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Open AccessFeature PaperArticle

Silver-Mediated Methoxylation of Aryl C(sp2)–H Bonds Directing by DMEDA

College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
*
Author to whom correspondence should be addressed.
Catalysts 2019, 9(2), 171; https://doi.org/10.3390/catal9020171
Received: 24 January 2019 / Revised: 3 February 2019 / Accepted: 7 February 2019 / Published: 12 February 2019
(This article belongs to the Special Issue Transition-Metal-Catalyzed Reactions in Organic Synthesis)

Abstract

The first example of silver-mediated phosphine-promoted methoxylation of aryl C(sp2)–H bonds with the commercially available reagent for the preparation of alkyl aryl ethers has been developed. This protocol is characterized by mild reaction conditions, broad substrate scope, and high regioselectivity.
Keywords: Silver-mediated; phosphine-promoted; C–H functionalization; DMEDA; pharmaceutical development Silver-mediated; phosphine-promoted; C–H functionalization; DMEDA; pharmaceutical development

1. Introduction

Alkyl aryl ethers are ubiquitous structural motifs present in both natural and synthetic compounds, particularly in bioactive molecules targeted as pharmaceuticals (Scheme 1) [1,2]. Compared to the traditional method for carbon-oxygen bond coupling [3,4,5,6], transition metal catalyzed C–H alkoxylation with alcohols has received much attention in recent decades in terms of atom and step economy [7,8,9,10]. However, direct C–H bond alkoxylation has been mostly limited to a palladium- [11,12,13,14,15] or copper-catalyzed system [16,17,18,19,20] which are both more biological toxicity metals.
Recently, the first-row transition metals such as iron, cobalt, and nickel for C–H alkoxylation, have attracted more attention owing to low biological toxicity as well as low cost [21,22,23,24,25]. In 2015, Niu and co-workers have first reported cobalt-catalyzed alkoxylation of C(sp2)–H bond in aromatic and olefinic carboxamides with Ag2O as oxidant (Scheme 2a) [21]. Lately, a new cobalt-catalyzed system has reported by same group for C8 alkoxylation of naphthylamine derivatives with both primary and secondary alcohols [22]. In 2018, an efficient Nickel-catalyzed C–H bond alkoxylation of benzamides and olefinic carboxamides with alcohols was also achieved for the first time by Sundararaju’s group (Scheme 2b) [23]. In the same year, our group also reported an iron-catalyzed ethoxylation of aryl C(sp2)–H bonds with cobalt co-catalyst (Scheme 2c) [24]. However, all of these reactions were carried out with silver reagents. While silver is also a common transition metal catalyst for C–H functionalization [26,27,28,29,30,31,32], silver-mediated alkoxylation of aryl C(sp2)–H bonds will be attractive but challenging.
As a part of our continuous interest towards using the newly developed directing group derived from the drug structure N,N′-dimethylethanediamine (DMEDA), we also realized the copper-catalyzed DMEDA-directed methoxylation recently [33]. Considering silver is the heavier congener of copper in the Periodic Table and it also has high catalytic activity for C–H functionalization, we speculated that the DMEDA directing group may facilitate the silver-mediated methoxylation of aryl C(sp2)–H bonds. We found that this is indeed the case, and we report herein a silver-mediated methoxylation of aryl C(sp2)–H bonds with methanol to prepare Alkyl aryl ethers for the first time (Scheme 2d).

2. Results

Initially, the synthesis study was carried out with N-(2-(dimethylamino)ethyl)benzamide (1a) as a model substrate (Table 1). While this transformation is a cross-dehydrogenative coupling (CDC) reaction, high-valent metal is needed for the electrophilic activation of C(sp2)–H bonds [34,35,36,37]. Since high-valent silver is rare in relation to copper under normal conditions, [38] the combination of Ag(I) and K2S2O8 which proved to be efficient for a silver-catalyzed or silver-mediated system was used in this system [31,32]. However, no good result was observed after the preliminary screening. Fortunately, the reaction was found to proceed efficiently in the presence of triphenylphosphine as a ligand (Entry 1, 63%). It is obviously that the phosphine ligand was critical for this transformation, when the desired product 3a was almost unobserved except without the phosphine ligand (Entry 8). In this system, we also found that a large number of phosphine ligands were oxidized to phosphine oxides, while phosphine oxides did not promote this transformation (Entry 3). Subsequently, 1.5 equivalents were screened out as the necessary amount of phosphine ligand (for more details, see Supplementary Materials). The effects of various structures of phosphine ligands for this system was also investigated, and trivalent phosphine ligands were found to promote this transformation efficiently (Scheme 3, Entry 1–7). What’s more, by comparing the results of L2 and L4, it was obvious that the steric effect had a great influence on this reaction (Entry 2,4). On the basis of that, a series of silver salts such as AgNO3, Ag2CO3, AgOAc, AgOTf, Ag2O, Ag2SO4, AgOPiv, and AgF were screened, then AgOPiv was found to be the optimal condition for this reaction (for more details, see SI). Meanwhile, different cosolvents were evaluated, it could be found that polar solvents such as DMSO, DMF and DMA were favorable for promoting the reaction, and DMA was found to be the most suitable cosolvent (Entry 9–12). Various additives were then tested, and the results showed that methoxylated yield increased in the presence of Na2SO4 (Entry 13, 72%). While MgSO4 were used as an additive, the yield was improved to 78% (Entry 14, Isolated yield 71%). However, no obvious improvement could be observed when other additives were added to this system (Entry 15–19). This may due to the high binding energy of Ag(3d5/2) states for AgSO4, a Ag(II) compuond [39]. The effect of the amount of AgOPiv was also investigated, decreasing the amount of AgOPiv to 3.0 equivalent reduced the yield of 1a to 55% (Entry 20). Furthermore, the reaction was found to be sensitive to air and moisture, switching the atmosphere from argon to air led to no reaction at all (Entry 21). Finally, different temperatures were also evaluated, and 55 °C was found to be the optimum temperature (for more details, see SI).
Using the optimal reaction conditions, the reaction scope with respect to aromatic substrates is presented in Table 2. In general, the demonstrated transformation was found to be compatible with a variety of benzamide derivatives bearing either electron-withdrawing or electron-donating groups, providing the corresponding methoxylated products with moderate to good yields (2b–2s). For example, fluoro (2c,2o), chloro (2d,2n,2s), bromo (2b,2p), nitro (2e), and cyano (2h) groups are well tolerated, which are convenient handles for further functionality. Due to the reactive activity of the iodine functional group, the reaction of 1g only gave the methoxylated product in 14% yield accompanied by the compounds 1a (yield 23%) and 2a (yield 31%). The reaction protocol was sensitive to steric hindrance, methoxylation with ortho-substituted substrates gave no encouraging results. But gratifyingly, the methoxylation of meta-substituted substrates showed high regioselectivity, which proceeded exclusively at the less hindered C–H bonds irrespective of the electronic properties of the substrates (2l–2r). Disubstituted substrate such as 3,5-dichloro-N-(2-(dimethylamino)ethyl) benzamide were also tolerated well under the optimized conditions (2s). Finally, other alcohols such as ethanol, propanol, isopropanol, butanol, and 2-butyl alcohol were also screened; however, encouraging results were not obtained.

3. Discussion

A plausible mechanism is proposed in Scheme 4 on the basis of the above observations and preliminary mechanistic studies. [38,39,40,41] It is known that in the presence of peroxydisulfate, the silver(I) salt is oxidized to a silver(II) species [40,41]. Complexation of benzamide 1a and phosphine ligand (L) to the silver(II) species (intermediate A), followed by C–H activation, affords the intermediate B. The intermediate B undergoes reductive elimination to give intermediate C, which was followed by protonation to generate the desired product 2a. While silver also existed as an oxidant in the stage of C–H activation, the stoichiometric silver reagent was indispensable.

4. Materials and Methods

4.1. Materials

Methanol, MeCN, THF, Toluene, EA, DMSO, DMF, DMA, 1,4-dioxane was dried by distillation over CaH2 and distilled under reduced pressure, then stored in dry argon atmosphere. All reagents were purchased from commercial suppliers and used without purification unless otherwise stated. Column chromatography was performed with silica gel (300–400 mesh) produced by Qingdao Marine Chemical Factory, Qingdao (China). NMR spectra were recorded on Bruker AVANCE III 500MHz instrument (Bruker, Hamburg, Germany) with TMS as internal standard. Coupling constants were reported in Hertz (Hz). HRMS analysis of determination of conversion was performed on the instrument of Waters Q-TOF.

4.2. General Procedure for Silver-Mediated Methoxylation

Under argon atmosphere, AgOPiv (0.40 mmol), K2S2O8 (0.40 mmol), L1 (0.15 mmol), 1a (0.10 mmol), MgSO4 (0.20 mmol), and MeOH/DMA (1/1, 1 mL) were introduced into a 15 mL seal tube. The mixture was fiercely stirred at 55 °C for 3 h. After cooling in an ice bath, the mixture was diluted in the mixed solvent of dichloromethane (30 mL) and edetate tetrasodium saturated aqueous solution (30 mL). After separated, the aqueous phase was extracted thrice with dichloromethane (30 mL). The organic layers were combined and evaporated under vacuum and the crude product was purified by column chromatograph using silica gel with n-hexane/ethyl acetate (v/v 1:2) to n-hexane/ethyl acetate/triethylamine (v/v/v 1:2:0.03) as eluent to afford 2a. Isolated yield: 15.8 mg (71%).

5. Conclusions

We presented the first example of silver-mediated phosphine-promoted methoxylation of aryl C(sp2)–H bonds with the commercially available reagent for the preparation of alkyl aryl ethers. This protocol is characterized by mild reaction conditions, broad substrate scope, and high regioselectivity. In addition, without the use of more biological toxicity metals such as copper and palladium, this system will be more suitable for the synthesis of related active drug molecules. Further exploration of this strategy to the synthesis of related active drug molecules is currently in progress.

Supplementary Materials

The following are available online at https://www.mdpi.com/2073-4344/9/2/171/s1.

Author Contributions

Conceptualization, C.D; methodology, J.Z.; formal analysis, L.X.; and Writing—Original Draft preparation, G.Z.

Funding

This research was funded by the National Natural Science Foundation of China (no. 20702051), the Natural Science Foundation of Zhejiang Province (LY13B020017).

Conflicts of Interest

The authors declare no conflict of interest.

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Scheme 1. Selected pharmaceuticals containing aryl alkyl ether units.
Scheme 1. Selected pharmaceuticals containing aryl alkyl ether units.
Catalysts 09 00171 sch001
Scheme 2. Direct alkoxylation of C–H bonds using low biotoxicity transition metals.
Scheme 2. Direct alkoxylation of C–H bonds using low biotoxicity transition metals.
Catalysts 09 00171 sch002
Scheme 3. The structure of phosphine ligands.
Scheme 3. The structure of phosphine ligands.
Catalysts 09 00171 sch003
Scheme 4. Plausible mechanism for C–H ethoxylation catalyzed by iron.
Scheme 4. Plausible mechanism for C–H ethoxylation catalyzed by iron.
Catalysts 09 00171 sch004
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Catalysts 09 00171 i001
EntryLigandAdditiveCosolventYield [%] b
1L1-DMA63
2L2-DMA54
3L3-DMATrace
4L4-DMA17
5L5-DMA51
6L6-DMA9
7L7-DMA36
8--DMAn.r
9L1-DMSO51
10L1-DMF56
11L1-Toluene4
12L1-EA30
13L1Na2SO4DMA72
14L1MgSO4DMA78(71 c)
15L1Na2CO3DMA30
16L1K2CO3DMAn.r
17L1Li2CO3DMA20
18L1Li3PO4DMA38
19L1NaOAcDMA50
20 dL1MgSO4DMA55
21 eL1MgSO4DMAn.r
a Reaction condition: 1a (0.1 mmol), Ligand (1.5 equiv.), AgOPiv (4.0 equiv.), K2S2O8 (4.0 equiv.), Additive (2.0 equiv.), in MeOH/cosolvent (1/1) 1 mL, 55 °C for 3 h, under Ar atmosphere. b 1H NMR yield using CH2Br2 as the internal standard. c Isolated yield. d AgOPiv (3.0 equiv.). e Under air atmosphere.
Table 2. Substrate scope of aromatic compounds a.
Table 2. Substrate scope of aromatic compounds a.
Catalysts 09 00171 i002
Entry12Yield b
1 Catalysts 09 00171 i003 Catalysts 09 00171 i00465
2 Catalysts 09 00171 i005 Catalysts 09 00171 i00658
3 Catalysts 09 00171 i007 Catalysts 09 00171 i00862
4 Catalysts 09 00171 i009 Catalysts 09 00171 i01035
5 Catalysts 09 00171 i011 Catalysts 09 00171 i01262
6 Catalysts 09 00171 i013 Catalysts 09 00171 i01414
7 Catalysts 09 00171 i015 Catalysts 09 00171 i01661
8 Catalysts 09 00171 i017 Catalysts 09 00171 i01863
9 Catalysts 09 00171 i019 Catalysts 09 00171 i02072
10 Catalysts 09 00171 i021 Catalysts 09 00171 i02255
11 Catalysts 09 00171 i023 Catalysts 09 00171 i02468
12 Catalysts 09 00171 i025 Catalysts 09 00171 i02667
13 Catalysts 09 00171 i027 Catalysts 09 00171 i02860
14 Catalysts 09 00171 i029 Catalysts 09 00171 i03054
15 Catalysts 09 00171 i031 Catalysts 09 00171 i03240
16 Catalysts 09 00171 i033 Catalysts 09 00171 i03464
17 Catalysts 09 00171 i035 Catalysts 09 00171 i03664
18 Catalysts 09 00171 i037 Catalysts 09 00171 i03855
a Reaction condition: 1 (0.1 mmol), L1 (1.5 equiv.), AgOPiv (4.0 equiv.), K2S2O8 (4.0 equiv.), MgSO4 (2.0 equiv.), in MeOH /DMA (1/1) 1 mL at 55 °C under Ar atmosphere. b Isolated yield.
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