Suzuki-Miyaura cross coupling reactions with Phenoldiazonium salts

Article abstract of DOI:10.1039/c1ob05256j

The Suzuki-Miyaura coupling of phenol diazonium salts and aryl trifluoroborates yields 4-hydroxybiaryls in a protecting group-free synthesis. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05256j

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Suzuki–Miyaura cross coupling reactions with Phenoldiazonium salts†
Bernd Schmidt* and Frank Ho¨lter
Received 17th February 2011, Accepted 5th April 2011
DOI: 10.1039/c1ob05256j
The Suzuki–Miyaura coupling of phenol diazonium salts and aryl trifluoroborates yields
4-hydroxybiaryls in a protecting group-free synthesis.
The most commonly used methods for the synthesis of biaryl
compounds are Pd-catalyzed cross coupling reactions.11,12 In
Introduction
particular, the Suzuki–Miyaura reaction13 is a valuable tool for
this purpose. In most cases, aryl halides are used as electrophiles
in this transformation, with aryl iodides being significantly more
reactive than aryl bromides or -chlorides. However, a major
disadvantage of aromatic iodo compounds is their light sensitivity
and the comparatively high price. Over the past two decades,
arene diazonium salts were established as interesting alternatives in
various Pd-catalyzed C–C-bond forming reactions,14–16 including
Suzuki–Miyaura cross coupling reactions with boronic acids,17–23
boronates,24 dioxazaborocanes25 and organotrifluoroborates.26–30
While unprotected iodophenols have been successfully used in
Suzuki–Miyaura couplings,31,32 free phenol diazonium salts have,
to the best of our knowledge, never been investigated. A single ex-
ample of a biaryl formation from a phenol diazonium compound
was reported by Goeldner et al., however, this reaction is a photo-
chemical C–H-insertion and proceeds via a different mechanism.33
We have very recently reported, that arene diazonium salts can
be synthesized from acetanilides in a one-flask deacetylation-
diazotation sequence.34,35 This method can be extended to phenol
diazonium salts, which were found to be superior arylating agents
in Mizoroki–Heck-reactions than their O-alkylated analogues.36,37
In the course of this study, we discovered that the preferred
conditions for these Mizoroki–Heck-reactions are methanol as
a solvent and addition of a base, whereas basefree conditions are
advantageous if alkoxy arene diazonium salts are used.37 As a
working hypothesis, we proposed that phenol diazonium cations
such as 4a are protected against hydrodediazonation under the
preferred conditions by partial or complete deprotonation. This
results in the formation of a quinone diazide structure 4a¢, which is
supported by NMR-spectroscopical investigations (Scheme 1).37
4-Hydroxybiaryls are structural motifs present in many drugs,
drug candidates or compounds which are otherwise of interest
in medicinal chemistry. A representative example is diflunisal
(1), an antiinflammatory drug which acts by inhibition of
cyclooxygenase-2 (Fig. 1).1 Analogues of diflunisal were synthe-
sized with the aim to study and eventually reduce its undesired
binding to human serum albumin, which causes a significant loss
of efficacy and makes rather high dosing of the drug necessary.2
The discovery that several non-steroidal anti inflammatory drugs
(NSAID’s) stabilize the native structure of the amyloidogenic
plasma protein transthyretin (TTR) sparked new interest in
these drugs.3 Thus, analogues of flufenamic acid,4 diclofenac,5
flurbiprofen6,7 and diflunisal8 were synthesized and evaluated for
their potency as amyloidogenesis inhibitors. From the crystal
structures of TTR-drug complexes6 it was deduced that small
molecule inhibitors should have two aromatic moieties and at
least one polar functional group. Therefore, numerous biaryls were
included in a screening for TTR amyloid fibril inhibitors and iden-
tified as promising lead structures.9 4-Hydroxybiaryls have also
been used as intermediates in the synthesis of pharmacologically
relevant compounds, such as the H3 receptor antagonist 2, which
is available in few steps from phenol 3 (Fig. 1).10
Fig. 1 Target molecules containing the 4-hydroxybiaryl motif.
Universitaet Potsdam, Institut fuer Chemie, Organische Synthese-
chemie, Karl-Liebknecht-Straße 24-25, D-14476, Potsdam-Golm, Germany.
E-mail: bernd.schmidt@uni-potsdam.de
Scheme 1 Phenol diazonium vs. quinone diazide structure.
† Electronic supplementary information (ESI) available: Experimental
1
details for all new compounds and copies of H and 13C-NMR spectra.
The interesting results obtained in Mizoroki–Heck reactions
See DOI: 10.1039/c1ob05256j
with phenol diazonium salts 4 and the attractive perspective of a
4914 | Org. Biomol. Chem., 2011, 9, 4914–4920
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protecting group free synthesis of 4-hydroxy biaryls under mild
conditions prompted us to investigate these reagents in Suzuki-
Miyaura coupling reactions.
82% by addition of a base (entry 8). Replacing Pd(OAc)2 by Pd/C
as a catalyst gives very similar results as for 4b (entries 9 and 10).
It should be noted that Pd/C can be a highly active catalyst for
Suzuki–Miyaura coupling reactions with arene diazonium salts,
however, parameters such as particle size, distribution of the metal
and degree of reduction play a crucial role.22 These parameters are
difficult to control if the catalyst was obtained from a commercial
source. As a result of the findings described above, we refrained
from using Pd/C and dioxane in further experiments. However, we
have previously observed that the beneficial effect of added base is
not general for all phenol diazonium salts and therefore decided
to test both basic and base-free conditions, using methanol as a
solvent and Pd(OAc)2 as a catalyst. The results of this investigation
into the scope and limitations of Suzuki–Miyaura-couplings with
unprotected phenol diazonium salts are summarized in Table 2.
The reaction of 4a with substituted arene trifluoroborates 5b,c
gives results which are similar to those obtained with 5a: addition
of a base (entries 1 and 3 vs. entries 2 and 4) substantially improves
the yield of coupling products 6ab and 6ac. Remarkably, the
attempted cross coupling with amide-substituted trifluoroborate
5e fails completely both under basic and base-free conditions,
and we could neither isolate 6ae nor any homocoupling products
(entries 5 and 6). As expected from the results discussed above,
cross coupling reactions of 4-methoxy substituted diazonium salt
4b with 5b,c are preferably conducted under base-free conditions
(entries 7–10). The reaction of 4b with 5c (entry 9) is remarkable, as
this is the only example where we observed a significant amount of
an aryltrifluoroborate-homocoupling product. In this experiment,
the desired cross coupling product 6bc and a symmetrical biaryl
were obtained as an inseparable mixture in a 5 : 1 ratio (Scheme 2).
Formation of such homocoupling products has been reported
as a side reaction in Suzuki–Miyaura couplings with aryl boronic
acids, when oxygen was not rigorously excluded.39,40 Very recently,
Lloyd-Jones et al. investigated the mechanism of Suzuki–Miyaura
reactions with organotrifluoroborates in detail and proposed a
rationale for the observation that homocoupling products are
Results and discussion
We started with a comparison of 4-phenol diazonium salt 4a
and its O-methyl derivative 4b. As organotrifluoroborates26 are
readily available,38 very stable and highly nucleophilic reagents
for Suzuki–Miyaura coupling reactions,30 we chose potassium
phenyltrifluoroborate 5a for the initial reactions. For practical
purposes, Pd(OAc)2 and Pd/C are the most convenient precat-
alysts, and we therefore decided to test both in this study. The
Suzuki–Miyaura coupling of non-phenolic arene diazonium salts
and organotrifluoroborates has previously been accomplished by
Geneˆt et al.,28 who identified Pd(OAc)2 in dioxane in the absence
of a base as best conditions. Based on the experiences we made
during the investigation of Mizoroki–Heck reactions, we decided
to test in addition to Geneˆt’s conditions, methanol as a solvent
and optional addition of NaOAc as a base (Table 1).
The results listed in Table 1 confirm that for 4-methoxy-benzene
diazonium salt 4b Geneˆt’s conditions (entry 1) give the highest
yields of coupling product 6ba. In methanol, the isolated yield is
significantly lower, but still useful (entry 2). The combination of
methanol as a solvent and addition of a base, however, results in
a low yield of 32% (entry 3). This observation is in accord with
results obtained for the Mizoroki–Heck reaction of 4b and methyl
acrylate and can be attributed to a competing decomposition of the
diazonium salt in the presence of nucleophiles.37 No conversion to
the desired coupling product was observed with Pd/C in dioxane
(entry 4),20 whereas a fair yield of 6ba was obtained with this
catalyst in methanol (entry 5). The same conditions were then
applied to phenol diazonium salt 4a. In contrast to 4b and other
non-phenolic diazonium salts, dioxane is not a suitable solvent in
this case (entry 6). Switching to methanol results in a significantly
improved yield of 70% (entry 7), which can be further improved to
Table 1 Optimization of conditions for the coupling of 4a,b and 5aa
Entry
4
Catalyst
NaOAc (equiv.)
Solvent
Product
Yield
1
4b
4b
4b
4b
4b
4a
4a
4a
4a
4a
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd/C
none
none
3.0
none
none
none
none
3.0
dioxane
6ba
6ba
6ba
6ba
6ba
6aa
6aa
6aa
6aa
6aa
79%
64%
32%
0%
48%
18%
70%
82%
0%
2
methanol
methanol
dioxane
3
4
5
6
7
8
9
Pd/C
methanol
dioxane
methanol
methanol
dioxane
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd/C
none
none
10
Pd/C
methanol
41%
a Reagents and conditions: 4a or 4b (1.0 equiv.), 5a (1.0 equiv.), solvent (10 mL mmol-1), then add NaOAc (3.0 equiv., optional), then add catalyst
(2.5 mol%), 20 ◦C, 12 h.
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Table 2 Suzuki–Miyaura coupling reactions with various 4-phenol diazonium saltsa
Entry
1
ArN2BF4
4
Ar¢BF3K
5
NaOAc (equiv.)
none
Ar–Ar¢
6
Yield
36%
4a
5b
6ab
2
3
3.0
none
74%
48%
5c
5e
6ac
6ae
4
5
3.0
none
66%
< 5%
6
7
3.0
none
< 5%
40%
4b
5b
5c
6bb
6bc
8
9
3.0
none
16%
(94%)b
10
11
3.0
none
36%
70%
4c
5a
5b
5c
6ca
6cb
6cc
12
13
3.0
none
< 5%
82%
14
15
3.0
none
< 5%
44%
16
17
3.0
none
< 5%
99%
5d
5e
6cd
6ce
18
19
none
none
70%
59%
4d
5a
5b
5c
6da
6db
6dc
20
21
3.0
none
18%
34%
22
23
3.0
none
27%
46%
24
3.0
31%
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Table 2 (Contd.)
Entry
25
ArN2BF4
4
Ar¢BF3K
5
NaOAc (equiv.)
none
Ar–Ar¢
6
1
Yield
34%
5d
26
4e
4f
5a
none
6ea
6fa
94%
27
28
3.0
none
56%
44%
29
3.0
18%
a Reagents and conditions: 4 (1.0 equiv.), 5a (1.0 equiv.), methanol (10 mL mmol-1), NaOAc (3.0 equiv., optional), Pd(OAc)2 (2.5 mol%), 20 ◦C, 12 h.
b Yield is based on trifluoroborate 5c and refers to an inseparable 5 : 1 mixture of 6bc and homocoupling product 7.
(6cd, entry 17) was obtained quantitatively, and morpholino amide
6ce (entry 18), a potential H3-antagonist precursor, in 70% yield.10
This result is remarkable, considering the complete failure for 6ae
(entries 5, 6). Suzuki–Miyaura coupling reactions with the highly
polar carboxylic acid diazonium salt 4d were also successful, e.g.
for the synthesis of diflunisal (1, entry 25).
Conclusions
Scheme 2 Suzuki–Miyaura coupling of 4b and 5c with competing
formation of homocoupling product 7.
In summary, various 4-hydroxy biaryls are accessible in a protect-
ing group free Suzuki-Miyaura coupling from phenol diazonium
salts and aryl trifluoroborates. Depending on the diazonium salt
formed in significantly smaller amounts with these reagents. For
used, basic or base-free conditions are preferred. The precatalyst
phosphine containing catalysts, fluoride ions can accelerate the
Pd(OAc)2 gives good yields and selectivities in most cases and
reduction of the Pd(II)-precatalyst in the presence of water, thereby
makes sophisticated catalytic systems unnecessary for these reac-
suppressing the oxidative homocoupling of boronates.41 However,
tions.
in the absence of phosphine ligands and water this explanation
appears to be improbable. It is more likely that hydrolysis of
Experimental
the aryltrifluoroborates under our reaction conditions is slow,42
and the suppressed formation of homocoupling products may be
attributed to a low concentration of boronic acid. This would, as
outlined by Lloyd-Jones et al., imply that the transmetallation step
in the catalytic cycle occurs directly from the aryl trifluoroborate.41
We do not know whether or not this explains our findings,
but it is striking that the formation of a homocoupling product
is an exception under the conditions used by us. In those cases
where conversions and isolated yields are rather low, products
resulting from a hydrodediazonation could be detected, but no
homocoupling products.
General remarks
All experiments were conducted in dry reaction vessels under an
atmosphere of dry nitrogen. Solvents were purified by standard
procedures. 1H NMR spectra were obtained at 300 MHz in CDCl3
with CHCl3 (d = 7.26 ppm) as an internal standard, or in methanol-
d4 with CD2HOD (d = 3.31ppm) as aninternal standard. Coupling
constants (J) are given in Hz. 13C NMR spectra were recorded at
75 MHz in CDCl3 with CDCl3 (d = 77.0 ppm) as an internal
standard or in methanol-d4 with CD3OD (d = 49.2 ppm) as an
internal standard. The number of coupled protons was analyzed
by DEPT- or APT-experiments and is denoted by a number in
parantheses following the chemical shift value. Whenever signal
assignments in 1H- or 13C-NMR spectra are given, these are
based on H,H- and H,C-correlation spectroscopy, and NOE-
spectroscopy if necessary. 19F NMR spectra were recorded at
282 MHz in CDCl3 with C6F6 (d = -163 ppm) as an internal
standard. IR spectra were recorded in substance on NaCl or KBr
plates. Wavenumbers (n) are given in cm-1. The peak intensities
are defined as strong (s), medium (m) or weak (w). Mass spectra
were obtained at 70 eV.
Next, we extended our investigations to meta-substituted 4-
phenol diazonium salts 4c–f (entries 11 to 29). The most important
result from these experiments is that in contrast to 4a base-
free conditions are strongly preferred. This observation might be
explained by a reduced participation of a quinone diazide structure
analogous to 4a¢, if electron withdrawing groups are located
ortho to the phenol. Under these circumstances, the beneficial
effect of added base (i.e. quinone diazide formation) is probably
outweighed by the detrimental effect of nucleophiles on the
stability of diazonium salts. Particularly useful for target molecule
synthesis is diazonium salt 4c. For example, diflunisal methylester
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General experimental procedures
2H), 5.93 (s, 2H); 13C NMR (75 MHz, MeOD-d4) d 157.9 (0), 149.7
(0), 148.0 (0), 137.1 (0), 133.9 (0), 128.9 (1), 120.9 (1), 116.7 (1),
109.5 (1), 108.1 (1), 102.4 (2); IR (neat): n 3420 (w), 2888 (w), 1610
(w), 1491 (m), 1239 (m), 1110 (w), 1044 (m); MS (ESI): m/z 214
([M]+, 28), 194 (100); HRMS (ESI): calcd. for C13H11O3[M+H]+:
215.0708, found: 215.0708.
Basic conditions. To a solution of the appropriate diazonium
salt 4 (0.5 mmol) in methanol (5.0 mL) were added NaOAc
(123 mg, 1.5 mmol) and Pd(OAc)2 (2.8 mg, 2.5 mol%). The mixture
was stirred at ambient temperature for 10 min, and the appropriate
potassium trifluoroborate 5 (0.5 mmol) was added. Stirring at
ambient temperature was continued for 12 h, and active charcoal
(100 mg) was added. All volatiles were removed in vacuo, ethyl
acetate (25 mL) or MTBE (100 mL) was added and the mixture
was immersed in an ultrasonic bath. It was then filtered through
celite, the solvent was evaporated and the residue was purified by
chromatography on silica using the eluents stated for the individual
examples.
4-Methoxybiphenyl (6ba). The title compound was obtained
from 4b (111 mg, 0.5 mmol) and 5a (92 mg, 0.5◦mmol) using base-
free conditions as a colourless solid, mp 86–87 C.45 Yield: 58 mg,
64%. 1H NMR (300 MHz, CDCl3) d 7.60–7.56 (2H), 7.56 (d, J =
8.8, 2H), 7.48–7.40 (2H), 7.36–7.29 (m, 1H), 7.01 (d, J = 8.8, 2H),
3.88 (s, 3H); 13C NMR (75 MHz, CDCl3) d 159.2 (0), 140.8 (0),
133.8 (0), 128.7 (1), 128.1 (1), 126.7 (1), 114.2 (1), 55.4 (3); IR
(neat) n 3003 (w), 1607 (m), 1487 (m), 1250 (s); Anal. calcd. for
C13H12O: C, 84.8; H, 6.6. Found: C, 84.8; H, 6.3.
Base-free conditions. To a solution of the appropriate diazo-
nium salt 4 (0.5 mmol) in methanol (5.0 mL) was added Pd(OAc)2
(2.8 mg, 2.5 mol%). The mixture was stirred for 10 min, and the
appropriate potassium trifluoroborate 5 (0.5 mmol) was added.
Stirring at ambient temperature was continued for 12 h, and active
charcoal (100 mg) was added. All volatiles were removed in vacuo,
ethyl acetate (25 mL) or MTBE (100 mL) was added and the
mixture was immersed in an ultrasonic bath. It was then filtered
through celite, the solvent was evaporated and the residue was
purified by chromatography on silica using the eluents stated for
the individual examples.
4-Fluoro-4¢-methoxybiphenyl (6bb). The title compound was
obtained from 4b (111 mg, 0.5 mmol) and 5b (101 mg, 0.5 m◦mol)
using base-free conditions as a colourless solid, mp 88–91 C.46
Yield: 40 mg, 40%. 1H NMR (300 MHz, CDCl3) d 7.50 (dd, J =
8.9, 5.2, 2H), 7.48 (d, J = 8.9, 2H), 7.11 (dd, J = 8.7, 8.7, 2H), 6.98
(d, J = 8.7, 2H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) d 162.1
(d, J = 245.6, 0), 159.1 (0), 132.8 (0), 137.0 (d, J = 3.2, 0), 128.2 (d,
J = 7.9, 1), 128.0 (1), 115.5 (d, J = 21.4, 1), 114.2 (1), 55.3 (3); 19
F
NMR (282 MHz, CDCl3) d -117.9 (tt, J = 5.3, 3.3); IR (neat) n
2920 (w), 1606 (w), 1466 (m), 1235 (s); Anal. calcd. for C13H11OF:
C, 77.2; H, 5.5. Found: C, 77.2; H, 5.7.
Analytical data and details
Methyl 4-hydroxybiphenyl-3-carboxylate (6ca). The title com-
pound was obtained from 4c (133 mg, 0.5 mmol) and 5a (92 mg,
0.5◦mmol) using base-free conditions as a colourless solid, mp 94–
95 C.47 Yield: 80 mg, 70%. 1H NMR (300 MHz, CDCl3) d 10.79
(s, 1H), 8.08 (d, J = 2.4, 1H), 7.71 (dd, J = 8.6, 2.4, 1H), 7.58–7.53
(2H), 7.48–7.40 (2H), 7.34 (m, 1H), 7.07 (d, J = 8.6, 1H), 3.98 (s,
3H); 13C NMR (75 MHz, CDCl3) d 170.5 (0), 161.0 (0), 139.9 (0),
134.4 (1), 132.4 (0), 128.8 (1), 128.1 (1), 127.0 (1), 126.6 (1), 118.0
(1), 112.5 (0), 52.3 (3); IR (neat) n 3170 (w), 2954(w), 1676 (s), 1440
(m), 1345 (m), 1209 (s); MS (EI): m/z 228 ([M]+, 38), 196 (100),
168 (20); HRMS (EI): calcd. for C14H12O3[M]+: 228.0781, found:
228.0792; Anal. calcd. for C14H12O3: C, 73.7; H, 5.3. Found: C,
73.4; H, 5.0.
Biphenyl-4-ol (6aa). The title compound was obtained from
4a (104 mg, 0.5 mmol) and 5a (92 mg, 0.5 mmol) using basic
◦
conditions as a colourless solid, mp 162–164 C.43 Yield: 70 mg,
82%. 1H NMR (300 MHz, MeOD-d4) d 7.55–7.50 (2H), 7.44 (d,
J = 8.7, 2H), 7.40–7.33 (2H), 7.24 (m, 1H), 6.85 (d, J = 8.7, 2H);
13C NMR (75 MHz, MeOD-d4) d 158.3 (0), 142.6 (0), 134.0 (0),
129.8 (1), 129.2 (1), 127.6 (1), 127.5 (1), 116.8 (1); IR (neat) n 3421
(w), 1598 (w), 1534 (w), 1489 (w), 1263 (w); MS (ESI): m/z 170
([M]+, 10), 122 (100); HRMS (ESI): calcd. for C12H11O[M+H]+:
171.0810, found: 171.0819; Anal. calcd. for C12H10O: C, 84.7; H,
5.9. Found: C, 84.2; H, 5.8.
4¢-Fluorobiphenyl-4-ol (6ab). The title compound was ob-
tained from 4a (104 mg, 0.5 mmol) and 5b (101 mg, 0.5 m◦mol)
using basic conditions as a colourless solid, mp 167–170 C.44
Methyl 4¢-fluoro-4-hydroxybiphenyl-3-carboxylate (6cb). The
title compound was obtained from 4c (133 mg, 0.5 mmol) and
5b (101 mg, 0.5 mmol) using base-free conditions as a colourless
1
Yield: 69 mg, 74%. H NMR (300 MHz, MeOD-d4) d 7.50 (dd,
J = 8.2, 5.6, 2H), 7.39 (d, J = 8.5, 2H), 7.10 (d, J = 8.7, 1H),
7.06 (d, J = 8.7, 1H), 6.84 (d, J = 8.7, 2H); 13C NMR (75 MHz,
MeOD-d4) d 162.6 (d, J = 242.3, 0), 157.1 (0), 137.8 (d, J = 3.0,
0), 131.9 (0), 128.1 (d, J = 8.3, 1), 127.9 (1), 115.7 (1), 115.3 (d,
J = 21.0, 1); 19F NMR (282 MHz, MeOD-d4) d -117.2 (tt, J = 8.8,
5.3); IR (neat): n 3406 (w), 1600 (w), 1500 (m), 1450 (w), 1375 (w),
1246 (m), 1164 (w); MS (ESI): m/z 188 ([M]+, 100), 159 (27), 133
(22); HRMS (ESI): calcd. for C12H10FO[M+H]+: 189.0716, found:
189.0734; Anal. calcd. for C12H9FO: C, 76.6; H, 4.8. Found: C,
76.4; H, 4.8.
◦
1
solid, mp 50–52 C.1 Yield: 100 mg, 82%. H NMR (300 MHz,
CDCl3) d 10.77 (s, 1H), 8.00 (d, J = 2.4, 1H), 7.63 (dd, J = 8.6,
2.4, 1H), 7.49 (d, J = 8.8, 1H); 7.47 (d, J = 8.8, 1H), 7.12 (d, J =
8.7, 1H), 7.09 (d, J = 8.7, 1H), 7.05 (d, J = 8.7, 1H), 3.98 (s, 3H);
13C NMR (75 MHz, CDCl3) d 170.4 (0), 162.3 (d, J = 246.2, 0),
136.0 (d, J = 3.2, 0), 134.2 (1),131.5 (0), 128.1 (d, J = 8.0, 1), 128.0
(1),118.1 (1), 115.6 (d, J = 21.5, 1), 112.5 (0), 52.3 (3); 19F NMR
(282 MHz, CDCl3) d -117.1 (tt, J = 5.3, 3.3); IR (neat): n 2957
(w), 1679 (m), 1483 (m), 1208 (s); Anal. calcd. for C14H11O3F: C,
68.3; H, 4.5. Found: C, 68.2; H, 4.6.
4-(Benzo[d][1,3]dioxol-5-yl)phenol (6ac). The title compound
was obtained from 4a (104 mg, 0.5 mmol) and 5c (114 mg,
0.5 mmol) using basic conditions as a colourless solid, mp 143–
144 ◦C. Yield: 71 mg, 66%. 1H NMR (300 MHz, MeOD-d4) d 7.34
(d, J = 8.7, 2H), 7.03–6.94 (2H), 6.82 (m, 1H), 6.81 (d, J = 8.7,
Methyl 5-(benzo[d][1,3]dioxol-5-yl)-2-hydroxybenzoate (6cc).
The title compound was obtained from 4c (133 mg, 0.5 mmol) and
5c (114 mg, 0.5 mmol) using base-free conditions as a colourless
◦
1
solid, mp 134–136 C. Yield: 60 mg, 44%. H NMR (300 MHz,
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CDCl3) d 10.73 (s, 1H), 7.98 (d, J = 2.4, 1H), 7.61 (dd, J = 8.7,
2.4, 1H), 7.06–6.96 (3H), 6.86 (dd, J = 7.8, 0.6, 1H), 5.99 (s, 2H),
3.97 (s, 3H); 13C NMR (75 MHz, CDCl3) d 170.5 (0), 160.7 (0),
148.2 (0), 146.9 (0), 134.3 (0), 134.2 (1), 132.2 (0), 127.8 (1), 120.1
(1), 118.0 (1), 112.4 (0), 108.6 (1), 107.2 (1), 101.2 (2), 52.3 (3);
IR (neat) n 3194 (w), 2895 (w), 1628 (m), 1677 (s), 1476 (s), 1223
(s); MS (EI) m/z 272 ([M]+, 64), 240 (100), 126 (86); HRMS (EI)
calcd. for C15H12O5[M]+: 272.0679; found: 272.0679; Anal. calcd.
for C15H12O5: C, 66.2; H, 4.4. Found: C, 65.9; H, 4.2.
(101 mg, 0.5 mmol) using base-free conditions as a colourless
solid, mp 204–205 ◦C.50 Yield: 40 mg, 34%. 1H NMR (300 MHz,
MeOD-d4) d 8.02 (s, 1H), 7.66 (d, J = 8.4, 1H), 7.55–7.45 (2H),
7.17–7.07 (2H), 6.98 (d, J = 8.5, 1H); 13C NMR (75 MHz, MeOD-
d4) d 173.4 (0), 163.8 (d, J = 244.7, 0), 162.7 (0), 137.7 (d, J = 3.1, 0),
135.2 (1), 132.7 (0), 129.6 (1), 129.4 (d, J = 8.1, 1), 118.9 (1), 116.6
(d, J = 21.7, 1), 114.3 (0); 19F NMR (282 MHz, MeOD-d4) d -116.0
(m); IR (neat): n 2925 (w), 1676 (w), 1516 (w), 1585 (w), 1439 (w),
1200 (m); MS (ESI): m/z 233 ([M+H]+, 35), 215 (100); HRMS
(ESI) calcd. for C13H10FO3[M+H]+: 233.0614; found: 233.0597;
Anal. calcd. for C13H9FO3: C, 67.2; H, 3.9. Found: C, 67.1; H, 4.0.
Methyl 4¢,6¢-difluoro-4-hydroxybiphenyl-3-carboxylate (diflu-
nisal methyl ester, 6cd). The title compound was obtained from
4c (133 mg, 0.5 mmol) and 5d (110 mg, 0.5 mmol) using base-free
5-(Benzo[d][1,3]dioxol-5-yl)-2-hydroxybenzoic acid (6dc). The
title compound was obtained from 4d (126 mg, 0.5 mmol) and
5c (114 mg, 0.5 mmol) using base-free conditions as a colourless
◦
conditions as a colourless solid, mp 97–99 C.48 Yield: 130 mg,
99%. 1H NMR (300 MHz, CDCl3) d 10.83 (s, 1H), 7.97 (dd, J =
2.1, 1.3, 1H), 7.62–7.55 (m, 1H), 7.34 (dd, J = 8.7, 6.4, 1H), 7.05
(d, J = 8.7, 1H), 6.91 (d, J = 8.2, 1H), 6.91–6.84 (m, 1H), 3.96
(s, 3H). 13C NMR (75 MHz, CDCl3) d 170.3 (0), 162.2 (dd, J =
249.0, 11.9, 0), 161.2 (0), 159.8 (dd, J = 250.1, 11.9, 0), 136.1 (d,
J = 3.1, 1), 131.0 (dd, J = 9.4, 4.8, 1), 130.1 (d, J = 6.9, 1), 126.0
(d, J = 1.1, 0), 124.1 (dd, J = 13.6, 3.8, 0), 117.8 (1), 112.4 (0),
111.5 (dd, J = 21.1, 3.8, 1), 104.3 (dd, J = 16.5 15.4, 1), 52.34 (3);
19F NMR (282 MHz, CDCl3) d -112.6 (m), -115.0 (m); IR (neat)
n 3135 (w), 1678 (s), 1484 (s), 1441 (m), 1212 (m); MS (EI): m/z
264 ([M]+, 45), 232 (100); HRMS (EI) calcd. for C14H10F2O3[M]+:
264.0598; found: 264.0574; Anal. calcd. for C14H10F2O3: C, 63.6;
H, 3.8. Found: C, 63.6; H, 3.7.
◦
1
solid, mp 241–245 C. Yield: 59 mg, 46%. H NMR (300 MHz,
MeOD-d4) d 8.00 (d, J = 2.4, 1H), 7.67 (dd, J = 8.6, 2.5, 1H), 7.05–
7.03 (2H), 6.98 (d, J = 8.6, 1H), 6.87 (d, J = 8.5, 1H), 5.97 (s, 2H);
13C NMR (75 MHz, MeOD-d4) d 173.6 (0), 162.5 (0), 149.9 (0),
148.5 (0), 135.9 (0), 135.2 (1), 133.6 (0), 129.4 (1), 121.2 (1), 118.8
(0), 114.2 (0), 109.7 (1), 108.1 (1), 102.7 (1); IR (neat) n 2917 (w),
2850 (w), 1665 (m), 1455 (m), 1251 (m); MS (EI): m/z 258 ([M]+,
43), 240 (100), 126 (73); HRMS (EI): calcd. for C14H10O5[M]+:
258.0523; found: 258.0536; Anal. calcd. for C14H10O5: C, 65.1; H,
3.9. Found: C, 65.1; H, 3.8.
4¢,6¢-Difluoro-4-hydroxybiphenyl-3-carboxylic acid (diflunisal,
1). The title compound was obtained from 4d (126 mg, 0.5 mmol)
and 5d (110 mg, 0.5 mmol) using base-free conditions as a
Methyl
4-hydroxy-4¢-(morpholine-4-carbonyl)biphenyl-3-
◦
1
carboxylate (6ce). The title compound was obtained from 4c
(133 mg, 0.5 mmol) and 5e (149 mg, 0.5 mm◦ol) using base-free
conditions as a colourless solid, mp 120–122 C. Yield: 120 mg,
colourless solid, mp 204–206 C.51 Yield: 42 mg, 34%. H NMR
(300 MHz, MeOD-d4) d 7.97 (s, 1H), 7.60 (dd, J = 1.5, 8.6, 1H),
7.43 (dd, J = 7.9, 15.6, 1H), 7.05–6.95 (3H); 13C NMR (75 MHz,
MeOD-d4) d 173.4, 163.7 (dd, J = 247.5, 11.9), 163.0, 161.2 (dd,
J = 248.7, 11.9) 137.1 (d, J = 2.9), 132.6 (dd, J = 9.5, 4.8), 131.9
(d, J = 3.1), 127.2, 125.7 (dd, J = 13.6, 3.9), 118.6, 114.2, 112.8
(dd, J = 21.4, 3.8), 105.3 (dd, J = 27.1, 25.8); 19F NMR (282 MHz,
MeOD-d4) d -111.3 (m), -113.3 (“q”, J = 9.9); IR (neat): n 3344
(s), 2950 (w), 2838 (w), 1651 (m), 1450 (m); MS (EI) m/z 250 ([M]+,
50), 232 (100); HRMS (EI) calcd. for C13H8F2O3[M]+: 250.0442.
Found: 250.0449; Anal. calcd. for C13H8F2O3: C, 62.4; H, 3.2.
Found: C, 62.5; H, 3.6.
1
70%. H NMR (300 MHz, MeOD-d4) d 8.03 (d, J = 2.4, 1H),
7.73 (dd, J = 8.7, 2.4, 1H), 7.60 (d, J = 8.3, 2H), 7.47 (d, J =
8.3, 2H), 6.99 (d, J = 8.7, 1H), 3.94 (s, 3H), 3.40–3.80 (broad
due to hindered rotation around the amide bond, 8H); 13C NMR
(75 MHz, MeOD-d4) d 172.3 (0), 171.6 (0), 162.6 (0), 142.9 (0),
135.4 (1), 135.1 (0), 132.6 (0), 129.3 (1), 129.1 (1), 127.7 (1), 119.3
(1), 114.1 (0), 67.9 (2), 53.2 (3), signal for CH2N not observed due
to hindered rotation and/or quadrupole broadening; IR (neat)
n 2957 (w), 2855 (w), 1676 (s), 1628 (s), 1429 (s), 1340 (m), 1275
(s), 1247 (s), 1209 (s); MS (EI) m/z 341 ([M]+, 51), 255 (95), 223
(100), 139 (65); HRMS (EI) calcd. for C19H19NO5[M]+: 341.1258;
found: 341.1278; Anal. calcd. for C19H19NO5: C, 66.9; H, 5.6; N,
4.1. Found: C, 66.7; H, 5.4; N, 4.3.
3-Nitrobiphenyl-4-ol (6ea). The title compound was obtained
from 4e (127 mg, 0.5 mmol) and 5a (92 mg, 0.5 mmol) using base-
free conditions as a colourless solid, mp 65–67 ◦C.52 Yield: 100 mg,
94%. 1H NMR (300 MHz, CDCl3) d 10.59 (s, 1H), 8.33 (d, J = 2.1,
1H), 7.84 (dd, J = 8.7, 2.2, 1H), 7.50–7.44 (2H), 7.46–7.39 (2H),
7.39 (m, 1H), 7.25 (d, J = 8.7, 1H); 13C NMR (75 MHz, CDCl3)
d 154.3 (0), 138.2 (0), 136.3 (1), 133.9 (0), 133.8 (0), 129.1 (1),
128.0 (1), 126.7 (1), 122.8 (1), 120.4 (1); IR (neat) n 3243 (w), 3032
(w), 1628 (m), 1536 (s), 1476 (s), 1310 (s); MS (EI) m/z 215 ([M]+,
13), 181 (100), 130 (28); HRMS (EI): calcd. for C12H9NO3[M]+:
215.0582; found: 215.0596; Anal. calcd. for C12H9NO3: C, 67.0; H,
4.2; N, 6.5. Found: C, 67.0; H, 4.2; N, 6.4.
4-Hydroxybiphenyl-3-carboxylic acid (6da). The title com-
pound was obtained from 4d (126 mg, 0.5 mmol) and 5a (92 mg,
0.5 mmol) using base-free conditions as a colourless solid, mp
212–214 ◦C.49 Yield: 63 mg, 59%. 1H NMR (300 MHz, MeOD-d4)
d 8.07 (d, J = 2.4, 1H), 7.71 (dd, J = 8.6, 2.4, 1H), 7.57–7.50 (2H),
7.43–7.36 (2H), 7.28 (m, 1H), 6.99 (d, J = 8.6, 1H); 13C NMR
(75 MHz, MeOD-d4) d 173.55, 162.72, 141.38, 135.29, 133.72,
130.03, 129.65, 128.15, 127.60, 118.86, 114.24; IR (neat) n 2922
(w), 1667 (m), 1447 (m), 1237 (m); MS (ESI) m/z 215 ([M+H]+,
42), 197 (100); HRMS (ESI) calcd. for C13H11O3[M+H]+: 215.0708,
found: 215.0716; Anal. calcd. for C13H10O3: C, 72.9; H, 4.7. Found:
C, 72.7; H, 4.6.
3-Bromobiphenyl-4-ol (6fa). The title compound was obtained
from 4f (143 mg, 0.5 mmol) and 5a (92 mg, 0.5◦mmol) using base-
free conditions as a colourless solid, mp 94–95 C.53 Yield: 55 mg,
44%. 1H NMR (300 MHz, CDCl3) d 7.71 (d, J = 2.2, 1H), 7.54–
7.49 (2H), 7.48–7.39 (3H), 7.33 (m, 1H), 7.09 (d, J = 8.4, 1H),
5.54 (s, 1H); 13C NMR (75 MHz, CDCl3) d 151.6 (0), 139.4 (0),
4¢-Fluoro-4-hydroxybiphenyl-3-carboxylic acid (6db). The title
compound was obtained from 4d (126 mg, 0.5 mmol) and 5b
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135.4 (0), 130.4 (1), 128.8 (1), 127.9 (1), 127.2 (1), 126.7 (1), 116.3
(1), 110.6 (0); IR (neat) n 3320 (m), 2360 (w), 1488 (m) 1450 (m)
1412 (s) 1273 (s); MS (EI) m/z 248 ([M]+, 100), 139 (80), 115 (25);
HRMS (EI) calcd. for C12H9BrO[M]+: 247.9831; found: 247.9836;
Anal. calcd. for C12H9BrO: C, 57.9; H, 3.6. Found: C, 57.6; H, 3.5.
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This work was performed in the course of a research and
development project with the Zylum-Beteiligungsgesellschaft
mbH & Co. Patente II KG, Scho¨nefeld (Germany). Zylum-
Beteiligungsgesellschaft mbH & Co. Patente II KG owns the
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