Ortho-Quinol Acetate Chemistry: Reactivity toward Aryl-Based Nucleophiles and Applications to the Synthesis of Natural Products

Article abstract of DOI:10.1021/acs.joc.7b00250

Two model ortho-quinol acetates were easily prepared by iodane-mediated acetoxylative phenol dearomatization and evaluated for their reactivity toward 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.

Full text of DOI:10.1021/acs.joc.7b00250

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Note
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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ortho-Quinol Acetate Chemistry - Reactivity towards Aryl-
Based 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
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aUniv. Bordeaux, Institut des Sciences Moléculaires (ISM, CNRSꢀUMR 5255), 351 cours de la Libération,
33405 Talence, France
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bITAV, Université de Toulouse, CNRS, UPS, France
ABSTRACT
Two model orthoꢀquinol acetates were easily prepared by iodaneꢀmediated acetoxylative phenol
dearomatization and evaluated for their reactivity towards various arylꢀbased 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
Ph
AcO
O
PhMgBr
OMe
OH
AcO
R1
O
MeO
OH
OH
R1 =
H
CO2Me
OH
PhMgBr
R2 = CO2Me
OH
R1 = OMe
R2 = H
R2
Ph
OMe
noraucuparin
HO
OH
O
O
MeO
natural dibenzopyranone
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orthoꢀQuinones A, orthoꢀquinols B and orthoꢀquinone 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)oxocyclohexaꢀ2,4ꢀdienone 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 crossꢀcoupling reactions,1ꢀ4 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.
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orthoꢀQuinol acetates D1,2, other quinonoid cyclohexaꢀ2,4ꢀdienone variants accessible via OPD,
have been much less investigated than their AꢀC 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,6ꢀ11 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 arylꢀbased nucleophiles, i.e., arylꢀbearing organometallics and phenolic derivatives.
R1
O
HO
O
O
O
orthoꢀquinol B
orthoꢀquinone A
(R1 = OH)
R1
(R1 = alkyl)
OH
R1
R2O
OPD
OPD
R1
AcO
O
orthoꢀquinol acetate
D1: R1 = alkoxy
D2: R1 = alkyl
orthoꢀquinone
monoketal C
(R1 = alkoxy, R2 = alkyl)
(-)-bacchopetiolone2e
O
OH
O
OMe
OMe
OH
MeO
OH
MeO
O
O
O
O
O
O
HO
HO
O
3
O
O
MeO
(-)-wasabidienone B0
O
Cl
O
NMe
OMe
MeO
O
MeO
OMe
OMe
(±)-cleomiscosin C2a
MeO
(-)-acutumine5
O
5-epi-eupomatilone-64
Scheme 1 – Quinonoid cyclohexa-2,4-dienones A-D and examples of natural products synthesized
using these key building blocks
The D1ꢀtype orthoꢀquinol acetates 2a and 2b, readily prepared from methyl 3ꢀhydroxyꢀ4ꢀ
methoxybenzoate 1a and 2,3ꢀdimethoxyphenol 1b under standard λ3ꢀiodaneꢀmediated 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 orthoꢀquinone A and orthoꢀquinone
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,
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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 orthoꢀquinol
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 0.3ꢀ0.4 M (entry 3 vs entries 1, 2, 4).
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Noteworthy is that preꢀcomplexation 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 orthoꢀquinol acetate 3a was not produced either when using PhM (M = MgBr, Li) in
combination with 1 equiv of CuI or Ph2CuMꢀtype cuprate reagents (M = MgBr, Li) (entries 9ꢀ12).
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 Gilmanꢀtype lowerꢀ
order 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
and optimizationa
entry conditions
3ab
36
32
47
34
29
30
ꢀ d
4ab
8
5ab
ꢀ d
ꢀ d
ꢀ d
ꢀ d
ꢀ d
ꢀ d
ꢀ d
1
2
PhMgBrc
PhMgBrc,e
9
3
PhMgBr
PhMgBrf
5
4
5
5
PhMgBr, BF3.Et2Of
6
f
6
PhMgBr, CeCl3
PhMgBrg
7
7
6
8
PhLi
ꢀ d
ꢀ d
ꢀ d
ꢀ d
ꢀ d
ꢀ d
ꢀ d
ꢀ d
ꢀ d
ꢀ d
9
PhMgBr, CuI
Ph2CuMgBr
PhLi, CuI
Ph2CuLi
12h
tracesi
tracesj
17k
10
11
12
ꢀ d
aOptimized conditions: reactions run for 2 h on a 1.4 mmol scale using 2a (1.0 equiv) at 0.3ꢀ0.4 M and PhM
b
c
d
e
(1.1 equiv). Isolated yields (%). [2a] = 0.04 M. Not detected. Reactions run at –10 °C. f[2a] = 0.7ꢀ0.8 M.
gReactions run with 2.2 equiv of PhMgBr. h1a isolated in 38% yield. i1a isolated in 44% yield. 1a isolated in
14% yield. k1a isolated in 52% yield.
j
We then investigated the addition of PhMgBr onto the orthoꢀquinol 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
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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 3ꢀdeꢀOꢀmethylaucuparin), a natural biarylic phytoalexin isolated from the trunk
of Berberis koreana (Berberidaceae)13a and reported in Pyrinae.13b,c
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9
Simply, the 2ꢀmethoxyphenolic 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 3ꢀstep orthoꢀ
quinol acetateꢀrelying synthesis from the commercially available phenol 1b constitutes a
convenient alternative to the only previous 3ꢀstep synthesis of noraucuparin (6), for which the
biarylꢀforming key step was based on a SuzukiꢀMiyaura crossꢀcoupling process.15,16
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Scheme 3 – Reactivity of 2b towards PhMgBr and synthesis of noraucuparin 6
These data reveal rather unusual and specific reactivity features of D1ꢀtype orthoꢀquinol acetates
towards phenyl metallic reagents. The orthoꢀquinol acetates 2a/2b are indeed inclined to favour
net substitution reactions affording here the orthoꢀquinol acetate 3a and the biaryl 5b (Table 1,
Scheme 3), whereas structurallyꢀrelated orthoꢀquinones A17,18 and orthoꢀquinone monoketals C19
were reported to privilege addition reactions under similar reaction conditions (Scheme 4).
oxophilic
addition
Ph
O
R
OH
R
O
R
BnO
OH
BnO
O
BnO
O
Ph
PhMgBr
+
THF, –78 °C
R = CO2Me: 55 % with a 1:3 ratio (see ref. 17)
R = H: 54 % with a 1:1 ratio (see ref. 18)
1,2-nucleophilic
addition
OMe
OH
Ph
MeO
MeO
OMe
MeO
MeO
PhMgBr
O
(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 D1ꢀtype orthoꢀquinol acetates 2a and 2b to
PhMgBr depend on their substitution pattern. When Cꢀ3 is unsubstituted as for 2b, the nucleophilic
phenyl group undergoes an initial 1,4ꢀaddition 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).
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The conversion of 2a into the analogous orthoꢀquinol acetate 3a is somewhat more intriguing,
but the presence of an electronꢀpulling substituent at Cꢀ3 is deemed to prevent the 1,4ꢀaddition
process observed for 2b. The steric hindrance and perturbation of the electrophilic character at Cꢀ3
would thus compel PhMgBr to add in a 1,2ꢀfashion onto the enone carbonyl group. In this scenario,
the coordinating αꢀacetate group at Cꢀ6 could direct the entry of the Grignard phenyl group in a
synꢀdiastereoselective manner. The resulting Mgꢀchelated alcoholate intermediate I2 would hence
be structurally well suited to undergo a 1,2ꢀsigmatropic shift with concomitant departure of the Cꢀ6
methoxy group to furnish the orthoꢀquinol acetate 3a (Scheme 5).
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OMe
AcO OMe
MeO
OH
MeO
OMgBr
– AcOH
1,4-addition
if R3 = H
H
Ph
Ph
I1
OMe
O
AcO
R5
5b
PhMgBr
MgBr
R3
2a / 2b
AcO
O
Ph
AcO
O
O
Ph
1,2 -shift
1,2-addition
if R3 = H
CO2Me
CO2Me
3a
I2
Scheme 5 – Mechanistic rationale for the formation of biaryl 5b and ortho-quinol acetate 3a
We next evaluated the potential reactivity of D1ꢀtype orthoꢀquinol 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 1,3ꢀshifts 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 orthoꢀquinol acetate 2b, lacking the presence of an
electronꢀpulling group at Cꢀ3, did not react whatever the phenolic derivative used and was
recovered intact even after prolonged reaction time. Therefore, the orthoꢀquinol 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 Cꢀ4) are dictated by the
nucleofugacity of the acetate group and directed by the steric encumberment at Cꢀ2 (Scheme 6).
We shall, however, note that this electrophilic Cꢀ2 position was on the contrary the sole locus of
attack by phenyl cuprateꢀtype reagents, leading to the minor formation of the biaryl 5a (Table 1,
entries 9ꢀ12).
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Table 2 – Reactivity of 2a towards phenolic derivatives – Screening studiesa
4
5
6
7
entry
1
phenol
product
yieldb
ꢀ c
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2
46
3
4
40
7b
9
26d
aReactions run on a 1.4 mmol scale with 2a (1.0 equiv) and the phenolic derivative (5 equiv) in THF at room
temperature for 48ꢀ72 h, unless otherwise noted. bIsolated yields (%). cQuasi full recovery of starting 2a, with
traces of 8a and 8b. dReaction run using only 1.2 equiv of 7b.
Notwithstanding the moderate isolated yields we observed, this orthoꢀquinol acetateꢀbased
process constitutes a rapid and metalꢀfree route to the synthesis of polyoxygenated biaryls.20 Since
9 and 10 are methyl ether derivatives of the bioactive natural phenol 1,3,8,9ꢀtetrahydroxydiꢀ
benzo[b,d]pyranꢀ6ꢀone (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 SIBXꢀmediated 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 orthoꢀquinol acetateꢀbased route for the construction of dibenzopyranone skeleta, which
commonly necessitates longer multiꢀstep sequences involving transition metalꢀcatalyzed crossꢀ
coupling reactions and protectingꢀgroup chemistry.22
OMe
AcO
2a
OH
OH
O
MeO
RO
MeO
RO
4
2
lactonization
SN2'
O
CO2Me
CO2Me
+
– AcOH
– MeOH
OH
O
RO
OH
OR
OH
OR
9: R = H (46 %)
OR
7b: R = H
10: R = Me (40 %)
HO
HO
7c: R = Me
47% HI
ꢀ, 6 h
O
O
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 orthoꢀquinol acetates that are distinct from, yet complementary
with, those of their orthoꢀquinone A and orthoꢀquinone monoketal C variants have been identified.
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Thus, D1ꢀtype orthoꢀquinol acetates were shown to be prone to undergo net substitution reactions
with arylꢀbased 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 1,3,8,9ꢀtetrahydroxydibenzo[b,d]pyranꢀ6ꢀone (11). This work constitutes a
novel contribution to the unravelling of the versatile reactivity of orthoꢀquinonoid 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 thinꢀ
layer chromatography carried out on silica plates (silica gel 60 F254, Merck) using UVꢀlight for
visualization. Column chromatographies were performed on silica gel 60 (0.040ꢀ0.063 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 Bꢀ540 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
cmꢀ1. 1H and 13C NMR spectra were recorded on a Bruker Avance 300 spectrometer at 300 and 75
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MHz, respectively. Chemical shifts (
respectively. The signal multiplicity is described according to the following abbreviations: s
(singlet), bs (broad singlet), d (doublet), and m (multiplet). Chemical shifts ( are reported relative
to the residual solvent as an internal standard (CDCl3: = 77.0 ppm for
= 7.26 ppm for 1H and
= 29.8 ppm for 13C; benzeneꢀd6: = 7.16 ppm for 1H
= 3.31 ppm for 1H and = 49.0 ppm for 13C; DMSOꢀ
δ
and coupling constants (J) are given in ppm and Hertz (Hz),
δ
δ
δ
13C; acetoneꢀd6:
δ
= 2.05 ppm for 1H and
δ
δ
δ
and
d6:
δ
δ
= 128.0 ppm for 13C; methanolꢀd4:
δ
1
= 2.50 ppm for H and
δ
= 39.5 ppm for 13C). Carbon multiplicities were determined by
DEPT135 experiments. Diagnostic correlations were obtained by 2ꢀdimensional COSY, HSQC,
HMBC and NOESY experiments. Electron impact (EI), Chemical Ionization (CI) and Electrospray
(ESI) low/highꢀresolution 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 QꢀTOF 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 66ꢀ68 °C [lit.23 m.p. 61ꢀ63 °C]. Rf 0.26 (silica, PET/EtOAc 8:2). IR (neat)
νmax 3402, 1704
cmꢀ1. 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,
4
1H), 7.59 (d, 4J = 2.1 Hz, 1H), 7.62 (dd, 3J = 8.3 Hz, J = 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 DCMꢀAcOH (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
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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 orthoꢀquinol acetate 2a as a yellow oil (1.21 g, 5.0 mmol). Yield 70%. Rf =
0.51 (silica, PET/M 7:3). IR (neat)
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 =
ν δ 2.07 (s,
max 1725, 1689 cmꢀ1. 1H NMR (300 MHz, acetoneꢀd6)
3
4
0.8 Hz, 1H), 6.80 (dd, J = 10.2 Hz, J = 1.6 Hz, 1H). 13C NMR (75 MHz, acetoneꢀd6)
δ 192.5,
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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 orthoꢀquinol acetate 2b as a yellow solid (1.14 g, 5.4 mmol). Yield 75%. Mp 96ꢀ98 °C. –
1
Rf 0.49 (silica, PET/M 7:3). IR (neat) νmax 1730, 1622 cmꢀ1. H NMR (300 MHz, acetoneꢀd6)
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, J = 9.9 Hz, J = 7.2 Hz, 1H). 13C NMR (75 MHz, acetoneꢀd6)
δ 191.0, 169.6, 163.7,
3
3
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 orthoꢀquinol 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) ν δ
max 1724, 1685 cmꢀ1. 1H NMR (300 MHz, benzeneꢀd6)
1.66 (s, 3H), 3.27 (s, 3H), 5.97 (dd, 3J = 10.2 Hz, 5J = 0.7 Hz, 1H), 7.00ꢀ7.06 (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), 7.46ꢀ7.52 (m, 2H). 13C NMR (75
MHz, benzeneꢀd6)
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
1
7:3). IR (neat) νmax 1729 cmꢀ1. H NMR (300 MHz, CDCl3)
δ 3.85 (s, 3H), 3.90 (s, 3H), 6.94ꢀ6.97
(m, 2H), 7.02 (d, 3J = 8.6 Hz, 1H), 7.05ꢀ7.10 (m, 1H), 7.28ꢀ7.35 (m, 2H), 7.64 (d, 4J = 2.1 Hz, 1H),
7.86 (dd, J = 8.6 Hz, J = 2.1 Hz, 1H). 13C NMR (75 MHz, CDCl3)
3
4
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)
ν
max 3488, 3403, 1712, 1599 cmꢀ1. 1H NMR (300 MHz, CDCl3)
δ 3.59
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(s, 3H), 3.99 (s, 3H), 5.67 (bs, 1H, OH), 6.92 (d, 3J = 8.4 Hz, 1H), 7.27ꢀ7.33 (m, 2H), 7.36ꢀ7.49 (m,
1
2
3
3
3H), 7.56 (d, J = 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 71ꢀ74 °C. – Rf 0.30 (6:4 petroleum ether/M). IR (neat) νmax
4
5
6
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8
9
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3416 cmꢀ1. 1H NMR (300 MHz, CDCl3)
2.1 Hz, 1H), 6.84 (d, 4J = 2.1 Hz, 1H), 7.29ꢀ7.37 (m, 1H), 7.38ꢀ7.46 (m, 2H), 7.51ꢀ7.56 (m, 2H). 13
NMR (75 MHz, CDCl3) 152.4, 149.4, 140.9, 137.5, 135.1, 128.6, 127.2, 126.9, 107.0, 103.3,
δ
3.93 (s, 3H), 3.94 (s, 3H), 5.80 (bs, 1H, OH), 6.68 (d, 4J=
C
δ
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 102ꢀ104 °C. Rf 0.36 (silica, PET/M + 1% AcOH 3:7). IR (neat) νmax
3406 cmꢀ1. 1H NMR (300 MHz, CDCl3)
δ
3.95 (s, 3H), 5.38 (bs, 2H, OH), 6.70 (d, 4J = 1.8 Hz, 1H),
4
6.86 (d, J = 1.8 Hz, 1H), 7.28ꢀ7.35 (m, 1H), 7.38ꢀ7.45 (m, 2H), 7.50ꢀ7.56 (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). orthoꢀQuinol acetate 2a (480.4 mg,
2.0 mmol, 1 equiv) and 1,3,5ꢀtrihydroxybenzene 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
1
4
(neat) νmax 3288, 1680 cmꢀ1. H NMR (DMSOꢀd6, 300 MHz)
δ 3.91 (s, 3H), 6.23 (d, J = 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 (DMSOꢀd6,
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). orthoꢀQuinol acetate 2a (240.2
mg, 1.0 mmol, 1 equiv) and 3,5ꢀdimethoxyphenol 7c (770 mg, 5.0 mmol, 5 equiv) was dissolved in
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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 201ꢀ204 °C. Rf 0.49
1
(silica, PET/M + 1% AcOH 3:7). IR (neat) νmax 3403, 3140, 1683 cmꢀ1. H NMR (DMSOꢀd6, 300
MHz)
7.52 (s, 1H), 8.25 (s, 1H), 9.88 (bs, 1H, OH). 13C NMR (DMSOꢀd6, 75.5 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),
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)
9
10
11
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1
4
4
νmax 3288, 1682 cmꢀ1. H NMR (DMSOꢀd6, 300 MHz)
δ 6.20 (d, J = 2.4 Hz, 1H), 6.34 (d, J = 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 (DMSOꢀd6, 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: ꢁ
Full experimental details and characterization data for all compounds as well as
their 1H, 13C and DEPT NMR spectra
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AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: stefan.chassaing@itav.fr
*Eꢀmail: stephane.quideau@uꢀbordeaux.fr
ORCID
Stefan Chassaing: 0000ꢀ0001ꢀ5842ꢀ5288
Stéphane Quideau: 0000ꢀ0002ꢀ7079ꢀ9757
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.
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(16) For another relevant and recent Pdꢀcatalyzed method for the synthesis of oxygenated biaryl compounds
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