Metal-Free Aerobic C–N Bond Formation of Styrene and Arylamines via Photoactivated Electron Donor–Acceptor Complexation

This study processes a facile and green approach for the Markovnikov-selective hydroamination of styrene with naphthylamine through irradiation with UV LED light (365 nm) via an electron donor–acceptor complexation between naphthylamines and oxygen in situ. This protocol showcases the synthetic potential for aerobic C–N bond formation without using a metal catalyst and photosensitizer. Three naphthylamines were examined and afforded desired C–N bond formation product in moderate yield.


Introduction
Carbon-nitrogen (C-N) bond formation is crucial and has been intensively studied for amine synthesis, comprising important chemical building blocks such as illuminated materials and organocatalysts [1][2][3][4]. Hydroamination [5] and transition metal-mediated cross-coupling of amines and aryl halides [6,7] are the most commonly applied strategies for C-N bond-forming reactions. In particular, hydroamination, which can directly connect amines and alkenes with high atom economy and accessibility, is a powerful synthetic approach for C-N bond formation. However, these methods require transition metal catalysts such as palladium, copper, and iron complexes [8][9][10][11][12]. Owing to the recent rapid progress in green chemistry, more environmentally benign and facile C-N bond formation methods have emerged, such as radical-based photocatalysis [13,14]. However, most photocatalytic hydroaminations that employ high-oxidative/reductive potential photosensitizers still depend on transition metal catalysis. In addition, no control over the generation of nitrogen-centered radicals can result in various unexpected side reactions [15]. Therefore, more effective and environmentally friendly C-N bond formation methods, especially those that involve metal-free and photosensitizer-free transformations, are in high demand [16]. In 2011, Hoffmann et al. found that irradiation with UV light promoted the catalyst-free bond formation of electron-deficient alkenes, but resulted in an excess amount of naphthylamine derivatives (15 equiv.) as coupling partners [17].
The discovery of electron donor-acceptor (EDA) complexes that facilitate photocatalystfree transformation [18,19] has resulted in the evolution of a wide range of EDA complexbased synthetic C-N bond formation methods. Recently, an EDA complex-initiated annulation reaction of electron-deficient alkenes and alkyl anilines (electron donors) under visible-light irradiation was developed by Sundén et al. [20,21]. However, the hydroamination of arylamines with styrene is difficult because both substrates are electron donors with relatively low oxidation potentials [22]. To date, the C-N bond formation between arylamines and styrene has been accomplished mainly via reactions mediated by latetransition metals [23][24][25][26] or strong Brønsted acids [27][28][29]. Recently, naphthylamines were also included in the hydroamination reactions. In 2019, Zhang et al. reported visiblelight-triggered hydroamination of styrene with arylamines using a copper catalyst and a strong base, which provides facile access to amines with Markovnikov regioselectivity (Figure 1a) [30]. Thereafter, ortho-alkylation of arylamines with styrene was performed by Patureau [31] in 2019 and Gandon in 2020 [32] using AgBF 4 and the strong Lewis acid Ca(NTf 2 ) 2 , respectively (Figure 1b,c). mines were also included in the hydroamination reactions. In 2019, Zhang et al. reported visible-light-triggered hydroamination of styrene with arylamines using a copper catalyst and a strong base, which provides facile access to amines with Markovnikov regioselectivity ( Figure 1a) [30]. Thereafter, ortho-alkylation of arylamines with styrene was performed by Patureau [31] in 2019 and Gandon in 2020 [32] using AgBF4 and the strong Lewis acid Ca(NTf2)2, respectively (Figure 1b,c).
For establishing metal and photosensitizer-free transformations of electron-rich substrates, herein, we report the photocatalytic Markovnikov-selective hydroamination of naphthylamines and styrene via the EDA complexation of naphthylamines and oxygen in situ (Figure 1, This work). This photochemical strategy is eco-friendly, green, and simple to perform, making it a suitable alternative to C-N bond formation under irradiation with 365 nm UV LED light in an O2 atmosphere.

Results and Discussions
To investigate the feasibility of the targeted photocatalyst-free reaction triggered by LED light, 1-naphthylamine (1a), and 2-naphthylamine (1b) with styrene were employed (Table 1). Remarkably, when 1a was used in the photocatalytic reaction, N-(1-phenylethyl)-2-naphthylamine (2a, CCDC 2221784) was formed as the major product. In the case of substrate 1b, desired product 2b and 1-alkylated product 2b' were obtained. The molar ratio of the starting materials was an important factor affecting the yield of desired product 2 (entries 1-3, 5, [12][13][14]; the reaction in a 1:4 ratio of 1a and styrene gave a 61% yield of 2a (entry 5). Among the screened wavelengths from UV to visible light (entries 4-6), the 365 nm LED light was the most suitable for promoting the reaction (entry 5). The For establishing metal and photosensitizer-free transformations of electron-rich substrates, herein, we report the photocatalytic Markovnikov-selective hydroamination of naphthylamines and styrene via the EDA complexation of naphthylamines and oxygen in situ (Figure 1, This work). This photochemical strategy is eco-friendly, green, and simple to perform, making it a suitable alternative to C-N bond formation under irradiation with 365 nm UV LED light in an O 2 atmosphere.

Results and Discussions
To investigate the feasibility of the targeted photocatalyst-free reaction triggered by LED light, 1-naphthylamine (1a), and 2-naphthylamine (1b) with styrene were employed (Table 1). Remarkably, when 1a was used in the photocatalytic reaction, N-(1-phenylethyl)-2-naphthylamine (2a, CCDC 2221784) was formed as the major product. In the case of substrate 1b, desired product 2b and 1-alkylated product 2b' were obtained. The molar ratio of the starting materials was an important factor affecting the yield of desired product 2 (entries 1-3, 5, [12][13][14]; the reaction in a 1:4 ratio of 1a and styrene gave a 61% yield of 2a (entry 5). Among the screened wavelengths from UV to visible light (entries 4-6), the 365 nm LED light was the most suitable for promoting the reaction (entry 5). The solvent system was also a crucial factor that significantly affected the yield of 2 (entries 7-11). After thoroughly evaluating the solvent system (also see Supporting Information), we found that when a binary solvent dichloromethane (DCM) and H 2 O was used in a ratio of 4:1 as a mixed solvent system, better catalytic performance was observed for both substrates 1a and 1b (entries 5 and 14), respectively. During our screening of reaction conditions, the addition of Cs 2 CO 3 as an inorganic base could slightly improve the total yield of 2b and 2b' (entries 15-17) [33]. When photocatalysts were used, no reaction occurred (entries [18][19][20][21]. Finally, N-methyl-1-naphthylamine 1c was found to be the appropriate substrate. Under the optimized conditions, 30% yield of 2c (C-N product) and 22% yield of 2c' (C-C product) were obtained, as shown in entry 22. solvent system was also a crucial factor that significantly affected the yield of 2 (entries 7-11). After thoroughly evaluating the solvent system (also see Supporting Information), we found that when a binary solvent dichloromethane (DCM) and H2O was used in a ratio of 4:1 as a mixed solvent system, better catalytic performance was observed for both substrates 1a and 1b (entries 5 and 14), respectively. During our screening of reaction conditions, the addition of Cs2CO3 as an inorganic base could slightly improve the total yield of 2b and 2b' (entries 15-17) [33]. When photocatalysts were used, no reaction occurred (entries [18][19][20][21]. Finally, N-methyl-1-naphthylamine 1c was found to be the appropriate substrate. Under the optimized conditions, 30% yield of 2c (C-N product) and 22% yield of 2c' (C-C product) were obtained, as shown in entry 22. To elucidate the reaction mechanism of the proposed UV-light-promoted process, several control experiments were conducted, as shown in Figures 2 and 3. Although the UV-vis spectroscopic measurements of 1a, styrene, and a mixture of 1a and styrene in DCM did not show any peak shifting (Figure 2a), the UV-vis spectroscopic analysis of a mixture of 1a and O2 in DCM showed an increase in the bathochromic displacement and absorption (Figure 2b), which probably supported the formation of an electron donor-a NMR yield using 1,3,5-trimethoxybenzene as the internal standard. b DCM = dichloromethane. c isolated yield. d N.R. = no reaction.
To elucidate the reaction mechanism of the proposed UV-light-promoted process, several control experiments were conducted, as shown in Figures 2 and 3. Although the UV-vis spectroscopic measurements of 1a, styrene, and a mixture of 1a and styrene in DCM did not show any peak shifting (Figure 2a), the UV-vis spectroscopic analysis of a mixture of 1a and O 2 in DCM showed an increase in the bathochromic displacement and absorption (Figure 2b), which probably supported the formation of an electron donor-acceptor EDA complex between 1a and O 2 . After mixing oxygen with naphthylamine in DCM, a color change from colorless to orange was immediately observed, which might also support EDA complex generation (also see Supplementary Materials). Next, an "ON-OFF" UV light irradiation (365 nm) experiment was conducted (Figure 3). Under light irradiation, the mixture resulted in a reaction that formed the corresponding product 2a. However, the reaction was completely suppressed under no light irradiation. Finally, continuous 365 nm UV light irradiation resulted in the consumption of 1a to give 2a with 61% yield (see Supplementary Materials for details). In the presence of TEMPO (4 equiv.) as a radical scavenger, the reaction of 1a with styrene was avoided even under the optimized conditions ( Figure 4). a NMR yield using 1,3,5-trimethoxybenzene as the internal standard. b DCM = dichloromethane. c isolated yield. d N.R. = no reaction.
To elucidate the reaction mechanism of the proposed UV-light-promoted process, several control experiments were conducted, as shown in Figures 2 and 3. Although the UV-vis spectroscopic measurements of 1a, styrene, and a mixture of 1a and styrene in DCM did not show any peak shifting (Figure 2a), the UV-vis spectroscopic analysis of a mixture of 1a and O2 in DCM showed an increase in the bathochromic displacement and absorption (Figure 2b), which probably supported the formation of an electron donoracceptor EDA complex between 1a and O2. After mixing oxygen with naphthylamine in DCM, a color change from colorless to orange was immediately observed, which might also support EDA complex generation (also see Supplementary Materials). Next, an "ON-OFF" UV light irradiation (365 nm) experiment was conducted (Figure 3). Under light irradiation, the mixture resulted in a reaction that formed the corresponding product 2a. However, the reaction was completely suppressed under no light irradiation. Finally, continuous 365 nm UV light irradiation resulted in the consumption of 1a to give 2a with 61% yield (see Supplementary Materials for details). In the presence of TEMPO (4 equiv.) as a radical scavenger, the reaction of 1a with styrene was avoided even under the optimized conditions (Figure 4).       A Job plot study to determine the correlation of generating the EDA complex in situ with various ratios of O2 is challenging because of the difficulty in measuring the exact amount of O2 against naphthylamine, although all of these obtained results will probably be in agreement with the proposed mechanism involving the formation of naphthylamine radicals ( Figure 5). Triggering of 1b and O2 via UV light induced the formation of EDA complex I*. The generated II species might be in equilibrium with IIA and IIB via electron transfer [34], after the bond formation of styrene with IIA and IIB led to the corresponding C-N formation product 2b and C-C formation product 2b', respectively [15] (Figure 5a). When 1a was used as the substrate, only C-N formation occurred, probably owing to the sole generation of N cation radicals (Figure 5b). Although the intramolecular hydroamination to give Markovnikov products via amine radical cation species was reported [15], a naphthylamine anion radical generated by a reaction of oxygen anion radical with 1 might be another possible pathway for this C-N bond formation. Currently, the exploration of mechanism is ongoing in our laboratory.  A Job plot study to determine the correlation of generating the EDA complex in situ with various ratios of O 2 is challenging because of the difficulty in measuring the exact amount of O 2 against naphthylamine, although all of these obtained results will probably be in agreement with the proposed mechanism involving the formation of naphthylamine radicals ( Figure 5). Triggering of 1b and O 2 via UV light induced the formation of EDA complex I*. The generated II species might be in equilibrium with IIA and IIB via electron transfer [34], after the bond formation of styrene with IIA and IIB led to the corresponding C-N formation product 2b and C-C formation product 2b', respectively [15] (Figure 5a). When 1a was used as the substrate, only C-N formation occurred, probably owing to the sole generation of N cation radicals (Figure 5b). Although the intramolecular hydroamination to give Markovnikov products via amine radical cation species was reported [15], a naphthylamine anion radical generated by a reaction of oxygen anion radical with 1 might be another possible pathway for this C-N bond formation. Currently, the exploration of mechanism is ongoing in our laboratory.  A Job plot study to determine the correlation of generating the EDA complex with various ratios of O2 is challenging because of the difficulty in measuring the amount of O2 against naphthylamine, although all of these obtained results will pr be in agreement with the proposed mechanism involving the formation of naphthy radicals ( Figure 5). Triggering of 1b and O2 via UV light induced the formation o complex I*. The generated II species might be in equilibrium with IIA and IIB via el transfer [34], after the bond formation of styrene with IIA and IIB led to the correspo C-N formation product 2b and C-C formation product 2b', respectively [15] (Figu When 1a was used as the substrate, only C-N formation occurred, probably owing sole generation of N cation radicals (Figure 5b). Although the intramolecular hyd nation to give Markovnikov products via amine radical cation species was reporte a naphthylamine anion radical generated by a reaction of oxygen anion radical might be another possible pathway for this C-N bond formation. Currently, the ex tion of mechanism is ongoing in our laboratory.

Spectroscopy and Spectrometry
1 H-and 13 C-NMR spectra were recorded at 25 • C using a JEOL JMN ECS400 FT NMR instrument ( 1 H-NMR 400 MHz; 13 C-NMR 100 MHz). The 1 H-NMR spectra are reported as follows: chemical shift in ppm downfield of tetramethylsilane and referenced to a residual solvent peak (CHCl 3 ) at 7.26 ppm, integration, multiplicities (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), and coupling constants (Hz). The 13 C-NMR spectra are reported in ppm relative to the central line of the triplet for CDCl 3 at 77.16 ppm. APCI-MS spectra were obtained using a JMS-T100LC instrument (JEOL). Thin-layer chromatography (TLC) analysis of the reaction mixture was performed on Merck silica gel 60 F254 TLC plates and visualized under UV light. Column chromatography on SiO 2 was performed using Kanto Silica Gel 60 (63-210 µm). UV and visible light irradiations were performed with an LED lamp (PER-AMP, Techno Sigma Co., Ltd. Okayama, Japan). Commercial LED lamps (PER-AMP, Techno Sigma Co., Ltd.) were used as a light source to irradiate the Schlenk tube at a distance of 0.5 cm with aluminum foil covering the outside of the tube. A water bath was used for cooling the setup. A thermo-stainless-steel chamber ensured a constant temperature of 25 • C during the reaction. The temperature inside the chamber was also monitored during the experiment to ensure no fluctuations and kept at 25 • C.

General Protocol for the Photocatalytic Hydroamination of Styrene
An oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with naphthylamines (0.2 mmol) and styrene (0.8 mmol). The tube was evacuated and backfilled with oxygen (three times). Then, 1.6 mL of DCM and 0.4 mL of H 2 O were added by syringe under an O 2 atmosphere. The solution was stirred at 25 • C with the irradiation of a 365 nm UV LED light. After stirring for 24 h, the organic solvent was removed in vacuo, and the remained water phase was extracted with EtOAc. The organic layer was collected and evaporated under vacuum. The residue was purified by column chromatography on silica gel using n-hexane/DCM (20/1) as eluent to obtain the desired products.

Procedures for UV-Vis Absorbance Analysis
1a and styrene were employed in the binary solvent system. The color of the reaction mixture immediately changed from colorless to an orange color, and finally to brown in 5 min at the irradiation of 365 nm UV LED under O 2 atmosphere (see Supporting Information). In order to understand the generation of EDA complex between substrate 1a and oxygen, a series of UV-vis absorption measurements were carried out. Initially, we took the optical absorption spectra of 1a and styrene in DCM (10 µM) and then measured the mixture of 1a and styrene (1:1 v/v) in DCM (10 µM). The UV-vis absorption spectra indicated that no electron donor-acceptor (EDA) complex formed between the two starting materials. Next, we checked the UV-vis absorption of 1a and oxygen. The sample was prepared by oxygen bubbling for 10 min in the DCM solution of 1a (10 µM). An obvious increasing bathochromic displacement and absorption can be observed in the spectrum, which supported the formation of the EDA complex between 1a and O 2 .

Conclusions
In summary, we have developed a new approach for the Markovnikov-selective hydroamination of styrene with naphthylamines by an irradiation of UV LED light (365 nm) via an in situ electron donor-acceptor (EDA) complexation between naphthylamines and oxygen. This protocol is eco-friendly, green, and facile, showcasing synthetic potential for aerobic C-N bond formation without using any metal catalyst or photosensitizer. The exploration of more C-N bond formation reactions involving naphthylamines and other alkenes is ongoing in our group.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules28010356/s1, Figure S1: Reaction setup and LED apparatus; Figure S2: "On-off" experiment; Figure S3: Visual characterization of the reaction mixture under UV irradiation; Figure S4: UV-Vis absorption analysis; Figure S5: Proposed mechanism of photoinduced C-N bond formation of 1b and styrene; Figure Table S1: Optimization of reaction conditions; Table S2: On-off experiment; Table S3