2,2′-biphenols via protecting group-free thermal or microwave-accelerated suzuki-miyaura coupling in water

Article abstract of DOI:10.1021/jo401398n

User-friendly protocols for the protecting group-free synthesis of 2,2′-biphenols via Suzuki-Miyaura coupling of o-halophenols and o-boronophenol are presented. The reactions proceed in water in the presence of simple additives such as K₂CO₃, KOH, KF, or TBAF and with commercially available Pd/C as precatalyst. Expensive or laboriously synthesized ligands or other additives are not required. In the case of bromophenols, efficient rate acceleration and short reaction times were accomplished by microwave irradiation.

Full text of DOI:10.1021/jo401398n

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Article
2,2’-Biphenols via protecting group free thermal or
microwave accelerated Suzuki-Miyaura coupling in water
Bernd Schmidt, Martin Riemer, and Manfred Karras
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401398n • Publication Date (Web): 30 Jul 2013
Downloaded from http://pubs.acs.org on August 1, 2013
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2,2’-Biphenols via protecting group free thermal or microwave accelerated Suzuki-
Miyaura coupling in water
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Bernd Schmidt,* Martin Riemer and Manfred Karras
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Universitaet Potsdam, Institut fuer Chemie (Organische Synthesechemie), KarlꢀLiebknechtꢀ
Straße 24ꢀ25, Dꢀ14476 PotsdamꢀGolm, Germany.
eꢀmail: bernd.schmidt@uniꢀpotsdam.de
Table of contents graphic:
for X = Br:
TBAF; ꢀ-wave
(150°C); 0.5 h
HO
HO
O
(HO)2B
Pd/C (cat.)
water
H
O
X
OH
H
OMe
for X = I:
K2CO3;
80°C; 2.5 h
OH
OMe
Abstract: Userꢀfriendly protocols for the protecting group free synthesis of 2,2’ꢀbiphenols via
SuzukiꢀMiyaura coupling of orthoꢀhalo phenols and ortho phenol boronic acid are presented.
The reactions proceed in water in the presence of simple additives such as K2CO3, KOH, KF
or TBAF and with commercially available Pd/C as precatalyst. Expensive or laboriously
synthesized ligands or other additives are not required. In the case of bromo phenols, efficient
rate acceleration and short reaction times were accomplished by microwave irradiation.
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Introduction
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The 2,2’ꢀbiphenol structure is a common motif in many natural products and in drugs or drug
candidates.1 Probably the most prominent example is vancomycin, often used as a last option
antibiotic for the treatment of staphylococcus aureus infections.2,3 More recently discovered
were the arylomycins,4,5 which share a 2,2’ꢀbiphenol bridged peptide structure and a high
antibiotic activity with vancomycin. Structurally less complex are biphenols isolated from
extracts of magnolia officinalis, such as magnolol,6 which shows high activity as an antiꢀ
oxidant, or the diarylheptanoid acerogenin E, which has been isolated from the tree acer
nikoense (Figure 1).7
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Figure 1. Selected natural products with a 2,2’ꢀbiphenol structure
O
H
H
HO
OH
N
N
O
O
NH
CO2H
NH
H
HO2C
N
N
OH
OH
Me
O
HO
Biphenol unit of arylomycin A2
Biphenol unit of vancomycin
OH
HO
HO
O
HO
Magnolol
Acerogenin E
Not surprisingly, the synthesis of 2,2’ꢀbiphenols has, like the synthesis of biaryls in general,1,8
attracted considerable attention. Very recent contributions to this field are methods using
radical cyclizations of acetal tethered phenols9 or an oxidative copper mediated intramolecular
biaryl formation, which was applied to the synthesis of strictinin.10 Probably the most
commonly used methods for biaryl formation are Pdꢀcatalyzed cross coupling reactions, in
particular the SuzukiꢀMiyaura coupling. In most cases when this reaction has been applied to
the synthesis of 2,2’ꢀbiphenols, either one or both coupling partners are OHꢀprotected, e. g. as
a methyl ether11,12 or as a MOMꢀether.13 Although scattered literature precedence for the
successful cleavage of aryl methyl ethers in the late stages of total syntheses of target
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molecules as complex as arylomycin12 and vancomycin11 exists, the harsh conditions
normally required for this transformation, in particular the use of strong Lewis acids in large
excess at elevated temperatures,14 often in combination with strongly nucleophilic reagents
such as thiols, makes the use of this protecting group impractical in many cases. A
straightforward solution to avoid the difficulties associated with the deprotection of aryl
methyl ethers would be the use of unprotected orthoꢀhalo phenols and orthoꢀphenol boronic
acids as coupling partners in the SuzukiꢀMiyaura reaction. This option has been pursued for
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15ꢀ17
18
surprisingly few examples. In most of these cases, Pd(PPh3)4
or Pd(OAc)2 have been
used as precatalysts in mixtures of organic solvents and water. The isolated yields of 2,2’ꢀ
biphenols obtained via this fully protecting groupꢀfree route rarely exceed 50%.
A catalyst system which has attracted considerable attention for coupling and cross coupling
reactions is palladium on charcoal.19ꢀ24 It is not only conveniently available, but due to its
heterogeneous nature easily removable from the reaction mixture. This is potentially very
useful, because the catalyst might be recycled and reused, and the contamination of the
reaction products with metal residues can be reduced. Examples for the successful application
of Pd/C as a catalyst for SuzukiꢀMiyaura reactions of various halo phenols in aqueous media
have been published by Hirao et al.25 and by Freundlich and Landis.26 We are, however, not
aware of any reports describing the completely protecting groupꢀfree synthesis of 2,2’ꢀ
biphenols via heterogeneously catalyzed SuzukiꢀMiyaura couplings. In this paper we report
our results on the optimization and scope of cross coupling reactions between unprotected
orthoꢀhalo phenols and orthoꢀphenol boronic acids, catalyzed by easily removable Pd/C.
Results and discussion
Optimization of conditions for ortho-iodo phenols. In the initial experiments, equimolar
amounts of 2ꢀiodo phenol (1a) and 2ꢀphenol boronic acid (2a) were subjected to cross
coupling conditions, using Pd(OAc)2 as a precatalyst in different solvents or solvent mixtures
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commonly used for the SuzukiꢀMiyaura reaction (Table 1). The reaction mixtures were
analyzed with GCꢀMS, revealing that neither DMSO/water nor DMF at a reaction temperature
of 130°C in the presence of Na2CO3 or K3PO4 as a base gave complete conversion (Table 1,
entries 1 and 3). Inspired by a literature report describing a beneficial effect of Cu(OAc)2 as a
coꢀcatalyst18 we tested this additive, unfortunately to no avail (entry 2). Similarly
disappointing was the addition of P(oꢀtol)3 as a ligand in DMF in the presence of K3PO4 as a
base (entry 4). Interestingly, with [η3ꢀ(C3H5)PdCl]2 as a precatalyst (entry 5) full conversion
was accomplished at 130°C. We then tested Pd/C under the conditions previously established
by Hirao et al. for the coupling of nonꢀphenolic aryl boronic acids,25 i.e. using water as a
solvent and K2CO3 as a base at ambient temperature (entry 6). Although some product
formation could be observed, substantial amounts of the starting materials did not react. The
reason for this incomplete conversion might be a significantly reduced reactivity of the 2ꢀ
phenol boronic acid (2a) used by us, compared to the phenyl boronic acid (2b) used by Hirao
et al., or a lower activity of the Pd/C used in our experiments. The reproducibility of
transformations catalyzed by Pd/C depends to a certain extent on the method used for its
preparation and in particular on the oxidation state of the Pd and its distribution on the solid
support.19,22 Both factors are difficult to control for commercial catalysts, as their exact nature
is sometimes insufficiently documented by the supplier. To test the activity of the commercial
Pd/C used by us, we decided to reproduce the coupling of 1a and 2b under the conditions
previously described by Hirao et al., with the only exception being a somewhat higher catalyst
loading of 2 mol % (entry 7). The conversion to the cross coupling product was quantitative at
ambient temperature and 3ab could be isolated in nearly quantitative yield. This observation
suggests that the unsatisfactory result obtained for 2ꢀphenol boronic acid (2a) is not caused by
an insufficiently active catalyst, but more likely by a reduced reactivity of 2a compared to 2b.
Therefore, the experiment listed in entry 6 was repeated at elevated temperature. Gratifyingly,
an almost quantitative conversion to 3aa, which was isolated in 91% yield, was observed at
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80°C (entry 8). In the next step, the catalyst loading was lowered to 1 mol %, resulting again
in a virtually quantitative conversion and a similar isolated yield under otherwise identical
conditions (entry 9). Reducing the amount of catalyst further to 0.25 mol % resulted in
incomplete conversion after 16 h, but the yield of isolated product 3aa was still acceptable
(entry 10). To ensure that the high conversions under these conditions do not originate from a
coincidentally particularly well suited Pd/C catalyst, two other commercial samples were
tested under the standard conditions (entries 11 and 12). In both cases high conversions and
isolated yields of 2,2’ꢀbiphenol (3aa) could be obtained by using 2 mol % of the catalyst,
which suggests that the established protocol should be robust and reliable irrespective of the
batch of Pd/C catalyst chosen. Although for optimization purposes a standardized reaction
time of 16 hours was applied, we observed complete conversion at 80°C already after 2.5
hours, if 2 mol % of catalyst were used. For these reasons, the reaction time was lowered to
2.5 hours in all further experiments.
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Table 1. Optimization of conditions for SuzukiꢀMiyaura coupling of 2ꢀiodophenol and 2ꢀ
phenol boronic acid
R
Cat. (mol %);
conditions
I
R
+
(see table)
OH
(HO)2B
OH
2a (R = OH)
2b (R = H)
3aa (R = OH)
3ab (R = H)
1a
entry
Catalyst (mol %)
Cond.a) Additive
(equiv.)
T
Complete
Product
2
conversion? (yield)b)
1
2
Pd(OAc)2 (5)
Pd(OAc)2 (5)
ꢀꢀ
130°C No
3aa (n. d.)
3aa (n. d.)
2a
2a
A
A
Cu(OAc)2 130°C No
(0.05)
3
Pd(OAc)2 (5)
ꢀꢀ
130°C No
3aa (n. d.)
2a
B
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Pd(OAc)2 (5)
P(oꢀtol)3
(0.30)
ꢀꢀ
130°C No
130°C No
3aa (n. d.)
3
4
5
6
7
8
9
2a
B
[η3ꢀ(C3H5)PdCl]2 (2.5)
Pd/C (2)c,d)
5
3aa (n. d.)
3aa (n. d.)
3ab (97%)
3aa (91%)
3aa (92%)
3aa (82%)
3aa (98%)
3aa (84%)
2a
2a
2b
2a
2a
2a
2a
2a
B
C
C
C
C
C
C
C
6
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
20°C
20°C
80°C
80°C
80°C
80°C
80°C
No
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Pd/C (2) c,d)
Yes
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Pd/C (2) c,d)
Yesg)
Yes
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Pd/C (1) c,d)
10
11
12
Pd/C (0.25) c,d)
Pd/C (2) c,e)
Yes
Yesg)
Yesg)
Pd/C (2) c,f)
a)Reaction conditions: A: DMSO/water (1 : 1), Na2CO3 (4 equiv.), 16 h; B: DMF, K3PO4 (4
equiv.), 16 h; C: Water; K2CO3 (4 equiv.), 16 h. b)n. d.: not determined. c)Catalyst contains 10
d)
e)
f)
wtꢀ% Pd. Catalyst batch 1. Catalyst batch 2. Catalyst batch 3; contains 50 wtꢀ% water.
g)Conversion complete after 2.5 h.
Synthesis of ortho-halo phenols 1 and 4. To investigate the scope of the SuzukiꢀMiyaura
reaction of orthoꢀhalo phenols and orthoꢀphenol boronic acid further, various iodo phenols 1
and bromo phenols 4 were synthesized by halogenation of the corresponding phenols 5 using
either the corresponding Nꢀhalo succinimides NIS or NBS27 or, in the case of 1g, ICl. The
results are summarized in Table 2.
Table 2. Synthesis of orthoꢀhalo phenols 1 and 4
R2
R2
X
Method A or B
OH
OH
R1
R1
1 (X = I)
4 (X = Br)
5
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entry
R1
R2
Method (reagent, equiv.)a)
A (NIS, 1.05)
product
1b
Yield
81%
24%
91%
19%
75%
72%
76%
5
1
2
3
4
5
6
7
H
Me
5b
5d
5e
5f
H
CHO
Me
A (NIS, 1.05)
A (NIS, 1.10)
A (NIS, 1.10)
B (ICl, 1.00)
A (NBS, 1.05)
A (NBS, 1.05)
1d
COMe
CHO
OMe
H
1e
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Br
1f
NO2
Me
5g
5b
5d
1g
4b
H
CHO
4d
a)Method A: CH3CN (5 mL/mmol), pꢀTSA (1 equiv.), NIS or NBS (1.05 equiv. – 1.10 equiv.),
20°C, 16 h. Method B: methanol/water (5 : 1, 4 mL/mmol), ICl (1 equiv.), 20°C, 16 h.
The 4ꢀbromoꢀ and 4ꢀchloroꢀ2ꢀiodo phenols 1h,i were synthesized similarly from 2ꢀiodo
phenol 1a using Nꢀchloro succinimide (NCS) or Nꢀbromo succinimide (NBS), respectively.
Precursor 1j was synthesized from 1c using a HornerꢀWadsworthꢀEmons olefination with
triethyl phosphonoacetate and NaH as a base (Scheme 1).
Scheme 1. Synthesis of precursor 1j
O
O
P
EtO
(2 equiv.)
OEt
I
EtO2C
I
OEt
O
NaH (2 equiv.),
THF, 65°C
OH
OH
OMe
OMe
1j (95%)
1c
Scope of the cross coupling reaction with ortho-iodo phenols. Various ortho iodo phenols
1aꢀj were coupled with ortho phenol boronic acid (2a) under the optimized conditions (Table
3). In most cases high yields were obtained with equimolar amounts of the coupling partners.
In the other cases, yields could be improved by increasing the amount of boronic acid to 1.3
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equivalents. A notable exception is the 4ꢀbromo derivative 3ia, which was formed in high
chemoselectivity but only moderate yield with 1.0 equivalents of 2a (entry 10). Control of
chemoꢀ and site selectivity in SuzukiꢀMiyaura reactions has been accomplished by using
leaving groups with different reactivity or by using identical leaving groups at electronically
distinct sites of the aromatic core, even if the coupling partner was present in excess.28
Therefore, we tested whether the bromo substituent can be effectively discriminated even in
the presence of 1.3 equiv. of 2a (entry 11), but the isolated yield of 3ia could only be slightly
improved to 52%. Under these conditions, 14% of the triphenol 3ia’ resulting from dual cross
coupling were isolated as a byproduct. We tried to synthesize 3ia’ selectively by further
increasing the amount of 2a to 2.6 equivalents and the amount of base to 6 equivalents. This
led to an increased yield of 43% of 3ia’, but the mono coupling product 3ia was still the major
product with 50% isolated yield (entry 12). When ester 1j was coupled with 2a under standard
conditions, ester hydrolysis occurred and the free carboxylic acid 3ka was isolated in 68%
yield (entry 13). The ester cleavage could be avoided by replacing K2CO3 by KF, and the
expected product 3ja was obtained in high yield (entry 14).
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Table 3. Scope of Pd/C catalyzed Suzuki coupling of ortho iodo phenols 1
Pd/C (2 mol %), water
HO
(10 mL/mmol), 2a (n equiv.),
R2
I
additive (4.0 equiv.),
R2
80°C, 2.5 h.
OH
R1
OH
R1
HO
1
3
OH
OH
3ia'
entry
1
R1
H
R2
equiv. Additive
Yield
98%
1
3
of 2a
H
1.0
K2CO3
1a
3aa
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H
Me
1.0
1.0
1.3
1.3
1.3
1.0
1.0
1.3
1.0
1.3
2.6
1.0
1.0
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KF
98%
80%
98%
86%
85%
65%
91%
88%
47%
52%a)
50%b)
68%c)
90%d)
3
4
5
6
7
8
9
1b
1c
1c
1d
1e
1f
1g
1h
1i
3ba
3ca
3ca
3da
3ea
3fa
3ga
3ha
3ia
3
OMe
OMe
H
CHO
4
CHO
5
CHO
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6
COMe
CHO
OMe
H
Me
7
Br
8
NO2
9
Cl
10
11
12
13
14
H
Br
H
Br
1i
3ia
H
Br
1i
3ia
OMe
OMe
CH=CHCO2Et
CH=CHCO2Et
1j
1j
3ka
3ja
a)Isolated along with 14% of triphenol 3ia’ resulting from double cross coupling. 6.0 Equiv.
of K2CO3 were used; product isolated along with 43% of 3ia’. c)Hydrolysis of the ester group
occurs under standard conditions, R2 in 3ka is CH=CHCO2H. d)Addition of ethanol (4
mL/mmol) is required to dissolve substrate.
b)
Optimization of conditions for ortho-bromo phenols. Aryl bromides are more stable and
considerably cheaper than the corresponding aryl iodides, but on the other hand significantly
less reactive in most Pdꢀcatalyzed transformations. We investigated the Suzuki coupling of
ortho bromo phenols 4b,c,d with 2ꢀphenol boronic acid (2a) under the standard conditions
used for the corresponding iodides, but at a slightly higher temperature of 100°C. Under these
conditions, the paraꢀmethyl derivative 3ba was obtained in a moderate yield of 55% (Table 4,
entry 1). Replacing K2CO3 by Cs2CO3 (entry 2) did not lead to an improvement. Under
thermal conditions, the reaction failed completely with the electron deficient paraꢀformyl
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compound 4d. Previous reports describing a rate accelerating effect of microwave
irradiation29ꢀ31 on SuzukiꢀMiyaura reactions in aqueous media26 prompted us to investigate
these conditions for the coupling of 4d and 2a, using otherwise identical conditions (entry 4).
Gratifyingly, the expected product 3da could be isolated in reaction times of 0.5 h in good
yield and high selectivity. Unfortunately, these conditions do not appear to be generally
applicable, as the microwave induced cross coupling of bromo phenol 4c and boronic acid 2a
furnished the desired biphenol 3ca only in poor selectivity, along with substantial amounts of
2,2’ꢀbiphenol resulting from oxidative homocoupling32ꢀ34 of 2a, and unreacted bromo phenol
4c (entry 5).
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43
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45
46
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53
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55
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59
60
Table 4. Optimization of conditions for SuzukiꢀMiyaura coupling of 2ꢀbromo phenols 4
Pd/C (2 mol %), water
HO
(10 mL/mmol), 2a (n equiv.),
R2
Br
additive (4.0 equiv.),
R2
Conditions: see table
OH
R1
OH
R1
4
3
entry
R1
H
H
H
H
R2
2a (equiv.)
1.0
Additive Conditions
K2CO3 100°C; 16 h
Cs2CO3 100°C; 16 h
Product Yield
4
1
2
3
4
Me
Me
55%
53%
ꢀꢀa)
4b
4b
4d
4d
3ba
3ba
3da
3da
1.0
CHO 1.0
CHO 1.3
K2CO3
K2CO3
100°C; 16 h
ꢁꢀwave irradiation
at 150°C; 0.5 h
ꢁꢀwave irradiation
at 150°C; 0.5 h
78%
5
OMe CHO 1.3
K2CO3
ꢀꢀb)
4c
3ca
a)No conversion. b)Substantial amount of oxidative boronic acid homocoupling product
formed.
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To suppress the undesired oxidative homocoupling, alternative additives were tested for the
reaction of 4c and 2a under microwave irradiation (Table 5). These experiments revealed that
synthetically useful yields and selectivities could be obtained with KF (entry 1), TBAF (entry
2) and KOH (entry 4) as additives, whereas only minor amounts of product were formed
when Cs2CO3 (entry 3) or NaOTf (entry 6) were added to the reaction mixture. We also tested
a combination of the Lewis acid BF3•MeOH and K2CO3 as a base (entry 5), unfortunately to
no avail. This additive combination was inspired by previous reports describing the mutual
activation of coupling partners through formation of borates, which are presumably activated
by additional Lewis acid.35 Further attempts to improve the yield involved varying the amount
of boronic acid and the equivalents of KOH, unfortunately to no avail (entries 7 – 11). Even
by using the threefold amount of catalyst, no further improvement could be achieved (entry
12).
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Table 5. Alternative additives for microwave induced cross coupling of 4c
Pd/C (2 mol %), water
(10 mL/mmol), 2a (n equiv.),
additive (n equiv.),
HO
O
O
Br
H
H
ꢀ-wave (150°C); t/h
OH
OH
OMe
OMe
4c
3ca
entry 2a (equiv.)
Additive (equiv.)
KF (4.0)
t/h Conversion complete?
0.5 Yes
Yielda)
43%
63%
n. d.
1
2
3
4
5
1.3
1.3
1.3
1.3
1.3
TBAF (4.0)
Cs2CO3 (4.0)
KOH (4.0)
0.5 Yes
0.5 No
0.5 Yes
65%
n. d.
BF3•MeOH
K2CO3 (4.0)
NaOTf (4.0)
(2.0); 0.5 No
6
1.3
0.5 No
n. d.
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2
7
1.05
1.3
1.5
1.5
1.5
1.5
KOH (6.0)
1.0 No
1.0 No
1.0 No
1.0 No
1.0 No
1.0 No
19%
43%
46%
46%
65%
65%
3
4
5
6
7
8
9
8
KOH (6.0)
KOH (6.0)
KOH (2.0)
KOH (4.0)
KOH (4.0)
9
10
11
12b)
10
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a)n. d.: not determined. b)Reaction performed with 6 mol % of Pd/C.
From these experiments we concluded that increasing the amount of catalyst beyond 2 mol %
and the amount of boronic acid beyond 1.3 equivalents has no beneficial effect on the
conversion of less reactive aryl bromides. With respect to the amount of base used, 4.0
equivalents of KOH appears to be the optimum, as both increasing and decreasing the
equivalents of base leads to significantly lower yields. In addition to KOH, KF and TBAF are
also suitable rate enhancing additives.
Scope of the cross coupling reaction with ortho-bromo phenols under microwave
conditions. The optimized protocol for SuzukiꢀMiyaura coupling under microwave
irradiation was then tested for several orthoꢀbromo phenols 4 (Table 6). In all cases, the
oxidative dimerization of 2ꢀphenol boronic acid could be efficiently suppressed, and in most
cases good yields of the desired coupling products 3 were obtained by using KOH as an
additive. Notable exceptions are the examples listed in entries 8 and 11, leading to products
3la and 3na, respectively, with hydrolyzable functional groups. In both cases, the yields could
be significantly improved by using TBAF instead of KOH as an additive (entries 9 and 12).
Similarly, the methyl ester 3ma (entry 10) could also be isolated in good yield without
concomitant saponification.
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Table 6. Scope of microwave induced SuzukiꢀMiyaura couplings of orthoꢀbromo phenols 4
4
5
6
with orthoꢀphenol boronic acid (2a)
7
8
9
Pd/C (2 mol %), water
HO
(10 mL/mmol),
2a (1.3 equiv.),
R2
Br
R2
additive (4.0 equiv.),
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
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36
37
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60
ꢀ-wave (150°C); 0.5 h
R1
OH
R1
4
3
entry
1a)
2
R1
H
R2
Additive
KOH
KOH
KF
Product 3
3aa
Yield
83%
88%
43%
63%
65%
78%
76%
47%
77%
78%
22%
70%
4
H
4a
4b
4c
4c
4c
4d
4h
4l
H
Me
3ba
3ca
3
OMe
OMe
OMe
H
CHO
CHO
CHO
CHO
Cl
4
KOH
TBAF
KOH
KOH
KOH
TBAF
TBAF
KOH
TBAF
3ca
5
3ca
6
3da
3ha
3la
7
H
8
H
CN
9
H
CN
4l
3la
10
11
12
H
CO2Me
NHAc
NHAc
4m
4n
4n
3ma
3na
3na
H
H
a)1.0 Equiv. of boronic acid 2a used.
Having established the beneficial effect of microwave irradiation on the rate of conversion for
orthoꢀbromo phenols, we reinvestigated the dual SuzukiꢀMiyaura coupling of 4ꢀbromoꢀ2ꢀ
iodoꢀphenol (1i), which was found to be unsuccessful with conventional heating (see Table 2,
entry 12). The best yield obtained under optimized thermal conditions was 43% of triphenol
3ia’, along with 50% of the bromo biphenol 3ia (Scheme 2).
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Scheme 2. Selective formation of triphenol 3ia’ via dual SuzukiꢀMiyaura coupling under
7
8
microwave conditions
9
HO
Pd/C (2 mol %), water
10
11
12
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60
(10 mL/mmol), 2a (2.6 equiv.),
Br
I
additive (6.0 equiv.),
OH
ꢀ-wave (150°C); 0.5 h
OH
OH
3ia' (72% for K2CO3,
78% for KOH as additive)
1i
When one equivalent of 1i was reacted with 2.6 equivalents of 2a under the optimized
conditions for microwave initiated SuzukiꢀMiyaura couplings in water, the triphenol 3ia’ was
obtained in 72% yield, along with trace amounts of 3ia if K2CO3 was used as a base.
Replacing K2CO3 by KOH led to an even better selectivity, as no mono coupling product 3ia
could be detected in the crude reaction mixture, and a slightly increased yield of 78% of 3ia’.
Recyclability of Pd/C used for the synthesis 2,2’-biphenols. The opportunity to recycle and
reuse the catalyst is generally considered as one of the major advantages of heterogeneous
catalysis. However, leaching and catalyst deactivation are sometimes serious obstacles,
resulting in continuously decreasing rates of conversion and hence isolated yields of the
desired product. Very recently, this issue has been investigated for Pd/Cꢀcatalyzed Suzukiꢀ
Miyaura coupling reactions of aryl bromides and aryl boronic acids.36 In this study, 2ꢀphenol
boronic acid was not investigated. Interestingly, the authors found only trace amounts of the
biaryl when the reaction was run in water, whereas water/ethanol mixtures gave up to
quantitative yields. The isolated yield of coupling product and the reaction time decreased
only very slightly with each run. This report prompted us to test the recyclability of the Pd/C
catalyst under our conditions, because we were anxious that the chelating properties of 2,2’ꢀ
biphenols, in particular under basic conditions, might lead to a substantial deactivation of the
catalyst by the product. As a test reaction, the coupling of 1c and 2a to 2,2’ꢀbiphenol 3ca
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under the standard conditions outlined in table 3, entry 4 was chosen. To enable catalyst
recovery, the workup procedure was modified: rather than aqueous extraction of the acidified
mixture to isolate the product, the reaction mixture was filtered through a glas filter funnel.
This procedure turned out to be inconvenient, because a considerable amount of the Pd/C was
absorbed by the glas filter and could not be used in subsequent reactions. For these reasons,
the catalyst was filtered off through a paper filter, which was added as a whole to the reaction
mixture prepared for the next run. For the second and all following experiments the same
amounts of 1c, 2a and base were used. The isolated yields of 3ca for runs 1 to 5 are shown in
Figure 2. In the first run, quantitative conversion was observed, but the isolated yield was
somewhat lower compared to the aqueous workup procedure (90% vs. 98%, see table 3, entry
4), presumably due to absorption of small amounts of product on the filter. In the second run,
set up immediately after recovery of the catalyst/filter paper mixture, the yield was lower than
in the first run, but still acceptable. We then checked whether the performance of the
recovered catalyst would be affected by storing it under air for a certain period of time before
reusing it. Therefore, we waited for 16 h before starting the third run, which gave the desired
product in 94% isolated yield. The yields obtained after runs 4 and 5 were virtually identical.
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Figure 2. Yields of isolated 3ca with recycled Pd/C
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Conclusions
4
5
6
7
8
In summary, orthoꢀhalo phenols and orthoꢀphenol boronic acids undergo the SuzukiꢀMiyaura
coupling to 2,2’ꢀbiphenols in high yields and selectivities, using water as a solvent and
commercially available Pd/C as a precatalyst. The protocols described herein are simple and
therefore user friendly, because no elaborate precatalysts and ligands are required to obtain
synthetically useful yields and short reaction times. While iodo phenols are coupled within 2.5
h in excellent yields under thermal conditions, the coupling of the analogous bromo phenols
proceeds effectively under microwave irradiation within 0.5 h.
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Experimental Section
General methods. All experiments were conducted in dry reaction vessels under an
atmosphere of dry nitrogen. Solvents were purified by standard procedures. Deionized water
1
was used for the cross coupling reactions. H NMR spectra were obtained at 300 MHz in
CDCl3 with CHCl3 (δ = 7.26 ppm) as an internal standard. Coupling constants are given in
13
Hz. C 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: DMSOꢀd6 (DMSOꢀd5 as internal
1
standard for H NMR spectroscopy, δ = 2.50 ppm, DMSOꢀd6 as internal standard for 13C
1
NMR spectroscopy, δ = 39.5 ppm); methanolꢀd4 (CD2HOD as internal standard for H NMR
spectroscopy, δ = 3.31 ppm, CD3OD as internal standard for 13C NMR spectroscopy, δ = 49.2
1
ppm; acetoneꢀd6 (CD2HC(O)CD3 as internal 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 ATRꢀFTIR spectra. Wavenumbers (ν
) are given in cm−1. The peak
intensities are defined as strong (s), medium (m) or weak (w). Lowꢀ and high resolution mass
spectra were obtained by EI/TOF. Microwave reactions were carried out in an AntonꢀPaarꢀ
monowaveꢀ300 reactor at 150°C (monowave, maximum power 850 W, temperature control
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via IRꢀsensor, vial volume: 20 mL, pressure ca. 5 bar under these conditions). The following
orthoꢀhalo phenols were purchased and used without further purification: 1a, 1c, 4a, 4c, 4h,
4l, 4m. Acetamide 4n was synthesized as previously reported in the literature.37
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General procedures for the synthesis of ortho-halo phenols 1 and 4. General procedure A:
To a solution of the corresponding phenol 5 or 1a (1.0 mmol) in CH3CN (5 mL) was added pꢀ
TSA mono hydrate (1.0 mmol), followed by NIS, NBS, or NCS (1.05 mmol or 1.10 mmol) as
indicated in the table. The mixture was stirred for 16 h at ambient temperature and then
quenched by addition of aqueous Na2SO3 solution. It was acidified by addition of aqueous
HCl (1 M), the organic solvent was evaporated, and the aqueous layer was extracted with
MTBE. The combined organic layers were dried with MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography on silica to furnish the
halo or dihalo phenols 1 or 4, using hexane/MTBE mixtures as eluent. General procedure B:
To a solution of the appropriate phenol 5 (5.0 mmol) in methanol/water (20 mL, 5:1) was
added ICl (810 mg, 5.0 mmol). The suspension was stirred for 16 h at ambient temperature,
then quenched with an aqueous solution of Na2SO3 (3 mL) and acidified with aqueous HCl (1
M). The organic solvent was removed in vacuo, and the aqueous phase was extracted with
MTBE. The combined organic layers were dried with MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography on silica to furnish the
2ꢀiodo phenol 1, using hexane/MTBE as eluent.
2-Iodo-4-methylphenol (1b).27 General procedure A: obtained from 4ꢀmethylphenol (5b,
540 mg, 5.0 mmol), pꢀTSA•H2O (950 mg, 5.0 mmol), NIS (1.125 g, 5.0 mmol); yield 952 mg
1
(4.1 mmol, 81 %). Yellow oil; H NMR (300 MHz, CDCl3)
δ
7.48 (d, 1H, J = 1.3 Hz), 7.04
13
(dd, 1H, J = 8.2, 1.5 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.21 (s, 1H), 2.25 (s, 3H); C NMR (75
MHz, CDCl3)
δ
152.6, 138.4, 132.1, 131.0, 114.8, 85.5, 20.1; IR (ATR) ν 3480 (m), 2921
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(w), 1485 (s), 1177 (s), 812 (s); HRMS (EI) calcd. for C7H7OI+ [M+]: 233.9542, found:
233.9538.
6
7
8
9
4-Hydroxy-3-iodobenzaldehyde (1d). General procedure A: obtained from 4ꢀ
hydroxybenzaldehyde (5d, 610 mg, 5.0 mmol), pꢀTSA•H2O (950 mg, 5.0 mmol), NIS (1.18 g,
10
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1
5.25 mmol); yield 294 mg (1.2 mmol, 24%). Yellow solid, mp 108ꢀ110°C; H NMR (300
MHz, CDCl3)
δ 9.8 (s, 1 H), 8.22 (d, 1H, J = 1.9), 7.79 (dd, 1H, J = 8.4, 1.9 Hz), 7.1 (d, 1H, J
= 8.4 Hz), 6.37 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ
189.6, 160.3, 140.9, 132.4, 131.6,
115.6, 86.2; HRMS (EI) calcd. for C7H5O2I+ [M+]: 247.9334, found: 247.9322.
1-(2-Hydroxy-3-iodo-5-methylphenyl)ethanone (1e). General procedure A: obtained from
1ꢀ(2ꢀhydroxyꢀ5ꢀmethylphenyl)ethanone (5e, 900 mg, 6.0 mmol), pꢀTSA•H2O (1.14 g, 6.0
mmol), NIS (1.35 g, 6.6 mmol); yield 1.51 g (5.5 mmol, 91%). Yellow solid, mp 101ꢀ102°C;
1H NMR (300 MHz, CDCl3)
Hz), 2.64 (s, 3H), 2.30 (s, 3H);13C NMR (75 MHz, CDCl3)
δ 12.95 (s, 1H), 7.80 (d, 1H, J = 2.0 Hz), 7.52 (d, 1H, J = 1.3
δ
204.1, 159.2, 146.7, 131.1,
130.1, 119.4, 86.5, 26.5, 20.2; IR (ATR)
ν 3017 (w), 1640(m), 1440 (m), 1247 (m), 746 (s);
HRMS (EI) calcd. for C9H9O2I+ [M+]: 275.9647, found: 275.9666. Anal. Calcd. for C9H9O2I
(276.07): C, 39.2; H, 3.3. Found: C, 39.2; H, 3.1.
5-Bromo-2-hydroxy-3-iodobenzaldehyde (1f). General procedure A: obtained from 5ꢀ
bromoꢀ2ꢀhydroxyꢀbenzaldehyde (5f, 1.21g, 6.0 mmol), pꢀTSA•H2O (1.14 g, 6.0 mmol), NIS
(1.35 g, 6.6 mmol); yield 370 mg (1.1 mmol, 19%). Yellow solid, mp 80ꢀ81°C; 1H NMR (300
MHz, CDCl3)
δ 11.72 (s, 1H), 9.72 (s, 1H), 8.10 (d, 1H, J = 2.3 Hz), 7.69 (d, 1H, J = 2.3 Hz);
13C NMR (75 MHz, CDCl3)
δ
194.9, 159.8, 147.9, 136.0, 121.2, 112.3, 86.8; IR (ATR) ν
79
3191 (w), 1660 (s), 1276 (s), 1143 (s), 708; HRMS (EI) calcd. for C7H4O2 BrI+ [M+]:
325.8439, found: 325.8444. Anal. Calcd. for C7H4O2BrI (326.91): C, 25.7; H, 1.2. Found: C,
25.7; H, 1.1.
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2-Iodo-6-methoxy-4-nitrophenol (1g). General procedure B: obtained from 2ꢀmethoxyꢀ4ꢀ
4
5
6
nitrophenol (5g, 843 mg, 5.0 mmol) and ICl (810 mg, 5.0 mmol); yield 1.11 g (3.8 mmol,
7
8
1
75%). Yellow solid, mp 142ꢀ143°C. H NMR (300 MHz, CDCl3)
δ 8.29 (d, 1H, J = 2.4 Hz),
9
7.75 (d, 1H, J = 2.4 Hz), 6.76 (s, 1H), 4.02 (s, 3H, J = 2.2 Hz); 13C NMR (75 MHz, CDCl3)
δ
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151.7, 145.3, 127.5, 118.7, 114.1, 106.3, 57.0; IR (ATR)
ν 3362 (w), 1509 (m), 1485 (m),
1237 (s), 1033 (s); HRMS (EI) calcd. for C7H6O4NI+ [M+]: 294.9342, found: 294.9323.
4-Chloro-2-iodophenol (1h).27 General procedure A: obtained from 2ꢀiodophenol (1a, 2.20
g, 10.0 mmol), pꢀTSA•H2O (1.90 mg, 10.0 mmol), NCS (1.46 g, 11.0 mmol) with a reaction
time of 2 weeks; yield 1.68 g (6.6 mmol, 66%). Colourless solid, mp 76ꢀ77°C; 1H NMR (300
MHz, CDCl3)
δ
7.63 (d, 1H, J = 2.5 Hz), 7.21 (dd, 1H, J = 8.7, 2.5 Hz), 6.92 (d, 1H, J = 8.7
13
Hz), 5.28 (s, 1H); C NMR (75 MHz, CDCl3)
δ 154.0, 137.3, 130.3, 126.3, 115.8, 85.6; IR
(ATR)
ν 3281 (w), 1397 (m), 1211 (m), 1101 (m), 808 (s); HRMS (EI) calcd. for
C6H4O35ClI+ [M+]: 253.8995, found: 253.8984. Anal. Calcd. for C6H4OClI (254.45): C, 28.3;
H, 1.6. Found: C, 28.6; H, 1.4.
4-Bromo-2-iodophenol (1i).38 General procedure B: obtained from 2ꢀiodophenol (1a, 1.10 g,
5 mmol), pꢀTSA•H2O (950, 5.0 mmol), NBS (935 mg, 5.3 mmol); yield 970 mg (3.3 mmol,
65%). Colourless solid, mp 70ꢀ71°C; 1H NMR (300 MHz, CDCl3)
δ
7.79 (d, 1H, J = 2.3 Hz),
13
7.36 (dd, 1H, J = 8.7, 2.3 Hz), 6.89 (d, 1H, J = 8.7 Hz), 5.35 (s, 1H); C NMR (75 MHz,
CDCl3)
δ 154.4, 140.0, 133.2, 116.5, 113.2, 86.2; IR (ATR) ν 3332 (s), 1402 (m), 1269 (m),
1030 (m), 808 (s); HRMS (EI) calcd. for C6H4O79BrI+ [M+]: 297.8490, found: 297.8480.
Anal. Calcd. for C6H4OBrI (298.90): C, 24.1; H, 1.4. Found: C, 24.1; H, 1.1.
2-Bromo-4-methylphenol (4b).39 General procedure A: obtained from 4ꢀmethylphenol (5b,
2.16 g, 20.0 mmol), pꢀTSA•H2O (3.79 g, 22.0 mmol), NBS (3.74 g, 21.0 mmol); yield 2.73 g
1
(14.6 mmol, 72%). Yellow oil; H NMR (300 MHz, CDCl3)
δ
7.29 (d, 1H, J = 1.3 Hz), 7.02
13
(dd, 1H, J = 8.3, 1.5 Hz), 6.94 (d, 1H, J = 8.3 Hz), 5.58 (s, 1H), 2.28 (s, 3H); C NMR (75
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δ
150, 132.2, 131.5, 129.8, 115.9, 109.9, 20.2; IR (ATR) ν 3502 (m), 1492 (s),
1177 (s), 1040 (m), 811 (s); HRMS (EI) calcd. for C7H7O79Br+ [M+]: 185.9680, found:
185.9674.
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8
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3-Bromo-4-hydroxybenzaldehyde (4d).40 General procedure A: obtained from 4ꢀ
hydroxybenzaldehyde (5d, 1.22, 10.0 mmol), pꢀTSA•H2O (1.90 g, 10.0 mmol), NBS (1.87 g,
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10.5 mmol); yield 1.54 g (7.6 mmol, 76%). Colourless solid, mp 120ꢀ121°C; H NMR (300
MHz, CDCl3)
δ 9.82 (s, 1H), 8.04 (s, 1H), 7.80 ꢀ 7.73 (m, 1H), 7.15 (d, 1H, J = 8.4 Hz), 6.45
(s, 1H); 13C NMR (75 MHz, CDCl3)
δ
189.7, 157.8, 134.2, 131.5, 131.1, 116.7, 111.3; IR
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(ATR)
ν
3093 (m), 1422 (s), 1274 (s), 1154 (s), 819 (s); HRMS (EI) calcd. for C7H5O2 Br+
[M+]: 199.9473, found: 199.9465.
(E)-Ethyl 3-(4-hydroxy-3-iodo-5-methoxyphenyl)acrylate (1j). To a solution of triethyl
phosphonoacetate (8.96 g, 40.0 mmol) in dry and degassed THF (100mL) was added NaH (60
wtꢀ% dispersion in mineral oil, 1.60 g, 40.0 mmol). The mixture was stirred at ambient
temperature for 0.5 h, and aldehyde 1c (5.56 g, 20.0 mmol) was added. The solution was
heated to reflux for 5 hours, cooled to ambient temperature, and carefully acidified with
aqueous HCl (1 M). The organic solvent was removed under reduced pressure, and the
aqueous phase was extracted with MTBE. The combined organic layers were dried with
MgSO4, filtered and concentrated under reduced pressure. The residue was purified by
column chromatography on silica, using hexane/MTBE as eluent; yield 6.61 g (19.0 mmol,
1
95%). Colourless solid, mp 145ꢀ146°C; H NMR (300 MHz, CDCl3)
δ 7.51 (d, 1H, J = 15.8
Hz), 7.49 (s, 1H) 6.97 (d, 1H, J = 1.7 Hz), 6.37 (s, 1H), 6.28 (d, 1H, J = 15.9 Hz), 4.25 (q, 2H,
J = 7.1 Hz), 3.92 (s, 3H), 1.32 (t, 3H, J = 7.1 Hz); 13C NMR (75 MHz, CDCl3)
δ
167.0, 147.8,
146.3, 143.2, 131.7, 128.8, 117.1, 109.5, 81.6, 60.6, 56.5, 14.5; IR (ATR)
ν 3251 (m), 1687
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(s), 1629 (s) 1373 (m), 1182 (s); HRMS (EI) calcd. for C12H13O4I+ [M+]: 347.9859, found:
347.9859.
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8
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General Procedure for the thermally initiated coupling of ortho-iodo phenols (1) and 2a
(procedure A). The appropriate 2ꢀiodo phenol 1 (0.75 mmol), boronic acid 2a (104 mg, 0.75
mmol, 1.0 equiv. or 135 mg, 0.98 mmol, 1.3 equiv., as indicated in the table), K2CO3 (415
mg, 3.0 mmol) and Pd/C (10 wtꢀ%, 15 mg, 2 mol %) were suspended in water (7.5 mL). The
mixture was immersed for 2.5 h in an oilbath preheated at 80°C. After cooling the mixture to
ambient temperature, it was carefully acidified by addition of HCl (aq., 1.0 M) and extracted
three times with MTBE (50 mL for each extraction). The combined organic layers were dried
with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by
column chromatography on silica, using hexane/MTBE mixtures of increasing polarity as
eluent to furnish the 2,2’ꢀbiphenols 3.
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General Procedure for the microwave initiated coupling of ortho-bromo phenols (4) and
2a (procedure B). The appropriate 2ꢀbromo phenol 4 (0.75 mmol), boronic acid 2a (104 mg,
0.75 mmol, 1.0 equiv. or 135 mg, 0.98 mmol, 1.3 equiv., as indicated in the table), the
appropriate additive (KOH (168 mg, 3.0 mmol) or KF (174 mg, 3.0 mmol) or TBAF•3H2O
(946 mg, 3.0 mmol), as indicated in the table) and Pd/C (10 wtꢀ%, 15 mg, 2 mol %) were
suspended in water (7.5 mL) in a vessel suited for microwave irradiation. The closed vessel
was placed in a microwave reactor, and irradiated at 150°C for 0.5 h. After cooling the
mixture to ambient temperature, it was carefully acidified by addition of HCl (aq., 1.0 M) and
extracted three times with MTBE (50 mL for each extraction). The combined organic layers
were dried with MgSO4, filtered and concentrated under reduced pressure. The residue was
purified by column chromatography on silica, using hexane/MTBE mixtures of increasing
polarity as eluent.
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Biphenyl-2-ol (3ab). General procedure A: obtained from 1a (165 mg, 1.00 mmol), and 2b
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5
6
7
8
(1.0 equiv.) at 20°C with a reaction time of 16 h; yield: 165 mg (0.97 mmol, 97%). Colourless
1
solid, mp 56–57°C; H NMR (300 MHz, CDCl3) δ 7.54 – 7.38 (m, 5H), 7.31 – 7.24 (m, 2H),
9
13
7.07 – 6.97 (m, 2H), 5.27 (s, 1H); C NMR (75 MHz, CDCl3) δ 152.6, 137.2, 130.4, 129.4,
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129.3, 129.2, 128.3, 128.0, 121.0, 116.0; IR (ATR)
ν 3526 (m), 1434 (m), 1324 (m), 1100
(m), 753 (s); HRMS (EI) calcd. for C12H10O+ [M+]: 170.0732, found: 170.0738; Anal. calcd.
for C12H10O (170.21): C, 84.7; H, 5.9. Found: C, 84.3; H, 5.8.
Biphenyl-2,2'-diol (3aa). General procedure A: obtained from 1a (165 mg, 0.75 mmol) and
2a (1.0 equiv.); yield: 137 mg (0.74 mmol, 98%). General procedure B: obtained from 4a
(130 mg, 0.75 mmol) and 2a (1.0 equiv.); yield: 116 mg (0.62 mmol, 83%). Colourless solid,
mp 109ꢀ111°C; 1H NMR (300 MHz, CDCl3) δ 7.32 (ddd, 2H, J = 9.2, 7.4, 1.7), 7.28 (dd, 2H,
13
J = 6.1, 1.5), 7.11 – 7.00 (m, 4H), 5.85 (s, 2H); C NMR (75 MHz, CDCl3) δ 153.0, 131.5,
130.1, 123.9, 121.8, 116.8; IR (ATR)
ν 3131 (w), 1483 (m), 1439 (m), 1225 (m), 745 (s);
+
HRMS (EI) calcd. for C12H10O2 [M+]: 186.0681, found: 186.0672. Anal. Calcd. for C12H10O2
(186.21): C, 77.4; H, 5.4. Found: C, 77.4; H, 5.5.
5-Methylbiphenyl-2,2'-diol (3ba). General procedure A: obtained from 1b (176 mg, 0.75
mmol) and 2a (1.0 equiv.); yield: 147 mg (0.74 mmol, 98%). General procedure B: obtained
from 4b (140 mg, 0.75 mmol) and 2a (1.3 equiv.); yield: 132 mg (0.66 mmol, 88%).
Colourless solid, mp 81ꢀ83°C; 1H NMR (300 MHz, CDCl3) δ 7.34 (dd, 1H, J = 7.6, 1.6), 7.29
(ddd, 1H, J = 7.4, 7.3, 1.4 Hz), 7.15 (d, 1H, J = 1.7), 7.13 – 7.04 (m, 2H), 7.00 (dd, 1H, J =
8.1, 1.0), 6.90 (d, 1H, J = 8.2), 2.37 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 152.6, 150.3,
132.0, 131.5, 131.1, 130.3, 129.7, 129.6, 124.9, 124.5, 121.8, 116.8, 116.7, 20.6; IR (ATR)
ν
3297 (w), 1579 (w), 1489 (m), 1447 (s), 1101 (m); HRMS (EI) calcd. for C13H12O2 [M+]:
+
200.0837, found: 200.0825.
2',6-Dihydroxy-5-methoxybiphenyl-3-carbaldehyde (3ca). General procedure A: obtained
from 1c (209 mg, 0.75 mmol) and 2a (1.3 equiv.); yield: 179 mg (0.73 mmol, 98%). General
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procedure B: obtained from 4c (173 mg, 0.75 mmol), 2a (1.3 equiv.) and TBAF•3H2O (4.0
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5
6
1
equiv.) as additive; yield: 119 mg (0.58 mmol, 65%). Colourless solid, mp 130°C; H NMR
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8
9
(300 MHz, CDCl3) δ 9.87 (s, 1H), 7.50 (d, 1H, J = 1.8), 7.47 (d, 1H, J = 1.8), 7.40 – 7.29 (m,
2H), 7.12 – 7.02 (m, 2H), 6.84 (s, 1H), 5.96 (s, 1H), 4.03 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 190.9, 153.6, 147.8, 147.6, 131.2, 130.4, 130.2, 129.9, 124.7, 124.0, 121.5, 117.9, 108.0,
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56.7; IR (ATR)
ν 3334 (bw), 1672 (s), 1589 (s), 1148 (s), 867 (m); HRMS (EI) calcd. for
C14H12O4 [M+]: 244.0736, found: 244.0742. Anal. Calcd. for C14H12O4 (244.24): C, 68.8; H,
5.0. Found: C, 68.3; H, 5.0.
+
2',6-Dihydroxybiphenyl-3-carbaldehyde (3da). General procedure A: obtained from 1d
(124 mg, 0.50 mmol) and 2a (1.3 equiv.); yield: 92 mg (0.86 mmol, 86%). General procedure
B: obtained from 4d (101 mg, 0.75 mmol), 2a (1.3 equiv.); yield: 84 mg (0.39 mmol, 78%).
Colourless solid, mp 119°C; 1H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 8.15 (s, 1H), 7.81 (d,
1H, J = 2.1), 7.76 (dd, 1H, J = 8.4, 2.1), 7.33 – 7.23 (m, 2H), 7.10 (d, 1H, J = 8.4), 7.07 – 6.96
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 192.4, 159.8, 152.8, 134.8, 131.9, 131.7, 130.2, 129.8,
126.6, 123.7, 121.9, 117.9, 116.9; IR (ATR)
ν 3248 (bm), 1670 (s), 1592 (s), 1305 (m), 1182
+
(m); HRMS (EI) calcd. for C13H10O3 [M+]: 214.0630, found: 214.0628. Anal. Calcd. for
C13H10O3 (214.22): C, 72.9; H, 4.7. Found: C, 72.2; H, 5.0.
1-(2,2'-Dihydroxy-5-methylbiphenyl-3-yl)ethanone (3ea). General procedure A: obtained
from 1e (207 mg, 0.75 mmol) and 2a (1.3 equiv.); yield: 155 mg (0.64 mmol, 85%).
1
Colourless solid, mp 165°C; H NMR (300 MHz, CDCl3) δ 13.45 (s, 1H), 7.63 (d, 1H, J =
1.5), 7.43 (d, 1H, J = 2.1), 7.32 (td, 1H, J = 7.6, 7.6, 1.6), 7.26 (dd, 1H, J = 7.6, 1.6), 7.08 (dd,
13
1H, J = 7.8, 1.0), 7.02 (ddd, 1H, J = 7.5, 1.1), 6.69 (s, 1H), 2.71 (s, 3H), 2.39 (s, 3H); C
NMR (75 MHz, CDCl3) δ 205.5, 156.0, 154.2, 140.2, 131.2, 130.6, 129.8, 129.5, 128.3,
125.6, 121.4, 119.7, 118.6, 27.0, 20.7; IR (ATR)
ν 3370 (bw), 1635 (m), 1437 (m), 1329 (m),
+
1217 (m); HRMS (EI) calcd. for C15H14O3 [M+]: 242.0943, found: 242.0955. Anal. Calcd.
for C15H14O3 (242.27): C, 74.4; H, 5.8. Found: C, 74.6; H, 5.7.
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5-Bromo-2,2'-dihydroxybiphenyl-3-carbaldehyde (3fa). General procedure A: obtained
from 1f (164 mg, 0.50 mmol) and 2a (1.0 equiv.); yield: 95 mg (0.32 mmol, 65%). Colourless
solid, mp 115°C; 1H NMR (300 MHz, CDCl3) δ 11.94 (s, 1H), 9.92 (s, 1H), 7.76 (s, 2H), 7.35
9
13
(ddd, 1H, J = 8.2, 7.9, 1.6), 7.25 (dd, 1H, J = 8.0, 1.4), 7.13 – 6.97 (m, 2H), 6.08 (s, 1H); C
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NMR (75 MHz, CDCl3) δ 196.0, 156.5, 153.9, 141.9, 135.5, 131.2, 130.6, 130.3, 123.4,
121.9, 121.7, 118.5, 112.7; IR (ATR)
ν 3402 (bw), 1656 (s), 1436 (m), 1415 (m), 1281 (s);
HRMS (EI) calcd. for C13H9O3 Br+ [M+]: 291.9735, found: 291.9724. Anal. Calcd. for
C13H9O3Br (293.11): C, 53.3; H, 3.1. Found: C, 53.4; H, 3.2.
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3-Methoxy-5-nitrobiphenyl-2,2'-diol (3ga). General procedure A: obtained from 1g (221
mg, 0.75 mmol) and 2a (1.0 equiv.); yield: 179 mg (0.69 mmol, 91%). Colourless solid, mp
1
184ꢀ185°C; H NMR (300 MHz, acetoneꢀd6) δ 7.88 (d, 1H, J = 2.7), 7.78 (d, 1H, J = 2.6),
7.30 (dd, 1H, J = 7.6, 1.6), 7.24 (ddd, 1H, J = 8.1, 7.4, 1.7), 7.00 (dd, 1H, J = 8.1, 0.9), 6.93
(ddd, 1H, J = 7.5, 7.5, 1.2); 13C NMR (75 MHz, acetoneꢀd6) δ 155.5, 151.6, 148.6, 140.8,
132.3, 130.2, 126.3, 124.4, 121.1, 120.4, 117.0, 106.2, 57.0; IR (ATR)
ν 3411 (bw), 1488 (m),
1332 (s), 1252 (s), 1094 (m); HRMS (EI) calcd. for C13H11O5N+ [M+]: 261.0637, found:
261.0632. Anal. Calcd. for C13H11O5N (261.23): C, 59.8; H, 4.2; N, 5.4. Found: C, 59.6; H,
4.2; N, 5.3.
5-Chlorobiphenyl-2,2'-diol (3ha). General procedure A: obtained from 1h (191 mg, 0.75
mmol) and 2a (1.3 equiv.); yield: 146 mg (0.66 mmol, 88%). General procedure B: obtained
from 4h (127 mg, 0.50 mmol) and 2a (1.3 equiv.); yield: 84 mg (0.38 mmol, 76%).
1
Colourless solid, mp 154°C; H NMR (300 MHz, CDCl3) δ 7.32 (ddd, 1H, J = 8.1, 7.4, 1.7),
7.28 – 7.21 (m, 3H), 7.07 (td, 1H, J = 7.5, 7.5, 1.1), 6.98 (dd, 1H, J = 8.1, 0.9), 6.95 (dd, 1H, J
= 6.9, 2.2), 5.97 (s, 1H), 5.80 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 152.6, 151.8, 131.6,
131.0, 130.5, 129.8, 126.5, 126.0, 123.0, 122.2, 118.4, 116.9; IR (ATR)
ν 3278 (bw), 1484
35
(m), 1262 (m), 1220 (m), 1104 (w); HRMS (EI) calcd. for C12H9O2 Cl+ [M+]: 220.0291,
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found: 220.0274. Anal. Calcd. for C12H9O2Cl (220.65): C, 65.3; H, 4.1. Found: C, 65.3; H,
4.0.
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5-Bromobiphenyl-2,2'-diol (3ia) and 5-(phenyl-2''-ol)-biphenyl-2,2'-diol (3ia’). General
procedure A: obtained from 1i (224 mg, 0.75 mmol) and 2a (1.3 equiv.); yield of 3ia: 103 mg
(0.39 mmol, 52%), along with byproduct 3ia’ (30 mg, 0.11 mmol, 14%). Modified general
procedure A: obtained from 1i (224 mg, 0.75 mmol), 2a (2.6 equiv.), and K2CO3 (6.0 equiv.);
yield: yield of 3ia: 100 mg (0.38 mmol, 50%), along with byproduct 3ia’ (89 mg, 0.32 mmol,
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43%). Analytical data for 5ꢁbromobiphenylꢁ2,2'ꢁdiol (3ia): colourless solid, mp ###°C; H
NMR (300 MHz, CDCl3) δ 7.41 (s, 1H), 7.39 (dd, 1H, J = 9.5, 2.5), 7.32 (ddd, 1H, J = 9.6,
7.5, 1.7), 7.26 (dd, 1H, J = 7.7, 1.7), 7.07 (ddd, 1H, J = 7.6, 7.5, 1.1), 6.98 (dd, 1H, J = 8.1,
13
1.0), 6.89 (d, 1H, J = 8.2), 6.07 (s, 1H), 5.90 (s, 1H); C NMR (75 MHz, CDCl3) δ 152. 6,
152.3, 133.9, 132.7, 131.6, 130.5, 126.6, 123.0, 122.1, 118.8, 116.9, 113.7; IR (ATR)
ν 3276
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(bm), 1481 (m), 1447 (m), 1262 (m), 1219 (s); HRMS (EI) calcd. for C12H9O2 Br+ [M+]
263.9786, found: 263.9780. Anal. Calcd. for C12H9O2Br (265.10): C, 54.4; H, 3.4. Found: C,
54.9; H, 3.5. Analytical data for 5ꢁ(phenylꢁ2''ꢁol)ꢁbiphenylꢁ2,2'ꢁdiol (3ia’): colourless solid,
1
mp 64°C; H NMR (300 MHz, CDCl3) δ 7.40 (d, 1H, J = 2.1), 7.36 (dd, 1H, J = 8.3, 2.2),
7.32 – 7.26 (m, 2H), 7.26 – 7.18 (m, 2H), 7.09 – 7.01 (m, 2H), 7.01 – 6.91 (m, 3H), 6.50 (s,
2H), 5.57 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 152.7, 152.6, 152.5, 132.4, 131.7, 130.6,
130.5 (2C), 130.1, 129.0, 127.8, 125.3, 124.1, 122.0, 121.1, 117.6, 117.0, 116.1; IR (ATR)
ν
+
3338 (bm), 1484 (s), 1400 (m), 1221 (s), 754 (s); HRMS (EI) calcd. for C18H14O3 [M+]
278.0943, found: 278.0953. Anal. Calcd. for C18H14O3 (278.30): C, 77.7; H, 5.1. Found: C,
77.6; H, 5.3.
(E)-Ethyl 3-(2',6-dihydroxy-5-methoxybiphenyl-3-yl)acrylate (3ja). General procedure A:
obtained from 1j (696 mg, 2.00 mmol), 2a (1.0 equiv.), KF (4.0 equiv.) as an additive instead
of K2CO3, and ethanol (4 mL/mmol) as coꢀsolvent; yield: 566 mg (1.80 mmol, 90%).
Colourless solid, mp 110°C; 1H NMR (300 MHz, CDCl3) δ 7.64 (d, 1H, J = 15.9), 7.37 – 7.26
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(m, 2H), 7.14 (d, 1H, J = 1.8), 7.07 (d, 1H, J = 2.1), 7.07 – 7.00 (m, 2H), 6.59 (s, 1H), 6.34 (d,
1H, J = 15.9), 6.18 (s, 1H), 4.26 (q, 2H, J = 7.1), 3.98 (s, 3H), 1.33 (t, 3H, J = 7.1); 13C NMR
(75 MHz, CDCl3) δ 167.2, 153.6, 147.2, 144.4, 144.0, 131.1, 129.9, 127.9, 125.3, 124.8,
9
124.6, 121.4, 117.9, 116.9, 108.7, 60.6, 56.5, 14.5; IR (ATR)
ν 3373 (bm), 1694 (m), 1632
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+
(m), 1264 (s), 1159 (s); HRMS (EI) calcd. for C18H18O5 [M+] 314.1154, found: 314.1152.
Anal. Calcd. for C18H18O5 (314.33): C, 68.8; H, 5.8. Found: C, 68.9; H, 5.8.
(E)-3-(2',6-Dihydroxy-5-methoxybiphenyl-3-yl)acrylic acid (3ka). General procedure A:
obtained from 1j (261 mg, 0.75 mmol) and 2a (1.0 equiv.) after a prolonged reaction time of
1
16 h; yield: 147 mg (0.51 mmol, 68%). Colourless solid, mp >300°C; H NMR (300 MHz,
DMSOꢀd6) δ 7.77 – 7.63 (m, 1H), 7.51 (d, 1H, J = 15.9 Hz), 7.30 (d, 1H, J = 1.8 Hz), 7.18 –
7.09 (m, 2H), 7.02 (d, 1H, J = 1.7 Hz), 6.89 (d, 1H, J = 7.4 Hz), 6.82 (dd, 1H, J = 7.4, 1.0
13
Hz), 6.39 (d, 1H, J = 15.9 Hz), 3.89 (s, 3H); C NMR (75 MHz, DMSOꢀd6) δ 168.0, 154.6,
148.0, 146.5, 144.7, 131.3, 128.3, 126.2, 125.3, 124.9, 124.8, 118.6, 115.7, 115.6, 109.1, 56.0,
39.5; IR (ATR)
ν 3187 (bm), 1682 (s), 1627 (s), 1420 (s), 1263 (s); HRMS (EI) calcd. for
+
C16H14O5 [M+]: 286.0841, found: 286.0837.
2',6-Dihydroxybiphenyl-3-carbonitrile (3la). General procedure B: obtained from 4l (149
mg, 0.75 mmol), 2a (1.3 equiv.) and TBAF•3H2O (4.0 equiv.); yield: 122 mg (0.58 mmol,
77%). Colourless solid, mp 145°C; 1H NMR (300 MHz, methanolꢀd4) δ 7.54 (d, 1H, J = 1.9),
7.51 (dd, 1H, J = 8.4, 2.2), 7.25 – 7.15 (m, 2H), 7.00 (d, 1H, J = 8.4), 6.95 – 6.87 (m, 2H); 13C
NMR (75 MHz, methanolꢀd4) δ 160.3, 155.5, 137.0, 133.7, 132.5, 130.4, 128.9, 125.1, 120.9,
120.5, 118.0, 117.0, 103.4; IR (ATR)
ν 3286 (s), 2230 (s), 1601 (m), 1488 (s), 1282 (s);
HRMS (EI) calcd. for C13H9O2N+ [M+]: 211.0633, found: 211.0631. Anal. Calcd. for
C13H9NO2 (211.22): C, 73.9; H, 4.3. Found: C, 74.4; H, 3.9.
Methyl 2',6-dihydroxybiphenyl-3-carboxylate (3ma). General procedure B: obtained from
4l (116 mg, 0.50 mmol), 2a (1.3 equiv.) and TBAF•3H2O (4.0 equiv.); yield: 96 mg (0.39
1
mmol, 78%). Colourless solid, mp 132°C; H NMR (300 MHz, CDCl3) δ 8.00 (d, 1H, J =
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1.9), 7.97 (dd, 1H, J = 8.4, 2.2), 7.37 – 7.26 (m, 2H), 7.07 (dd, 1H, J = 7.5, 1.1), 7.07 – 7.00
4
5
6
13
(m, 3H), 6.79 (s, 1H), 6.31 (s, 1H), 3.89 (s, 3H); C NMR (75 MHz, CDCl3) δ 167.4, 157.7,
7
8
152.8, 133.7, 131.9, 131.6, 130.3, 124.8, 123.4, 123.2, 122.0, 117.0, 116.9, 52.3; IR (ATR)
ν
9
+
3363 (m), 1700 (m), 1684 (s), 1253 (s), 1175 (s); HRMS (EI) calcd. for C14H12O4 [M+]:
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13
14
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17
18
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244.0736, found: 244.0725.
N-(2',6-dihydroxybiphenyl-3-yl)acetamide (3na). General procedure B: obtained from 4n
(150 mg, 0.50 mmol), 2a (1.3 equiv.) and TBAF•3H2O (4.0 equiv.); yield: 84 mg (0.35 mmol,
1
70%). Colourless oil; H NMR (300 MHz, methanolꢀd4) δ 7.41 – 7.36 (m, 2H), 7.27 – 7.17
13
(m, 2H), 6.96 – 6.85 (m, 3H), 3.35 (s, 1H), 2.08 (s, 3H); C NMR (75 MHz, methanolꢀd4) δ
171.5, 155.1, 152.0, 132.6, 132.3, 129.9, 127.8, 127.2, 125.3, 122.5, 121.4, 117.4, 117.3, 23.6;
IR (ATR)
ν 3263 (w), 1624 (m), 1488 (s), 1223 (s), 755 (s); HRMS (EI) calcd. for
C14H13O3N+ [M+]: 243.0895, found: 243.0891.
Procedure for catalyst recovery and reuse experiments. In the first run, orthoꢀiodo phenol
1c (209 mg, 0.75 mmol), orthoꢀphenol boronic acid 2a (135 mg, 0.98 mmol), K2CO3 (415
mg, 3.00 mmol) and Pd/C (10 wtꢀ%, 15 mg, 2 mol %) were suspended in water (7.5 mL). The
reaction mixture was immersed in an oil bath preheated to 80°C for 2.5 h. The mixture was
then cooled to ambient temperature and filtered through a filter paper, which was
subsequently washed with water (10 mL). The separated aqueous layer was carefully acidified
by addition of aqueous HCl (1.0 M) and extracted three times with MTBE (50 mL for each
extraction). The combined organic layers were dried with MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by column chromatography on silica, using
hexane/MTBE mixtures of increasing polarity as eluent to furnish the product 3ca (165 mg,
1
0.68 mmol, 90%) as a colourless solid, which was checked for purity and identity by H
NMRꢀspectroscopy. In the following runs, the filter paper impregnated with the catalyst from
the first run was added to the aqueous suspension of base and starting materials. The volume
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of water, the amounts of all starting materials, the reaction temperature and reaction time were
identical to those reported above for the first run. After each run, the product 3ca was isolated
as described for run 1, and identity and purity were checked by 1H NMR spectroscopy. Yield
of 3ca after run 2: 147 mg (0.60 mmol, 80%); after run 3 (started with a delay of 16 h after
recovery of the catalyst from run 2): 172 mg (0.71 mmol, 94%); after run 4: 167 mg (0.68
mmol, 91%); after run 5: 174 mg (0.71 mmol, 95%).
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Acknowledgments
We thank Evonik Oxeno for generous donations of solvents and Umicore (Hanau, Germany)
for generous donations of catalysts.
Supporting Information Available statement
1
13
Copies of H and C NMR spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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