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ortho-Quinol Acetate Chemistry - Reactivity towards Aryl-Based Nucleophiles and Applications to the Synthesis of Natural Products Simon Companys, Laurent Pouységu, Philippe A. Peixoto, Stefan CHASSAING, and Stephane Quideau J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00250 • Publication Date (Web): 10 Mar 2017 Downloaded from http://pubs.acs.org on March 10, 2017

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The Journal of Organic Chemistry

ortho-Quinol Acetate Chemistry - Reactivity towards ArylBased Nucleophiles and Applications to the Synthesis of Natural Products Simon Companys,a,b Laurent Pouységu,a Philippe A. Peixoto,a Stefan Chassaing,*b and Stéphane Quideau*a a

Univ. Bordeaux, Institut des Sciences Moléculaires (ISM, CNRS-UMR 5255), 351 cours de la Libération, 33405 Talence, France b ITAV, Université de Toulouse, CNRS, UPS, France

ABSTRACT Two model ortho-quinol acetates were easily prepared by iodane-mediated acetoxylative phenol dearomatization and evaluated for their reactivity towards various aryl-based nucleophiles, i.e., aryl metallic reagents and phenolic derivatives. Novel modes of reactivity, allowing the formation of biaryl linkages, were revealed and here exploited for the synthesis of two natural phenolics.

GRAPHICAL ABSTRACT AcO PhMgBr OH MeO

OH

Ph noraucuparin

PhMgBr R1 = OMe R2 = H

AcO OMe R1 O

R2

Ph O

CO 2Me R1 = H R 2 = CO 2Me OH

OH OH

OMe

MeO

OH

HO O O natural dibenzopyranone

ACS Paragon Plus Environment


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ortho-Quinones A, ortho-quinols B and ortho-quinone monoketals C are regarded as highly valuable building blocks in organic synthesis (Scheme 1).1 Easy to prepare by oxidative phenol dearomatization (OPD), these 6(,6)-(di)oxocyclohexa-2,4-dienone derivatives ABC exhibit such a rich reactivity profile that they are prone to participate in a large panel of organic reactions, including cycloaddition, rearrangement and cross-coupling reactions,1-4 as well as electrophilic, nucleophilic and radical addition or substitution reactions.1a,4,5 This chemical versatility has been successfully exploited for the total synthesis of numerous natural products,1 such as the few illustrating examples shown in Scheme 1. ortho-Quinol acetates D1,2, other quinonoid cyclohexa-2,4-dienone variants accessible via OPD, have been much less investigated than their A-C counterparts (Scheme 1).1,6 Nevertheless, species D1, where R1 is an alkoxy group, have been used in a handful of compelling nucleophilic addition and substitution, cycloaddition, radical addition and rearrangement reactions1a,6-11 by taking advantage of the good nucleofugacity of the acetate group. These quinonoid species D1 thus offer valuable reactivity opportunities for diverse chemical transformations. Herein, we wish to report novel observations on the reactivity profile of these electrophilic building blocks towards two types of simple aryl-based nucleophiles, i.e., aryl-bearing organometallics and phenolic derivatives. O

R1

HO

O

O ortho-quinone A (R1 = OH)

ortho-quinol B (R1 = alkyl)

R1 OH

R 2O

R1

OPD

O

ortho-quinol acetate D1: R1 = alkoxy D 2: R1 = alkyl O

(-)-bacchopetiolone 2e

OH OMe

MeO

OH OH

O (-)-wasabidienone B 03

O O

O O

(±)-cleomiscosin C 2a

O OMe

O

HO

O

O

MeO

O O

O MeO

AcO R1

OPD

O ortho-quinone monoketal C (R1 = alkoxy, R 2 = alkyl)

HO

Cl NMe OMe

MeO MeO OMe MeO 5-epi-eupomatilone-64

O

OMe O (-)-acutumine 5

Scheme 1 – Quinonoid cyclohexa-2,4-dienones A-D and examples of natural products synthesized using these key building blocks

The D1-type ortho-quinol acetates 2a and 2b, readily prepared from methyl 3-hydroxy-4methoxybenzoate 1a and 2,3-dimethoxyphenol 1b under standard λ3-iodane-mediated OPD conditions,7c,d,11 were chosen as substrates for this model study (Scheme 2). This choice was driven by the fact that both 2a and 2b are isolatable and stable quinonoid compounds, whose reactivity features can be compared with those of their ortho-quinone A and ortho-quinone monoketal C variants (vide infra).1,11,12

Scheme 2 – Preparation of ortho-quinol acetates 2a and 2b

A first series of experiments was conducted by treating 2a with a variety of phenyl metallic (PhM) species under various conditions (Table 1). Using 1.1 equiv of PhMgBr in THF at –78 °C for 2 h, ACS Paragon Plus Environment

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the reaction led to the isolation of two products, which were separated and unambiguously characterized by NMR analyses (entry 1). The major product was the unexpected ortho-quinol acetate 3a (36% yield), a truly original compound resulting from the formal substitution of the methoxy group of 2a by the phenyl moiety of the Grignard reagent. The minor product was the diaryl ether 4a (8%), whose formation resulted from an oxophilic attack of PhMgBr onto the ketonic carbonyl group of 2a. Performing the reaction at a higher temperature, i.e., –10 °C, had no major impact on the reaction outcomes (entry 2). However, the molar concentration of 2a played a noticeable role, since a significant increase of the yield of 3a (47%) was observed at an optimized [2a] of 0.3-0.4 M (entry 3 vs entries 1, 2, 4). Noteworthy is that pre-complexation of 2a with 1.1 equiv of oxophilic Lewis acids (i.e., BF3.Et2O or CeCl3) prior to addition of PhMgBr affected neither the yields of 3a nor the product ratio 3a:4a (entries 5, 6 vs entry 4). The use of PhMgBr in excess (entry 7) or PhLi instead of PhMgBr (entry 8) were unsuccessful, both attempts leading to complex mixtures, in which 3a was not even detected. The ortho-quinol acetate 3a was not produced either when using PhM (M = MgBr, Li) in combination with 1 equiv of CuI or Ph2CuM-type cuprate reagents (M = MgBr, Li) (entries 9-12). Under all of these conditions, 2a was reduced to give back the starting phenol 1a as major product. However, the two reactions using either the PhMgBr/CuI combination or the Gilman-type lowerorder cuprate reagent interestingly furnished the biaryl 5a as minor product (entries 9, 12). Table 1 – Reactivity of 2a towards phenyl-bearing organometallics – Reaction conditions screening a and optimization

entry

PhMgBr

c

2

PhMgBr

c,e

3

PhMgBr

1

3a

f

4

PhMgBr

5

PhMgBr, BF3.Et2O

6

PhMgBr,

7

PhMgBr

8

b

conditions

f CeCl3

g

PhLi

f

36

8

-

d

32

9

-

d

47

5

-d

34

5

-d

29

6

-

d

30

7

-

d

-

d

6

-

d

-

d

-

d

-

d

-

d

12h

-

d

traces

-

d

traces

-

d

9

PhMgBr, CuI

-

10

Ph2CuMgBr

-

d

-

d

-

d

12

PhLi, CuI Ph2CuLi

b

5a

d

11

b

4a

i j

k

17

a

Optimized conditions: reactions run for 2 h on a 1.4 mmol scale using 2a (1.0 equiv) at 0.3-0.4 M and PhM (1.1 equiv). bIsolated yields (%). c[2a] = 0.04 M. dNot detected. eReactions run at –10 °C. f[2a] = 0.7-0.8 M. g Reactions run with 2.2 equiv of PhMgBr. h1a isolated in 38% yield. i1a isolated in 44% yield. j1a isolated in k 14% yield. 1a isolated in 52% yield.

We then investigated the addition of PhMgBr onto the ortho-quinol acetate 2b (Scheme 3). Using the conditions optimized for accessing 3a (Table 1, entry 3), the reaction did not lead to the formation of the expected counterpart of 3a, but instead gave rise to the biaryl 5b in a moderate ACS Paragon Plus Environment


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yield. The production of this interesting biaryl connection was optimized by simply doubling the amount of PhMgBr, hence leading to an increase of the yield of 5b from 33 % to 77 % (Scheme 3). This unexpected biaryl formation opened the door to a straightforward access to noraucuparin (6, also referred to as 3-de-O-methylaucuparin), a natural biarylic phytoalexin isolated from the trunk of Berberis koreana (Berberidaceae)13a and reported in Pyrinae.13b,c Simply, the 2-methoxyphenolic motif of biaryl 5b was chemoselectively demethylated by treatment with SIBX (i.e., stabilized IBX)14 to afford 6 in 74 % yield (Scheme 3). This 3-step orthoquinol acetate-relying synthesis from the commercially available phenol 1b constitutes a convenient alternative to the only previous 3-step synthesis of noraucuparin (6), for which the biaryl-forming key step was based on a Suzuki-Miyaura cross-coupling process.15,16

Scheme 3 – Reactivity of 2b towards PhMgBr and synthesis of noraucuparin 6

These data reveal rather unusual and specific reactivity features of D1-type ortho-quinol acetates towards phenyl metallic reagents. The ortho-quinol acetates 2a/2b are indeed inclined to favour net substitution reactions affording here the ortho-quinol acetate 3a and the biaryl 5b (Table 1, Scheme 3), whereas structurally-related ortho-quinones A17,18 and ortho-quinone monoketals C19 were reported to privilege addition reactions under similar reaction conditions (Scheme 4).

oxophilic addition

O BnO

O

O BnO

PhMgBr

Ph

OH

OH

BnO +

O

Ph

THF, –78 °C R R R = CO 2Me: 55 % with a 1:3 ratio (see ref. 17) R = H: 54 % with a 1:1 ratio (see ref. 18)

R

1,2-nucleophilic addition MeO MeO

OMe O

PhMgBr

MeO MeO

OMe OH Ph

(see ref. 19)

THF, 0 °C > 77 %

Scheme 4 – Reactivity of structurally-related ortho-quinones A and ortho-quinone monoketals C towards PhMgBr

The variations of reaction outcome when exposing the D1-type ortho-quinol acetates 2a and 2b to PhMgBr depend on their substitution pattern. When C-3 is unsubstituted as for 2b, the nucleophilic phenyl group undergoes an initial 1,4-addition to its enone moiety to afford the transient magnesium enolate I1, which would then evolve into the biaryl 5b (Scheme 5). The release of an equivalent of AcOH during this aromatization step justifies the efficient role played by a second equivalent of PhMgBr as base (Scheme 3). ACS Paragon Plus Environment

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The conversion of 2a into the analogous ortho-quinol acetate 3a is somewhat more intriguing, but the presence of an electron-pulling substituent at C-3 is deemed to prevent the 1,4-addition process observed for 2b. The steric hindrance and perturbation of the electrophilic character at C-3 would thus compel PhMgBr to add in a 1,2-fashion onto the enone carbonyl group. In this scenario, the coordinating α-acetate group at C-6 could direct the entry of the Grignard phenyl group in a syn-diastereoselective manner. The resulting Mg-chelated alcoholate intermediate I2 would hence be structurally well suited to undergo a 1,2-sigmatropic shift with concomitant departure of the C-6 methoxy group to furnish the ortho-quinol acetate 3a (Scheme 5).

AcO MeO

OMe MeO OMgBr – AcOH

1,4-addition if R 3 = H H AcO R5

Ph

OMe OH

Ph

I1

OMe O

5b

PhMgBr R3 2a / 2b

AcO O

MgBr O Ph

1,2-addition if R 3 = H

CO 2Me I2

Ph

AcO

O

1,2 -shift

CO2Me 3a

Scheme 5 – Mechanistic rationale for the formation of biaryl 5b and ortho-quinol acetate 3a

We next evaluated the potential reactivity of D1-type ortho-quinol acetates towards representative phenolic derivatives. The most interesting results were obtained using 2a and are summarized in Table 2. Phenol (7a, 5 equiv) failed to undergo reaction with 2a, even upon heating (entry 1). The only products detected as traces after heating the reaction mixture were the rearranged and rearomatized species 8a and 8b, resulting from intramolecular 1,3-shifts of the acetoxy group as previously reported.11 In contrast, the stronger nucleophilic phloroglucinol (7b) and its dimethyl ether derivative 7c (5 equiv) reacted with 2a and gave rise to the dibenzopyranonic biaryls 9 and 10, respectively (entries 2, 3), via a regioselective SN2’-type pathway, followed by lactonization (Scheme 6). The utilization of a stoechiometric amount of 7b proved much less efficient for accessing 9 (entry 4 vs entry 2), and the activation of 7c under its sodium phenolate form led to a complex mixture of intractable products. Moreover, the utilization of the trimethyl ether derivative of phloroglucinol (7b) was also unsuccessful, as no conversion of 2a was observed at room temperature even after prolonged reaction time.

These results indicate that a favorable reaction between 2a and a phenolic derivative requires that the phenolic derivative be characterized by a minimal nucleophilicity and the presence of a free phenolic function. Unfortunately, the ortho-quinol acetate 2b, lacking the presence of an electron-pulling group at C-3, did not react whatever the phenolic derivative used and was recovered intact even after prolonged reaction time. Therefore, the ortho-quinol acetate partner must also be characterized by an adequately modulated electrophilicity, which is the case for 2a, whose choices of reaction pathway and regiochemistry (i.e., SN2’ at C-4) are dictated by the nucleofugacity of the acetate group and directed by the steric encumberment at C-2 (Scheme 6). We shall, however, note that this electrophilic C-2 position was on the contrary the sole locus of attack by phenyl cuprate-type reagents, leading to the minor formation of the biaryl 5a (Table 1, entries 9-12).



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Table 2 – Reactivity of 2a towards phenolic derivatives – Screening studiesa entry

phenol

yieldb

product

c

1

-

2

46

3

40

4

7b

d

26

9

a

Reactions run on a 1.4 mmol scale with 2a (1.0 equiv) and the phenolic derivative (5 equiv) in THF at room b c temperature for 48-72 h, unless otherwise noted. Isolated yields (%). Quasi full recovery of starting 2a, with d traces of 8a and 8b. Reaction run using only 1.2 equiv of 7b.

Notwithstanding the moderate isolated yields we observed, this ortho-quinol acetate-based process constitutes a rapid and metal-free route to the synthesis of polyoxygenated biaryls.20 Since 9 and 10 are methyl ether derivatives of the bioactive natural phenol 1,3,8,9-tetrahydroxydibenzo[b,d]pyran-6-one (11), recently isolated from the bark of Eucalyptus exserta F. Muell (Myrtaceae),21 we completed this work by achieving the synthesis of 11 through a demethylation step (Scheme 6). The application of our SIBX-mediated chemoselective demethylation protocol onto 9 led to a complex product mixture. However, treatment of 10 in a refluxing 47% HI solution for 6 h furnished 11 in 64% yield. This first synthesis of 11 in only 3 steps illustrates the value of this ortho-quinol acetate-based route for the construction of dibenzopyranone skeleta, which commonly necessitates longer multi-step sequences involving transition metal-catalyzed crosscoupling reactions and protecting-group chemistry.22 AcO OMe O 2a 4

RO

2

OH MeO

RO

lactonization CO 2Me OH – MeOH RO

SN2'

CO 2Me – AcOH + OH

OH

MeO

OR OR

OR 9: R = H (46 %) 10: R = Me (40 %)

OH

7b: R = H 7c: R = Me

O O

HO O HO

O

47% HI ∆, 6 h

11 (64 % from 10) OH

Scheme 6 – Formation of dibenzopyranonic biaryls 9 and 10, and synthesis of the natural lactonic biphenol 11

In summary, modes of reactivity for ortho-quinol acetates that are distinct from, yet complementary with, those of their ortho-quinone A and ortho-quinone monoketal C variants have been identified. ACS Paragon Plus Environment

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Thus, D1-type ortho-quinol acetates were shown to be prone to undergo net substitution reactions with aryl-based nucleophiles, hence enabling the formation of valuable biaryl linkages. This reactivity was successfully exploited for the concise synthesis of two natural biaryl compounds, noraucuparin (6) and 1,3,8,9-tetrahydroxydibenzo[b,d]pyran-6-one (11). This work constitutes a novel contribution to the unravelling of the versatile reactivity of ortho-quinonoid species as useful building blocks for the construction of biaryl motifs and the synthesis of biarylic natural products.



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EXPERIMENTAL SECTION General. Reactions were performed under inert atmosphere with magnetic stirring in anhydrous solvents. Tetrahydrofuran (THF) and dichloromethane (DCM) were purified immediately before use by passage through activated alumina under inert atmosphere. Ethyl acetate (EtOAc), cyclohexane, petroleum ether (PET), diethyl ether (Et2O) and acetone were used as received. All starting materials were purchased at the highest commercial quality and used without further purification unless otherwise stated. Reactions run at room temperature were performed between 20 and 25 °C. Solvent evaporations were conducted under reduced pressure at temperatures less than 40 °C unless otherwise noted (e.g., volatile compounds). Reactions were monitored by thinlayer chromatography carried out on silica plates (silica gel 60 F254, Merck) using UV-light for visualization. Column chromatographies were performed on silica gel 60 (0.040-0.063 mm, Merck) using the indicated eluent given in volume ratio. Eluent M is a 8:2 mixture of DCM/EtOAc. Evaporation of solvents were conducted under reduced pressure at temperatures less than 45°C. Melting points (Mp) were measured in open capillary tubes on a Buchi B-540 and are uncorrected. IR spectra were obtained from the Service Commun de Spectroscopie Infrarouge of the Plateforme Scientifique et Technique, Institut de Chimie de Toulouse (FR2599), and values are reported in cm-1. 1H and 13C NMR spectra were recorded on a Bruker Avance 300 spectrometer at 300 and 75 MHz, respectively. Chemical shifts (δ and coupling constants (J) are given in ppm and Hertz (Hz), respectively. The signal multiplicity is described according to the following abbreviations: s (singlet), bs (broad singlet), d (doublet), and m (multiplet). Chemical shifts (δ are reported relative to the residual solvent as an internal standard (CDCl3: δ = 7.26 ppm for 1H and δ = 77.0 ppm for 13 C; acetone-d6: δ = 2.05 ppm for 1H and δ = 29.8 ppm for 13C; benzene-d6: δ = 7.16 ppm for 1H and δ = 128.0 ppm for 13C; methanol-d4: δ = 3.31 ppm for 1H and δ = 49.0 ppm for 13C; DMSOd6: δ = 2.50 ppm for 1H and δ = 39.5 ppm for 13C). Carbon multiplicities were determined by DEPT135 experiments. Diagnostic correlations were obtained by 2-dimensional COSY, HSQC, HMBC and NOESY experiments. Electron impact (EI), Chemical Ionization (CI) and Electrospray (ESI) low/high-resolution mass spectra were obtained from the Service Commun de Spectrométrie de Masse of the Plateforme Scientifique et Technique, Institut de Chimie de Toulouse (FR2599). Accurate mass measurements (HRMS) were performed with a Q-TOF analyzer. Methyl 3-hydroxy-4-methoxybenzoate (1a).23 To a solution of isovanillic acid (12.5 g, 74.3 mmol, 1 equiv.) in MeOH (300 mL) was added a catalytic amount of H2SO4 (40 mL, 0.74 mmol, 0.01 equiv.). After stirring for 24 h under reflux, the reaction mixture was concentrated under reduced pressure and diluted with EtOAc (200 mL). The organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate (3x50 mL), with brine (50 mL), dried over MgSO4, filtered and evaporated under reduced pressure. Purification of the residue by silica gel chromatography (PET/EtOAc 7:3) furnished 1a as a white powder (11.9 g, 65.4 mmol). Yield 88%. Mp 66-68 °C [lit.23 m.p. 61-63 °C]. Rf 0.26 (silica, PET/EtOAc 8:2). IR (neat) νmax 3402, 1704 cm-1. 1H NMR (300 MHz, CDCl3) δ 3.88 (s, 3H), 3.95 (s, 3H), 5.63 (s, 1H, OH), 6.87 (d, 3J = 8.3 Hz, 1H), 7.59 (d, 4J = 2.1 Hz, 1H), 7.62 (dd, 3J = 8.3 Hz, 4J = 2.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 166.8, 150.5, 145.2, 123.0, 122.6, 115.6, 109.8, 55.8, 51.9. – CIMS m/z (%) 200 (100) [M+NH4]+, 183 (95) [M+H]+. General procedure for the preparation of ortho-quinol acetates 2a,b. To a stirred solution of PhI(OAc)2 (2.33 g, 7.2 mmol, 1 equiv.) in DCM-AcOH (3:1, 48 mL) was added dropwise a solution of phenol 1a,b (7.2 mmol, 1 equiv.) in dry DCM (60 mL) at rt. The reaction mixture became immediately yellow. After 30 min, the mixture was poured over an aqueous solution of potassium hydrogen sulfate (1M, 2x10 mL) and then extracted with DCM (3x30 mL). The combined organic phases were washed with brine (10 mL), dried over MgSO4, filtered and evaporated under reduced ACS Paragon Plus Environment

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pressure. Purification of the resulting oily residue by silica gel chromatography furnished 2a,b in good yield. Methyl 4-acetoxy-4-methoxy-3-oxocyclohexa-1,5-dienecarboxylate (2a).11 Chromatography (PET/M 7:3) furnished ortho-quinol acetate 2a as a yellow oil (1.21 g, 5.0 mmol). Yield 70%. Rf = 0.51 (silica, PET/M 7:3). IR (neat) νmax 1725, 1689 cm-1. 1H NMR (300 MHz, acetone-d6) δ 2.07 (s, 3H), 3.44 (s, 3H), 3.89 (s, 3H), 6.48 (dd, 3J = 10.2 Hz, 5J = 0.8 Hz, 1H), 6.66 (dd, 4J = 1.6 Hz, 5J = 0.8 Hz, 1H), 6.80 (dd, 3J = 10.2 Hz, 4J = 1.6 Hz, 1H). 13C NMR (75 MHz, acetone-d6) δ 192.5, 170.2, 165.6, 140.0, 136.5, 128.3, 124.3, 93.3, 53.3, 51.6, 20.2. CIMS m/z (%) 258 (100) [M+NH4]+, 241 (20) [M+H]+. 1,2-Dimethoxy-6-oxocyclohexa-2,4-dienyl acetate (2b).24 Chromatography (PET/M 8:2) furnished ortho-quinol acetate 2b as a yellow solid (1.14 g, 5.4 mmol). Yield 75%. Mp 96-98 °C. – Rf 0.49 (silica, PET/M 7:3). IR (neat) νmax 1730, 1622 cm-1. 1H NMR (300 MHz, acetone-d6) δ 2.06 (s, 3H), 3.38 (s, 3H), 3.74 (s, 3H), 5.48 (d, 3J = 7.2 Hz, 1H), 5.74 (dd, 3J = 9.9 Hz, 4J = 0.6 Hz, 1H), 7.10 (dd, 3J = 9.9 Hz, 3J = 7.2 Hz, 1H). 13C NMR (75 MHz, acetone-d6) δ 191.0, 169.6, 163.7, 143.7, 118.5, 95.9, 95.1, 56.5, 52.3, 20.2. ESIMS m/z (%) 230 (100) [M+Na]+. General procedure for the reaction between ortho-quinol acetate 2a and PhMgBr. To a stirred solution of 2a (330 mg, 1.4 mmol, 1 equiv.) in THF (3.1 mL) cooled to –78°C was added dropwise a 3 M solution of PhMgBr in Et2O (0.54 mL, 1.56 mmol, 1.1 equiv.). The resulting mixture was then allowed to warm up to –10 °C over ca. 2 h, after which time it was poured over a saturated aqueous solution of ammonium chloride (2 mL) and extracted with EtOAc (3x10 mL). The combined organic phases were washed with brine (10 mL), dried over MgSO4, filtered and evaporated under reduced pressure. Purification of the residue by silica gel chromatography, (gradient elution PET/Et2O 95:5 to 85:15 then PET/M 8:2 to 1:1) furnished ortho-quinol acetate 3a and diarylether 4a. Methyl 4-acetoxy-3-oxo-4-phenylcyclohexa-1,5-dienecarboxylate (3a). Colorless oil. Yield 47%. Rf 0.39 (silica, PET/M 7:3). IR (neat) νmax 1724, 1685 cm-1. 1H NMR (300 MHz, benzene-d6) δ 1.66 (s, 3H), 3.27 (s, 3H), 5.97 (dd, 3J = 10.2 Hz, 5J = 0.7 Hz, 1H), 7.00-7.06 (m, 3H), 7.26 (dd, 3J = 10.2 Hz, 4J = 2.3 Hz, 1H), 7.37 (dd, 4J = 2.3 Hz, 5J = 0.7 Hz, 1H), 7.46-7.52 (m, 2H). 13C NMR (75 MHz, benzene-d6) δ 194.6, 169.5, 164.2, 148.2, 138.0, 133.8, 129.4, 129.2, 127.4, 126.9, 126.1, 81.6, 51.8, 19.8. – CIMS m/z (%) 304 (100) [M+NH4]+. HRMS (ESI, positive mode) calcd for C16H14O5Na [M+Na]+ 309.07334, found 309.07272. Methyl 4-methoxy-3-phenoxybenzoate (4a). Colorless oil. Yield 5%. Rf 0.63 (silica, PET/M 7:3). IR (neat) νmax 1729 cm -1. 1H NMR (300 MHz, CDCl3) δ 3.85 (s, 3H), 3.90 (s, 3H), 6.94-6.97 (m, 2H), 7.02 (d, 3J = 8.6 Hz, 1H), 7.05-7.10 (m, 1H), 7.28-7.35 (m, 2H), 7.64 (d, 4J = 2.1 Hz, 1H), 7.86 (dd, 3J = 8.6 Hz, 4J = 2.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 166.3, 157.4, 155.3, 144.8, 129.7, 126.9, 123.1, 122.9, 121.9, 117.4, 111.8, 56.1, 52.0. CIMS m/z (%) 276 (20) [M+NH4]+, 259 (100) [M+H]+. HRMS (CI, positive mode) calcd for C15H15O4 [M+H]+ 259.0970, found 259.0959. Methyl 6-hydroxy-5-methoxybiphenyl-2-carboxylate (5a). To a mixture of CuI (293 mg, 1.54 mmol, 1.1 equiv.) in THF (1.5 mL) was added dropwise at 0 °C a 1.9 M solution of PhLi in Et2O (1.6 mL, 3.08 mmol, 2.2 equiv.). After stirring for 10 min at –10 °C, the resulting solution of Ph2CuLi was canulated dropwise to a solution of 2a (330 mg, 1.4 mmol, 1 equiv.) in THF (1.4 mL) cooled to –78 °C. After stirring for 30 min at –78 °C, the mixture was poured over a saturated aqueous solution of ammonium chloride (2 mL) and extracted with EtOAc (3x10 mL). The combined organic phases were washed with brine (10 mL), dried over MgSO4, filtered and evaporated under reduced pressure. Purification of the residue by silica gel chromatography (gradient elution PET/M 85:15 to 1:1) furnished 1a (133 mg, 52%) and biaryl 5a (62 mg, 17%) as a colorless oil. Rf 0.39 (silica, 7:3 petroleum ether/M). IR (neat) νmax 3488, 3403, 1712, 1599 cm-1. 1H NMR (300 MHz, CDCl3) δ 3.59 ACS Paragon Plus Environment


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(s, 3H), 3.99 (s, 3H), 5.67 (bs, 1H, OH), 6.92 (d, 3J = 8.4 Hz, 1H), 7.27-7.33 (m, 2H), 7.36-7.49 (m, 3H), 7.56 (d, 3J = 8.4 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 167.8, 149.4, 143.0, 136.1, 129.2, 129.0, 127.9, 127.3, 123.9, 122.6, 108.9, 56.1, 51.6. CIMS m/z (%) 276 (20) [M+NH4]+, 259 (100) [M+H]+. HRMS (ESI, negative mode) calcd for C15H13O4 [M–H]— 257.080804, found 257.08154. 4,5-Dimethoxybiphenyl-3-ol (5b). To a stirred solution of 2b (425 mg, 2 mmol, 1 equiv.) in THF (4.4 mL) cooled to –78°C was added dropwise a 3 M solution of PhMgBr in Et2O (1.46 mL, 4.4 mmol, 2.2 equiv.). The resulting mixture was then allowed to warm up to –10 °C over ca. 2 h, after which time it was poured over a saturated aqueous solution of ammonium chloride (2 mL) and extracted with EtOAc (3x10 mL). The combined organic phases were washed with brine (10 mL), dried over MgSO4, filtered and evaporated under reduced pressure. Purification of the residue by silica gel chromatography (gradient elution PET/M 8:2 to 6:4) furnished 5b as a yellow solid (346 mg, 1.5 mmol). Yield 75%. Mp 71-74 °C. – Rf 0.30 (6:4 petroleum ether/M). IR (neat) νmax 3416 cm-1. 1H NMR (300 MHz, CDCl3) δ 3.93 (s, 3H), 3.94 (s, 3H), 5.80 (bs, 1H, OH), 6.68 (d, 4J = 2.1 Hz, 1H), 6.84 (d, 4J = 2.1 Hz, 1H), 7.29-7.37 (m, 1H), 7.38-7.46 (m, 2H), 7.51-7.56 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 152.4, 149.4, 140.9, 137.5, 135.1, 128.6, 127.2, 126.9, 107.0, 103.3, 61.0, 55.9. ESIMS m/z (%), 229 (100) [M–H]–. HRMS (ESI, negative mode) calcd for C14H13O3 [M– H]– 229.08592, found 229.08635. 5-Methoxybiphenyl-3,5-diol or noraucuparin (6).13a,b To a stirred suspension of SIBX (169 mg, 0.3 mmol, 1.5 equiv.) in THF (4 mL) was added 5b (46 mg, 0.2 mmol, 1 equiv.). After stirring overnight in the dark at room temperature, the white suspension was filtered out from the resulting red solution. The filter cake was washed with DCM (2x10 mL) and the combined filtrate and washings were poured into water (10 mL). After separation, the aqueous layer was further extracted with DCM (3x20 mL). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (20 mL) and treated with an aqueous solution (2 mL) of Na2S2O4 (208 mg, 1.2 mmol, 6 equiv.) for 30 min with vigorous stirring under nitrogen in the dark. The resulting yellow solution was washed with water (5 mL), brine (10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. Purification of the residue by silica gel chromatography (gradient elution PET/M + 1% AcOH 6:4 to 1:1) furnished 6 as a yellow solid (32 mg, 0.15 mmol). Yield 74%. Mp 102-104 °C. Rf 0.36 (silica, PET/M + 1% AcOH 3:7). IR (neat) νmax 3406 cm-1. 1H NMR (300 MHz, CDCl3) δ 3.95 (s, 3H), 5.38 (bs, 2H, OH), 6.70 (d, 4J = 1.8 Hz, 1H), 6.86 (d, 4J = 1.8 Hz, 1H), 7.28-7.35 (m, 1H), 7.38-7.45 (m, 2H), 7.50-7.56 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 147.1, 144.1, 141.1, 133.5, 132.0, 128.7, 126.9, 126.8, 107.8, 102.3, 56.2. ESIMS m/z (%), 215 (100) [M–H]–. HRMS (ESI, negative mode) calcd for C13H11O3 [M–H]– 215.07027, found 215.07068. 1,3,8-Trihydroxy-9-methoxydibenzo[b,d]pyran-6-one (9). ortho-Quinol acetate 2a (480.4 mg, 2.0 mmol, 1 equiv) and 1,3,5-trihydroxybenzene 7b (305 mg, 2.4 mmol, 1.2 equiv) were dissolved in THF (8 mL). The reaction was stirred 3 days at room temperature under nitrogen atmosphere. Then the mixture was evaporated under reduced pressure. Purification of the residue by silica gel chromatography (PET/acetone + 1% AcOH 7:3 to 1:9) furnished 9 as a white solid (248 mg, 0.9 mmol). Yield 46%. Mp 321 °C (decomposition). Rf 0.45 (silica, PET/acetone + 1% AcOH 1:1). IR (neat) νmax 3288, 1680 cm-1. 1H NMR (DMSO-d6, 300 MHz) δ 3.91 (s, 3H), 6.23 (d, 4J = 2.4 Hz, 1H), 6.38 (d, 4J = 2.4 Hz, 1H), 7.52 (s, 1H), 8.52 (s, 1H), 10.17 (bs, 3H, OH). 13C NMR (DMSO-d6, 75.5 MHz) δ 160.4, 158.1, 156.6, 153.7, 152.9, 145.6, 129.4, 113.8, 111.7, 108.0, 99.7, 99.2, 94.9, 55.5. ESIMS m/z (%), 273 (100) [M–H]–. HRMS (ESI, negative mode) calcd for C14H9O6 [M–H]– 273.03936, found 273.04015. 8-Hydroxy-1,3,9-trimethoxydibenzo[b,d]pyran-6-one (10). ortho-Quinol acetate 2a (240.2 mg, 1.0 mmol, 1 equiv) and 3,5-dimethoxyphenol 7c (770 mg, 5.0 mmol, 5 equiv) was dissolved in ACS Paragon Plus Environment

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THF (17 mL). After stirring for 48 h at room temperature, the reaction mixture was evaporated under reduced pressure. Crystallization of the resulting residue with acetonitrile afforded pure dibenzopyranone 10 as a white solid (132 mg, 0.4 mmol). Yield 40%. Mp 201-204 °C. Rf 0.49 (silica, PET/M + 1% AcOH 3:7). IR (neat)νmax 3403, 3140, 1683 cm-1. 1H NMR (DMSO-d6, 300 MHz) δ 3.82 (s, 3H), 3.92 (s, 3H), 3.96 (s, 3H), 6.49 (d, 4J = 2.4 Hz, 1H), 6.51 (d, 4J = 2.4 Hz, 1H), 7.52 (s, 1H), 8.25 (s, 1H), 9.88 (bs, 1H, OH). 13C NMR (DMSO-d6, 75.5 MHz) δ 160.0, 159.8, 157.9, 153.5, 152.5, 146.1, 128.1, 113.8, 112.2, 108.0, 101.2, 95.6, 93.9, 56.2, 55.6, 55.4. ESIMS m/z (rel intensity), 301 (100) [M–H]–. HRMS (CIMS) calcd for C16H15O6 303.0869, found 303.0881. 1,3,8,9-Tetrahydroxy-dibenzo[b,d]pyran-6-one (11).21 Phenol 10 (24 mg, 0.087 mmol, 1 equiv) was suspended in 2 mL of an aqueous solution of 47% iodhydric acid. After refluxing for 24 h at 130 °C, the mixture was cooled at 0 °C and filtrated. The filter cake was washed with cold water (2x2 mL) and dried under reduced pressure to give 11 as a white solid (15 mg, 0.059 mmol). Yield 64%. Mp 400 °C (decomposition). Rf 0.24 (silica, PET/acetone + 1% AcOH 1:1). IR (neat) νmax 3288, 1682 cm-1. 1H NMR (DMSO-d6, 300 MHz) δ 6.20 (d, 4J = 2.4 Hz, 1H), 6.34 (d, 4J = 2.4 Hz, 1H), 7.50 (s, 1H), 8.38 (s, 1H), 9.63 (bs, 1H, OH), 9.87 (bs, 1H, OH), 10.23 (bs, 1H, OH), 10.60 (s, 1H, OH). 13C NMR (DMSO-d6, 75.5 MHz) δ 160.4, 157.9, 156.5, 152.8, 152.5, 144.8, 129.3, 114.4, 112.0, 110.6, 99.5, 99.2, 94.8. ESIMS m/z (%), 259 (100) [M–H]—.



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ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: P Full experimental details and characterization data for all compounds as well as their 1H, 13C and DEPT NMR spectra

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] *E-mail: [email protected] ORCID Stefan Chassaing: 0000-0001-5842-5288 Stéphane Quideau: 0000-0002-7079-9757 Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS The authors thank the National Center for Scientific Research (CNRS) and the Universities of Bordeaux and Toulouse for financial support, and the French Ministry of Higher Education and Research for S.C. doctoral scholarship.

REFERENCES (1) For reviews on the dearomatization of phenols into ortho-quinonoid building blocks in organic synthesis, see: (a) Quideau, S.; Pouységu, L. Org. Prep. Proced. Int. 1999, 31, 617-680. (b) Liao, C.-C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856-866. (c) Quideau, S.; Pouységu, L.; Deffieux, D. Curr. Org. Chem. 2004, 8, 113-148. (d) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104, 1383-1429. (e) Roche, S. P.; Porco Jr., J. A. Angew. Chem. Int. Ed. 2011, 50, 4068-4093. (f) Ding, Q.; Ye, Y.; Fan, R. Synthesis 2013, 1-16. (2) (a) Kuboki, A.; Maeda, C.; Arishige, T.; Kuyama, K.; Hamabata, M.; Ohira, S. Tetrahedron Lett. 2008, 49, 4516-4518. (b) Pouységu, L.; Chassaing, S.; Dejugnac, D.; Lamidey, A.-M.; Miqueu, K.; Sotiropoulos, J.-M.; Quideau, S. Angew. Chem. Int. Ed. 2008, 47, 3552-3555. (c) Dong, S.; Zhu, J.; Porco Jr., J. A. J. Am. Chem. Soc. 2008, 130, 2738-3739. (d) Coffinier, R.; El Assal, M.; Peixoto, P. A.; Bosset, C.; Miqueu, K.; Sotiropoulos, J.-M.; Pouységu, L.; Quideau, S. Org. Lett. 2016, 18, 1120-1123. (3) Pouységu, L.; Marguerit, M.; Gagnepain, J.; Lyvinec, G.; Eatherton, J.; Quideau, S. Org. Lett. 2008, 10, 5211-5214. (4) Hong, S.-p.; Mcintosh, M. C. Org. Lett. 2002, 4, 19-21. (5) (a) Reeder, M. D.; Srikanth, G. S. C.; Jones, S. P.; Castle, S. L. Org. Lett. 2005, 7, 1089-1092. (b) Li, F.; Tartakoff, S. S.; Castle, S. L. J. Am. Chem. Soc. 2009, 131, 6674-6675. (6) Budzikiewicz, H. Monatsch. Chem. 2016, 147, 627-663. (7) (a) Wessely, F.; Grossa, M. Monatsch. Chem. 1966, 97, 571-578. (b) Grossa, M.; Wessely, F. Monatsch. Chem. 1966, 97, 1385-1390. (c) Quideau, S.; Pouységu, L.; Looney, M. A. J. Org. Chem. 1998, 63, 95979600. (d) Quideau, S.; Pouységu, L.; Oxoby, M.; Looney, M. A. Tetrahedron 2001, 57, 319-329. (e) Hoshino, O.; Suzuki, M.; Ogasawara, H. Tetrahedron 2001, 57, 265-271. (8) (a) Hoshino, O.; Ohtani, M.; Umezawa, B. Chem. Pharm. Bull. 1979, 27, 3101-3105. (b) Hara, H.; Hashimoto, F.; Hoshino, O.; Umezawa, B. Tetrahedron Lett. 1984, 25, 3615-3616. (c) Banwell, M. G.; Lambert, J. N.; Mackay, M. F.; Greenwood, R. J. J. Chem. Soc., Chem. Commun. 1992, 974. (d) Feldman, K. S. J. Org. Chem. 1997, 62, 4983-4990. (9) (a) Coleman, R. S.; Grant, E. B. J. Org. Chem. 1991, 56, 1357-1359. (b) Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1995, 117, 10889-10904.


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(10) For recent examples of radical additions onto D1-type ortho-quinol acetates, see: Vitaku, E.; Njardarson, J. T. Eur. J. Org. Chem. 2016, 3679-3683. (11) Quideau, S.; Looney, M. A.; Pouységu, L.; Ham, S.; Birney, D. M. Tetrahedron Lett. 1999, 40, 615-618. (12) Liao, C.-C.; Chu, C.-S.; Lee, T.-H.; Rao, P. D.; Ko, S.; Song, L.-D.; Shiao, H.-C. J. Org. Chem. 1999, 64, 4102-4110. (13) (a) Kim, K. H.; Choi, S. U.; Ha, S. K.; Kim, S. Y.; Lee, K. R. J. Nat. Prod. 2009, 72, 2061-2064. (b) Hüttner, C.; Beuerle, T.; Scharnhop, H.; Ernst, L.; Beerhues, L. J. Agric. Food Chem. 2010, 58, 1197711984. (c) Chizzali, C.; Beerhues, L. Beilstein J. Org. Chem. 2012, 8, 613-620. (14) Ozanne, A.; Pouységu, L.; Depernet, D.; François, B.; Quideau, S. Org. Lett. 2003, 5, 2903-2906. (15) Schmidt, B.; Riemer, M. J. Org. Chem. 2014, 79, 4104-4118. (16) For another relevant and recent Pd-catalyzed method for the synthesis of oxygenated biaryl compounds using C-type ortho-quinone monoketals, see: Chittimalla, S. K.; Kuppusamy, R.; Akavaram, N. Synlett 2015, 613-618. (17) Feldman, K. S.; Quideau, S.; Appel, H. M. J. Org. Chem. 1996, 61, 6656-6665. (18) Miller, L. A.; Marsini, M. A.; Pettus, T. R. R. Org. Lett. 2009, 11, 1955-1958. (19) Hou, H.-F.; Peddinti, R. K.; Liao, C.-C. Org. Lett. 2002, 4, 2477-2480. (20) For another relevant and recent Lewis acid-mediated method for the synthesis of oxygenated biaryl compounds using C-type ortho-quinone monoketals, see: Parumala, S. K. R.; Peddinti, R. K. Org. Lett. 2013, 15, 3546-3549. (21) Li, J.; Xu, H. Ind. Crops Prod. 2012, 40, 302-306. (22) For representative examples, see: (a) Vishnumurthy, K.; Makriyannis, A. J. Comb. Chem. 2010, 12, 664-669. (b) Jung, M. E.; Allen, D. A. Org. Lett. 2009, 11, 757-760. (c) Molander, G. A.; George, K. M.; Monovich, L. G. J. Org. Chem. 2003, 68, 9533-9540. (23) Li, R.-D.; Zhang, X.; Li, Q.-Y.; Ge, Z.-M.; Li, R.-T. Bioorg. Med. Chem. Lett. 2011, 21, 3637-3640. (24) (a) Catlin, J. C.; Daves Jr, G. D.; Folkers, K. J. Med. Chem. 1971, 14, 45-48. (b) Kürti, L.; Herczegh, P.; Visy, J.; Simonyi, M.; Antus, S.; Pelter, A. J. Chem. Soc. Perkin Trans. 1 1999, 379-380.


ortho-Quinol Acetate Chemistry: Reactivity toward ... - ACS Publications

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