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Communication

Transition-Metal-Free C(sp3)–H Oxidation of Diarylmethanes

by
Fan Yang
1,2,
Bihui Zhou
1,2,
Pu Chen
1,
Dong Zou
1,2,
Qiannan Luo
1,
Wenzhe Ren
1,
Linlin Li
1,
Limei Fan
1 and
Jie Li
1,*
1
Department of Pharmacy, School of Medicine, Zhejiang University City College, No. 48, Huzhou Road, Hangzhou 310015, China
2
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(8), 1922; https://doi.org/10.3390/molecules23081922
Submission received: 10 July 2018 / Revised: 25 July 2018 / Accepted: 27 July 2018 / Published: 1 August 2018
(This article belongs to the Special Issue Recent Development on Metal-Free Catalysis)
Browse Figure
Versions Notes

Abstract

:
An efficient direct C(sp3)–H oxidation of diarylmethanes has been demonstrated by this study. This method employs environment-friendly O2 as an oxidant and is promoted by commercially available MN(SiMe3)2 [M = K, Na or Li], which provides a facile method for the synthesis of various diaryl ketones in excellent yields. This protocol is metal-free, mild and compatible with a number of functional groups on substrates.

1. Introduction

The oxidation reaction is one of the most important transformations in organic synthesis by which oxygenated products of hydrocarbons were prepared and these compounds are valuable structural core in chemical and pharmaceutical industries [1]. Of these transformations, direct oxidation of methylene group of arylalkanes to ketones have attracted comprehensive attention, as diverse aryl ketone motifs are important structural units in numerous pharmaceuticals, naturally occurring molecules and organic functional materials [2,3,4,5,6]. Besides the traditional oxidation using KMnO4 as oxidant [7,8,9,10], advances in the synthetic method of aryl ketones were mainly based on three approaches: (1) classical Friedel-Crafts acylation of arenes [11], (2) oxidation of secondary alcohols [12] and CO insertion reactions [13,14]. Recently, significant progress has been made for the formation of aromatic ketones by transition-metal catalyzed oxidation of alkylarenes [15,16,17]. Notably, the latter represent a powerful tool in organic synthesis, while inevitably they will suffer from the use of toxic or expensive metals and ligands, harsh reaction conditions and generation of metal waste in most cases. Obviously, it is desirable to develop more practical protocols to achieve the synthesis of aryl ketones without the use of corrosive metal catalysts, hazardous stoichiometric oxidants and reductants [18,19,20,21]. Therefore, transition-metal-free methods for oxidation of alkylarenes are desirable in the pharmaceutical industry which can avoid the use of the heavy metal. For oxidation process, Molecular oxygen (O2) represents one of the best choices because of its low cost and has attracted substantial attention [22,23,24,25,26,27,28,29,30,31,32,33]. Herein, we wish to report the direct oxidation of diarylmethanes to diaryl ketones using O2-mediation by MN(SiMe3)2 [M = K, Na or Li], which represent a green and efficient synthetic method for this transformation.

2. Results

Initially, we commenced the reaction studies using 4-benzylpyridine (1a) as the model substrate. The control experiment was performed by stirring 4-benzylpyridine (1a) in THF under O2 at 60 °C for 16 h and no reaction occurred (entry 1, Table 1). To optimize the reaction conditions, various parameters such as temperature, bases, solvents were investigated. The strong bases play an important role in this transformation. As indicated in Table 1, the silylamides [MN(SiMe3)2, M = Li, Na, K] overwhelmed other bases (entries 2–8), giving the oxidative product in 76–85% yields. We anticipated that the inert sp3 C–H bond was transferred to carbanion before the direct insertion of O2, which needs the strong bases to achieve the deprotonation step. The solvent was next examined using LiN(SiMe3)2 as a base. Of the six solvents screened, THF showed the best performance (entries 4 and 9–13). Further screen of the reaction temperature indicated 60 °C is most appropriate. Only 35% yield of oxidation product 2a was obtained at 40 °C after 12 h (entry 14), while no elevated yield was observed when the reaction was conducted in higher temperature 80 °C (entry 15). Furthermore, there is no oxidation product if the O2 was replaced with N2.
With the optimal condition in hand, we then turn our attention to investigate the generality of this protocol. As presented in Figure 1, a variety of diarylmethanes were subjected to these reaction conditions. These reactions were conducted at 60 °C, except where noted. Diarylmethanes with different electronic and steric properties, such as 2-benzylpyridine (1b), diphenylmethane (1c), xanthene (1d), 9,10-dihydroanthracene (1e) and fluorene (1f), were proved to be good substrates, with corresponding products isolated in 79–91% yields. The family of fluorene analogues bearing various functional groups was examined next. The carbon-halo (electron-withdrawing) groups were compatible with this procedure and the oxidation products were obtained in excellent isolated yields (2h, 2i, 2j, 2k). Additionally, remarkable chemoselectivity is observed with fluorene derivatives containing acetal, nitro and amino moieties, which all underwent oxygenation delivering the corresponding functionalized products (2l, 2m, 2n) in 81–87% yields.
To illustrate the scalablitlity of this methodology, we commenced the oxidation reaction of 4-benzylpyridine (1a) on a 5 mmol scale. The oxidation product 2a was isolated in 80% yield (0.73 g).

3. Materials and Methods

3.1. General

1H- and 13C-NMR spectra were obtained on Bruker AVANCE III 500 MHz and 600 MHz spectrometers (Bruker Co., Billerica, MA, USA) with TMS as the internal standard; MS spectra were measured on a Finnigan LCQDECA XP instrument and an Agilent Q-TOF 1290 LC/6224 MS system (Santa Clara, CA, USA); silica gel GF254 and H (10–40 mm, Qingdao Marine Chemical Factory, Qingdao, China) were used for TLC and CC. Unless otherwise noted, all reactions were carried out under an atmosphere of oxygen.

3.2. Representative Procedure for the Oxidation of Diarylmethane

To an 8 mL oven-dried vial, 4-benzylpyridine (0.1 mmol), dry THF (1 mL), LiHMDS (0.15 mmol) were added subsequently. The reaction system was sealed by a rubber septum with a needle connected with O2 balloon. After stirring at 60 °C for 12 h, the reaction mixture was passed through a short pad of silica gel and eluted with ethyl acetate (1 mL × 3). The combined organics were concentrated under reduced pressure. The residue was purified by flash chromatography to give the diarylketone 2a as white solid (15.6 mg, 85% yield). 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 7.3 Hz, 2H), 7.54–7.43 (m, 4H), 7.33–7.25 (m, 2H). The 1H NMR data of 2a was identical to those reported in the literature [34].
Analogous compounds 2b–n were prepared according to the similar procedure for 2a. 2b: 1H NMR (500 MHz, CDCl3) δ 8.73 (d, J = 4.1 Hz, 1H), 8.10–8.03 (m, 3H), 7.90 (td, J = 7.8, 1.7 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.52–7.44 (m, 3H). The 1H NMR data of 2b was identical to those reported in the literature [34]. 2c: 1H NMR (500 MHz, CDCl3) δ 7.72 (dd, J = 5.2, 3.2 Hz, 2H), 7.54–7.47 (m, 1H), 7.43–7.36 (m, 2H). The 1H NMR data of 2c was identical to those reported in the literature [35]. 2d: 1H NMR (500 MHz, CDCl3) δ 8.34 (d, J = 7.9 Hz, 2H), 7.73 (t, J = 7.7 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H). The 1H NMR data of 2d was identical to those reported in the literature [36]. 2e: 1H NMR (500 MHz, CDCl3): δ 8.26–8.37 (m, 2H), 7.56 (t, J = 7.4 Hz, 2H), 7.36–7.47 (m, 4H), 4.32 (s, 2H). The 1H NMR data of 2e was identical to those reported in the literature [37]. 2f: 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 7.3 Hz, 2H), 7.54–7.43 (m, 4H), 7.33–7.25 (m, 2H). The 1H NMR data of 2f was identical to those reported in the literature [36]. 2g: 1H NMR (500 MHz, CDCl3): δ 8.14 (s, 1H), 7.88 (s, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 10.50 Hz, 1H), 7.73 (d, J = 9.5 Hz, 1H), 7.69 (d, J = 9.5 Hz, 1H), 7.75–7.55 (m, 2H), 7.45 (t, J = 9.2 Hz, 1H), 7.32 (t, J = 9.2 Hz, 1H). The 1H NMR data of 2g was identical to those reported in the literature [38]. 2h: 1H NMR (500 MHz, CDCl3): δ 7.78 (s, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.53–7.52 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.35–7.34 (m, 1H). The 1H NMR data of 2h was identical to those reported in the literature [39]. 2i: 1H NMR (500 MHz, CDCl3): δ 7.66 (d, J = 1.8 Hz, 2H), 7.52 (dd, J = 7.9 Hz, 1.8 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H). The 1H NMR data of 2i was identical to those reported in the literature [39]. 2j: 1H NMR (500 MHz, CDCl3) δ 7.62 (d, J = 1.8 Hz, 2H), 7.47 (dd, J = 8.0, 2.0 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H). The 1H NMR data of 2j was identical to those reported in the literature [40]. 2k: 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 7.8, 1.6 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.63 (dd, J = 7.9, 1.9 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.28 (s, 1H). The 1H NMR data of 2k was identical to those reported in the literature [41]. 2l: 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 0.98 Hz, 1H), 8.13 (dd, J = 7.8, 2.0 Hz, 1H), 7.70 (d, J = 7.3 Hz, 1H), 7.63–7.51 (m, 3H), 7.40–7.35 (m, 1H), 2.63 (s, 3H). The 1H NMR data of 2l was identical to those reported in the literature [42]. 2m: 1H NMR (500 MHz, CDCl3): δ 8.48 (d, J = 1.9 Hz, 1H), 8.43 (dd, J = 1.9 Hz, 8.2 Hz, 1H), 7.77 (d, J = 7.3 Hz, 1H), 7.72–7.67 (m, 2H), 7.62 (t, 1H), 7.46 (t, 1H). The 1H NMR data of 2m was identical to those reported in the literature [39]. 2n: 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 7.3 Hz, 1H), 7.43–7.23 (m, 2H), 7.20 (d, J = 7.0 Hz, 1H), 7.16–7.00 (td, J = 7.2 Hz, 1.2 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.65 (dd, J = 7.9, 2.3 Hz, 1H), 3.82 (s, 2H). The 1H NMR data of 2n was identical to those reported in the literature [43].

4. Conclusions

In conclusion, we have developed a metal-free, environmentally benign method for C(sp3)–H oxidation of various diarylmethanes using silylamides [MN(SiMe3)2, M = Li, Na, K] as base and O2 as an oxidant. This protocol provides a complementary method to prepare diaryl ketones in good to excellent yields. The detailed mechanism study is still underway.

Author Contributions

J.L. conceived and designed the experiments and wrote the manuscript; F.Y., B.Z., P.C., D.Z., Q.L. and W.R. performed the experiments and analyzed the data; L.F. and L.L. interpreted the results and helped write the paper.

Funding

We are grateful to the National Natural Science Foundation of China (81302668) and Hangzhou Science and Technology Information Institute of China (20150633B45).

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 2a–2n are available from the authors.
Molecules 23 01922 g001 550
Figure 1. Scope of diarylmethanes in metal-free oxidation a,b. a Reactions were conducted on a 0.1 mmol scale using 1 equiv of 1, 1.5 equiv of LiN(SiMe3)2 at 0.1 M. b Isolated yield. c Reaction conducted on 5 mmol scale. d LiHMDS was replaced with NaHMDS. e LiHMDS was replaved with KHMDS. f 80 °C.
Figure 1. Scope of diarylmethanes in metal-free oxidation a,b. a Reactions were conducted on a 0.1 mmol scale using 1 equiv of 1, 1.5 equiv of LiN(SiMe3)2 at 0.1 M. b Isolated yield. c Reaction conducted on 5 mmol scale. d LiHMDS was replaced with NaHMDS. e LiHMDS was replaved with KHMDS. f 80 °C.
Molecules 23 01922 g001
Table
Table 1. Optimization of the reaction conditions.
Table 1. Optimization of the reaction conditions.
Molecules 23 01922 i001
Entry aBaseSolventTemp [°C]Yield [%] b
1–THF60 °C–
2KHMDSTHF60 °C76
3NaHMDSTHF60 °C79
4LiHMDSTHF60 °C85
5KOtBuTHF60 °C11
6NaOtBuTHF60 °C6
7LiOtBuTHF60 °Ctrace
8CS2CO3THF60 °C–
9LiHMDSdioxane60 °C23
10LiHMDStoluene60 °C15
11LiHMDSDME60 °C79
12LiHMDSCPME60 °C56
13LiHMDSCH2Cl260 °C11
14LiHMDSTHF80 °C84
15LiHMDSTHF40 °C35
16 cLiHMDSTHF60 °C–
a Reactions were carried out using 4-benzylpyridine (0.1 mmol) and base (0.15 mmol) in anhydrous solvent (1.0 mL) under O2 for 12 h. b Isolated yields. c O2 was replaced with N2.

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MDPI and ACS Style

Yang, F.; Zhou, B.; Chen, P.; Zou, D.; Luo, Q.; Ren, W.; Li, L.; Fan, L.; Li, J. Transition-Metal-Free C(sp3)–H Oxidation of Diarylmethanes. Molecules 2018, 23, 1922. https://doi.org/10.3390/molecules23081922

AMA Style

Yang F, Zhou B, Chen P, Zou D, Luo Q, Ren W, Li L, Fan L, Li J. Transition-Metal-Free C(sp3)–H Oxidation of Diarylmethanes. Molecules. 2018; 23(8):1922. https://doi.org/10.3390/molecules23081922

Chicago/Turabian Style

Yang, Fan, Bihui Zhou, Pu Chen, Dong Zou, Qiannan Luo, Wenzhe Ren, Linlin Li, Limei Fan, and Jie Li. 2018. "Transition-Metal-Free C(sp3)–H Oxidation of Diarylmethanes" Molecules 23, no. 8: 1922. https://doi.org/10.3390/molecules23081922

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