Tuning the Reactivity of Peroxo-Anhydrides for ... - ACS Publications

Hosseini,┴ Marina Šekutor,‡ Heike Hausmann,┴ Jonathan Becker,§ Kevin ... ┴Institute of Organic Chemistry, Justus Liebig University, Hein...
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Cite This: J. Org. Chem. 2018, 83, 10070−10079

Tuning the Reactivity of Peroxo Anhydrides for Aromatic C−H Bond Oxidation Afsaneh Pilevar,⊥ Abolfazl Hosseini,⊥ Marina Š ekutor,‡ Heike Hausmann,⊥ Jonathan Becker,§ Kevin Turke,# and Peter R. Schreiner*,⊥ ⊥

Institute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia § Institute of Inorganic and Analytical Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany # Institute of Physical Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany

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‡

S Supporting Information *

ABSTRACT: Phenol moieties are key structural motifs in many areas of chemical research from polymers to pharmaceuticals. Herein, we report on the design and use of a structurally demanding cyclic peroxide (spiro[bicyclo[2.2.1]heptane-2,4′-[1,2]dioxolane]-3′,5′-dione, P4) for the direct hydroxylation of aromatic substrates. The new peroxide benefits from high thermal stability and can be synthesized from readily available starting materials. The aromatic C−H oxidation using P4 exhibits generally good yields (up to 96%) and appreciable regioselectivities.

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INTRODUCTION The direct hydroxylation of aromatic compounds is a highly desirable synthetic transformation, providing access to a large number of diversely substituted phenols. Phenol moieties are ubiquitous in numerous pharmaceutically and biologically active compounds, and consequently, extensive studies of efficient methods for their preparation were undertaken.1−3 Although a variety of metal catalysts can be employed in this context,4 use of organic peroxides as a facile means for arene oxidation is just being explored. Common strategies for preparation of phenols include use of hydrogen peroxide in combination with strong acids, organic peroxy acids, and organic peroxides (Scheme 1).5−7

therefore highly desirable to develop efficient and selective strategies for the oxidation of arenes under mild conditions.12 It has been previously demonstrated that organic peroxides serve as reagents for the safe and environmentally benign conversion of arenes to phenols.13,14 Although the performance of organic peroxides in arene oxidation reactions usually suffers from low selectivity and poor reactivity,14,15 these shortcomings can be improved by varying the structure of the organic backbone, which significantly affects their efficiency. In that sense, strained cyclic peroxides are likely candidates in designing the next-generation reagents for arene oxidation. Although cyclic peroxides already found broad application in synthetic organic chemistry,16 research on cyclic diacyl peroxides (CDPs) has so far been mostly focused on their decomposition reactions.17−19 Phthaloyl peroxide (PPO) is one of the oldest CDPs known, but its practical use is limited due to its potential for exothermic decomposition and difficulties associated with its preparation.20−22 Russell and Green reported that the reactions of phthaloyl peroxide with styrene and stilbene furnished mixtures of esters formed by the addition of the peroxide oxygens to double bonds.23−25 Similarly, aliphatic CDPs were synthesized and their unusual decomposition to α-hydroxy esters was studied by Adam.26 More recently, Siegel and Tomkinson showed in their pioneering reports on the use of CDPs in organic synthesis that both aromatic and aliphatic diacyl cyclic peroxides readily react with a range of electron-rich double bonds to produce dihydroxylated products.22,27,28 In addition, they demonstrated that CDPs could also react with electron-rich arenes to provide phenols (Scheme 2).29−31

Scheme 1. Established Strategies for the Preparation of Phenols and Their Limitations

However, the applicability of such methods remains limited due to harsh reaction conditions, lack of selectivity, and frequently poor yields. It is striking that even with the advancement of metal catalysis for arene oxidation, the regioselective hydroxylation of aromatic compounds remains one of the most challenging chemical transformations. What is more, metalcatalyzed regioselective oxidation of arenes8 often requires the use of directing groups that pose severe limitations.9−11 It is © 2018 American Chemical Society

Received: June 3, 2018 Published: July 31, 2018 10070

DOI: 10.1021/acs.joc.8b01392 J. Org. Chem. 2018, 83, 10070−10079

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The Journal of Organic Chemistry Scheme 2. CDPs-Mediated Hydroxylation of Arenes

Scheme 4. Synthesis of Peroxide P4 and Its Single-Crystal X-ray Diffraction Structure

Even though two mechanisms, radical vs ionic, were proposed for arene oxidation reactions with phthaloyl and malonoyl peroxides, respectively, both CDPs yielded the same products.29,30 These newly developed approaches offer ample opportunities in organic synthesis, providing a way to avoid (toxic) metals and harsh reaction conditions in the preparation of valuable arenes. In particular, the development of new peroxides capable of regioselective or even enantioselective transformations is a highly desirable goal. Factors controlling the orientation of electrophilic aromatic substitutions (EAS) are well documented. Norman and Taylor have discussed that steric hindrance, electronic effects, interactions between substituent and reagent, and solvent effects contribute to controlling the regioselectivities.32−35 Later on, Olah et al. disclosed that steric effects could not be the only reason for ortho vs para selectivity, with the latter being greatly favored when the transition state is late.36 Our objective was therefore to design a safe and efficient peroxide possessing a sterically demanding scaffold incorporating a rigid moiety, and moderate reactivity, in order to regioselectively prepare a variety of phenol derivatives. To achieve this goal, two key criteria were taken into consideration: (1) use of inexpensive starting materials and simple preparative procedures and (2) use of bench-stable and nonexplosive peroxides. With these in mind, we decided against using the phthaloyl peroxide framework P1 (Scheme 3)

Thermogravimetric studies (TGA) were conducted to compare the stability of the P4 relative to that of cyclopropyl (T3) and cyclopentyl malonoyl peroxides (T5, see the SI). The results show that P4 is thermally more stable than these two and that the initial mass loss starts at about 100 °C with gradual decomposition, which is at least 30 °C higher than for T3 and T5 (Figure S6). Even though P4 displays significantly improved thermal stability, which is an important aspect when using peroxides for oxidations, appropriate precautions must always be taken. With this new peroxide in hand, we first examined its reactivity toward the oxidation of anisole (5a). Gratifyingly, the reaction performed in fluorinated alcohols at 40 °C afforded ortho and para products in good yields (Table 1). As such Table 1. Optimization of Reaction Conditions Using Peroxide P4

Scheme 3. Sterically Demanding Cyclic Diacyl Peroxides

because of the inherent explosion hazards and difficulties in the synthesis.20,37 One option we considered during the peroxide design was incorporation of suitable substituents into a three- or five-membered spiro rings, leading to derivatives P2 or P3 (Scheme 3), which would also be amenable for probing enantioselective oxidations.38 Ultimately, aliphatic cyclic peroxide P4, which incorporates a five-membered malonoyl acid motif combined with a norbornane framework, proved to be an excellent new oxygen transfer reagent that fulfills the necessary reactivity and scaffold rigidity prerequisites.

no.

peroxide P4 (equiv)

solvent

yielda (%)

regioselectivityb

1 2 3 4 5 6i 7 8 9 10j

2 2 2 2 2 2 1.5 1.3 1 2

TFEc HFIPd PFBe TCEf CEOg CEO PFB PFB PFB PFB

47 60 65 35 30h 51 60 56 44 64

1:1.8 1:1.8 1:2 1:1.8 1:2.6 1:2.5 1:2 1:2 1:2 1:2

a

Yield of isolated product. bOrtho/para ratio determined by NMR. 2,2,2-Trifluoroethanol (TFE). dHexafluoroisopropanol (HFIP). e Perfluoro-tert-butyl alcohol (PFB). f2,2,2-Trichloroethanol (TCE). g 2-Chloroethanol (CEO). hAfter 72 h. iReaction at 60 °C. jReaction at 0.5 M. c

guaiacol products are highly volatile compounds, the reaction mixture was treated with trimethylsilyl diazomethane to give the methylated products and thereby facilitating product isolation. Since the interpretation of reaction regioselectivity with the resulting 1H NMR spectra was ambiguous, we carried out a quantitative 13C NMR product analysis by dissolving the samples in CDCl3 containing traces of chromium(III) acetoacetonate. The spectra were obtained at 150 MHz in the inverse-gated decoupling mode. The signals at 157.38 and 157.33 as well as 151.32 and 151.30 ppm were assigned to C-1 of the endo/exo ester product mixture of [6a1] and [6a2], respectively, and the regioselectivity of the reaction was determined by integration of the corresponding signals (Figure 1). The use of fluorinated alcohols for the activation of malonoyl peroxide has already been thoroughly investigated.41

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RESULTS AND DISCUSSION The preparation of target peroxide P4 was accomplished using inexpensive reagents and chromatographic purification was not needed. As illustrated in Scheme 4, commercially available 5-norbornene-2-carboxaldehyde (1) was converted to 5-norbornene-2,2-dimethanol (2),39 via an aldol−Cannizzaro condensation with formaldehyde, followed by alkene reduction to afford 3. Oxidation of dialcohol 3 to diacid 440 and subsequent peroxide synthesis in the presence of urea−hydrogen peroxide/MsOH provided spiro[bicyclo[2.2.1]heptane-2,4′-[1,2]dioxolane]-3′, 5′-dione (P4) in ca. 46% yield over four steps (Scheme 4). 10071

DOI: 10.1021/acs.joc.8b01392 J. Org. Chem. 2018, 83, 10070−10079

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The Journal of Organic Chemistry Table 2. Hydroxylation of Arenes with Peroxide P4

Figure 1. Inverse-gated decoupled 13C NMR spectrum of [6a1] and [6a2] to determine the regioselectivity of the oxidation.

Tomkinson et al. have shown that the rate of styrene dihydroxylation was consistently increased with an increase of solvent alcohol acidity. They suggested that this could be attributed to an increase in the hydrogen bond donation ability of the alcohol, consistent with the literature finding that the aggregation of fluorinated alcohols enhances H-bonding interactions.42 During the optimization of the reaction conditions (using design of experiment as outlined in the SI), we tested various fluorinated alcohols as solvents. The yield of hydroxylated product steadily increased with the solvent pKa, from TFE (pKa = 12.4) to HFIP (pKa = 9.3) and finally to PFB (pKa = 5.4); the latter also showed an improvement in regioselectivity of the desired product (Table 1, entries 1−3). Conversion was found to be lower in TCE (pKa = 12.2) and CEO (pKa = 14.3) (Table 1, entries 4 and 5). While CEO appears to be a good solvent in terms of cost and selectivity, attempts to increase the yield by heating the reaction mixture to 60 °C resulted in a lower yield when compared to PFB, albeit with higher regioselectivity (Table 1, entry 6). We therefore decided to use PFB (method A) as the solvent of choice and proceeded with further optimization of the reaction conditions (Table 1, entries 7−10). Overall, the best results for anisole (5a) oxidation using peroxide P4 were slightly superior (65%, 1:2 ortho/para) to those reported for malonoyl (63%, 1:1.6) and phthaloyl peroxide (45%, 1.4:1, with opposite regioselectivity) and that with trifluoroperoxyacetic acid (34%, 3.6:1),6 both in terms of yield and regioselectivity. Hence, we had grounds to believe that the new peroxide with the norbornane scaffold would allow improvements over existing reagents. We further investigated the use of mixed solvents in order to decrease the amount of expensive PFB, with CEO serving as a cosolvent (method B). The selectivity toward the para isomer improved when the reaction was performed in a mixture of CEO/PFB (7:3), with an ortho/para ratio of 1:2.5 and 63% yield of isolated product, while using a lower amount of peroxide (1.6 equiv). With the optimized reaction conditions in hand, we investigated the oxidation of various arenes using P4 (Table 2). 1,3-Dimethoxybenzene (5b) also underwent regioselective C−O bond formation to give 6b1 as the sole product in 70% yield, a feat very similar to rutheniumcatalyzed oxygenation reported previously (Table 2, entry 2).43 Such excellent regioselectivity is likely due to the 2-hydroxylation being inhibited by steric repulsion between the P4 framework and the methoxy substituents. Benzene is inactive under our standard conditions, and no product was observed even after four days (Table 2, entry 3), indicating that electron-donating groups arerequired. The hydroxylation of naphthalene (5d) efficiently proceeded to give the corresponding α- and β-naphthols in

a

Major isomer shown; second and third preferred positions for hydroxylation are numbered accordingly. bMethod A: P4 (2 equiv), PFB (1.7 mL), 40 °C. Method B: P4 (1.6 equiv), CEO/PFB (7:3, 1 mL), 50 °C. cMethod B was used for the hydroxylation of methoxy bearing arenes; in the case of naphthalenes and alkyl arenes, method A was employed. dYield of isolated products. eThe reaction was performed at rt using 1.2 equiv of P4. fReaction at rt.

96% yield with excellent regioselectivity (Table 2, entry 4). This result is a marked improvement of the yield and selectivity obtained with phthaloyl peroxide (63% yield, 5.8:1 ratio of α/β), and the resulting regioselectivity is close to that of the metalloporphyrin oxidation of naphthalene (44% yield, 13.3:1 ratio of α/β).44 Oxidation of 1-methoxynaphthalene 5e selectively occurred on the ring carrying the methoxy group and afforded ortho and para regioisomers, with a preference for the ortho position. Toluene (5f) exhibited low reactivity under our conditions, and only 25% yield was obtained even after prolonged reaction time, but the reaction occurred with enhanced para selectivity compared to previous reports (Table 2, entry 6).29 This result suggested that both steric and electronic factors are 10072

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The Journal of Organic Chemistry responsible for controlling reactivity and selectivity in our system. Good yields were also obtained for xylenes (5g−i) and tetralin (5j) due to the increased electron density resulting from the second alkyl group (Table 2, entries 7−10). Notably, the regioselectivity observed for o-xylene (5g) was opposite to that previously reported,29 and the corresponding 3,4-dimethylphenol was obtained as the main product (Table 2, entry 7). Similarly, m-xylene (5h) underwent C−O bond formation almost exclusively at the less hindered position (Table 2, entry 8). Hydroxylation regioselectivities for arenes bearing various donating groups were also investigated. Treatment of 4-methylanisole (5k) with P4 resulted in the clean formation of 3-hydroxy-4-methoxytoluene. Such preferential formation of the 3-hydroxy over the 2-hydroxy derivative implies a dependence of the regioselectivity on the electronic nature of the directing groups. This is in marked contrast to the product ratio observed using PPO, where both isomers formed in approximately equal amounts. Unlike for 5k, oxidation of 2-methoxytoluene (5l) provided a mixture of regioisomers. Preferential formation of 3-methoxy-o-cresol (6l2) over 2-methoxy-m-cresol (6l3) could be explained by the steric hindrance between the methoxy moiety and adjacent methyl group, which defines the methoxy group conformation to be cis relative to H-6 (Scheme 5, 5l-cis). This conformation suffers from steric

Scheme 6. Direct Oxidation of [2.2]Paracyclophane Using Peroxide P4

Furthermore, to exploit the synthetic utility of P4 in an asymmetric reaction, we also investigated the enantioselective hydroxylation of 5p. The enantiopure dicarboxylic acid was synthesized according to an established procedure and was then converted to peroxide P4′ (Scheme 7). Enantiopure P4′ Scheme 7. Synthesis of Enantiopure Peroxide P4′

Scheme 5. Preferred Cis Conformation of the Methoxy Group

was subjected to the same reaction conditions for mono hydroxylation of 5p. However, the HPLC product analysis showed no ee (Figure S2). Further modification of the reaction conditions for both arene and alkene oxidations using various hydrogen bond catalysts are currently under investigation in our laboratory. To emphasize broad applicability and group tolerance, we next applied our protocol to the direct C−H bond hydroxylation of guaiacol estrogen (5q), a naturally occurring mammalian tubulin polymerization inhibitor.53 Structural modifications and syntheses of new estrogen derivatives are of interest due to their potent biological activities and their potential applications in medicine,54,55 with the regioselective hydroxylation of the estrogen aromatic ring being a rather challenging transformation.56,57 Therefore, direct hydroxylation of guaiacol estrogen using P4 provides an efficient and improved synthetic strategy (Scheme 8) when compared to previously utilized

crowding around the position 6 of the ring and substantially reduces the approach of P4 to this position.45,46 Hydroxylation of methoxybiphenyls 5m and 5n occurred only at the activated rings and left the unsubstituted phenyl moiety untouched, further implying that donor substituents are essential to promote the reaction. Acetamides generally yield the para-substituted products in EAS reactions.47 Contrary to the previous reports, phenyl-bearing amide substituents represented equal activity on both ortho and para positions. Encouraged by these results, we tested peroxide P4 in the synthesis of the challenging substrate 4-hydroxy[2.2]paracyclophane. Mono- and dihydroxy[2.2]paracyclophanes are valuable synthons in the preparation of [2.2]paracyclophane-based building blocks and chiral ligands for asymmetric catalysis.48 To the best of our knowledge, direct transformation of [2.2]paracyclophane (5p) to 4-hydroxy[2.2]paracyclophane has not been reported so far, and the existing methods rely on bromination49 or formylation50 of 5p and subsequent transformation to hydroxyl products, with an overall yield of 63% for 4-hydroxy[2.2]paracyclophane (hydroformylation, two steps). To our delight, [2.2]paracyclophane (5p) was efficiently hydroxylated with P4, furnishing the monohydroxylated product (6p1) in good yield and selectivity (Scheme 6). Pseudo-para (6p2) and ortho (6p3) products were confirmed by analysis of their single-crystal X-ray diffraction structures (SI).51,52 Encouraged by the results achieved for the monohydroxylation of 4-hydroxy[2.2]paracyclophane, we explored the selective synthesis of dihydroxylated products 6p2 and 6p3 simply by increasing the amounts of peroxide P4. Indeed, treatment of 5p with 2.2 equiv of P4 produced the 6p2 and 6p3 in appreciable yields (Scheme 6).

Scheme 8. Direct Oxidation of Guaiacol Estrogen Using Peroxide P4

multistep procedures through aromatic deprotonation of a reactive chromium arene complex (ca. 50% of 6q1, over four steps)58 and also proved superior to a protocol using m-CPBA (12.6%, 6q1/6q2 1:4).59 The mechanism for the reaction of P4 with arenes has not been established but is likely to follow the well-investigated 10073

DOI: 10.1021/acs.joc.8b01392 J. Org. Chem. 2018, 83, 10070−10079

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The Journal of Organic Chemistry path for the reactions of cyclic malonoyl peroxides.10 Given the reported mechanism and rather structural similarity of P4 with malonoyl peroxide, oxidation of arenes using P4 is likely to proceed through an ionic mechanism.30 When P4 is treated with an activated arene, a nucleophilic addition reaction occurs to give intermediate 14. Intramolecular deprotonation of aromatic ring by carboxylate anion gives product 15 and is consequently hydrolyzed to release the corresponding phenol (Scheme 9).

formaldehyde (91 mL, 1.13 mol), and methanol (185 mL) were added dropwise to an aqueous KOH solution (45.3 wt %, 73 mL) over a period of 30 min at rt. The reaction mixture was stirred under reflux for 5 h. The solvent was removed under reduced pressure, and ice/ water added to the resulting slurry, filtered off to give a yellowish crude product. Recrystallization from hot water afforded the title compound as a white crystalline solid (50 g, 70%). NMR spectral data are in accordance with a previous report.39 1H NMR (400 MHz, CDCl3): δ = 6.14 (t, J = 1.9 Hz, 2H), 3.92−3.77 (m, 2H), 3.59 (d, J = 10.5 Hz, 1H), 3.46 (d, J = 10.5 Hz, 1H), 3.16 (s, 1H), 3.04−2.87 (m, 2H), 2.85−2.75 (m, 1H), 1.54 (dt, J = 8.8, 1.6 Hz, 1H), 1.49−1.42 (m, 1H), 1.27 (dd, J = 12.1, 3.7 Hz, 1H), 0.70 (dd, J = 12.0, 2.6 Hz, 1H) ppm. 13 C NMR (100 MHz, CDCl3): δ = 137.2, 135.2, 71.6, 70.7, 48.7, 47.0, 44.6, 42.1, 33.0 ppm. Bicyclo[2.2.1]heptane-2,2-dimethanol (3). A catalytic amount of 10% Pd/C (2.7 g) was added to a solution of 5-norbornene-2, 2-dimethanol (50 g, 0.32 mol) in ethanol (500 mL) and stirred under hydrogen atmosphere at room temperature until TLC analysis indicated completion of reaction. Reaction time needed 18−24 h. Pd/C was then filtered off, and the solvent was removed under reduced pressure. The crude product was recrystallized from ethyl acetate to obtain the title compound as a colorless crystal (43.5 g, 87%). NMR spectral data are in accordance with a previous report.40 1H NMR (400 MHz, CDCl3): δ = 3.79 (d, J = 10.9 Hz, 1H), 3.65 (d, J = 10.9 Hz, 2H), 3.50 (d, J = 10.6 Hz, 1H), 2.66 (s, 2H), 2.46−2.34 (m, 1H), 2.27−2.14 (m, 1H), 1.74−1.41 (m, 4H), 1.27−1.20 (m, 1H), 1.16−1.01 (m, 2H), 0.71 (dd, J = 12.5, 2.6 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 70.8, 69.6, 46.5, 39.2, 37.9, 37.3, 36.5, 28.9, 24.6 ppm. Bicyclo[2.2.1]heptane-2,2-dicarboxylic Acid (4). KMnO4 (18 g, 0.11 mol) and K2CO3 (7.86 g, 0.06 mol) were added successively to a suspension of bicyclo[2.2.1]heptane-2,2-dimethanol (4.5 g, 0.03 mol) in H2O (125 mL) and stirred for 24 h at room temperature. Then ethanol (74 mL) was added, and the mixture reaction was stirred for 1.5 h. The precipitate was filtered off and concentrated under reduced pressure, the remaining solution acidified with 1 N HCl to pH ∼ 2, and extracted with Et2O (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a white solid (4.4 g, 80%). NMR spectral data are in accordance with a previous report.40 1H NMR (400 MHz, DMSO-d6): δ = 12.47 (s, 2H), 2.66 (d, J = 3.3 Hz, 1H), 2.19 (t, J = 4.2 Hz, 1H), 2.05 (dd, J = 12.9, 2.7 Hz, 1H), 1.72−1.61 (m, 1H), 1.52−1.34 (m, 3H), 1.32−1.24 (m, 1H), 1.19−1.07 (m, 2H) ppm. 13 C NMR (100 MHz, DMSO-d6): δ = 173.4, 172.1, 60.8, 42.8, 39.0, 38.1, 35.7, 27.6, 24.6 ppm. Spiro[bicyclo[2.2.1]heptane-2,4′-[1,2]dioxolane]-3′,5′-dione (P4). Urea hydrogen peroxide (1.52 g, 16.1 mmol) was added to methanesulfonic acid (4.65 mL) and stirred in a water bath for 3 min. Bicyclo[2.2.1]heptane-2,2-dicarboxylic Acid (1 g, 5.4 mmol) was added to the solution and the reaction stirred for 24 h in water bath.27 A mixture of ice/ethyl acetate (13 g/15 mL) was added to the reaction mixture and stirred for 5 min. The phases were separated and the aqueous layer was extracted with ethyl acetate (3 × 15 mL) The combined organic layers were successively washed with NaHCO3 (2 × 8 mL) and brine (10 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure yielding P4 (0.9 g, 91%) as a white solid. 1H NMR (400 MHz, CDCl3): δ = 2.87−2.81 (m, 1H), 2.57−2.51 (m, 1H), 2.25−2.17 (m, 1H), 2.10 (dt, J = 12.8, 3.6 Hz, 1H), 2.04−1.93 (m, 1H), 1.79−1.66 (m, 2H), 1.56−1.43 (m, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.0, 173.8, 50.2, 47.3, 39.6, 38.5, 36.9, 27.8, 23.5 ppm. HRMS (ESI) m/z: [M + MeOH + Na]+ calcd for C10H14O5Na 237.0733, found 237.0738. CAUTION: Organic peroxides are potentially dangerous compounds. The procedures must be handled with sufficient care; avoid exposure to strong heat or mechanical shock. Preparation of Peroxide P4′. Di-l-menthyl malonate (7). A solution of malonic acid (0.36 g, 3.46 mmol) and l-menthol (1.1 g, 7.0 mmol) in absolute diethyl ether (5 mL) was cooled to −10 °C with an ice−salt bath. A solution of DCC (1.44 g, 7.0 mmol) in absolute diethyl ether (2.5 mL) was added, and the reaction mixture was stirred at 0 °C for 15 min. The resulting solution was allowed to warm

Scheme 9. Plausible Mechanism for Oxidation of Arenes by P4

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CONCLUSIONS We have synthesized a new sterically hindered cylic peroxide for the direct hydroxylation of aromatic systems. The peroxide can readily be prepared using inexpensive reagents, and it is stable at room temperature allowing its storage for at least several months in the freezer without decomposition. The present peroxide provides easy access to para-substituted phenols, which are of particular interest in the synthesis of biologically active compounds and therapeutics. A rational approach toward paraselectivity using cyclic peroxides led to the synthesis of the structurally demanding bicyclic peroxide P4 bearing a norbornane moiety. The peroxide is effective for a range of activated aromatics and favors para-hydroxylation, thereby demonstrating its utility. The enantiopure variant of P4 can readily be synthesized with high enantiomeric purity and awaits its application to stereoselective oxidation processes.

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EXPERIMENTAL SECTION

General Remarks. All chemicals were purchased from TCI, Sigma-Aldrich, Alfa Aesar, and Acros Organics in reagent grade and used without further purification. All solvents were distilled before use. Flash column chromatography was performed using MN silica gel 60 M (0.040−0.063 mm) or Büchi Reveleris Silica columns (0.040 mm). Analytical thin-layer chromatography (TLC) was performed using precoated polyester sheets Polygram SIL G/UV254 from Macherey Nagel with a fluorescence indicator. Visualization of the TLC plate was accomplished by UV lamp at 254 nm, 5% phosphomolybdic acid solution. Nuclear magnetic resonance (NMR) spectra were recorded on Bruker AV600 or AV400 spectrometers at 298 K. Chemical shifts (δ) were expressed in ppm downfield from the internal standard tetramethylsilane (TMS, δ = 0.00 ppm) or to the respective solvent residual peaks (CDCl3: δ = 7.26 ppm; DMSO-d6: δ = 2.50 ppm) and were reported as (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, m = multiplet, br = broad, etc.). The coupling constants (J) were recorded in Hz. The progress of reactions was monitored by NMR or GC−MS analyses with a Quadrupol-MS HP MSD 5971(EI) and HP 5890A GC equipped with a J & W Scientific fused silica GC column (30 m × 0.250 mm, 0.25 μm DB−5MS stationary phase: 5% phenyl and 95% methyl silicone) using He (4.6 grade) as carrier gas; T-program standard 60−250 °C (15 °C/min heating rate), injector and transfer line 250 °C. TG analyses were performed by STA 409 PC from NETZSCH. Preparation of Peroxide P4. 5-Norbornene-2,2-dimethanol (2). A mixture of 5-norbornene-2-carboxaldehyde (56 g, 0.46 mol), 10074

DOI: 10.1021/acs.joc.8b01392 J. Org. Chem. 2018, 83, 10070−10079

Article

The Journal of Organic Chemistry to rt and stirred for further 2 h. The precipitate was filtered off, the solvent was removed under reduced pressure, and the crude product was recrystallized from methanol to obtain the title compound as a colorless crystal (1.25 g, 95%). NMR spectral data are in accordance with a previous report.40 1H NMR (400 MHz, CDCl3): δ = 4.73 (td, J = 10.9, 4.4 Hz, 2H), 3.32 (s, 2H), 2.07−1.97 (m, 2H), 1.96−1.83 (m, 2H), 1.73−1.62 (m, 4H), 1.55−1.42 (m, 2H), 1.42−1.32 (m, 2H), 1.11−0.80 (m, 18H), 0.76 (d, J = 6.9 Hz, 6H) ppm. 13 C NMR (100 MHz, CDCl3): δ = 166.4, 75.6, 47.0, 42.5, 40.8, 34.3, 31.5, 26.2, 23.4, 22.1, 20.9, 16.3 ppm. Di-l-menthyl Methylenemalonate (8). Di-l-menthyl malonate (4.56 g, 12 mmol) was added to a mixture of paraformaldehyde (0.36 g, 12 mmol) and anhydrous copper(II) acetate (0.25 g, 1.37 mmol) in acetic acid (7 mL), and the suspension was stirred at 100 °C for 4 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography eluting with n-hexane/Et2O (40/1) to obtain the desired product (1.3 g, 27%) as colorless oil. NMR spectral data are in accordance with a previous report.40 1H NMR (400 MHz, CDCl3): δ = 6.41 (s, 2H), 4.82 (td, J = 10.9, 4.4 Hz, 2H), 2.10−2.01 (m, 2H), 1.96−1.86 (m, 2H), 1.74−1.64 (m, 4H), 1.57−1.35 (m, 4H), 1.14−0.97 (m, 4H), 0.94−0.86 (m, 14H), 0.77 (d, J = 6.9 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.9, 136.2, 133.0, 75.6, 47.2, 40.8, 34.3, 31.5, 26.2, 23.4, 22.2, 21.0, 16.3 ppm. Di-l-menthyl Bicyclo[2.2.1]hept-5-ene-2,2-dicarboxylate (10). TiC14 (0.21 mL) was added to a solution of freshly distilled cyclopentadiene (1.61 mL, 19.5 mmol) and di-l-menthyl methylenemalonate (1.6 g, 4.1 mmol) in dry toluene (22 mL) at −78 °C and stirred under argon for 2 h. The reaction mixture was quenched with water and extracted with toluene (2 × 8 mL). The combined organic layers were washed with water (2 × 10 mL), dried over Na2SO4, and filtered, and the solvent was removed under reduced pressure. Column chromatography eluting with n-hexane/Et2O (30:1) afforded the title product as a white solid which was recrystallized from methanol to separate diastereomers (0.92 g, 50%). NMR spectral data are in accordance with a previous report.40 1H NMR (400 MHz, CDCl3): δ = 6.27 (dd, J = 5.7, 3.1 Hz, 1H), 5.86 (dd, J = 5.7, 2.9 Hz, 1H), 4.72 (td, J = 10.9, 4.3 Hz, 1H), 4.57 (td, J = 10.9, 4.3 Hz, 1H), 3.43 (br s, 1H), 2.89 (br s, 1H), 2.13 (dd, J = 12.5, 2.8 Hz, 1H), 2.02−1.94 (m, 3H), 1.93−1.85 (m, 2H), 1.74−1.60 (m, 5H), 1.56−1.34 (m, 5H), 1.09−0.80 (m, 18H), 0.75 (dd, J = 7.0, 4.2 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.5, 170.4, 140.1, 132.6, 77.4, 75.4, 75.2, 60.3, 51.0, 49.8, 49.6, 47.0, 46.9, 42.0, 40.9, 40.8, 35.6, 34.4, 31.5, 31.4, 26.2, 25.9, 23.2, 23.0, 22.1, 21.0, 21.0, 16.1, 15.9 ppm. Di-l-menthyl Bicyclo[2.2.1]heptane-2,2-dicarboxylate (11). A catalytic amount of 5% Pd/C (0.13 g) was added to a solution of di-l-menthyl bicyclo[2.2.1]hept-5-ene-2,2-dicarboxylate (2.47 g, 5.4 mmol) in a mixture of Et2O (50 mL) and methanol (27 mL) and stirred under hydrogen atmosphere at room temperature until TLC analysis indicated completion of reaction. Reaction time needed 18−24 h. Pd/C was then filtered off, and the solvent was removed under reduced pressure. The crude product was recrystallized from Et2O/methanol to obtain the title compound as a colorless crystal (2.3 g, 92%). NMR spectral data are in accordance with a previous report.40 1H NMR (400 MHz, CDCl3): δ = 4.66 (tdd, J = 10.9, 4.3, 2.2 Hz, 2H), 2.91−2.80 (m, 1H), 2.33−2.21 (m, 2H), 2.06−1.84 (m, 4H), 1.74−1.62 (m, 5H), 1.59−1.34 (m, 9H), 1.32−1.24 (m, 1H), 1.16−0.83 (m, 18H), 0.74 (dd, J = 7.0, 1.7 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.2, 170.9, 77.4, 75.4, 74.7, 62.2, 47.1, 46.9, 43.5, 40.9, 40.9, 40.0, 38.9, 36.4, 34.4, 34.4, 31.5, 31.5, 28.0, 26.0, 25.9, 25.0, 23.2, 23.1, 22.2, 21.0, 21.0, 16.1, 16.1 ppm. Bicyclo[2.2.1]heptane-2,2-dimethanol (12). To a solution of di-lmenthyl bicyclo[2.2.1]heptane-2,2-dicarboxylate (2.35 g, 5.1 mmol) in dry THF (53 mL) under argon at 0 °C was added lithium aluminum hydride (LiAlH4) (0.96 g, 25.4 mmol), and the reaction mixture was stirred under reflux for 2 h. The reaction mixture was quenched with wet Et2O and filtered, and the solvent was removed under reduced pressure. Column chromatography eluting with n-hexane/ethyl acetate (4:1) afforded the title product as a white solid (0.64 g, 80%). NMR spectral data are in accordance with a previous report.40

General Procedure for the Oxidation (Method A). Arene (0.5 mmol) was placed inside a 4 mL vial (screw top with solid green Thermoset cap with PTFE liner) equipped with a magnetic stirrer bar. PFB (1.7 mL) and P4 (0.182 g, 1 mmol) were subsequently added. The liner was sealed, and the material was stirred to ensure the reactants were well dispersed in the reaction medium. The vial was placed inside an oil bath heated to 40 °C for the indicated time. The reaction mixture was then cooled to room temperature, diluted with EtOAc (15 mL), stirred with a saturated solution of Na2S2O5 (15 mL) for 2 h. After separation of the layers, the aqueous phase was extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (15 mL) and concentrated under reduced pressure. The residue was hydrolyzed overnight using 5 mL of methylamine (33 wt % in ethanol). Ethanol was removed under reduced pressure, and the crude product was purified by column chromatography over silica gel. General Procedure for the Oxidation (Method B). Arene (0.5 mmol) was placed inside a 4 mL vial (screw top with solid green Thermoset cap with PTFE liner) equipped with a magnetic stirrer bar. A mixture of CEO/PFB (7:3, 1 mL) and P4 (0.15 g, 0.8 mmol) was added. The liner was sealed, and the material was stirred to ensure the reactants were well dispersed in the reaction medium. The vial was placed inside an oil bath preheated to 50 °C for the indicated time. The reaction mixture was then cooled to room temperature, diluted with EtOAc (15 mL), and stirred with a saturated solution of Na2S2O5 (15 mL) for 2 h. After separation of the layers, the aqueous phase was extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (15 mL) and concentrated under reduced pressure. The residue was hydrolyzed overnight using 5 mL of methylamine (33 wt % in ethanol). Ethanol was removed under reduced pressure, and the crude product was purified by column chromatography over silica gel. 4-Methoxyphenol (6a1) and 2-Methoxyphenol (6a2). Prepared following general procedure B. The residue was purified by column chromatography (pentane/Et2O 10/1) to give the products 6a1 (28 mg, 45%) and 6a2 (11 mg, 18%). 4-Methoxyphenol (6a1). Colorless solid. 1H NMR (400 MHz, CDCl3): δ = 6.82−6.74 (m, 4H), 4.70 (s, 1H), 3.76 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3): δ = 153.9, 149.5, 116.2, 115.0, 55.9 ppm.60 2-Methoxyphenol (6a2). Colorless oil. 1H NMR (400 MHz, CDCl3): δ = 6.97−6.91 (m, 1H), 6.91−6.85 (m, 3H), 5.64 (s, 1H), 3.89 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 146.5, 145.6, 121.4, 120.1, 114.5, 110.7, 55.8 ppm.60 2,4-Dimethoxyphenol (6b1). Prepared following general procedure B. The residue was purified by column chromatography (pentane/Et2O 10/1) to give the product 6b1 (54 mg, 70%). Colorless oil. 1H NMR (400 MHz, CDCl3): δ = 6.83 (d, J = 8.6 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 6.39 (dd, J = 8.6, 2.7 Hz, 1H), 5.26 (s, 1H), 3.86 (s, 3H), 3.76 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.7, 147.1, 139.9, 114.2, 104.4, 99.6, 56.0, 55.9 ppm.61 Naphthalen-1-ol (6d1) and Naphthalen-2-ol (6d2). Prepared following general procedure A. The residue was purified by column chromatography (pentane/Et2O 5/1) to give the products 6d1 (64 mg, 90%) and 6d2 (5 mg, 6%). Naphthalen-1-ol (6d1). White solid. 1H NMR (400 MHz, CDCl3): δ = 8.24−8.16 (m, 1H), 7.87−7.80 (m, 1H), 7.55−7.44 (m, 3H), 7.32 (t, J = 7.9 Hz, 1H), 6.82 (dd, J = 7.4, 1.0 Hz, 1H), 5.26 (s, 1H) ppm. 13 C NMR (100 MHz, CDCl3): δ = 151.4, 134.9, 127.8, 126.6, 125.9, 125.4, 124.4, 121.6, 120.9, 108.8 ppm.62 Naphthalen-2-ol (6d2). Light brown solid. 1H NMR (400 MHz, CDCl3): δ = 7.82−7.75 (m, 2H), 7.69 (d, J = 8.2 Hz, 1H), 7.49−7.42 (m, 1H), 7.39−7.32 (m, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.13 (dd, J = 8.7, 2.5 Hz, 1H), 5.31 (br s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.3, 134.7, 130.0, 129.1, 127.9, 126.7, 126.5, 123.8, 117.8, 109.7 ppm.63 1-Methoxy-2-naphthol (6e1) and 4-Methoxy-1-naphthol (6e2). Prepared following general procedure B. The residue was purified by column chromatography (pentane/Et2O 5/1) to give the products 6e1 (50 mg, 57%) and 6e2 (8 mg, 9%). 10075

DOI: 10.1021/acs.joc.8b01392 J. Org. Chem. 2018, 83, 10070−10079

Article

The Journal of Organic Chemistry 1-Methoxy-2-naphthol (6e1). Yellow solid. 1H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.50 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.35 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 5.80 (s, 1H), 3.98 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.5, 139.7, 129.7, 128.5, 128.0, 126.5, 125.4, 123.7, 120.4, 117.6, 61.8 ppm.64 4-Methoxy-1-naphthol (6e2). Yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.25−8.19 (m, 1H), 8.15−8.08 (m, 1H), 7.56−7.47 (m, 2H), 6.74 (d, J = 8.1 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 4.90 (s, 1H), 3.96 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.0, 145.2, 126.5, 126.0, 125.9, 125.4, 122.2, 121.5, 108.0, 103.6, 55.9 ppm.65 4-Methylphenol (6f1) and 2-Methylphenol (6f2). Prepared following general procedure A. The residue was purified by column chromatography (pentane/Et2O 10/1) to give the products 6f1 (8 mg, 15%) and 6f2 (6 mg, 10%). 4-Methylphenol (6f1). Colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.06−7.00 (m, 2H), 6.75−6.70 (m, 2H), 4.78 (s, 1H), 2.27 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.6, 130.5, 130.4, 115.5, 20.9 ppm.66 2-Methylphenol (6f2). Colorless solid. 1H NMR (400 MHz, CDCl3): δ = 7.15−7.03 (m, 2H), 6.84 (td, J = 7.4, 1.2 Hz, 1H), 6.76 (dd, J = 7.9, 1.1 Hz, 1H), 4.74 (s, 1H), 2.25 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.8, 131.1, 127.2, 123.8, 120.8, 115.0, 15.8 ppm.66 3,4-Dimethylphenol (6g1) and 2,3-Dimethylphenol (6g2). Prepared following general procedure A. The residue was purified by column chromatography (pentane/Et2O 10/1) to give the products 6g1 (25 mg, 41%) and 6g2 (15 mg, 24%). 3,4-Dimethylphenol (6g1). Colorless solid. 1H NMR (400 MHz, CDCl3): δ = 7.00 (d, J = 8.1 Hz, 1H), 6.66 (d, J = 2.7 Hz, 1H), 6.60 (dd, J = 8.1, 2.7 Hz, 1H), 4.96 (s, 1H), 2.23 (s, 3H), 2.20 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.5, 138.1, 130.6, 128.8, 116.7, 112.5, 19.9, 18.9 ppm.66 2,3-Dimethylphenol (6g2). Colorless solid. 1H NMR (400 MHz, CDCl3): δ = 6.98 (t, J = 7.9 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 4.78 (s, 1H), 2.30 (s, 3H), 2.19 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3): δ = 153.6, 138.4, 126.1, 122.6, 122.5, 112.7, 20.2, 11.6 ppm.66 2,4-Dimethylphenol (6h1) and 2,6-Dimethylphenol (6h2). repared following general procedure A. The residue was purified by column chromatography (pentane/Et2O 10/1) to give the products 6h1 (48 mg, 78%) and 6h2 (3 mg, 5%). 2,4-Dimethylphenol (6h1). Colorless solid. 1H NMR (400 MHz, CDCl3): δ = 6.93 (s, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 4.48 (s, 1H), 2.25 (s, 3H), 2.22 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.6, 131.8, 130.0, 127.5, 123.5, 114.8, 20.6, 15.8 ppm.66 2,6-Dimethylphenol (6h2). Colorless solid. 1H NMR (400 MHz, CDCl3): δ = 7.00 (d, J = 7.5 Hz, 2H), 6.78 (t, J = 7.5 Hz, 1H), 4.62 (s, 1H), 2.27 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.2, 128.7, 123.1, 120.3, 15.9 ppm.66 2,5-Dimethyl phenol (6i). Prepared following general procedure A. The residue was purified by column chromatography (pentane/Et2O 10/1) to give the product 6i (46 mg, 75%). Colorless solid. 1H NMR (400 MHz, CDCl3): δ = 7.02 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.61 (s, 1H), 4.66 (s, 1H), 2.29 (s, 3H), 2.23 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.6, 137.2, 130.9, 121.5, 120.5, 115.8, 21.1, 15.4 ppm.66 5,6,7,8-Tetrahydronaphthalen-1-ol (6j1) and 5,6,7,8-Tetrahydronaphthalen-2-ol (6j2). Prepared following general procedure A. The residue was purified by column chromatography (pentane/Et2O 15/1) to give the products 6j1 (29 mg, 40%) and 6j2 (20 mg, 26%). 5,6,7,8-Tetrahydronaphthalen-1-ol (6j1). White solid. 1H NMR (400 MHz, CDCl3): δ = 7.00 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 7.9 Hz, 1H), 4.67 (s, 1H), 2.77 (t, J = 6.2 Hz, 2H), 2.65 (t, J = 6.3 Hz, 2H), 1.91−1.73 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.5, 139.1, 126.1, 123.4, 121.7, 111.9, 29.7, 22.9, 22.9, 22.8 ppm.62 5,6,7,8-Tetrahydronaphthalen-2-ol (6j2). Pale yellow solid. 1 H NMR (400 MHz, CDCl3): δ = 6.94 (d, J = 8.2 Hz, 1H), 6.60 (dd, J = 8.1, 2.7 Hz, 1H), 6.55 (d, J = 2.6 Hz, 1H), 4.65 (s, 1H),

2.76−2.65 (m, 4H), 1.83−1.72 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.2, 138.6, 130.2, 129.5, 115.4, 112.9, 29.6, 28.7, 23.5, 23.2 ppm.67 3-Hydroxy-4-methoxytoluene (6k1). Prepared following general procedure B. The residue was purified by column chromatography (pentane/Et2O 10/1) to give the product 6k1 (38 mg, 55%). Colorless oil. 1H NMR (400 MHz, CDCl3): δ = 6.79−6.71 (m, 1H), 6.64 (dd, J = 8.1, 1.7 Hz, 1H), 5.54 (s, 1H), 3.86 (s, 3H), 2.26 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.6, 144.6, 131.3, 120.4, 115.5, 110.8, 56.2, 20.9 ppm.68 4-Methoxy-3-methylphenol (6l1), 3-Methoxy-2-methylphenol (6l2), and 2-Methoxy-3-methylphenol (6l3). Prepared following general procedure B. The residue was purified by column chromatography (pentane/Et2O 10/1) to give the products 6l1 (24 mg, 35%), 6l2 (12 mg, 18%) and 6l3 (9 mg, 12%). 4-Methoxy-3-methylphenol (6l1). White solid. 1H NMR (400 MHz, CDCl3): δ = 6.70 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 3.1 Hz, 1H), 6.62 (dd, J = 8.6, 3.1 Hz, 1H), 4.71 (br s, 1H), 3.78 (s, 3H), 2.19 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.2, 149.2, 128.2, 118.1, 112.6, 111.4, 56.1, 16.3 ppm.69 3-Methoxy-2-methylphenol (6l2). White solid. 1 H NMR (400 MHz, CDCl3): δ = 7.03 (t, J = 8.5 Hz, 1H), 6.51−6.41 (m, 2H), 4.68 (s, 1H), 3.82 (s, 3H), 2.12 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.8, 154.6, 126.6, 112.2, 108.2, 103.2, 55.8, 8.1 ppm.70 2-Methoxy-3-methylphenol (6l3). White solid. 1 H NMR (400 MHz, CDCl3): δ = 6.91 (t, J = 7.8 Hz, 1H), 6.80 (dd, J = 8.1, 1.6 Hz, 1H), 6.73−6.66 (m, 1H), 5.61 (s, 1H), 3.80 (s, 3H), 2.30 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 149.0, 145.6, 131.0, 124.7, 122.6, 113.2, 60.8, 16.1 ppm.71 2-Methoxy-5-phenylphenol (6m1) and 5-Methoxy-2-phenylphenol (6m2). Prepared following general procedure B. The residue was purified by column chromatography (pentane/Et2O 16/1 → 7/1) to give the products 6m1 (21 mg, 21%) and 6m2 (4 mg, 4%). 2-Methoxy-5-phenylphenol (6m1). White solid. 1H NMR (400 MHz, CDCl3): δ = 7.59−7.53 (m, 2H), 7.45−7.38 (m, 2H), 7.35−7.28 (m, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 8.3, 2.2 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 5.67 (s, 1H), 3.94 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3): δ = 146.3, 145.9, 140.9, 135.0, 128.8, 127.0, 126.9, 118.9, 113.5, 111.0, 56.2 ppm.72 5-Methoxy-2-phenylphenol (6m2). White solid. 1H NMR (400 MHz, CDCl3): δ = 7.50−7.35 (m, 5H), 7.19−7.12 (m, 1H), 6.61−6.53 (m, 2H), 5.26 (s, 1H), 3.83 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 160.6, 153.4, 136.9, 130.7, 129.3, 129.1, 127.5, 120.8, 107.0, 101.3, 55.4 ppm.73 6-Methoxy-[1,1′-biphenyl]-3-ol (6n1), 2-Methoxy-[1,1′-biphenyl]-3-ol (6n2), and 6-Methoxy-[1,1′-biphenyl]-2-ol (6n3). Prepared following general procedure B. The residue was purified by column chromatography (n-hexane/ethyl acetate 7/1 → 3/1) to give the products 6n1 (34 mg, 34%), 6n2 (23 mg, 23%), and 6n3 (18 mg, 18%). 6-Methoxy-[1,1′-biphenyl]-3-ol (6n1). Colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.55−7.49 (m, 2H), 7.44−7.37 (m, 2H), 7.36−7.30 (m, 1H), 6.87 (d, J = 8.7 Hz, 1H), 6.83 (d, J = 3.0 Hz, 1H), 6.78 (dd, J = 8.7, 3.1 Hz, 1H), 4.72 (br s, 1H), 3.74(s, 3H) ppm. 13 C NMR (100 MHz, CDCl3): δ = 150.9, 149.6, 138.2, 132.0, 129.5, 128.2, 127.2, 118.0, 114.7, 113.1, 56.5 ppm.74 2-Methoxy-[1,1′-biphenyl]-3-ol (6n2). White solid. 1H NMR (400 MHz, CDCl3): δ = 7.61−7.56 (m, 2H), 7.47−7.40 (m, 2H), 7.39−7.33 (m, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.97 (dd, J = 8.1, 1.7 Hz, 1H), 6.88 (dd, J = 7.6, 1.7 Hz, 1H), 5.93 (s, 1H), 3.43 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3): δ = 149.3, 144.5, 138.1, 134.4, 128.9, 128.6, 127.6, 124.8, 122.3, 114.5, 60.8 ppm.75 6-Methoxy-[1,1′-biphenyl]-2-ol (6n3). Colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.53−7.47 (m, 2H), 7.44−7.34 (m, 3H), 7.22 (t, J = 8.3 Hz, 1H), 6.67 (dd, J = 8.2, 1.0 Hz, 1H), 6.57 (dd, J = 8.3, 1.0 Hz, 1H), 4.99 (s, 1H), 3.73 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.5, 153.8, 132.5, 130.9, 129.3, 129.3, 128.2, 117.2, 108.5, 103.3, 56.0 ppm.76 N-(4-Hydroxyphenyl)benzamide (6o1) and N-(2-Hydroxyphenyl)benzamide (6o2). Prepared following general procedure A. The residue 10076

DOI: 10.1021/acs.joc.8b01392 J. Org. Chem. 2018, 83, 10070−10079

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The Journal of Organic Chemistry

was purified by column chromatography (n-hexane/ethyl acetate 16/1 → 5/1) to give the products 6q1 (55 mg, 37%) and 6q2 (27 mg, 18%). 3-Methoxy-2-hydroxy-1,3,5 (10)-estratrien-17-one (6q1). Colorless solid. 1H NMR (400 MHz, CDCl3): δ = 6.87 (s, 1H), 6.58 (s, 1H), 5.43 (s, 1H), 3.85 (s, 3H), 2.94−2.75 (m, 2H), 2.50 (dd, J = 19.0, 8.4 Hz, 1H), 2.38−1.89 (m, 6H), 1.68−1.35 (m, 6H), 0.91 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 221.0, 144.8, 143.7, 132.7, 127.9, 111.7, 111.3, 56.1, 50.5, 48.2, 44.2, 38.5, 36.0, 31.8, 29.3, 26.9, 26.1, 21.7, 14.0 ppm.81 3-Methoxy-4-hydroxy-1,3,5 (10)-estratrien-17-one (6q2). Colorless solid. 1H NMR (400 MHz, CDCl3): δ = 6.81 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 5.69 (s, 1H), 3.87 (s, 3H), 2.99 (dd, J = 17.7, 5.9 Hz, 1H), 2.68 (ddd, J = 18.3, 12.2, 6.9 Hz, 1H), 2.51 (dd, J = 18.5, 8.7 Hz, 1H), 2.46−2.36 (m, 1H), 2.30−1.90 (m, 5H), 1.70−1.31 (m, 6H), 0.91 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 221.2, 144.2, 143.0, 133.6, 123.2, 116.1, 108.1, 56.2, 50.6, 48.1, 44.3, 38.0, 36.0, 31.7, 26.2, 26.1, 23.3, 21.8, 14.0 ppm.82

was purified by column chromatography (pentane/Et2O 3/1 → 1/1) to give the products 6o1 (29 mg, 28%) and 6o2 (29 mg, 28%). N-(4-Hydroxyphenyl)benzamide (6o1). Yellow solid. 1H NMR (400 MHz, DMSO-d6): δ = 10.01 (s, 1H), 9.24 (s, 1H), 7.96−7.88 (m, 2H), 7.59−7.47 (m, 5H), 6.77−6.70 (m, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 164.9, 153.7, 135.1, 131.2, 130.7, 128.3, 127.5, 122.3, 114.9 ppm.77 N-(2-Hydroxyphenyl)benzamide (6o2). White solid. 1H NMR (400 MHz, DMSO-d6): δ = 9.74 (s, 1H), 9.51 (s, 1H), 8.01−7.94 (m, 2H), 7.69 (dd, J = 7.9, 1.6 Hz, 1H), 7.63−7.57 (m, 1H), 7.56−7.49 (m, 2H), 7.08−7.00 (m, 1H), 6.93 (dd, J = 8.1, 1.5 Hz, 1H), 6.84 (td, J = 7.6, 1.5 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 165.2, 149.3, 134.4, 131.7, 128.5, 127.5, 125.9, 125.7, 124.1, 119.0, 116.0 ppm.78 Procedure for the Synthesis of 4-Hydroxy[2.2]paracyclophane (6p1). [2.2]Paracyclophane (0.21, 1 mmol) was placed inside a 25 mL flask equipped with a magnetic stirrer bar. A mixture of CHCl3/PFB (1:1, 8 mL) and P4 (0.09 g, 0.5 mmol) was subsequently added. The flask was placed inside an oil bath heated to 40 °C for 24 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc (15 mL), and stirred with a saturated solution of Na2S2O5 (10 mL) for 2 h. After separation of the layers, the aqueous phase was extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was hydrolyzed overnight using 5 mL of methylamine (33 wt % in ethanol). Ethanol was removed under reduced pressure, and the crude product was purified by column chromatography (n-hexane/ethyl acetate 16/1 → 5/1) to give 6p1 (160 mg, 71%), 6p2 (10 mg, 4%) and 6p3 (15 mg, 6%). 4-Hydroxy[2.2]paracyclophane (6p1). Pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 7.01 (dd, J = 7.8, 1.9 Hz, 1H), 6.56 (dd, J = 7.8, 1.9 Hz, 1H), 6.45 (dd, J = 7.8, 1.9 Hz, 1H), 6.42−6.36 (m, 2H), 6.27 (dd, J = 7.8, 1.7 Hz, 1H), 5.54 (d, J = 1.7 Hz, 1H), 4.44 (s, 1H), 3.39−3.28 (m, 1H), 3.16−2.86 (m, 6H), 2.72−2.61 (m, 1H) ppm. 13 C NMR (100 MHz, CDCl3): δ = 153.8, 142.1, 139.7, 138.9, 135.6, 133.7, 132.9, 132.0, 128.1, 125.6, 125.2, 122.7, 35.4, 34.9, 33.9, 31.2 ppm.79 Procedure for the Synthesis of Dihydroxy[2.2]paracyclophanes (6p2 and 6p3). [2.2]Paracyclophane (0.21, 1 mmol) was placed inside a 25 mL flask equipped with a magnetic stirrer bar. A mixture of CHCl3/PFB (1:1, 8 mL) and P4 (0.4 g, 2.2 mmol) was subsequently added. The flask was placed inside an oil bath heated to 40 °C for 24 h. The reaction mixture was then cooled to room temperature and diluted with EtOAc (15 mL) and stirred with a saturated solution of Na2S2O5 (20 mL) for 2 h. After separation of the layers, the aqueous phase was extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was hydrolyzed overnight using 10 mL of methylamine (33 wt % in ethanol). Ethanol was removed under reduced pressure, and the crude product was purified by column chromatography (n-hexane/ethyl acetate 16/1 → 5/1) to give 6p1 (41 mg, 18%), 6p2 (73 mg, 30%), 6p3 (58 mg, 24%). 4,16-Dihydroxy[2.2]paracyclophane (6p2). White crystal. 1H NMR (400 MHz, acetone-d6): δ = 7.57 (d, J = 7.3 Hz, 2H), 6.84 (d, J = 7.6 Hz, 1H), 6.53 (dd, J = 7.6, 1.7 Hz, 1H), 6.26 (d, J = 7.7 Hz, 1H), 6.08 (dd, J = 7.7, 1.8 Hz, 1H), 5.66 (dd, J = 5.9, 1.7 Hz, 2H), 3.42 (ddd, J = 12.9, 10.0, 2.6 Hz, 1H), 3.25−3.15 (m, 1H), 3.00−2.90 (m, 1H), 2.89− 2.78 (m, 3H), 2.78−2.68 (m, 1H), 2.58−2.48 (m, 1H) ppm. 13C NMR (100 MHz, acetone-d6): δ = 156.6, 156.4, 142.1, 141.4, 135.0, 130.8, 126.7, 125.6, 124.1, 123.2, 122.3, 121.8, 35.1, 33.9, 31.3, 30.5 ppm.80 4,12-Dihydroxy[2.2]paracyclophane (6p3). White crystal. 1H NMR (400 MHz, acetone-d6): δ = 7.43 (s, 2H), 6.38 (d, J = 7.7 Hz, 2H), 6.26 (d, J = 1.7 Hz, 2H), 6.08 (dd, J = 7.7, 1.7 Hz, 2H), 3.38−3.29 (m, 2H), 2.91−2.84 (m, 4H), 2.57−2.46 (m, 2H) ppm. 13C NMR (100 MHz, acetone-d6): δ = 156.3, 143.1, 136.3, 125.7, 124.9, 118.7, 34.2, 31.9 ppm.51 Procedure for the Oxidation of Guaiacol Estrogen. Prepared according general procedure A following an acidic workup. The residue

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01392. Experimental details, X-ray crystallographic data, and spectra for all compounds (PDF) X-ray data for compound P4 (CIF) X-ray data for compound 6p3 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Marina Š ekutor: 0000-0003-1629-3672 Peter R. Schreiner: 0000-0002-3608-5515 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Justus Liebig University. REFERENCES

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DOI: 10.1021/acs.joc.8b01392 J. Org. Chem. 2018, 83, 10070−10079