Suzuki-Miyaura coupling of halophenols and phenol boronic acids: Systematic investigation of positional isomer effects and conclusions for the synthesis of phytoalexins from pyrinae

Article abstract of DOI:10.1021/jo500675a

The Suzuki-Miyaura couplings of o-, m-, and p-halophenols with o-, m-, and p-phenol boronic acids were investigated for all combinations under standardized conditions, using Pd/C as a heterogeneous catalyst and water as a solvent. In the case of iodophenols, conventional heating was used, while for bromophenols significantly better results could be obtained using microwave irradiation. This systematic study revealed that 2,4′-biphenol is particularly difficult to access, irrespective of the starting materials used, but that these difficulties can be overcome by using different additives. The conclusions drawn from this investigation allowed us to identify conditions for the protecting group-free or minimized total synthesis of biaryl-type phytoalexins. These compounds possess antibacterial activity and are produced by fruit trees as a response to microbial infection.

Full text of DOI:10.1021/jo500675a

Article
pubs.acs.org/joc
Suzuki−Miyaura Coupling of Halophenols and Phenol Boronic Acids:
Systematic Investigation of Positional Isomer Effects and
Conclusions for the Synthesis of Phytoalexins from Pyrinae
Bernd Schmidt* and Martin Riemer
Institut fuer Chemie (Organische Synthesechemie), Universitaet Potsdam, Karl-Liebknecht-Straße 24-25, D-14476 Potsdam-Golm,
Germany
S
* Supporting Information
ABSTRACT: The Suzuki−Miyaura couplings of o-, m-, and p-
halophenols with o-, m-, and p-phenol boronic acids were
investigated for all combinations under standardized conditions,
using Pd/C as a heterogeneous catalyst and water as a solvent.
In the case of iodophenols, conventional heating was used, while
for bromophenols significantly better results could be obtained
using microwave irradiation. This systematic study revealed that
2,4′-biphenol is particularly difficult to access, irrespective of the
starting materials used, but that these difficulties can be
overcome by using different additives. The conclusions drawn
from this investigation allowed us to identify conditions for the
protecting group-free or minimized total synthesis of biaryl-type
phytoalexins. These compounds possess antibacterial activity
and are produced by fruit trees as a response to microbial
infection.
largely independent of the source and manufacturing process of
the Pd/C used, which is not necessarily the case for this
catalyst.22 Our main motivation for this study was the
occurrence of the 2,2′-biphenol structural pattern in various
plant-derived natural products, such as acerogenin E (1)23 or
magnolol (2).24 However, 2,2′-biphenols are not the only
common plant metabolites. Other examples are 2′-hydrox-
yaucuparin (o-3),25 3′-hydroxyaucuparin (m-3),26 and garcibi-
phenyl C (p-3),27 which are phytoalexins isolated from fruit
trees of the subtribe Pyrinae. The plants produce these
compounds in response to infection with bacterial diseases
such as fire flight, which may cause severe economic damages in
fruit tree plantations.28 Apart from the biphenols, partially
methylated derivatives (e.g., rhaphiolepsin (4),29 2′-methox-
yaucuparin (o-5),30,31 and 4′-methoxyaucuparin (p-5)29,30), a
benzodioxol derivative 6,32,33 or partially deoxygenated
derivatives (e.g., aucuparin (7a)25,34 or its 3-O-demethylated
derivative 7b34) have also been isolated and identified as
Pyrinae metabolites (Figure 1).
INTRODUCTION
■
Since its discovery in the late 1970s, the Suzuki−Miyaura
coupling1 has emerged as one of the most widely used C−C-
bond forming reactions.2 In particular, its potential for the
synthesis of biaryls3 has led to numerous applications, not only
on laboratory scale but also in process chemistry.4 In the latter
field, the development of more active catalyst/ligand
combinations has been an important topic because for large-
scale applications low catalyst loadings and the use of the
cheaper but less reactive aryl chlorides or bromides is required
for economic reasons.5 Other important developments include
the search for alternative organoboron reagents,6−8 the use of
immobilized catalysts, in particular Pd/C,9,10 heating by
microwave irradiation,11 and using water as an environmentally
benign solvent.12,13 It has also been reported that two or more
of these special reaction conditions can be advantageously
combined, e.g., by conducting Suzuki−Miyaura coupling
reactions in water under microwave irradiation and with Pd/
C as an easily recoverable catalyst.14−20
Based on this literature precedence, we have recently
investigated the protecting group-free synthesis of 2,2′-
biphenols via Suzuki−Miyaura coupling of 2-iodo- or 2-
bromophenols with 2-boronophenols.21 Essentially, we were
able to establish user-friendly protocols for this cross-coupling
using commercial Pd/C as a catalyst, water as a solvent, and
heating by microwave irradiation for the less reactive
bromophenols. Notably, we were able to show that the success
of Suzuki−Miyaura couplings under these reaction conditions is
When we started to investigate protecting group-free
syntheses of phytoalexins of the 4,n′-biphenol type using our
previously established standard conditions,21 we quickly
discovered that some of these compounds were inaccessible
in synthetically useful yields. This observation prompted us to
systematically investigate all possible combinations of regioiso-
Received: March 24, 2014
Published: April 11, 2014
© 2014 American Chemical Society
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obtained only in mediocre conversion and yield. Obviously,
combinations in which both coupling partners possess an
electron-donating phenolate ortho- or para- to the reacting site
are disfavored, with the exception of the ortho-,ortho-
combination leading to 10a in quantitative yield. Our search
for an explanation for this remarkably different reactivity led us
to investigate the cross-coupling of the three regioisomeric
iodophenols (o-,m-,p-)-8a with the less electron-rich phenyl-
boronic acid 11 under our standard conditions (Scheme 1).
Electronic and steric effects have often been used to rationalize
different reactivities of haloarenes in cross-coupling reactions,
which is particularly important for regioselective trans-
formations of polyhalogenated aromatic compounds.35−37 In
most cases, the oxidative addition step is believed to be rate-
limiting, and a linear Hammett relationship has been found for
the rate constants of the oxidative addition of various para-
substituted iodobenzenes to a Pd(0)−phosphine complex.38
The authors of this study drew an analogy between nucleophilic
aromatic substitution and oxidative addition of haloarenes to
transition metals, which means that the oxidative addition
should be faster for electron-deficient haloarenes.38 This is in
line with an NMR-based model for predicting the order of
reactivity in cross-coupling reactions of polyhalogenated
hetarenes.39 The higher rates of oxidative addition observed
for haloarenes bearing electron-withdrawing substituents is also
in line with DFT studies of the mechanism40 that correlate the
energy barriers of oxidative addition with the energy levels of
the C−X σ*- and π*-orbitals.41 Based on computational
methods, Houk, Merlic, and co-workers proposed three crucial
molecular orbital interactions for the site-selective oxidative
addition of polyhalogenated hetarenes to a Pd(0)L2 complex:
dxy(Pd) → σ*(C−X), σ(C−X) → py(Pd), and dxy(Pd) →
π*(C−X). They found that the ease of oxidative addition, and
hence site selectivity, depends crucially on the HOMO−
LUMO gap, which is obviously a function of the energy of the
arene LUMO.42
Figure 1. Naturally occurring biphenols.
From the results shown in Scheme 1, it can be seen that all
three regioisomeric iodophenols 8a react with phenylboronic
acid (11) under standardized conditions in high yields and
selectivities to give the expected o-, m-, and p-hydroxybiphenyls
(o-,m-,p-12). In light of these results, it appears unlikely that
different reactivities of the three iodophenols in the oxidative
addition step are solely or predominantly responsible for the
unsatisfactory yields of biphenols 10c and 10f, although this
factor might well play a certain role for the overall outcome of
the cross-coupling reactions.
meric halophenols 8 and boronophenols 9 in Pd/C-catalyzed
aqueous Suzuki−Miyaura cross-coupling reactions, to identify
regioisomers which are difficult to access, and to devise
optimized protocols for these particular cases. In the next step,
we wanted to check whether conclusions drawn from this study
can assist in planning and executing the synthesis of various
phytoalexins from Pyrinae, in particular, compounds 3−7
shown in Figure 1.
We continued our investigation into the reasons for the low
conversions to biphenols 10c,f by reinvestigating the reaction of
p-8a and o-9 (Table 2). Testing various relative proportions of
o-boronophenol and additives other than K2CO3 appeared to
be most promising, and we therefore started with these
parameters. In all of these optimization experiments, the
RESULTS AND DISCUSSION
■
Systematic Study of All Regioisomeric Iodophenol/
Boronophenol Combinations. To study the effect of
positional isomerism of the coupling partners on the reactivity
in the Suzuki−Miyaura cross-coupling, o- (o-8a), m- (m-8a),
and p-iodophenol (p-8a) were reacted with o- (o-9), m- (m-9),
and p-boronophenol (p-9) in water in the presence of 4 equiv
of K2CO3 and 2 mol % of commercial Pd/C as a precatalyst at
80 °C (Table 1). These are the optimized conditions for the
protecting group-free synthesis of 2,2′-biphenols.21
1
conversion was quantified by H NMR spectroscopy based on
1,3,5-trimethoxybenzene as an internal standard. For economic
reasons and to simplify product isolation we had so far only
used equimolar amounts of the coupling partners. In the first
optimization experiments, the amount of o-boronophenol (o-9)
was increased in steps of 0.25 equiv until 2.00 equiv of the
boronic acid was present. All other parameters were maintained
from the standard conditions (entries 1−5). We transcribed the
results listed in Table 2, entries 1−5, into the graph shown in
Figure 2. The conversion of 4-iodophenol (p-8a) to 2,4′-
biphenol (10c) increases nearly linearly with the amount of o-
For almost all combinations, the conversions to the expected
biphenols 10 were reproducibly higher than 90%, correspond-
ing to yields between 80% and 98%. Notable exceptions are
both combinations leading to 2,4′-biphenol (10c), which
proceed with conversions lower than 20%, and the cross
coupling of p-8a and p-9 to 4,4′-biphenol (10f), which was
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Table 1. Suzuki−Miyaura Cross-Coupling of Iodophenols 8 and Boronophenols 9
a
1
Conversion/yield are reported in parentheses following the compound number. Conversion was determined on a 0.25 mmol scale by H NMR
analysis of the crude reaction mixture with 1,3,5-trimethoxybenzene as internal standard.
Scheme 1. Cross-Coupling of Regioisomeric Iodophenols 8a
with Phenylboronic Acid (11)
Table 2. Optimization of Reaction Conditions for the
Combination p-8a/o-9
a
entry n (equiv of o-9) base (equiv)
additive (equiv)
none
conv (%)
1
2
1.00
1.25
1.50
1.75
2.00
1.00
1.00
1.00
1.00
1.00
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
none
25
38
none
boronophenol (o-9) and reaches 88% when 2 equiv of o-9 is
used.
3
none
52
4
none
75
This observation might possibly be rationalized by assuming
that o-boronophenol (o-9) is deprotonated under the reaction
conditions to a phenolate o-13, which will be less electrophilic
at the boron center than the protonated parent compound or
an analogous alkyl ether. Similarly, deprotonation of the
phenolic hydroxy group in p-9 should also give a phenolate p-
13 with reduced Lewis acidity at the boron, whereas phenol
deprotonation should affect the Lewis acidity only to a minor
extent in the case of m-9 (Scheme 2).
5
none
88
6
B(Oi-Pr)3 (2.00)
B(Oi-Pr)3 (4.00)
BF3·CH3OH (2.00)
BF3·CH3OH (4.00)
KF (4.00)
31
7
37
8
41
9
75
10
>98
a
Conversion was determined by 1H NMR of the crude reaction
mixture with 1,3,5-trimethoxybenzene as internal standard.
A certain degree of Lewis acidity, however, is essential for the
transmetalation step, which is believed to proceed through a
hydroxy-Pd species C formed via substitution of the halide in B
by OH− after the oxidative addition step.7,43−45 This
mechanistic scenario involves the attack of the Pd-bound OH
group at the boron to form an intermediate D, which
subsequently fragments in the actual transmetalation event to
the Pd−diaryl complex E. The catalyst A is then regenerated by
reductive elimination of the biaryl Ar−Ar′ (Scheme 3).
Under our reaction conditions, the formation of the crucial
borate intermediate D might be disturbed by the reduced Lewis
acidity of the phenolates o-13 and p-13, which might account
for the low yields of biphenols 10c and 10f reported in Table 1
when equimolar amounts of the coupling partners were used.
The observation that the conversion to biphenol 10c increases
linearly with the amount of o-boronophenol (o-9) can be
explained by assuming borate formation between phenolate o-
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Figure 3. (a) Dimeric borate structure 14 with one capped phenolate
that might explain the beneficial effect of excess boronic acid. (b)
Proposed borate tethered transmetalation as a rationale for the high
reactivity of o-8a and o-9.
Figure 2. Influence of the molar ratio of o-9 to p-8a on the conversion
to 10c. Reactions were run under standard conditions stated in Table
1. Conversions were determined by H NMR spectroscopy of crude
1
reaction mixtures with 1,3,5-trimethoxybenzene as internal standard.
Scheme 2. Influence of Boronophenolate Formation on
Lewis Acidity of the Boronic Acid
One might even go one step further and propose the formation
of a palladacycle 15b through nucleophilic intramolecular attack
of the boronophenolate at the Pd. From 15b, the trans-
metalation would also be an intramolecular process and
probably furnish the cyclic borate 15c, which would eventually
undergo reductive elimination as an intramolecular process, due
to the boronate tether between the two phenolate oxygens
(Figure 3b). Admittedly, these mechanistic rationales are at
present purely speculative and we cannot provide any proof
beyond the circumstantial experimental evidence discussed
above. In particular, we could not yet observe borate structures
using spectroscopical methods. In light of a recent report by Yu
and Shi,46 however, our mechanistic speculations appear
plausible. These authors reported a Suzuki−Miyaura coupling
of naphtholates and boronic acids through “mutual activation”,
that is by formation of a Lewis acid/Lewis base adduct between
a phenolate and the boronic acid.
While improving the yield of 10c by increasing the amount
of o-boronophenol (o-9) as shown in Table 2, entries 1−5, and
Figure 2 is quite effective, it is unfortunately expensive and
complicates product isolation and purification. This led us to
return to using equimolar ratios of the reactants p-8a and o-9
and test a variety of additives for tuning this disfavored
combination. Based on the assumption that excess boronic acid
reacts with the o-boronophenolate to a boronate 14 (Figure 3a)
which maintains the required degree of Lewis acidity at the
boron, we reasoned that other Lewis acids should be similarly
effective. To test this hypothesis, the comparatively mild Lewis
acid tris-isopropoxy borate was added. With 2.00 (entry 6) and
4.00 (entry 7) equiv a small but noticeable improvement of the
conversion was observed. The stronger Lewis acid boron
trifluoride−methanol was significantly more effective, in
particular when 4 equiv was used (entries 8 and 9). However,
this is most likely not caused solely by the enhanced Lewis
acidity and the more efficient capping of the phenolate, but at
least to a certain extent by the hydrolysis of the Lewis acid and
the liberation of fluoride. It should be noted in this context that
potassium organotrifluoroborates, increasingly used nucleo-
philic coupling partners for Suzuki−Miyaura coupling reac-
tions,6,8 are also prone to hydrolysis47−51 and that the fluoride
ions liberated in the process coordinate to the catalytically
active species. It has been proposed that palladium-bound
fluoride promotes the transmetalation similar to a Pd-bound
hydroxide through a Lewis acid/Lewis base interaction
(analogous to structure D in Scheme 3). A second beneficial
Scheme 3. Mechanistic Scenario for the Transmetalation
Step via Hydroxy-Pd Pathway7
13 and excess boronic acid. In such a dimeric structure 14, the
electrophilicity of one boronic acid should be maintained,
whereas the other boron is present as a tetracoordinate
boronate, which might react through a competing trans-
metalation pathway (Figure 3a).
A similar reasoning might be used to explain why equimolar
amounts of o-8a and o-9 react to 2,2′-biphenol (10a)
quantitatively (see Table 1 and ref 21), although one would
expect this combination to be disfavored as both coupling
partners are present as phenolates under the reaction
conditions and hence very electron rich: upon oxidative
addition of the 2-iodophenol to the Pd (and possibly
substitution of the iodide by hydroxide) we speculate that a
borate 15a is formed, from which the nucleophilic aryl
substituent can be transferred to the Pd intramolecularly.
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Table 3. Unfavorable Combinations under Fluoride-Promoted (Base-Free) Conditions
a
Table 4. Suzuki−Miyaura Cross-Coupling of Iodophenols 8a and Methoxyphenylboronic Acids 16
a
b
Yields in parentheses. 1.3 equiv of boronic acid used.
effect of fluoride can be a facilitated reductive elimination of the
product by coordination of fluoride to the tetracoordinate Pd−
diaryl complex resulting from transmetalation (structure E in
Scheme 3).52 The enhancement of the transmetalation step by
bridging Pd and B via a fluoride ligand has, however, been
questioned. Instead, it has been suggested that fluoride
enhances the nucleophilicity of water through strong hydrogen
bonding and thereby facilitates the formation of a Pd−hydroxy
complex C, which is primarily responsible for catalytic
turnover.7,53 These considerations and previously reported
protocols for Suzuki−Miyaura couplings using alkali fluorides
as additives54,55 prompted us to repeat the reaction without any
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a
Table 5. Suzuki−Miyaura Cross-Coupling of Iodomethoxybenzenes 18a and Methoxyphenylboronic Acids 16
a
Yields in parentheses.
a
Table 6. Suzuki−Miyaura Cross-Coupling of Iodomethoxybenzenes 18a and Boronophenols 9
a
Yields in parentheses.
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a
Table 7. Cross-coupling of Bromoarenes under Microwave Irradiation
entry
Ar-Br
Ar′-B(OH)2
additive
R
R′
Ar-Ar′
yield (%)
1
o-8b
o-9
KOH
H
H
10a
10b
10c
10c
10b
10d
10e
10c
10c
10e
10f
83
87
33
90
80
94
87
<20
93
96
96
<10
90
46
89
85
94
91
93
95
94
96
62
65
81
80
71
72
87
78
63
61
64
62
86
71
52
76
69
67
2
o-8b
m-9
p-9
KOH
H
H
3
o-8b
KOH
H
H
4
o-8b
p-9
NBu4F
KOH
H
H
5
m-8b
m-8b
m-8b
p-8b
o-9
H
H
6
m-9
p-9
KOH
H
H
7
KOH
H
H
8
o-9
KOH
H
H
9
p-8b
o-9
NBu4F
KOH
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
p-8b
m-9
p-9
H
H
p-8b
KOH
H
H
o-8b
o-16
o-16
m-16
m-16
p-16
o-16
m-16
p-16
o-16
m-16
p-16
o-16
m-16
p-16
o-16
m-16
p-16
o-16
m-16
p-16
o-9
KOH
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
17a
17a
17b
17b
17c
17d
17e
17f
o-8b
NBu4F
KOH
H
o-8b
H
o-8b
NBu4F
KOH
H
o-8b
H
m-8b
m-8b
m-8b
p-8b
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
H
H
H
H
17g
17h
17i
p-8b
H
p-8b
H
o-18b
o-18b
o-18b
m-18b
m-18b
m-18b
p-18b
p-18b
p-18b
o-18b
o-18b
o-18b
m-18b
m-18b
m-18b
p-18b
p-18b
p-18b
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
19a
19b
19c
19b
19d
19e
19c
19e
19f
17a
17d
17g
17b
17e
17h
17c
17f
m-9
p-9
H
H
o-9
H
m-9
p-9
H
H
o-9
H
m-9
p-9
H
H
17i
a
See Tables 1 and 4−6 for structural formulas of products 10, 17, and 19.
base, but in the presence of potassium fluoride under otherwise
identical conditions (Table 2, entry 10). Gratifyingly, the
conversion to the desired 2,4′-biphenol (10c) was quantitative.
We attribute this remarkable improvement not only to the
“fluoride effect” discussed above but also to a smaller amount of
o-boronophenolate o-13 under these base-free (or at least less
basic) conditions and, hence, a higher electrophilicity at the
boron.
under these conditions and furnish 2,4′-biphenol in syntheti-
cally useful yields of 87% and 76%, respectively. In contrast, the
p-,p-combination remains problematic, as the yield of 4,4′-
biphenol (10f) could not be improved compared to the
standard conditions used to obtain the results shown in Table
1.
Systematic Study of All Regioisomeric Iodophenol/
Methoxyphenyl Boronic Acid Combinations. As phenol
deprotonation of the boronophenols under our aqueous basic
standard conditions might possibly be a reason for the
unsatisfactory results obtained in some experiments, we decided
With these results in hand, we reinvestigated the three
“unfavorable” combinations shown in Table 1. As can be seen
from the results in Table 3, both o-,p-combinations work well
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to repeat the systematic investigation of the various regioisomer
combinations for iodophenols 8a and the methoxy analogues
16 of the previously tested boronophenols 9. As can be seen
from the results in Table 4, almost all combinations give the
expected biaryls in high yields with equimolar amounts of the
coupling partners. A notable exception was the combination of
o-8a and o-16, which furnished the o-,o-disubstituted biphenyl
17a only in a moderate yield of 64%. Remarkably, for the
analogous coupling reactions of boronophenols the o-,o-
combination was among the most reactive (see Table 1 for
comparison). The comparatively low yield of 17a might result
from steric hindrance and the inability of the reactants to form
a dimeric borate, as discussed for the formation of 2,2′-biphenol
(10a) in Figure 3. By increasing the amount of boronic acid o-
16 to 1.3 equiv a quantitative conversion to 17a was achieved,
which was isolated in 95% yield. By the same measure, the
yields of 17b and 17c were improved by ca. 10%.
Systematic Study of All Regioisomeric Iodomethox-
ybenzene/Methoxyphenylboronic Acid Combinations.
In the next step, we tested the aqueous basic Suzuki−Miyaura
coupling conditions for all regioisomeric combinations of
iodophenol methyl ethers 18 and methoxyphenylboronic acids
16. The results in Table 5 show that the yields of coupling
products obtained with equimolar amounts of reactants are
synthetically useful but in most cases lower than those reported
for the iodophenol/boronophenol or the iodophenol/methoxy
phenylboronic acid combinations. This is probably not
exclusively caused by electronic effects of the substituents but
more likely to a larger extent by the limited solubility of the aryl
iodides 18a under the aqueous basic reactions conditions.
Systematic Study of All Regioisomeric Iodomethox-
ybenzene/Boronophenol Combinations. To conclude this
part of the study, we tested the standardized reaction
conditions for all combinations of regioisomeric iodomethox-
ybenzenes 18a and boronophenols 9 (Table 6). For all
products 17a−i the yields are significantly lower via this route
than for the iodophenol/methoxyphenylboronic acid combina-
tion (see Table 4 for comparison). In particular, all reactions
with p-boronophenol (p-9) give the desired coupling products
only in trace amounts, which is partly in agreement with the
results obtained for the synthesis of biphenols 10 (see Table 1
for comparison). As a possible explanation for these very low
yields, we suggest a combination of two factors. The
boronophenols will be deprotonated and therefore most likely
deactivated under the aqueous basic conditions. Additionally, in
contrast to the iodoarenes the boronophenolates will readily
dissolve in the aqueous medium, resulting in a phase separation
of the two reactants.
the synthesis of biphenols 10, their monomethyl ethers 17, and
their dimethyl ethers 19. In this study, the standardized
conditions using microwave irradiation were applied to all
possible combinations of bromoarenes 8b or 18b and boronic
acids 9 or 16. As can be seen from the results listed in Table 7,
all 36 combinations give the desired biaryls in synthetically
useful and sometimes even excellent yields. We comment only
on some experiments specifically.
Out of all bromophenol/boronophenol combinations
(entries 1−11), unsatisfactory results were only obtained for
o-8b/p-9 (entry 3) and p-8b/o-9 (entry 8) using KOH as a
base. Interestingly, low conversions to the expected product
10c were also found with the corresponding iodophenols for
both combinations under conventional heating conditions (see
Table 1 for comparison). Replacing the base KOH by the
fluoride source NBu4F led to increased yields of ca. 90%
(entries 4 and 9). 4,4′-Biphenol (10f) was isolated only in
moderate yields of ca. 40% from p-iodophenol (p-8a) under
thermal conditions with either K2CO3 as a base (Table 1) or
KF as an additive (Table 3, entry 3). In contrast, 10f was
obtained from p-bromophenol (p-8b) under microwave
irradiation in the presence of KOH in nearly quantitative
yield (entry 11).
Out of the three reactions of o-8b with the regioisomeric
methoxyphenylboronic acids 16 (entries 12−16), only the
combination o-8b/p-16 worked well under basic conditions
(entry 16). The cross-couplings with m- and p-16 could be
significantly tuned by switching to NBu4F as a rate-accelerating
additive (entries 13 and 15), which resulted in yields of ca. 90%
for 17a and 17b. From the experiments discussed so far, we
came to the conclusion that the additive NBu4F leads more
reliably to good results than the base KOH for most
combinations. For these reasons, only the fluoride was tested
for the remaining combinations. All reactions of m- and p-8b
with the three boronic acids 16 proceeded in yields higher than
90% for the expected monoethers 17 (entries 17−22). In
general, the yields of coupling products 17a−i are marginally
higher for reactions with bromophenols 8b under microwave
irradiation compared to the use of the analogous iodophenols
and conventional heating.
For the synthesis of dimethyl ethers 19 (entries 23−31),
yields vary between 62% and 87% under microwave conditions,
whereas the yields for conventional heating (see Table 5) range
from 58% to 93%. For these examples, we cannot state that
either one or the other method is clearly superior with respect
to yields.
A group of cross-coupling reactions which worked
significantly better with microwave irradiation than with
conventional heating are the halomethoxyarene/boronophenol
combinations (entries 32−40). Most yields of coupling
products 17 vary between 61% and 76%. The lowest yield
was observed for the reaction of m-18b and p-9 to 17h (52%,
entry 37), whereas the combination m-18b and o-9 furnished
17b in a yield of 86%, which is significantly above average for
this set of combinations. Particularly noteworthy is that p-
boronophenol (p-9) undergoes a cross coupling reaction with
all three regioisomers of 18b to the expected biaryls 17g,h,i,
respectively, in acceptable yields (entries 34, 37, and 40). Under
conventional heating and starting from the analogous
iodoarenes 18a, conversion to these cross-coupling products
was lower than 10% (see Table 6 for comparison). All other
combinations of regioisomers of 18a and boronophenols 9 gave
the products 17a−f in yields ranging from 25% to 47%.
Synthesis of All Regioisomeric Biphenols and Their
Mono- and Dimethyl Ethers from Bromoarenes.
Bromoarenes are cheaper and normally more conveniently
synthesized than the analogous iodoarenes, which can in part
be attributed to the light-sensitivity of many organic iodo
compounds. Unfortunately, bromoarenes are also generally less
reactive in Pd-catalyzed coupling reactions. In our previous
study,21 we discovered for some examples with a 2,2′-biphenol
substitution pattern that this drawback can be efficiently
compensated or even overcompensated by heating the aqueous
reaction mixture by microwave irradiation. In these experi-
ments, KOH was used as a base or alternatively NBu4F as a less
basic rate accelerating additive. The very useful results obtained
in these experiments prompted us to transfer the conditions for
microwave accelerated aqueous Suzuki−Miyaura couplings to
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Notably, the m-18/o-9 combination leading to 17b is the most
reactive one in this set of combinations under both conditions.
Irrespective of the heating conditions and the halide present in
the electrophilic coupling partner, it can be concluded that the
monomethyl ethers 17 are advantageously synthesized from
halophenols 8 (entries 12−22) rather than from the analogous
methyl ethers 18 (entries 32−40).
KOH rather than NBu4F in most cases. The reactivity trend
observed for the cross coupling of 4-halophenols p-8a or p-8b
and the regioisomeric boronophenols 9 (see, e.g., Table 1 for
comparison) correlates well with the results for the synthesis of
the natural products hydroxyaucuparines o-3 and m-3 and
garcibiphenyl C (p-3) (Table 8, entries 7−13). The m-
boronophenol (m-9) was found to be most reactive, followed
by the p-isomer p-9. As observed previously for the
combination p-8a and o-9 (or o-8a and p-9, see Table 1), the
cross-coupling of 21 and o-boronophenol (o-9) failed even
under the normally more effective microwave-accelerated
standard conditions, regardless of the additive used. 2′-
Hydroxyaucuparin (o-3) was eventually isolated in a moderate
yield of 37% by increasing the amount of o-boronophenol (o-9)
to 2.6 equiv (entry 13). All other phytoalexins synthesized from
21 were obtained in fair to good yields.
Next, the syntheses of rhaphiolepsin (4) and 3-de-O-
methylaucuparin (7b) were addressed, which require the
bromoarene 24 and the boronic acids p-16 or 11 as starting
materials. In a first experiment, 24 and p-16 were coupled
under standard conditions using the additive KOH (Table 9).
We could isolate the target molecule 4 only in a very low
yield of 15% (entry 1). This is insofar surprising, as the cross
coupling leading to the structurally closely related 4′-
methoxyaucuparin (p-5) works well under identical conditions
(see Table 8, entry 6). We suspected that the second acidic
group of the bromoarene is responsible for the low yield and
tested therefore the less basic additive NBu4F, but to no avail
(entry 2). Increasing the relative amount of additive to 6.0
equiv showed opposite effects for the two additives tested:
while the yield of the cross coupling product 4 dropped below
10% with 6.0 equiv of KOH, a slightly better result was
obtained with NBu4F (entries 3 and 4). A significant
improvement was eventually achieved by using a larger excess
of boronic acid and KOH as an additive (entry 5). As for the
cross-coupling reactions listed in Table 8, KOH appears to be
the superior rate-accelerating additive. Further increasing the
amount of boronic acid p-16 gives only a marginally higher
yield of rhaphiolepsin (4) (entry 7). Very similar results were
also obtained for the cross coupling of 24 and 11, which leads
to the natural product 3-de-O-methylaucuparin (7b). Under
standard conditions, both additives resulted in unsatisfactory
yields of 28% and 20%, respectively (entries 8 and 9). With a
relative amount of 2.6 equiv of boronic acid 11, however, 7b
was isolated in significantly higher yields of 74% and 65%,
respectively (entries 10, 11). As for the other cross-coupling
reactions involving bromoarene 24, KOH is the preferred
additive.
Application of Microwave Accelerated Aqueous
Suzuki−Miyaura Coupling in the Synthesis of Phytoa-
lexins. With the results obtained from the systematic
investigation of all haloarene/boronic acid cross-coupling
combinations in hand, we set out to synthesize the phytoalexins
3−7 shown in Figure 1. For the synthesis of target molecules,
the reactivity in cross-coupling reactions is only one criterion
for deciding which coupling partner is assigned the electrophilic
and which one the nucleophilic role. Equally important is the
accessibility of the starting materials required for the envisaged
combination. This led us to syntheses of the nine biaryl-type
phytoalexins 3−7 in which the less substituted aryl moiety is
introduced as a boronic acid and the more substituted one as an
aryl bromide. For the synthesis of aucuparin (7a), the
regioisomeric hydroxyaucuparins (3), and methoxyaucuparins
(5), the bromoarene 21 was required, which was synthesized
from 2,6-dimethoxyphenol (20) following a literature proce-
dure (Scheme 4).56,57
Scheme 4. Synthesis of Bromoarene 21
For rhaphiolepsin (4) and 3-de-O-methylaucuparin (7b), we
needed 5-bromo-3-methoxycatechol (24), which was also
synthesized according to a literature procedure in two steps
from vanillin (22).58 The intermediate bromovanillin 23 was
used in the second step without purification. The same authors
described the O-methylenation leading to the benzodioxole 25,
which is the starting material required for the synthesis of the
remaining biaryl natural product 6. We modified the literature
procedure58 by replacing bromochloromethane as the meth-
ylenating agent by diiodomethane (Scheme 5).
Phytoalexins with a 1-aryl-4-hydroxy-3,5-dimethoxy substitu-
tion pattern were synthesized from bromoarene 21 and boronic
acids 9, 11, and 16, respectively, using the standard conditions
established in the optimization experiments. The results are
summarized in Table 8. In contrast to the optimization
experiments, better yields were obtained using the additive
For the synthesis of the unnamed natural product 6 we
considered originally a two-step sequence comprising a cross
coupling of 24 and m-boronophenol (m-9), followed by
methylenation of the vic-diol moiety. However, the difficulties
observed for the cross-coupling reactions involving diol 24 (see
Table 9) prompted us to use bromoarene 25 (Scheme 5) and
m-boronophenol (m-9) as cross-coupling partners. Gratifyingly,
application of our standard conditions for the microwave-
accelerated aqueous Suzuki−Miyaura coupling furnished the
natural product 6 in good yield without any further
optimization efforts (Scheme 6).
Scheme 5. Synthesis of Bromoarenes 24 and 25
CONCLUSIONS
■
In summary, we could demonstrate that all regioisomeric n,n′-
biphenols and their mono- and dimethyl ethers are accessible
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Table 8. Synthesis of Phytoalexins 3, 5, and 7a Derived from 21
entry
ArB(OH)2 (equiv)
R1
R2
R3
additive
natural product (no.)
yield (%)
1
11 (1.3)
H
H
H
NBu4F
KOH
aucuparin (7a)
62
75
49
47
48
67
34
72
35
52
<5
<5
37
2
11 (1.3)
H
H
H
aucuparin (7a)
3
o-16 (1.3)
o-16 (1.3)
p-16 (1.3)
p-16 (1.3)
m-9 (1.3)
m-9 (1.3)
p-9 (1.3)
p-9 (1.3)
o-9 (1.3)
o-9 (1.3)
o-9 (2.6)
OMe
OMe
H
H
H
NBu4F
KOH
2′-methoxyaucuparin (o-5)
2′-methoxyaucuparin (o-5)
4′-methoxyaucuparin (p-5)
4′-methoxyaucuparin (p-5)
3′-hydroxyaucuparin (m-3)
3′-hydroxyaucuparin (m-3)
harcibiphenyl C (p-3)
garcibiphenyl C (p-3)
4
H
H
5
H
OMe
OMe
H
NBu4F
KOH
6
H
H
7
H
OH
OH
H
NBu4F
KOH
8
H
H
9
H
OH
OH
H
NBu4F
KOH
10
11
12
13
H
H
OH
OH
OH
H
NBu4F
KOH
2′-hydroxyaucuparin (o-3)
2′-hydroxyaucuparin (o-3)
2′-hydroxyaucuparin (o-3)
H
H
H
H
KOH
Table 9. Optimization of Suzuki−Miyaura Couplings with
tional heating conditions are in most cases sufficient to obtain
the desired coupling products in good yields, whereas
microwave heating was used advantageously for the corre-
sponding bromophenols and their methyl ethers. Our study
revealed that certain combinations of boronophenols and
halophenols are disfavored, resulting in low yields of the
biphenol coupling products, but that this problem can often be
overcome by using fluorides as rate-accelerating additives. The
optimized microwave-accelerated cross-coupling conditions
were eventually applied to the synthesis of nine naturally
occurring phytoalexins with biaryl structure. In further studies,
we will investigate how these conditions can be applied to other
natural or non-natural target molecules with biaryl moieties.
Bromoarene 24
Ar-B(OH)2
(equiv)
product (yield,
%)
entry
additive (equiv)
KOH (4.0)
R
1
p-16 (1.3)
p-16 (1.3)
p-16 (1.3)
p-16 (1.3)
p-16 (2.6)
p-16 (2.6)
p-16 (3.0)
11 (1.3)
OMe
4 (15)
4 (15)
4 (<10)
4 (24)
4 (70)
4 (40)
4 (72)
7b (28)
7b (20)
7b (75)
7b (65)
2
NBu4F·3H2O (4.0) OMe
KOH (6.0) OMe
NBu4F·3H2O (6.0) OMe
KOH (4.0) OMe
NBu4F·3H2O (4.0) OMe
EXPERIMENTAL SECTION
■
3
General Methods. All experiments were conducted in dry reaction
vessels under an atmosphere of dry nitrogen. Solvents were purified by
standard procedures. Deionized water was used for the cross-coupling
reactions. 1H NMR spectra were obtained at 300 MHz in CDCl3 with
CHCl3 (δ = 7.26 ppm) as an internal standard. Coupling constants are
given in hertz. 13C NMR spectra were recorded at 75 MHz in CDCl3
with CDCl3 (δ = 77.0 ppm) as an internal standard. Whenever the
solubility of the sample was insufficient in CDCl3, one of the following
solvents was used for NMR measurements: DMSO-d6 (DMSO-d5 as
internal standard for 1H NMR spectroscopy, δ = 2.50 ppm, DMSO-d6
as internal standard for 13C NMR spectroscopy, δ = 39.5 ppm);
4
5
6
7
KOH (4.0)
OMe
H
8
KOH (4.0)
9
11 (1.3)
NBu4F·3H2O (4.0)
KOH (4.0)
H
10
11
11 (2.6)
H
11 (2.6)
NBu4F·3H2O (4.0)
H
Scheme 6. Synthesis of Unnamed Natural Product 6
1
methanol-d4 (CD2HOD as internal standard for H NMR spectros-
copy, δ = 3.31 ppm, CD3OD as internal standard for 13C NMR
spectroscopy, δ = 49.2 ppm; acetone-d6 (CD2HC(O)CD3 as internal
1
standard for H NMR spectroscopy, δ = 2.05 ppm, CD3C(O)CD3 as
internal standard for 13C NMR spectroscopy, δ = 29.9 ppm). IR
spectra were recorded as ATR-FTIR spectra. Wavenumbers (ν) are
given in cm−1. The peak intensities are defined as strong (s), medium
(m), or weak (w). Low- and high-resolution mass spectra were
obtained by EI/TOF. Microwave reactions were carried out in an
Anton-Paar-monowave-300 reactor at 150 °C (monowave, maximum
power 850 W, temperature control via IR-sensor, vial volume: 20 mL).
Halophenols o-,m-,p-8a,b and o-,m-,p-18a,b, and boronic acids o-,m-,p-
9, 11 and o-,m-,p-16 were purchased and used without further
purification. The Pd/C used for all experiments was purchased from
Sigma-Aldrich (product no. 205699, 9.8−10.2% Pd on dry support,
via Suzuki−Miyaura cross coupling of the regioisomeric
haloarenes and the regioisomeric boronophenols or their
respective methyl ethers in water, using commercial Pd/C as
a catalyst. With iodophenols or their methyl ethers conven-
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reduced, average particle size of the carbon is 15 μm, surface area of
the carbon support is 750−1000 m2·g−1).59
NMR (75 MHz, methanol-d4) δ 157.1, 154.9, 131.4, 131.4, 129.8,
128.8, 128.4, 121.0, 116.8, 115.8; IR (ATR) ν 3331 (bm), 1608 (m),
+
General Procedure for the Synthesis of Biaryls 10, 12, 17,
and 19 from Iodoarenes 8a or 18a under Thermal Conditions
(Procedure A). The appropriate iodophenol 8a (150 mg, 0.75 mmol
or 100 mg, 0.50 mmol) or iodoanisol 18a (176 mg, 0.75 mmol or 217
mg, 0.50 mmol) and the appropriate boronic acid 9 (104 mg, 0.75
mmol, 1.0 equiv or 69 mg, 0.50 mmol, 1.0 equiv or 97.5 mg, 0.65
mmol, 1.3 equiv, as indicated in the corresponding Tables 1 to 6), 11
(91.5 mg, 0.75 mmol, 1.0 equiv), or 16 (76 mg, 0.50 mmol, 1.0 equiv
or 99 mg, 0.65 mmol, 1.3 equiv as indicated in the table) were
suspended in water (10.0 mL/mmol). To the suspension was added
either K2CO3 (4.0 equiv, 415 mg, 3.00 mmol or 276 mg, 2.00 mmol)
or KF (4.0 equiv, 174 mg, 3.00 mmol or 116 mg, 2.00 mmol) as
indicated in the corresponding Table 7, followed by Pd/C (10 wt %, 2
mol %; 15 mg for 0.75 mmol or 10 mg for 0.5 mmol scale). The
mixture was immersed in an oil bath preheated to 80 °C for 2.5 h,
cooled to ambient temperature, and carefully acidified by addition of
aqueous HCl (1.0 M). It was extracted three times with MTBE
(methyl tert-butyl ether, 50 mL each), and the organic layers were
separated and dried with MgSO4, filtered, and evaporated in vacuo.
The residue was purified by column chromatography on silica using
hexane/MTBE mixtures of increasing polarity as eluents.
1482 (s), 1218 (s), 1172 (s); HRMS (EI) calcd for C12H10O2 [M+]:
186.0681, found: 186.0682. Anal. Calcd for C12H10O2 (186.21): C,
77.4; H, 5.4. Found: C, 77.4; H, 5.2.
Biphenyl-3,3′-diol (10d).61 General procedure A: obtained from m-
8a (0.75 mmol) and m-9 (0.75 mmol); yield 133 mg (0.72 mmol,
95%). General procedure B: obtained from m-8b (0.50 mmol) and m-
9 (0.65 mmol); yield 87 mg (0.47 mmol, 94%). Colorless solid: mp
123 °C; 1H NMR (300 MHz, DMSO-d6) δ 9.51 (s, 2H), 7.23 (dd, J =
8.0, 8.0 Hz, 2H), 7.01−6.99 (m, 4H), 6.77 (d, J = 8.0 Hz, 2H);
13C{1H} NMR (75 MHz, DMSO) δ 157.8, 141.8, 129.8, 117.4, 114.4,
113.4; IR (ATR) ν 3150 (bw), 1578 (m), 1233 (m), 1024 (s), 998 (s);
+
HRMS (EI) calcd for C12H10O2 [M+] 186.0681, found 186.0684.
Anal. Calcd for C12H10O2 (186.21): C, 77.4; H, 5.4. Found: C, 77.3;
H, 5.2%.
Biphenyl-3,4′-diol (10e).62 General procedure A: obtained from m-
8a (0.75 mmol) and p-9 (0.75 mmol); yield 110 mg (0.59 mmol, 79%)
or obtained from p-8a (0.75 mmol) and m-9 (0.75 mmol); yield 120
mg (0.65 mmol, 86%). General procedure B: obtained from m-8b
(0.50 mmol) and p-9 (0.65 mmol); yield 81 mg (0.44 mmol, 87%) or
obtained from p-8b (0.50 mmol) and m-9 (0.65 mmol); yield 89 mg
1
(0.48 mmol, 96%). Colorless solid: mp 192 °C; H NMR (300 MHz,
General Procedure for the Synthesis of Biaryls 10, 17, and
19 from Bromoarenes 8b or 18b under Microwave Irradiation
(Procedure B). The appropriate bromophenol 8b (86.5 mg, 0.50
mmol) or bromoanisol 18b (93.5 mg, 0.50 mmol) and the appropriate
boronic acid 9 (97.5 mg, 0.65 mmol, 1.3 equiv) or 16 (99 mg, 0.65
mmol, 1.3 equiv) were suspended in water (10.0 mL/mmol) in a
reaction vessel suited for microwave irradiation. To the suspension was
added either KOH (4.0 equiv, 112 mg, 2.00 mmol) or NBu4F·3H2O
(4.0 equiv, 630 mg, 2.00 mmol) as indicated in the corresponding
table, followed by Pd/C (10 wt %, 10.0 mg, 2 mol %). The closed
vessel was placed in a microwave reactor, and irradiated at 150 °C for
0.5 h. The vessel was then cooled to ambient temperature, and the
reaction mixture was carefully acidified by addition of aqueous HCl
(1.0 M). It was extracted three times with MTBE (50 mL each), the
organic layers were separated and dried with MgSO4, filtered and
evaporated in vacuo. The residue was purified by column
chromatography on silica, using hexane/MTBE mixtures of increasing
polarity as eluents.
DMSO-d6) δ 9.54 (s, 1H), 9.43 (s, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.20
(dd, J = 8.1, 8.1 Hz, 1H), 7.00−6.98 (m, 2H), 6.86 (d, J = 8.5 Hz, 2H),
6.72 (dd, J = 8.0, 1.3 Hz, 1H); 13C{1H} NMR (75 MHz, DMSO-d6) δ
157.8, 157.1, 141.7, 131.2, 129.8, 127.7, 116.9, 115.7, 113.5, 112.9; IR
(ATR) ν 3286 (bm), 1601 (m), 1424 (m), 1256 (s), 1201 (s); HRMS
(EI) calcd for C12H10O2+ [M+] 186.0681, found 186.0683. Anal. Calcd
for C12H10O2 (186.21): C, 77.4; H, 5.4. Found: C, 77.3; H, 5.2.
Biphenyl-4,4′-diol (10f).63 General procedure A: obtained from p-
8a (0.75 mmol) and p-9 (0.75 mmol); yield 58 mg (0.31 mmol, 42%).
General procedure B: obtained from p-8b (0.50 mmol) and p-9 (0.65
mmol); yield 89 mg (0.48 mmol, 96%). Colorless solid: mp 280−282
1
°C; H NMR (300 MHz, methanol-d4) δ 7.35 (d, J = 8.5 Hz, 4H),
6.82 (d, J = 8.5 Hz, 4H); 13C{1H} NMR (75 MHz, methanol-d4) δ
157.2, 134.0, 128.4, 116.5; IR (ATR) ν 3377 (bw), 1604 (m), 1494
+
(m), 1246 (s), 1003 (m); HRMS (EI) calcd for C12H10O2 [M+]
186.0681, found 186.0671. Anal. Calcd for C12H10O2 (186.21): C,
77.4; H, 5.4. Found: C, 77.4; H, 5.2.
Biphenyl-2-ol (o-12). General procedure A: obtained from m-8a
(0.75 mmol) and 11 (0.75 mmol); yield 124 mg (0.73 mmol, 97%).
Analytical data have been previously reported.21
Biphenyl-2,2′-diol (10a). General procedure A: obtained from o-8a
(0.75 mmol) and o-9 (0.75 mmol); yield 137 mg (0.74 mmol, 98%).
General procedure B: obtained from o-8b (0.50 mmol) and o-9 (0.65
mmol); yield 77 mg (0.42 mmol, 83%). Analytical data have been
previously reported.21
Biphenyl-3-ol (m-12).64 General procedure A: obtained from m-8a
(0.75 mmol) and 11 (0.75 mmol); yield 120 mg (0.71 mmol, 94%).
Colorless solid: mp 74−75 °C; 1H NMR (300 MHz, CDCl3) δ 7.65−
7.54 (m, 2H), 7.49−7.27 (m, 4H), 7.20 (dm, J = 7.7 Hz, 1H), 7.09
(dd, J = 2.3, 1.8 Hz, 1H), 6.84 (dm, J = 8.0, Hz, 1H), 5.05 (s, 1H);
13C{1H} NMR (75 MHz, CDCl3) δ 155.9, 143.2, 140.8, 130.1, 128.9,
127.6, 127.2, 120.0, 114.3, 114.3; IR (ATR) ν 3390 (bw), 1593 (m),
1475 (m), 1247 (m), 1197 (m); HRMS (EI) calcd for C12H10O+ [M+]
170.0732, found 170.0730. Anal. Calcd for C12H10O (170.21): C, 84.7;
H, 5.9. Found: C, 84.4; H, 6.0.
Biphenyl-2,3′-diol (10b). General procedure A: obtained from o-8a
(0.75 mmol) and m-9 (0.75 mmol); yield 127 mg (0.68 mmol, 91%)
or obtained from m-8a (0.75 mmol) and o-9 (0.75 mmol); yield 130
mg (0.70 mmol, 93%). General procedure B: obtained from o-8b (0.50
mmol) and m-9 (0.65 mmol); yield 81 mg (0.44 mmol, 87%) or
obtained from m-8b (0.50 mmol) and o-9 (0.65 mmol); yield 74 mg
1
(0.40 mmol, 80%). Colorless solid: mp 96 °C; H NMR (300 MHz,
Biphenyl-4-ol (p-12).65 General procedure A: obtained from p-8a
(0.75 mmol) and 11 (0.75 mmol); yield 115 mg (0.68 mmol, 90%).
CDCl3) δ 7.35 (dd, J = 7.8, 7.8 Hz, 1H), 7.30−7.21 (m, 2H), 7.05−
6.95 (m, 3H), 6.92 (dd, J = 2.3, 1.6 Hz, 1H), 6.86 (dm, J = 8.1 Hz,
1H), 5.36 (s, 1H), 5.20 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ
156.4, 152.5, 138.9, 130.8, 130.2, 129.4, 127.8, 121.6, 121.0, 116.2,
116.0, 115.1; IR (ATR) ν 3370 (bm), 1592 (m), 1480 (m), 1436 (s),
1
Colorless solid: mp 162−170 °C; H NMR (300 MHz, CDCl3) δ
7.90−7.20 (m, 7H), 6.91 (d, J = 8.2 Hz, 2H), 4.88 (s, 1H); 13C{1H}
NMR (75 MHz, CDCl3) δ 155.2, 140.9, 134.3, 128.9, 128.5, 126.9,
126.9, 115.8; IR (ATR) ν 3420 (bw), 1604 (m), 1489 (m), 1257 (s),
757 (s); HRMS (EI) calcd. for C12H10O+ [M+] 170.0732, found
170.0726. Anal. Calcd for C12H10O (170.21): C, 84.7; H, 5.9. Found:
C, 84.9; H, 5.7.
+
1211 (s); HRMS (EI) calcd for C12H10O2 [M+] 186.0681, found
186.0693. Anal. Calcd for C12H10O2 (186.21): C, 77.4; H, 5.4. Found:
C, 77.6; H, 5.2.
Biphenyl-2,4′-diol (10c).60 General procedure A: obtained from o-
8a (0.75 mmol) and p-9 (0.75 mmol); yield 121 mg (0.65 mmol, 87%)
or obtained from p-8a (0.75 mmol) and o-9 (0.75 mmol); yield 106
mg (0.57 mmol, 76%). General procedure B: obtained from o-8b (0.50
mmol) and p-9 (0.65 mmol); yield 84 mg (0.45 mmol, 90%) or
obtained from p-8b (0.50 mmol) and o-9 (0.65 mmol); yield 87 mg
(0.47 mmol, 93%). Colorless solid: mp 158 °C; 1H NMR (300 MHz,
methanol-d4) δ 7.41 (dm, J = 8.7 Hz, 2H), 7.21 (dm, J = 7.7 Hz, 1H),
7.10 (ddd, J = 7.6, 7.6, 1.6 Hz, 1H), 6.90−6.80 (m, 4H); 13C{1H}
2′-Methoxybiphenyl-2-ol (17a).66 General procedure A: obtained
from o-8a (0.75 mmol) and o-16 (0.98 mmol); yield 143 mg (0.71
mmol, 95%) or obtained from o-18a (0.50 mmol) and o-9 (0.50
mmol); yield 38 mg (0.19 mmol, 38%). General procedure B:
obtained from o-8b (0.50 mmol) and o-16 (0.65 mmol); yield 90 mg
(0.45 mmol, 90%) or obtained from o-18b (0.50 mmol) and o-9 (0.65
1
mmol); yield 61 mg (0.31 mmol, 61%). Colorless oil: H NMR (300
MHz, CDCl3) δ 7.50−7.30 (m, 4H), 7.16 (dd, J = 7.5, 7.5 Hz, 1H),
4114
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7.12−7.03 (m, 3H), 6.34 (s, 1H), 3.92 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 155.6, 153.8, 132.5, 131.4, 129.4, 129.3, 127.1, 126.3,
122.2, 121.1, 117.5, 111.7, 56.2; IR (ATR) ν 3388 (bw), 1577 (w),
159.4, 156.0, 142.7, 133.4, 130.1, 128.3, 119.5, 114.4, 113.8, 113.8,
55.5; IR (ATR) ν 3420 (bm), 1597 (s), 1449 (s), 1205 (s), 1014 (s);
+
HRMS (EI) calcd for C13H12O2 [M+]: 200.0837, found: 200.0827.
+
1479 (s), 1228 (s), 1177 (s); HRMS (EI) calcd for C13H12O2 [M+]
Anal. Calcd for C13H12O2 (200.23): C, 78.0; H, 6.0. Found: C, 77.5;
H, 5.7.
200.0837, found 200.0829.
3′-Methoxybiphenyl-2-ol (17b).67 General procedure A: obtained
from o-8a (0.75 mmol) and m-16 (0.98 mmol); yield 143 mg (0.71
mmol, 95%) or obtained from m-18a (0.50 mmol) and o-9 (0.50
mmol); yield 47 mg (0.24 mmol, 47%). General procedure B:
obtained from o-8b (0.50 mmol) and m-16 (0.65 mmol); yield 89 mg
(0.45 mmol, 89%) or obtained from m-18b (0.50 mmol) and o-9 (0.65
mmol); yield 86 mg (0.43 mmol, 86%). Colorless solid, mp 92 °C; 1H
NMR (300 MHz, CDCl3) δ 7.41 (dd, J = 7.9, 7.9 Hz, 1H), 7.32−7.24
(m, 2H), 7.05 (dm, J = 7.5, Hz, 1H), 7.03−6.92 (m, 4H), 5.35 (s, 1H),
3.85 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 160.5, 152.6, 138.6,
130.5, 130.2, 129.4, 128.1, 121.3, 120.9, 115.9, 114.7, 113.8, 55.5; IR
(ATR) ν 3419 (bw), 1582 (m), 1476 (s), 1421 (s), 1271 (s); HRMS
2′-Methoxybiphenyl-4-ol (17g).68 General procedure A: obtained
from p-8a (0.75 mmol) and o-16 (0.98 mmol); yield 126 mg (0.63
mmol, 84%) or obtained from o-18a (0.50 mmol) and p-9 (0.50
mmol); yield 10 mg (0.05 mmol, 10%). General procedure B:
obtained from p-8b (0.50 mmol) and o-16 (0.65 mmol); yield 95 mg
(0.48 mmol, 95%) or obtained from o-18b (0.50 mmol) and p-9 (0.65
mmol); yield 62 mg (0.31 mmol, 62%). Colorless solid: mp 117−119
1
°C; H NMR (300 MHz, acetone-d6) δ 7.36 (d, J = 8.6 Hz, 2H),
7.31−7.22 (m, 2H), 7.04 (dd, J = 8.7, 0.9 Hz, 1H), 6.98 (ddd, J = 7.4,
7.4, 1.0 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 3.78 (s, 3H); 13C{1H}
NMR (75 MHz, acetone-d6) δ 157.5, 157.4, 131.5, 131.3, 131.1, 130.6,
128.8, 121.6, 115.6, 112.5, 55.8; IR (ATR) ν 3380 (bw), 1595 (m),
+
(EI) calcd for C13H12O2 [M+] 200.0837, found 200.0826.
+
1485 (s), 1236 (s), 1175 (s); HRMS (EI) calcd for C13H12O2 [M+]
4′-Methoxybiphenyl-2-ol (17c.67 General procedure A: obtained
from o-8a (0.75 mmol) and p-16 (0.98 mmol); yield 140 mg (0.70
mmol, 93%) or obtained from p-18a (0.50 mmol) and o-9 (0.50
mmol); yield 39 mg (0.20 mmol, 39%). General procedure B:
obtained from o-8b (0.50 mmol) and p-16 (0.65 mmol); yield 85 mg
(0.43 mmol, 85%) or obtained from p-18b (0.50 mmol) and o-9 (0.65
200.0837, found 200.0841. Anal. Calcd for C13H10O2 (200.08): C,
78.0; H, 6.0. Found: C, 77.4; H, 6.2.
3′-Methoxybiphenyl-4-ol (17h).69 General procedure A: obtained
from p-8a (0.75 mmol) and m-16 (0.98 mmol); yield 134 mg (0.67
mmol, 89%) or obtained from m-18a (0.50 mmol) and p-9 (0.50
mmol); yield 10 mg (0.05 mmol, 10%). General procedure B:
obtained from p-8b (0.50 mmol) and m-16 (0.65 mmol); yield 94 mg
(0.47 mmol, 94%) or obtained from m-18b (0.50 mmol) and p-9 (0.65
mmol); yield 52 mg (0.26 mmol, 52%). Colorless solid: mp 91 °C; 1H
NMR (300 MHz, CDCl3) δ 7.48 (d, J = 8.7 Hz, 2H), 7.34 (dd, J = 8.0,
8.0 Hz, 1H), 7.15 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.09 (dd, J = 2.0, 1.8
Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.87 (ddd, J = 8.0, 2.5, 0.8 Hz, 1H),
5.10 (s(br), 1H), 3.87 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
160.0, 155.4, 142.5, 134.0, 129.9, 128.6, 119.5, 115.8, 112.7, 112.3,
55.5; IR (ATR) ν 3421 (bw), 1597 (s), 1484 (s), 1172 (s), 1025 (s);
1
mmol); yield 76 mg (0.38 mmol, 76%). Colorless oil: H NMR (300
MHz, CDCl3) δ 7.40 (d, J = 8.8 Hz, 2H), 7.28−7.20 (m, 2H), 7.04 (d,
J = 8.8 Hz, 2H), 7.01−6.94 (m, 2H), 5.18 (s, 1H), 3.88 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 159.5, 152.7, 130.4, 130.4, 129.4,
128.9, 128.0, 120.9, 115.8, 114.9, 55.5; IR (ATR) ν 3378 (bw), 1517
+
(m), 1485 (s), 1234 (s), 1157 (s); HRMS (EI) calcd for C13H12O2
[M+] 200.0837, found 200.0844.
2′-Methoxybiphenyl-3-ol (17d). General procedure A: obtained
from m-8a (0.75 mmol) and o-16 (0.98 mmol); yield 132 mg (0.66
mmol, 88%) or obtained from o-18a (0.50 mmol) and m-9 (0.50
mmol); yield 39 mg (0.20 mmol, 39%). General procedure B:
obtained from m-8b (0.50 mmol) and o-16 (0.65 mmol); yield 94 mg
(0.47 mmol, 94%) or obtained from o-18b (0.50 mmol) and m-9 (0.65
+
HRMS (EI) calcd for C13H12O2 [M+] 200.0837, found 200.0840.
4′-Methoxybiphenyl-4-ol (17i.70 General procedure A: obtained
from p-8a (0.75 mmol) and p-16 (0.98 mmol); yield 118 mg (0.59
mmol, 79%) or obtained from p-18a (0.50 mmol) and p-9 (0.50
mmol); yield 10 mg (0.05 mmol, 10%). General procedure B:
obtained from p-8b (0.50 mmol) and p-16 (0.65 mmol); yield 96 mg
(0.48 mmol, 96%) or obtained from p-18b (0.50 mmol) and p-9 (0.65
mmol); yield 67 mg (0.34 mmol, 67%). Colorless solid: mp 181−182
°C; 1H NMR (300 MHz, acetone-d6) δ 7.48 (d, J = 8.9 Hz, 2H), 7.41
(d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H),
3.79 (s, 3H); 13C{1H} NMR (75 MHz, acetone-d6) δ 159.6, 157.5,
134.4, 132.9, 128.3, 128.1, 116.5, 115.0, 55.6; IR (ATR) ν 3413 (bw),
1502 (m), 1248 (m), 1178 (w), 1038 (m); HRMS (EI) calcd for
C13H12O2+ [M+] 200.0837, found 200.0838. Anal. Calcd for C13H10O2
(200.08): C, 78.0; H, 6.0. Found: C, 77.8; H, 6.1.
1
mmol); yield 64 mg (0.32 mmol, 64%). Colorless oil: H NMR (300
MHz, CDCl3) δ 7.38−7.27 (m, 3H), 7.11 (dm, J = 8.0, Hz, 1H),
7.07−6.97 (m, 3H), 6.81 (ddd, J = 8.1, 2.6, 0.9 Hz, 1H), 4.91 (s, 1H),
3.82 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 156.6, 155.2, 140.3,
130.9, 130.4, 129.3, 128.9, 122.3, 121.0, 116.7, 114.1, 111.5, 55.7; IR
(ATR) ν 3361 (bw), 1590 (m), 1429 (s), 1238 (s), 1183 (s); HRMS
+
(EI) calcd for C13H12O2 [M+] 200.0837, found 200.0831.
3′-Methoxybiphenyl-3-ol (17e).64 General procedure A: obtained
from m-8a (0.75 mmol) and m-16 (0.98 mmol); yield 138 mg (0.69
mmol, 92%) or obtained from m-18a (0.50 mmol) and m-9 (0.50
mmol); yield 26 mg (0.13 mmol, 26%). General procedure B:
obtained from m-8b (0.50 mmol) and m-16 (0.65 mmol); yield 91 mg
(0.46 mmol, 91%) or obtained from m-18b (0.50 mmol) and m-9
2,2′-Dimethoxy-1,1′-biphenyl (19a).71 General procedure A:
obtained from o-18a (0.50 mmol) and o-16 (0.50 mmol); yield 87
mg (0.41 mmol, 81%). General procedure B: obtained from o-18b
(0.50 mmol) and o-16 (0.65 mmol); yield 66 mg (0.31 mmol, 62%).
Colorless solid: mp 156−157 °C; 1H NMR (300 MHz, CDCl3) δ 7.39
(ddd, J = 8.2, 7.5, 1.8 Hz, 2H), 7.32 (dd, J = 7.5, 1.8 Hz, 2H), 7.07
(ddd, J = 7.5, 7.5, 1.1 Hz, 2H), 7.03 (dm, J = 8.2 Hz, 2H), 3.83 (s,
6H); 13C{1H} NMR (75 MHz, CDCl3) δ 157.2, 131.6, 128.7, 128.0,
120.5, 111.3, 55.8; IR (ATR) ν 2928 (bw), 1723 (w), 1590 (w), 1456
1
(0.65 mmol); yield 71 mg (0.36 mmol, 71%). Colorless oil: H NMR
(300 MHz, CDCl3) δ 7.35 (dd, J = 7.9, 7.9 Hz, 1H), 7.30 (dd, J = 7.9,
7.9 Hz, 1H), 7.20−7.14 (m, 2H), 7.12 (dd, J = 2.3, 1.7 Hz, 1H), 7.07
(dd, J = 2.3, 1.7 Hz, 1H), 6.92 (ddd, J = 8.2, 2.5, 0.7 Hz, 1H), 6.84
(ddd, J = 8.0, 2.5, 0.8 Hz, 1H), 5.31 (s, 1H), 3.87 (s, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ 160.0, 156.0, 143.0, 142.4, 130.1, 129.9,
119.9, 119.8, 114.5, 114.3, 113.1, 113.0, 55.5; IR (ATR) ν 3375 (bw),
1599 (m), 1576 (s), 1477 (m), 1168 (s); HRMS (EI) calcd for
+
(m), 1111 (m); HRMS (EI) calcd for C14H14O2 [M+] 214.0994,
+
C13H12O2 [M+] 200.0837, found 200.0834.
found 214.0976. Anal. Calcd for C14H14O2 (214.10): C, 78.5; H, 6.6.
Found: C, 78.3; H, 6.6.
4′-Methoxybiphenyl-3-ol (17f).64 General procedure A: obtained
from m-8a (0.75 mmol) and p-16 (0.98 mmol); yield 138 mg (0.69
mmol, 92%) or obtained from p-18a (0.50 mmol) and m-9 (0.50
mmol); yield 25 mg (0.13 mmol, 25%). General procedure B:
obtained from m-8b (0.50 mmol) and p-16 (0.65 mmol); yield 93 mg
(0.47 mmol, 93%) or obtained from p-18b (0.50 mmol) and m-9 (0.65
mmol); yield 69 mg (0.35 mmol, 69%). Colorless solid: mp 117 °C;
1H NMR (300 MHz, CDCl3) δ 7.51 (d, J = 8.9 Hz, 2H), 7.29 (dd, J =
7.9, 7.9 Hz, 1H), 7.14 (dm, J = 7.7, 1.6, 1.0 Hz, 1H), 7.03 (dd, J = 2.3,
1.7 Hz, 1H), 6.97 (d, J = 8.9 Hz, 2H), 6.79 (ddd, J = 8.0, 2.5, 0.9 Hz,
1H), 5.13 (s, 1H), 3.86 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
2,3′-Dimethoxy-1,1′-biphenyl (19b).71 General procedure A:
obtained from o-18a (0.50 mmol) and m-16 (0.50 mmol); yield 75
mg (0.35 mmol, 70%) or obtained from m-18a (0.50 mmol) and o-16
(0.50 mmol); yield 77 mg (0.36 mmol, 72%). General procedure B:
obtained from o-18b (0.50 mmol) and m-16 (0.65 mmol); yield 70 mg
(0.33 mmol, 65%) or obtained from m-18b (0.50 mmol) and o-16
(0.65 mmol); yield 86 mg (0.40 mmol, 80%). Colorless solid: mp 41
1
°C; H NMR (300 MHz, CDCl3) δ 7.46−7.36 (m, 3H), 7.24−7.18
(m, 2H), 7.11 (dd, J = 7.5, 7.5 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.97
(ddd, J = 8.1, 2.5, 0.8, 1H), 3.91 (s, 3H), 3.88 (s, 3H); 13C{1H} NMR
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(75 MHz, CDCl3) δ 159.4, 156.6, 140.1, 130.9, 130.7, 129.0, 128.8,
122.2, 120.9, 115.5, 112.6, 111.5, 55.6, 55.3; IR (ATR) ν 1592 (s),
IR (ATR) ν 3505 (bm), 1610 (m), 1504 (s), 1208 (s), 1111 (s);
HRMS (EI) calcd for C8H9O379Br+ [M+] 232.9735, found 231.9742.
5-Bromo-3-methoxybenzene-1,2-diol (24).58 5-Bromo-2-hy-
droxy-3-methoxybenzaldehyde (23). Vanillin (22, 7.37 g, 48.0
mmol) and sodium acetate (6.00 g, 73.0 mmol) were dissolved in
acetic acid (200 mL). A solution of bromine (2.50 mL, 48.0 mmol) in
acetic acid (20 mL) was added dropwise over a period of 0.5 h at
ambient temperature. All volatiles were then evaporated in vacuo, and
the residue was redissolved in CH2Cl2 (100 mL). The solution was
extracted with water (100 mL), and the organic layer was separated
and washed twice with water (100 mL each), and finally dried with
MgSO4. The solution was filtered, and all volatiles were evaporated in
vacuo to furnish crude aldehyde 23, which was sufficiently pure to be
used in the next step without further purification. Analytical data of 23:
1H NMR (300 MHz, CDCl3) δ 10.98 (s, 1H), 9.84 (s, 1H), 7.29 (d, J
+
1477 (s), 1215 (s), 1025 (s), 697 (s); HRMS (EI) calcd for C14H14O2
[M+] 214.0994, found 214.0998. Anal. Calcd for C14H14O2 (214.10):
C, 78.5; H, 6.6. Found: C, 78.0; H, 6.4.
2,4′-Dimethoxy-1,1′-biphenyl (19c).71 General procedure A:
obtained from o-18a (0.50 mmol) and p-16 (0.50 mmol); yield 75
mg (0.35 mmol, 70%) or obtained from p-18a (0.50 mmol) and o-16
(0.50 mmol); yield 88 mg (0.41 mmol, 82%). General procedure B:
obtained from o-18b (0.50 mmol) and p-16 (0.65 mmol); yield 87 mg
(0.40 mmol, 81%) or obtained from p-18b (0.50 mmol) and o-16
(0.65 mmol); yield 93 mg (0.47 mmol, 87%). Colorless solid: mp 67−
68 °C; 1H NMR (300 MHz, CDCl3) δ 7.62−7.54 (m, 2H), 7.44−7.34
(m, 2H), 7.11 (ddm, J = 7.5, 7.5 Hz, 1H), 7.08−7.01 (m, 3H), 3.92 (s,
3H), 3.88 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.8, 156.6,
131.0, 130.7, 130.7, 130.5, 128.2, 120.9, 113.6, 111.4, 55.6, 55.3; IR
(ATR) ν 1596 (w), 1464 (m), 1239 (s), 1022 (m), 547 (m); HRMS
(EI) calcd for C14H14O2+ [M+] 214.0994, found 214.0993. Anal. Calcd
for C14H14O2 (214.10): C, 78.5; H, 6.6. Found: C, 78.4; H, 6.6.
3,3′-Dimethoxy-1,1′-biphenyl (19d).72 General procedure A:
obtained from m-18a (0.50 mmol) and m-16 (0.50 mmol); yield 81
mg (0.38 mmol, 76%). General procedure B: obtained from m-18b
(0.50 mmol) and m-16 (0.65 mmol); yield 76 mg (0.36 mmol, 71%).
Colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.40 (dd, J = 7.9, 7.9 Hz,
2H), 7.24 (dm, J = 7.9, Hz, 2H), 7.19 (dd, J = 2.5, 1.7 Hz, 2H), 6.96
(ddd, J = 7.9, 2.5, 0.8 Hz, 2H), 3.90 (s, 6H); 13C{1H} NMR (75 MHz,
CDCl3) δ 160.1, 142.7, 129.8, 119.8, 113.1, 112.9, 55.3; IR (ATR) ν
1574 (s), 1475 (m), 1231 (s), 1029 (s), 693 (s); HRMS (EI) calcd for
= 2.1 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 3.90 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 195.5, 151.0, 149.4, 126.2, 121.5, 120.9, 111.2,
56.7.
5-Bromo-3-methoxybenzene-1,2-diol (24). The crude 23 (ca. 11
g) obtained from the previous step was dissolved in a solution of
NaOH (1.90 g) in water (200 mL). An aqueous solution of H2O2 (30
wt %, 30.00 g, 265.0 mmol) was diluted with water (200 mL) and then
slowly added at ambient temperature to the first solution. The mixture
was stirred for 0.5 h at this temperature and then carefully acidified by
addition of aqueous HCl (2 M, 30 mL). The resulting solution was
extracted thoroughly with CH2Cl2, and the combined organic extracts
were washed with a saturated aqueous solution of Na2SO3. The
organic layer was separated, dried with MgSO4, filtered, and
evaporated in vacuo. The residue was purified by chromatography
on silica using hexane/MTBE mixtures as eluent to furnish 24 (9.60 g,
43.8 mmol, 91% based on 22) as a colorless solid: mp 76 °C; 1H NMR
(300 MHz, CDCl3) δ 6.77 (d, J = 2.1 Hz, 1H), 6.61 (d, J = 2.1 Hz,
1H), 5.36 (s, 2H), 3.86 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
147.5, 144.8, 131.8, 112.4, 111.9, 107.0, 56.6; IR (ATR) ν 3432 (bm),
1615 (m), 1501 (s), 1198 (s), 1093 (s); HRMS (EI) calcd for
C7H7O379Br+ [M+]: 217.9579, found 217.9562.
+
C14H14O2 [M+] 214.0994, found 214.0983.
3,4′-Dimethoxy-1,1′-biphenyl (19e).71 General procedure A:
obtained from m-18a (0.50 mmol) and p-16 (0.50 mmol); yield 62
mg (0.29 mmol, 58%) or obtained from p-18a (0.50 mmol) and m-16
(0.50 mmol); yield 77 mg (0.36 mmol, 72%). General procedure B:
obtained from m-18b (0.50 mmol) and p-16 (0.65 mmol); yield 77 mg
(0.36 mmol, 72%) or obtained from p-18b (0.50 mmol) and m-16
(0.65 mmol); yield 83 mg (0.39 mmol, 78%). Colorless solid: mp 59
°C; 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J = 8.8 Hz, 2H), 7.38 (dd,
J = 7.9, 7.9 Hz, 1H), 7.19 (dd, J = 7.9, 0.8 Hz, 1H), 7.17−7.09 (m,
1H), 7.02 (d, J = 8.8 Hz, 2H), 6.90 (dd, J = 7.9, 2.5 Hz, 1H), 3.89 (s,
3H), 3.88 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 160.1, 159.4,
142.5, 133.7, 129.8, 128.3, 119.4, 114.3, 112.7, 112.2, 55.4, 55.3; IR
(ATR) ν 1598 (m), 1473 (m), 1241 (m), 1219 (s), 1032 (s); HRMS
6-Bromo-4-methoxybenzo[d][1,3]dioxole (25). Diol 24 (1.10 g,
5.0 mmol), K2CO3 (1.04 g, 7.5 mmol), and CH2I2 (0.58 mL, 7.5
mmol) were suspended in dry DMF (20 mL). The mixture was heated
for 1 h in an oil bath preheated to 100 °C. After the mixture was
cooled to ambient temperature, brine (10 mL) was added and the
aqueous layer was extracted three times with ethyl acetate (50 mL
each). The combined organic extracts were dried with MgSO4, filtered,
and evaporated in vacuo. The residue was purified by column
chromatography on silica to yield 25 (0.85 g, 3.7 mmol, 74%) as a
+
(EI) calcd for C14H14O2 [M+] 214.0994, found 214.1013.
4,4′-Dimethoxy-1,1′-biphenyl (19f).71 General procedure A:
obtained from p-18a (0.50 mmol) and p-16 (0.50 mmol); yield 99
mg (0.46 mmol, 93%). General procedure B: obtained from p-18b
(0.50 mmol) and p-16 (0.65 mmol); yield 67 mg (0.32 mmol, 63%).
Colorless solid: mp 175−178 °C; 1H NMR (300 MHz, CDCl3) δ 7.52
(d, J = 8.9 Hz, 4H), 7.00 (d, J = 8.9 Hz, 4H), 3.88 (s, 6H); 13C{1H}
NMR (75 MHz, CDCl3) δ 158.9, 133.7, 127.9, 114.3, 55.5; IR (ATR)
ν 1604 (m), 1495 (m), 1183 (s), 1242 (s), 1040 (s); HRMS (EI) calcd
1
colorless solid: mp 80−82 °C; H NMR (300 MHz, CDCl3) δ 6.67−
6.65 (m, 2H), 5.96 (s, 2H), 3.87 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 149.6, 144.3, 135.0, 113.4, 111.3, 106.29, 102.0, 56.9; IR
(ATR) ν 2913 (w), 1625 (m), 1420 (m), 1182 (s), 1102 (s); HRMS
(EI) calcd for C8H7O379Br+ [M+] 230.9657, found 230.9675.
Aucuparin (7a). General procedure B: obtained from 21 (175 mg,
0.75 mmol) and 11 (119 mg, 0.98 mmol) with KOH (168 mg, 3.00
mmol) as additive; yield 130 mg (0.57 mmol, 75%). 1H and 13C NMR
spectroscopical data match those reported for the natural product.25
+
for C14H14O2 [M+] 214.0994, found 214.1001. Anal. Calcd for
C14H14O2 (214.10): C, 78.5; H, 6.6. Found: C, 78.4; H, 6.6.
4-Bromo-2,6-dimethoxyphenol (21).56,57 To a solution of 20 (6.16
g, 40.0 mmol) in CHCl3 (120 mL) was added NaH (60 wt %
dispersion in mineral oil, 16 mg, 1 mol %) at ambient temperature.
The solution was cooled to −45 °C, and N-bromosuccinimide (7.12 g,
40.0 mmol) was added in one portion. Stirring was continued at a
temperature of ca. −35 °C for 0.5 h, and the mixture was then allowed
to warm to ambient temperature within 0.5 h. After reaching ambient
temperature, the solution was heated to reflux for another 0.5 h. The
mixture was then cooled to ambient temperature, and all volatiles were
evaporated in vacuo until dryness. The resulting solid was thoroughly
extracted with diethyl ether (200 mL) and removed by filtration. The
filter cake was again extracted with diethyl ether, and the combined
ethereal extracts were evaporated. The residue was purified by column
chromatography on silica, using hexane/MTBE mixtures as eluent, to
furnish 21 (3.40 g, 14.6 mmol, 37%) as a colorless solid: mp 95−97
°C; 1H NMR (300 MHz, CDCl3) δ 6.71 (s, 2H), 3.86 (s, 6H);
13C{1H} NMR (75 MHz, CDCl3) δ 147. 8, 134.3, 111.2, 108.8, 56.6;
1
Colorless solid: mp 80−82 °C; H NMR (300 MHz, CDCl3) δ 7.54
(dm, J = 8.1 Hz, 2H), 7.42 (ddm, J = 8.1, 7.2 Hz, 2H), 7.32 (tt, J = 7.2,
1.3 Hz, 1H), 6.81 (s, 2H), 5.56 (s, 1H), 3.96 (s, 6H); 13C{1H} NMR
(75 MHz, CDCl3) δ 147.5, 141.6, 134.7, 133.1, 128.9, 127.1, 127.1,
104.4, 56.6; IR (ATR) ν 3423 (bm), 1609 (m), 1222 (m), 1112 (s),
+
762 (m); HRMS (EI) calcd for C14H14O3 [M+] 230.0943, found
230.0947. Anal. Calcd for C14H14O3 (230.26): C, 73.0; H, 6.1. Found:
C, 72.5; H, 6.1.
2′-Methoxyaucuparin (o-5). General procedure B: obtained from
21 (117 mg, 0.50 mmol) and o-16 (99 mg, 0.65 mmol) with NBu4F·
3H2O (630 mg, 2.00 mmol) as additive; yield 64 mg (0.25 mmol,
1
49%). H NMR spectroscopical data match those reported for the
natural product.30 Colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.38−
7.28 (m, 2H), 7.08−6.97 (m, 2H), 6.81 (s, 2H), 5.60 (s(br), 1H), 3.92
(s, 6H), 3.83 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 156.5,
146.7, 134.2, 130.9, 130.7, 129.7, 128.4, 120.9, 111.5, 106.8, 56.4, 55.7;
4116
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Article
IR (ATR) ν 3502 (bm), 2938 (m), 1605 (m), 1241 (s), 1106 (s);
mmol) with KOH (112 mg, 2.00 mmol) as additive; yield 84 mg (0.35
mmol, 69%). All analytical data match those reported for the natural
product.33 Colorless solid: mp 93−95 °C; 1H NMR (300 MHz,
CDCl3) δ 7.27 (dd, J = 8.0, 7.7 Hz, 1H), 7.08 (ddd, J = 7.7, 1.5, 0.9 Hz,
1H), 6.99 (dd, J = 2.5, 1.5 Hz, 1H), 6.81 (dd, J = 8.0, 2.5 Hz, 1H),
6.74−6.72 (m, 2H), 5.99 (s, 2H), 5.50 (s (br), 1H), 3.93 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 155.9, 149.3, 143.7, 142.8, 135.9,
135.1, 130.0, 119.6, 114.2, 114.1, 107.2, 101.7, 101.6, 56.8; IR (ATR) ν
3401 (w), 1630 (m), 1583 (m), 1482 (s), 1422 (s); HRMS (EI) calcd
+
HRMS (EI) calcd for C15H16O4 [M+] 260.1049, found 260.1048.
4′-Methoxyaucuparin (p-5). General procedure B: obtained from
21 (117 mg, 0.50 mmol) and p-16 (99 mg, 0.65 mmol) with KOH
1
(112 mg, 2.00 mmol) as additive; yield 87 mg (0.34 mmol, 67%). H
and 13C NMR spectroscopical data match those reported for the
natural product.30 Colorless solid: mp 97−99 °C; 1H NMR (300
MHz, CDCl3) δ 7.49 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H),
6.77 (s, 2H), 5.56 (s, 1H), 3.96 (s, 6H), 3.87 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 159.0, 147.4, 134.2, 132.7, 128.0, 114.3, 104.0,
56.5, 55.5; IR (ATR) ν 3440 (bm), 1608 (m), 1502 (s), 1242 (s),
+
for C14H13O4 [M+H+] 245.0814, found 245.0798. Anal. Calcd for
C14H12O4 (246.26): C, 68.5; H, 5.0. Found: C, 68.9; H, 5.0.
+
1110 (s); HRMS (EI) calcd for C15H16O4 [M+] 260.1049, found
260.1032.
ASSOCIATED CONTENT
■
2′-Hydroxyaucuparin (o-3). General procedure B: obtained from
S
* Supporting Information
21 (117 mg, 0.50 mmol) and o-9 (179 mg, 1.30 mmol) with KOH
1
Copies of H and 13C NMR spectra for all compounds. This
1
(112 mg, 2.00 mmol) as additive; yield 45 mg (0.18 mmol, 37%). H
and 13C NMR spectroscopical data match those reported for the
natural product.25 Colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.37−
7.15 (m, 2H), 7.05−6.93 (m, 2H), 6.67 (s, 2H), 5.64 (s (br), 1H),
5.45 (s (br), 1H), 3.90 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ
152.6, 147.8, 134.7, 130.1, 129.1, 128.4, 128.1, 120.8, 115.8, 106.0,
56.5; IR (ATR) ν 3336 (bm), 1612 (m), 1342 (m), 1212 (s), 1111
(s); HRMS (EI) calcd for C14H14O4+ [M+] 246.0892, found 246.0894.
3′-Hydroxyaucuparin (m-3). General procedure B: obtained from
21 (117 mg, 0.50 mmol) and m-9 (90 mg, 0.65 mmol) with KOH
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: bernd.schmidt@uni-potsdam.de.
■
Notes
The authors declare no competing financial interest.
1
(112 mg, 2.00 mmol) as additive; yield 88 mg (0.36 mmol, 72%). H
and 13C NMR spectroscopical data match those reported previously.26
Colorless solid: mp 153−155 °C; 1H NMR (300 MHz, methanol-d4) δ
7.19 (dd, J = 8.0, 7.7 Hz, 1H), 7.01 (dm, J = 7.7 Hz, 1H), 6.99 (m,
1H), 6.80 (s, 2H), 6.73 (ddd, J = 8.0, 2.3, 1.0 Hz, 1H), 3.86 (s, 6H);
13C{1H} NMR (75 MHz, methanol-d4) δ 158.6, 149.4, 144.1, 136.3,
133.6, 130.7, 119.1, 114.7, 114.5, 105.4, 56.9; IR (ATR) ν 3403 (bm),
1585 (s), 1485 (s), 1215 (s), 1111 (s); HRMS (EI) calcd for
ACKNOWLEDGMENTS
■
We thank Evonik Oxeno for generous donations of solvents.
REFERENCES
■
867.
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+
C14H14O4 [M+] 246.0892, found 246.0883.
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1
Colorless solid: mp 204−205 °C; H NMR (300 MHz, acetone-d6) δ
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1
Colorless solid: mp 93−95 °C; H NMR (300 MHz, CDCl3) δ 7.47
(d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 6.84 (s, 1H), 6.67 (s,
1H), 5.73 (s (br), 1H), 5.69 (s (br), 1H), 3.92 (s, 3H), 3.85 (s, 3H);
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1
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1
CDCl3) δ 7.57 (d, J = 7.3 Hz, 2H), 7.44 (dd, J = 7.3, 7.3 Hz, 2H), 7.36
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