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Article

Bis(2-butoxyethyl) Ether-Promoted O2-Mediated Oxidation of Alkyl Aromatics to Ketones under Clean Conditions

by
Yangyang Xie
1,†,
Zeping Li
1,†,
Xudong Xu
1,
Han Jiang
1,
Keyi Chen
1,
Jinhua Ou
1,*,
Kaijian Liu
1,*,
Yihui Zhou
2,3,* and
Kejun Luo
4,*
1
Department of Material and Chemical Engineering, Hunan Institute of Technology, Hengyang 421002, China
2
Collaborative Innovation Center, Hunan Automotive Engineering Vocational College, Zhuzhou 412001, China
3
College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
4
Changsha Research Institute of Mining and Metallurgy Co., Ltd., Changsha 410012, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2024, 29(20), 4909; https://doi.org/10.3390/molecules29204909
Submission received: 26 September 2024 / Revised: 11 October 2024 / Accepted: 15 October 2024 / Published: 17 October 2024
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Abstract

:
Conventional oxidation processes for alkyl aromatics to ketones employ oxidants that tend to generate harmful byproducts and cause severe equipment corrosion, ultimately creating critical environmental problems. Thus, in this study, a practical, efficient, and green method was developed for the synthesis of aromatic ketones by applying a bis(2-butoxyethyl) ether/O2 system under external catalyst-, additive-, and base-free conditions. This O2-mediated oxidation system can tolerate various functional groups and is suitable for large-scale synthesis. Diverse target ketones were prepared under clean conditions in moderate-to-high yields. The late-stage functionalization of drug derivatives with the corresponding ketones and one-pot sequential chemical conversions to ketone downstream products further broaden the application prospects of this approach.

1. Introduction

The selective oxidation of hydrocarbons to aromatic ketones is an important organic conversion process in both the laboratory and fine chemicals industry [1,2,3]. Compared with the selective oxidation of styrene [4,5,6], 1-phenyl ethanol [7,8,9], isopropyl benzene [10], etc., the oxygenation of alkyl aromatics is a more popular pathway for preparing ketones because of its low cost and easy availability [11,12,13]. In conventional oxidation processes for alkyl aromatics to ketones, stoichiometric oxidants such as Oxone [14], K2S2O8 [15], [PhIO]n/KBr [16], IBX [17], and m-CPBA [18] are typically adopted, but these oxidants tend to generate harmful byproducts and cause severe equipment corrosion, ultimately leading to critical environmental problems. Molecular oxygen is considered to be an attractive oxidant and O-atom source for the synthesis of O-containing compounds because it is environmentally friendly, abundant, and inexpensive [19,20,21,22,23]. In recent years, excellent C(sp3)–H bond oxygenation of aromatics to ketones has been achieved under an atmosphere of air or dioxygen by using metal salt [24,25,26], metal–organic complexes [27,28,29], metal-supported nanoparticles [30,31,32], zeolite [33,34], and carbon [35] as catalysts.
Compared to metal-based catalyzed reactions, metal-free oxidation is more practical in the production of agrochemical and pharmaceuticals [36,37,38], as it does not require the removal of metal residues and reduces the cost of wastewater treatment. In 2004, Xu et al. developed a three-component biomimetic catalytic system for the ketonization of hydrocarbons driven via electron transfer by using N-hydroxyphthalimide (NHPI) as a nonmetallic redox center and O2 as the ultimate oxidant [39]. In 2015, Yi et al. reported on Acr+-Mes ClO4−-promoted benzylic sp3 C–H oxidation by visible light, whereby Acr+-Mes ClO4− radical anions were oxidized by O2 to ensure the regeneration of a photocatalyst; their findings offered a new perspective on obtaining various kinds of ketones under relatively mild conditions [40]. In 2021, Shi and colleagues applied N-doped carbon nanotubes and TBHP/O2 as the catalyst and oxidants, respectively, for ethylbenzene oxidation; they found that the addition of TBHP promoted α-H abstraction and radical propagation, thereby enabling a considerable degree of conversion [41]. Recently, Zhang et al. prepared an NHPI-functionalized activated carbon catalyst system for the aerobic oxidation of ethylbenzene and successfully enhanced the space–time yield of acetophenone [42] (Scheme 1a). Although metal-free catalytic systems have demonstrated significant potential for application in the process of oxygenating benzylic C-H bonds to convert them into the corresponding ketones, they all require an additional catalyst to activate O2 and achieve a sufficient level of conversion. Furthermore, they have limitations such as high reagent costs, poor thermal stability, overoxidized byproducts, and being difficult to separate. Additionally, their limited substrate generalizability, low atom efficiency, and poor reusability limit their industrial application.
Thus, researchers have channeled their efforts toward exploring novel green, highly efficient, and insignificant capital investment oxidation approaches for alkyl aromatics that are suitable for industrial needs [43,44,45]. However, there are no reports on the ether-promoted oxygenation of ketones from alkyl aromatics in the absence of an external catalyst or an additive. As an extension of our interest in green chemistry and O2-mediated oxygenation reactions [46,47,48,49,50], we present a practical, efficient, and green method for the synthesis of aromatic ketones in the presence of O2 that entails applying bis(2-butoxyethyl) ether as a promoter and solvent under external catalyst-, additive-, and base-free conditions (Scheme 1b).

2. Results and Discussion

The primary aim of this study was to identify a suitable promoter for the conversion of 4-ethyltoluene 1a into the corresponding 4-acetyltoluene 2a (Table 1). Firstly, we optimized the reaction conditions with 4-ethyltoluene as raw material and ether as promoter in the presence of O2 at 120 °C. Several common solvents were investigated in the presence of O2, including 2-methoxyethyl ether, dimethoxydipropylene glycol, triethylene glycol, and dimethyl ether (Entries 1–8 in Table 1). Among these solvents, bis(2-butoxyethyl) ether, as a promoter, exhibited the highest catalytic efficiency, achieving a 70% yield. Methoxypropoxypropanol resulted in the lowest yield (31%), possibly because of the quenching of free radicals by the hydroxyl groups (Entry 8). The temperature optimization tests confirmed that 150 °C was an appropriate temperature in this oxidation reaction (Entries 9–14). It was also notable that, after the optimal promoter load was determined (Entries 15–17), 4-acetyltoluene 2a was obtained in 97% GC-MS yield under an O2 atmosphere at 150 °C for 15 h (Entry 16). Extending the reaction time or conducting the experiment in a dark room minimally influenced oxidation (Entries 18 and 19). In contrast, oxidation either did not occur or was significantly constrained when dioxygen was replaced with N2 and air, respectively (Entries 20 and 21). This shows that molecular oxygen plays a key role in oxidation, and that the oxygen concentration significantly affects the system. No target product was obtained when the system was implemented without bis(2-butoxyethyl) ether, which shows that bis(2-butoxyethyl) ether promotes the oxidation reaction (Entry 22).
Subsequently, the scope and limitations of alkyl aromatics that exhibit a variety of substitution patterns were explored under the optimal conditions; the results are illustrated in Table 2. Ethyl aromatics with electron-withdrawing or electron-donating groups were successfully transformed into the desired ketones with good to excellent yield (2a–2m). It is noteworthy that substituent groups with an electron-withdrawing nature reduced the reaction efficiency of the substrate; this may be ascribed to the reduced electron cloud density in the benzene ring, which impeded benzyl radical formation. Additionally, compared with the para- and meta-substituted substrates (2a and 2l), the use of the ortho-substituted ethylbenzene with strong steric hindrance effects also resulted in a relatively low yield (2m). Although the oxidation strategy of accessing di-oxygenated products by using di-alkyl aromatics as substrates is often ineffective because the electron-withdrawing effect of the carbonyl groups on the mono-ketones reduces the reactivity, our reaction proceeded well with di-ethyl benzene under standard conditions; particularly, we obtained the double-oxidation product (2n) at 78% yield. Poly-substituted ethylbenzenes were also evaluated, and the target ketones were obtained in excellent yields (2o and 2p). Moreover, various aromatic hydrocarbons with (hetero)cyclic rings containing methylene were perfectly tolerated under the standard conditions, resulting in yields of 74–95% for the corresponding ketones (2q–2t). Notably, heterocyclic and polycyclic alkylbenzenes also yielded the desired product (2u–2y), but the presence of electron-withdrawing nitrogen atoms in the aromatic ring resulted in slightly lower yields of 4-acetylpyridine (2w), further confirming the influence of the electronic effect on the reaction. Similarly, a variety of β-substituted alkylbenzenes were also found to be compatible with the bis(2-butoxyethyl) ether-promoted oxidation reaction, and a moderate yield (61–78%) of product was obtained because of steric hindrance (2z–2ab). Moreover, substituted diarylmethane with H, Me, or Cl groups were readily converted, generating corresponding ketone yields within the range of 84–92% (2ac–2af). Unfortunately, no target product was observed with the less active 2-ethyl or 2-benzylpyridine as the substrate. It is also noteworthy that, when 9,10-dihydroanthracene was applied in this reaction, anthracene was obtained as the main product at 78% yield (4a); this is likely because the fully aromatized product was more stable. When benzyl alcohol was used as substrate, the deep oxidation product benzoic acid (2ah) was obtained with almost quantitative yield, which further expanded the adaptive range of the system.
In consideration of the greenness and practicability of the oxidation approach and the importance of late-stage functionalization of natural products for drug research, several drug derivatives were subjected to this system under optimal reaction conditions. Notably, the anti-inflammatory indomethacin (2ah); cholesterol (2ai), which sources cholic acid and hormones in the body; dehydroandrosterone (2aj), which is used for anti-aging and protein assimilation; and the lipid-lowering drug fenofibrate (2ak) were all successfully converted into the corresponding ketones with yields ranging from 69 to 77%. These findings indicate the wide-ranging applicability of the proposed oxidation system in the pharmaceutical industry.
We also attempted a scaled-up oxidation reaction with 4-ethyltoluene 1a as the substrate under standard conditions; we obtained a 4-acetyltoluene 2a yield of 86%, further revealing the superiority of the proposed green oxidation method (Figure 1a). To prove the operating convenience of the proposed oxidation system, we confirmed that several one-pot sequential chemical conversions, i.e., aldol condensation (1b → 4b) [51], cyclization (1b → 4c) [52], and amidation (1b → 4d) [53], could be generated from a crude reaction mixture (Figure 1b). The desired ketone downstream products were smoothly isolated in overall yields ranging from 60 to 78%, demonstrating the efficiency and cleanliness of this method for subsequent direct transformations. The conversion of ethylbenzene 1b over time was monitored by applying GC-MS under the optimal conditions; the relative results are displayed in Figure 1c. In the first 6 h, 9% acetophenone 2b and 25% 1-phenylethanol 3b yields were observed, in addition to a 34% consumption of the starting substrate 1b, indicating that the transformation of 1b into 3b was the primary reaction in the initial phase. Subsequently, the target product 2b rapidly increased until ethylbenzene 1b was exhausted, whereas 1-phenylethanol 3b gradually disappeared over time at a later stage. These trends may be attributable to the fact that the oxidation of 1b was first converted into alcohol 3b and then further oxidized to the target ketone 2b [36,40,42].
The aforementioned results prompted us to gain insight into the reaction mechanism. Thus, several experiments were performed, as shown in Figure 2. In the first experiment, we induced the oxidation reaction by applying 1-phenylethanol 3b as the substrate under the standard reaction conditions, consequently obtaining acetophenone 2b in 99% yield (Figure 2a). This result, combined with the fact that 1-phenylethanol 3b was present throughout the experimental monitoring period (Figure 1c), indicates that 3b may be involved in oxygenation as a critical intermediate. The oxidation reaction was largely ineffective in the presence of a trapping agent, i.e., TEMPO or BHT (Figure 2b), suggesting that the system may involve a free radical mechanism [24,39,40]. In a subsequent oxidation reaction experiment, we replaced dioxygen with TBHP or H2O2 as an oxidizing agent in a N2 atmosphere and only obtained a 21–30% acetophenone 2b yield (Figure 2c), further confirming the critical role of O2 in this oxidation approach.
When 18O2 was used as the sole oxidant under the optimized conditions, only 18O-labeled 2b was detected (Figure 2d), revealing that the O atom of the carbonyl group was derived from molecular oxygen rather than bis(2-butoxyethyl) ether. We subsequently performed a kinetic isotope effect experiment by applying the same molar amount of ethylbenzene 1b and ethylbenzene-D10 (1b–D10) to produce a mixed substrate (Figure 2e). The clear k1b/k1b-D10 value of 1.1 obtained for this oxidation system indicates that the cleavage of the methylene C(sp3)–H bond may not be the rate-determining step. To further clarify the crucial role of bis(2-butoxyethyl) ether, we evaluated the promoter concentration (Figure 2f). No target compounds were observed when the reaction was performed in the absence of bis(2-butoxyethyl) ether. Reducing the concentration of the promoter also negatively impacted the oxidation process, as 0.1 eq. of bis(2-butoxyethyl) ether only resulted in a 30% yield of acetyltoluene 2b. We can infer from this phenomenon that bis(2-butoxyethyl) ether promotes the oxidation reaction as both a catalyst and reaction medium.
Based on the above-mentioned results and related reports [54,55,56,57], a possible bis(2-butoxyethyl) ether-promoted oxidation mechanism was constructed, as shown in Figure 3. First, the bis(2-butoxyethyl) ether reacted with O2 under heating conditions to form the peroxyl radical A, which seized an α-H atom from ethylbenzene 1b to produce the benzyl radical intermediate B and peroxide C. Then, the peroxide C was converted into the oxygen radical D and hydroxyl radical by homolysis. Then, the hydroxyl radical induced the production of 1-phenylethanol 3b through the benzyl radical B (detected via GC-MS), which was captured an α-H atom by peroxyl radical A and further transformed into the carbon-center radical E. The intermediate E was found to readily join with hydroxyl radicals to form the diol intermediate F, which is unstable and dehydrates to produce the ketone 2b. Additionally, the benzyl radical B was found to be able to act with molecular oxygen to produce the peroxide radical G, which seized an α-H atom of ethylbenzene 1b to form the peroxide molecule H with concomitant release of benzyl radical B. Lastly, the β-H cleavage of the peroxide molecule H and elimination of H2O resulted in the formation of the ketone 2b.

3. Experimental Section

3.1. General Procedure for the Synthesis of Ketones 2

A mixture of alkyl benzene 1 (0.6 mmol) and bis(2-butoxyethyl) ether (1.2 mmol) was added to a 15 mL glass tube with an O2 balloon at room temperature. Then the contents were stirred at 150 °C for 15 h. The reaction mixture was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to afford the desired 2 (Sections S1 and S2).

3.2. Characterization Data of Products 2a–2ak and 4a–4d

  • 1-(p-tolyl)ethan-1-one (2a) [56]: Colorless liquid (74 mg, 92%); 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 2.65 (s, 3H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.7, 143.8, 134.6, 129.1, 128.3, 26.4, 21.5.
  • Acetophenone (2b) [56]: Colorless liquid (65 mg, 90%); 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.0 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 8.0 Hz, 2H), 2.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.1, 137.0, 133.0, 128.5, 128.2, 26.5.
  • 1-(4-(tert-butyl)phenyl)ethan-1-one (2c) [58]: Colorless liquid (98 mg, 93%); 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 2.57 (s, 3H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 197.7, 156.7, 134.5, 128.2, 125.4, 35.0, 31.0, 26.4.
  • 1-(4-methoxyphenyl)ethan-1-one (2d) [56]: White solid (80 mg, 89%); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 2.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 196.5, 163.3, 130.4, 130.1, 113.5, 55.2, 26.1.
  • 1-(4-fluorophenyl)ethan-1-one (2e) [56]: Colorless liquid (72 mg, 87%); 1H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 8.80, 5.6 Hz, 2H), 7.09 (t, J = 8.4 Hz, 2H), 2.55 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 196.4, 165.6 (d, J = 255.6 Hz), 133.5 (d, J = 3.0 Hz), 130.9 (d, J = 9.4 Hz), 115.5 (d, J = 21.9 Hz), 26.4; 19F NMR (376 MHz, CD3Cl) δ −105.4.
  • 1-(4-chlorophenyl)ethan-1-one (2f) [56]: Colorless liquid (84 mg, 91%); 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.7, 139.4, 135.3, 129.6, 128.7, 26.4.
  • 1-(4-bromophenyl)ethan-1-one (2g) [56]: White solid (95 mg, 80%); 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 2.58 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.0, 135.8, 131.9, 129.8, 128.3, 26.5.
  • 1-(4-iodophenyl)ethan-1-one (2h) [56]: Brown solid (115 mg, 78%); 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 2.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.3, 137.9, 136.3, 129.7, 101.1, 26.4.
  • 1-(4-(trifluoromethyl)phenyl)ethan-1-one (2i) [56]: Colorless liquid (81 mg, 72%); 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 2.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.9, 139.6, 134.4 (q, J = 32.8 Hz), 128.6, 125.6 (q, J = 63.3 Hz), 123.6 (q, J = 273.7 Hz), 26.7; 19F NMR (376 MHz, CD3Cl) δ −63.2.
  • 4-acetylbenzonitrile (2j) [59]: Yellowish solid (60 mg, 69%); 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 2.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.5, 139.9, 132.5, 128.7, 117.9, 116.4, 26.7.
  • methyl 4-acetylbenzoate (2k) [59]: White solid (87 mg, 82%); 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 3.95 (s, 3H), 2.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.6, 166.2, 140.2, 133.9, 129.8, 128.2, 52.5, 26.9.
  • 1-(m-tolyl)ethan-1-one (2l) [56]: Colorless liquid (68 mg, 85%); 1H NMR (400 MHz, CDCl3) δ 7.74–7.71 (m, 2H), 7.35–7.29 (m, 2H), 2.55 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.2, 138.1, 137.0, 133.7, 128.6, 128.3, 125.4, 26.5, 21.1.
  • 1-(o-tolyl)ethan-1-one (2m) [56]: Colorless liquid (60 mg, 75%); 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.35–7.30 (m, 2H), 2.65 (s, 3H), 2.61 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.6, 138.3, 137.5, 131.9, 131.4, 129.3, 125.6, 29.4, 21.5.
  • 1,1’-(1,4-phenylene)bis(ethan-1-one) (2n) [56]: Grayish white solid (76 mg, 78%); 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 4H), 2.63 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 197.5, 140.1, 128.4, 26.9.
  • 1-(3,4-dimethylphenyl)ethan-1-one (2o) [58]: Colorless liquid (82 mg, 92%); 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 2.52 (s, 3H), 2.27 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 197.8, 142.4, 136.6, 134.9, 129.5, 129.2, 125.9, 26.3, 19.7, 19.5.
  • 1-(3,4-dichlorophenyl)ethan-1-one (2p) [60]: white solid (102 mg, 90%); 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 2.57 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.6, 137.6, 136.5, 133.2, 130.7, 130.3, 127.3, 26.5.
  • 2,3-dihydro-1H-inden-1-one (2q) [56]: Light yellow solid (59 mg, 74%); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 3.12 (t, 6.0 Hz, 2H), 2.67 (t, J = 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 207.0, 155.1, 137.0, 134.5, 127.2, 126.6, 123.6, 36.1, 25.7.
  • 9H-fluoren-9-one (2r) [56]: Yellow solid (103 mg, 95%); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.2 Hz, 2H), 7.44–7.39 (m, 4H), 7.25–7.21 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 193.8, 144.3, 134.5, 134.0, 128.9, 124.1, 120.2.
  • 2-amino-9H-fluoren-9-one (2s) [60]: Brown solid (95 mg, 81%); 1H NMR (400 MHz, DMSO-d6) δ 7.43–7.39 (m, 3H), 7.35 (d, J = 8.0 Hz, 1H), 7.14–7.09 (m, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.66 (dd, J = 8.0, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 194.7, 150.9, 146.4, 135.9, 135.5, 127.4, 124.2, 122.6, 119.7, 119.0, 109.9.
  • 9H-xanthen-9-one (2t) [56]: Grayish white solid (108 mg, 92%); 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.0 Hz, 2H), 7.71 (t, J = 7.6 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 177.2, 156.1, 134.8, 126.7, 123.8, 121.8, 117.9.
  • 1-(naphthalen-1-yl)ethan-1-one (2u) [56]: Colorless liquid (84 mg, 82%); 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 2.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.7, 135.2, 133.8, 132.9, 130.0, 128.6, 128.3, 127.9, 126.3, 125.9, 124.2, 29.8.
  • 1-(naphthalen-2-yl)ethan-1-one (2v) [56]: White solid (87 mg, 85%); 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.90–7.86 (m, 2H), 7.62–7.53 (m, 2H), 2.72 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.1, 135.5, 134.4, 132.5, 130.1, 129.5, 128.4, 128.4, 127.7, 126.7, 123.8, 26.6.
  • 1-(pyridin-4-yl)ethan-1-one (2w) [56]: Colorless liquid (40 mg, 56%); 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 4.8 Hz, 2H), 7.66 (d, J = 4.8 Hz, 2H), 2.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.2, 150.8, 142.5, 121.0, 26.5.
  • 1-(thiophen-2-yl)ethan-1-one (2x) [56]: Light yellow liquid (49 mg, 65%);1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 3.6 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.08 (t, J = 4.0 Hz, 1H), 2.51 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.6, 144.3, 133.7, 132.4, 128.0, 26.7.
  • 1-(benzo[b]thiophen-5-yl)ethan-1-one (2y) [61]: White solid (93 mg, 88%); 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.88 (t, J = 8.4 Hz, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H), 2.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.2, 143.9, 142.6, 139.1, 129.6, 127.4, 125.9, 125.0, 123.0, 26.8.
  • propiophenone (2z) [56]: Colorless liquid (57 mg, 71%); 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 3.01 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.8, 136.9, 132.8, 128.5, 127.9, 31.7, 8.2.
  • 1-phenylbutan-1-one (2aa) [61]: Colorless liquid (61 mg, 69%); 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 2.96 (t, J = 7.2 Hz, 2H), 1.83–1.74 (m, 2H), 1.02 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.3, 137.0, 132.8, 128.4, 127.9, 40.4, 17.7, 13.8.
  • 1-phenyloctan-1-one (2ab) [60]: Colorless liquid (76 mg, 62%); 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 2.96 (t, J = 7.2 Hz, 2H), 1.77–1.70 (m, 2H), 1.36–1.25 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.7, 137.1, 132.8, 128.5, 128.0, 38.6, 31.7, 29.3, 29.1, 24.4, 22.6, 14.1.
  • Benzophenone (2ac) [56]: White solid (100 mg, 92%); 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.6 Hz, 4H), 7.59 (t, J = 7.6 Hz, 2H), 7.48 (t, J = 7.6 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 196.7, 137.6, 132.4, 130.0, 128.2.
  • phenyl(p-tolyl)methanone (2ad) [56]: White solid (100 mg, 85%); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.6 Hz, 2H), 7.72 (t, J = 7.6 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.4, 143.2, 137.9, 134.8, 132.1, 130.2, 129.9, 128.9, 128.1, 21.6.
  • (4-methoxyphenyl)(phenyl)methanone (2ae) [56]: White solid (114 mg, 90%); 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.8 Hz, 2H), 7.75 (t, J = 7.6 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.2 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.6, 163.2, 138.3, 132.5, 131.9, 130.1, 129.7, 128.2, 113.5, 55.5.
  • (4-chlorophenyl)(phenyl)methanone (2af) [56]: White solid (109 mg, 84%); 1H NMR (400 MHz, CDCl3) δ 7.76 (t, J = 8.0 Hz, 4H), 7.59 (t, J = 7.6 Hz, 1H), 7.48 (q, J = 8.4 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 195.4, 138.8, 137.2, 135.8, 132.6, 131.4, 129.9, 128.6, 128.3.
  • Anthracene-9,10-dione (2ag) [56]: Yellow solid (22 mg, 18%); 1H NMR (400 MHz, CDCl3) δ 8.32 (dd, J = 5.2, 3.2 Hz, 4H), 7.81 (dd, J = 5.2, 3.2 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 183.2, 134.1, 133.5, 127.2.
  • Benzoic acid (2ah) [46]: White solid (72 mg, 99%); 1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 7.95 (d, J = 6.8 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 167.9, 133.4, 131.3, 129.8, 129.1.
  • Methyl 2-(1-(4-acetylbenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate (2ai) [56]: White solid (175 mg, 77%); 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 7.6 Hz, 2H), 6.96 (s, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 8.8 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 3.67 (s, 2H), 2.68 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.3, 171.3, 168.5, 156.2, 139.8, 139.6, 135.9, 130.8, 130.7, 129.7, 128.6, 115.1, 112.9, 111.7, 101.4, 55.7, 52.2, 30.1, 29.7, 26.9, 13.5.
  • (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-acetylbenzoate (2aj): White solid (233 mg, 73%); 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H), 5.43 (d, J = 4.4 Hz, 1H), 4.92–4.84 (m, 1H), 2.65 (s, 3H), 2.48 (d, J = 7.6 Hz, 2H), 2.04–1.98 (m, 3H), 1.86–1.74 (m, 2H), 1.58–1.43 (m, 6H), 1.37–1.21 (m, 6H), 1.19–1.09 (m, 5H), 1.07 (s, 3H), 1.06–0.96 (m, 4H), 0.92 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 2.0 Hz, 3H), 0.86 (d, J = 2.0 Hz, 3H), 0.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.6, 165.1, 140.0, 139.4, 134.6, 129.8, 128.1, 123.0, 75.2, 56.7, 56.1, 50.0, 42.3, 39.5, 36.6, 35.8, 31.8, 28.0, 26.9, 23.8, 22.8, 22.6, 19.4, 18.7, 11.9. HRMS (ESI) calcd for C36H52O3Na [M + Na]+: 555.3809, found 555.3818.
  • (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-acetylbenzoate (2ak): White solid (195 mg, 75%); 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H), 5.47 (d, J = 4.8 Hz, 1H), 4.93–4.84 (m, 1H), 2.65 (s, 3H), 2.51–2.46 (m, 2H), 2.17–2.08 (m, 2H), 1.98–1.92 (m, 2H), 1.89–1.78 (m, 2H), 1.73–1.67 (m, 4H), 1.55–1.41 (m, 2H), 1.34–1.25 (m, 4H), 1.10 (s, 3H), 0.96 (t, J = 7.2 Hz, 1H), 0.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.7, 165.1, 140.1, 139.7, 134.5, 129.8, 128.2, 122.2, 74.9, 51.7, 50.2, 47.6, 38.1, 37.0, 36.8, 35.9, 31.5, 31.4, 30.8, 27.8, 26.9, 21.9, 20.4, 19.4, 13.6. HRMS (ESI) calcd for C28H34O4Na [M + Na]+: 457.2349, found 457.2354.
  • Isopropyl 2-(4-(4-acetylbenzoyl)phenoxy)-2-methylpropanoate (2al) [56]: White solid (152 mg, 69%); 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.0 Hz, 2H), 7.77 (dd, J = 19.2, 8.0 Hz, 4H), 6.86 (d, J = 8.4 Hz, 2H), 5.12–5.04 (m, 1H), 2.65 (s, 3H), 1.65 (s, 6H), 1.19 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 197.5, 194.6, 173.0, 160.0, 142.0, 139.2, 132.1, 129.8, 129.6, 128.1, 117.2, 79.4, 69.3, 26.8, 25.3, 21.5.
  • Anthracene (4a) [62]: Grayish white solid (83 mg, 78%); 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 2H), 8.02 (q, J = 3.2 Hz, 4H), 7.48 (q, J = 3.2 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 131.7, 128.1, 126.2, 125.3.
  • Chalcone (4b) [61]: Yellow solid (97 mg, 78%);1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.6 Hz, 2H), 7.82 (d, J = 15.6 Hz, 1H), 7.66–7.42 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 190.6, 144.9, 138.2, 134.9, 132.8, 130.5, 128.9, 128.6, 128.5, 128.4, 122.1.
  • 2-phenyl-1H-benzo[d]imidazole (4c) [61]: White solid (72 mg, 62%); 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 7.2 Hz, 2H), 7.60–7.48 (m, 5H), 7.24–7.19 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 152.1, 130.9, 130.7, 129.9, 127.3, 123.2.
  • N-phenylacetamide (4d) [61]: Grayish white solid (49 mg, 60%); 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.05–8.03 (m, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.55–7.48 (m, 4H), 2.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 208.2, 136.7, 131.0, 128.8, 128.2, 126.8, 126.6, 125.5, 124.3, 33.8.

4. Conclusions

We have presented an efficient and clean approach for the synthesis of ketones from alkyl aromatics through the use of bis(2-butoxyethyl) ether as the catalyst and reaction medium and O2 as the sole oxidant. This new oxidation protocol can tolerate various functional groups and is suitable for large-scale synthesis. Notably, diverse target ketones were prepared in moderate to high yields in the absence of an external catalyst or additive. The late-stage functionalization of drug derivatives with the corresponding ketones and one-pot sequential chemical conversions to ketone downstream products that we have demonstrated here further broadens their application prospects, particularly in the pharmaceutical industry. Furthermore, by monitoring the reaction progress and conducting mechanistic experiments, we developed a bis(2-butoxyethyl) ether-promoted O2-mediated oxidation pathway for alkyl aromatics to ketones.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29204909/s1, Section S1: General information; Section S2: Experimental procedure; Section S3: Mechanism Research; Copies of the 1H NMR and 13C NMR spectra for compounds 2a–2ak and 4a–4d.

Author Contributions

Y.X., Z.L., X.X., H.J. and K.C. performed the experiments and analyzed the data. Y.Z. and K.L. (Kejun Luo) analyzed the data. J.O. wrote the original draft. K.L. (Kaijian Liu) was responsible for reviewing and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No. 22202067), the Hunan Provincial Natural Science Foundation of China (No. 2023JJ30206, No. 2024JJ5121), the Research Project of Hunan Provincial Department of Education (No. 22A0620, No. 23A0631), the Science and technology innovation project of Hengyang (No. 202330046118), Hunan Young Scientific and Technological Innovative Talents (2020RC3055), and the National Students’ project for innovation and entrepreneurship training program (S202411528030, S202411528118).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available on request from the corresponding authors.

Conflicts of Interest

Author Kejun Luo was employed by the company Changsha Research Institute of Mining and Metallurgy Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Molecules 29 04909 sch001
Scheme 1. Oxidation of alkyl aromatics to ketones.
Scheme 1. Oxidation of alkyl aromatics to ketones.
Molecules 29 04909 sch001
Molecules 29 04909 g001
Figure 1. (a) Scaled-up oxidation reaction; (b) several one-pot sequential conversions; (c) time course of oxygenation.
Figure 1. (a) Scaled-up oxidation reaction; (b) several one-pot sequential conversions; (c) time course of oxygenation.
Molecules 29 04909 g001
Molecules 29 04909 g002
Figure 2. Control experiments.
Figure 2. Control experiments.
Molecules 29 04909 g002
Molecules 29 04909 g003
Figure 3. Plausible bis(2-butoxyethyl) ether promoted oxidation mechanism.
Figure 3. Plausible bis(2-butoxyethyl) ether promoted oxidation mechanism.
Molecules 29 04909 g003
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 29 04909 i001
EntryPromoter (eq.)[O]T/°CTimeYield b (%)
12-Methoxyethyl ether (1)O212015 h63
2Bis(methoxypropyl) ether (1)O212015 h60
3Triethylene glycol dimethyl ether (1)O212015 h37
4Tetraethylene glycol dimethyl ether (1)O212015 h40
52-Ethoxyethyl ether (1)O212015 h65
6Bis(2-butoxyethyl) ether (1)O212015 h70
71,2-Dibutoxyethane (1)O212015 h47
8Methoxypropoxypropanol (1)O212015 h31
9Bis(2-butoxyethyl) ether (1)O213015 h77
10Bis(2-butoxyethyl) ether (1)O214015 h90
11Bis(2-butoxyethyl) ether (1)O215015 h92
12Bis(2-butoxyethyl) ether (1)O211015 h31
13Bis(2-butoxyethyl) ether (1)O210015 h-
14Bis(2-butoxyethyl) ether (1)O2r.t.15 h-
15Bis(2-butoxyethyl) ether (3)O215015 h91
16Bis(2-butoxyethyl) ether (2)O215015 h97
17Bis(2-butoxyethyl) ether (0.5)O215015 h76
18Bis(2-butoxyethyl) ether (2)O215018 h97
19 cBis(2-butoxyethyl) ether (2)O215015 h97
20Bis(2-butoxyethyl) ether (2)N215015 h-
21Bis(2-butoxyethyl) ether (2)air15015 h58
22-O215015 h-
a Conditions: unless others noted, 1a (0.6 mmol, 1 eq.), Promoter (2 eq.), 150 °C, 15 h. b Estimated based GC-MS results. c This oxidation was carried out in the dark.
Table 2. Reaction scope.
Table 2. Reaction scope.
Molecules 29 04909 i002
Molecules 29 04909 i003
Molecules 29 04909 i004
Conditions: 1a (0.6 mmol, 1 eq.), bis(2-butoxyethyl) ether (2 eq.), O2 balloon, 150 °C, 15 h, isolated yields.
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MDPI and ACS Style

Xie, Y.; Li, Z.; Xu, X.; Jiang, H.; Chen, K.; Ou, J.; Liu, K.; Zhou, Y.; Luo, K. Bis(2-butoxyethyl) Ether-Promoted O2-Mediated Oxidation of Alkyl Aromatics to Ketones under Clean Conditions. Molecules 2024, 29, 4909. https://doi.org/10.3390/molecules29204909

AMA Style

Xie Y, Li Z, Xu X, Jiang H, Chen K, Ou J, Liu K, Zhou Y, Luo K. Bis(2-butoxyethyl) Ether-Promoted O2-Mediated Oxidation of Alkyl Aromatics to Ketones under Clean Conditions. Molecules. 2024; 29(20):4909. https://doi.org/10.3390/molecules29204909

Chicago/Turabian Style

Xie, Yangyang, Zeping Li, Xudong Xu, Han Jiang, Keyi Chen, Jinhua Ou, Kaijian Liu, Yihui Zhou, and Kejun Luo. 2024. "Bis(2-butoxyethyl) Ether-Promoted O2-Mediated Oxidation of Alkyl Aromatics to Ketones under Clean Conditions" Molecules 29, no. 20: 4909. https://doi.org/10.3390/molecules29204909

APA Style

Xie, Y., Li, Z., Xu, X., Jiang, H., Chen, K., Ou, J., Liu, K., Zhou, Y., & Luo, K. (2024). Bis(2-butoxyethyl) Ether-Promoted O2-Mediated Oxidation of Alkyl Aromatics to Ketones under Clean Conditions. Molecules, 29(20), 4909. https://doi.org/10.3390/molecules29204909

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