasaki, and Toshifumi Dohi. 2023. "Efficient Metal-Free Oxidative C–H Amination for Accessing Dibenzoxazepinones via μ-Oxo Hypervalent Iodine Catalysis" Chemistry 5, no. 4: 2155-2165. https://doi.org/10.3390/chemistry5040145

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