Suzuki cross-coupling reaction of sterically hindered aryl boronates with 3-iodo-4-methoxybenzoic acid methylester

Article abstract of DOI:10.1016/S0040-4020(00)00928-5

The cross-coupling reaction of 3-iodo-4-methoxybenzoic acid methylester with sterically hindered arylboronic esters and especially 5,5-dimethyl-2-mesityl-1,3,2-dioxaborinane, is reported. The optimisation of the process in order to obtain biaryls in good yield by using anhydrous benzene at reflux and sodium phenoxide in the presence of 0.06 equiv. of Pd(PPh₃)₄ is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00928-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9655±9662
Suzuki Cross-Coupling Reaction of Sterically Hindered Aryl
Boronates with 3-Iodo-4-methoxybenzoic Acid Methylester
²
H. Chaumeil, S. Signorella and C. Le Drian
*
Á Â
Laboratoire de Synthese Organique et de Chimie Microbienne, Universite de Haute Alsace, CNRS UPRES-A 7015, 3 rue Alfred Werner,
68093 Mulhouse Cedex, France
Received 20 May 2000; revised 10 July 2000; accepted 29 September 2000
AbstractÐThe cross-coupling reaction of 3-iodo-4-methoxybenzoic acid methylester with sterically hindered arylboronic esters and
especially 5,5-dimethyl-2-mesityl-1,3,2-dioxaborinane, is reported. The optimisation of the process in order to obtain biaryls in good
yield by using anhydrous benzene at re¯ux and sodium phenoxide in the presence of 0.06 equiv. of Pd(PPh3)4 is described. q 2000 Elsevier
Science Ltd. All rights reserved.
Introduction
acids which are sterically hindered generally give low yields
and hydrolytic deboronation of the C±B bond predomi-
nates.7 Furthermore, both electron-withdrawing and
electron-attracting groups could, at least, in some cases,
accelerate the protonolysis.7b,8 One of the alternative is to
replace the boronic acids by the corresponding esters. This
allows the use of anhydrous conditions in which no
protonolysis occurs, enabling the synthesis of hindered
biaryls in good yields.1e,7b,9 However, until now, no
systematic investigation of the cross-coupling reaction of
hindered arylboronic esters seems to have been published.
A large number of precursors to drugs, polymers, liquid
crystals as well as ligands for organo-metallic chemistry
possess a biaryl structure. Therefore, numerous catalytic
methods devoted to the preparation of biaryls by cross-
coupling reactions have been developed over the last two
decades. One of the most useful approaches, commonly
referred as Suzuki coupling,1 is based on Pd(0) catalysed
cross-coupling reactions of various organoboron derivatives
with aryl halides, tri¯ates or diazonium salts under basic
conditions. The original procedure, using Pd(PPh3)4 and
aqueous Na2CO3 in benzene at re¯ux gives good yields
with many substituted arylboronic acids.1c In general,
cross-coupling reactions of organobon derivatives with
organic halides are believed to process through a catalytic
cycle1d,1f,1g,1j,1k,1l,2 related to the cycles proposed for the
cross-couplings induced by other metals such as Mg,3 Zn4
and Sn.5 However, a particularity of the Suzuki cross-
coupling reaction is that it proceeds only in the presence
of bases.1a,2 One of the admitted possibilities is that the
catalytic cycle includes a step in which the base is intro-
duced in the coordination sphere of palladium since the
formation of Ar-PdL2-OR from Ar-PdL2-X is known to
accelerate the transmetalation step.1b,2a,6
Therefore, since in literature, ortho±ortho0 tetrasubstituted
biaryls could not be prepared in acceptable yields,7b,7d,8c we
decided to focus our efforts on the Suzuki coupling of
sterically hindered arylboronic esters 2±8 with a substituted
anisic acid derivative 1 (Scheme 1). The other retrosynthetic
possibility: the coupling of an hindered aromatic halide with
a boronic ester seemed less favourable. Among the various
boronic esters, mostly cyclic, already used in literature for
coupling reactions, we chose 1,2,3-dioxaborinanes,10 since
2,2-dimethyl-1,3-propanediol is known to give easily
crystallised acetals.
Results and Discussion
Another important feature of the Suzuki coupling reaction,
in the usual conditions, must be emphasized. Arylboronic
In a ®rst set of experiments, the coupling reaction of 1 with
the unsubstituted boronic ester 2 and the two ortho-substi-
tuted 5,5-dimethyl-2-aryl-1,3,2-dioxaborinanes 3 and 4
(Table 1, entries 1 to 3) was studied. The two latter reactions
of 1 were conducted using conditions already reported in
literature,9 i.e. Pd(Ph3)4 as catalyst, Tl2CO3 as base, benzene
at re¯ux as solvent. It appeared that the cross-coupling reac-
tion occurred in high yields and no trace of protonolysis
could be observed. A prolonged reaction time was required
Keywords: Suzuki cross-coupling reaction; hindered arylboronic esters;
biaryls.
* Corresponding author. Fax: 133-389336860;
e-mail: h.chaumeil@univ-mulhouse.fr
Present address: Departamento de Quõmica, Facultad de Ciencias
²
Â
Bioquõmicas y Farmaceuticas, UNR. Suipacha 531, 2000 Rosario, Argen-
tina.
Â
Â
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00928-5

9656
H. Chaumeil et al. / Tetrahedron 56 (2000) 9655±9662
Scheme 1.
for the sterically hindered mesitylene derivative 5 (entry 4).
This is in agreement with previous studies from Thomson et
al. who reported the slow rate of coupling reaction of ortho±
ortho0 disubstituted arylboronic acids.11
Amount and nature of the base
It has been suggested that the overall stoichiometry of the
cross-coupling reaction between a boronic acid and an aryl
halide requires one equivalent of water and two equivalents
of base: one mole of base is needed to activate the boronic
acid and the other to neutralise the formed boric acid.2c We
found that the minimal amount of Tl2CO3 required for the
coupling reaction of 1 with the boronic ester 5, was 0.5
molar equivalent (if CO2 is formed, this corresponds to
one equivalent of base) (Table 2). In the presence of smaller
amount of base, unconsumed 1 was recovered. Never-
theless, an excess of base could be employed with no
negative effect on the yield. We observed a signi®cant
formation of CO2 during the coupling reaction (see Experi-
mental). This allows us to write the tentative equation
shown in Scheme 2.
Then, in an attempt to accelerate the reaction and eventually
to use less toxic conditions, we screened, not only different
solvents but also a variety of bases on the coupling reaction
of 1 with 5.
Solvent effect
Among the eight solvents screened (entries 4 to 13), the
reactions were best conducted in benzene. Astonishingly,
the yield of the coupling reaction decreased to 47% in
toluene. Nevertheless, the use of the less toxic solvents
THF, DMF or DME could be considered as alternatives.
Furthermore, a propensity to protonolysis with formation
of 14 was evident when the reaction conditions were not
strictly anhydrous. This result was not unexpected since, in
our hands, the coupling reaction of mesitylene boronic acid
with 1 under the usual Suzuki conditions (aqueous Na2CO3,
Pd(PPh3)4, toluene/ethanol) afforded a yield of biaryl of only
6%. Therefore, we chose to run our reaction in strictly
anhydrous conditions using a Dean±Stark apparatus, with
benzene as solvent.
During our initial efforts, a yield of 96% was achieved using
Tl2CO3 (Table 1). Unfortunately this base is highly toxic
and therefore unsuitable for larger scale processes. There-
fore, the effect of a large range of mineral and organic bases
(Table 3) was examined.
Thallium (I) salts were successfully used by Kishi et al. for
the coupling reaction of 1-alkenylboronic acid with
iodoole®ns in THF.12 Suzuki et al. have reported, in
Table 1. Coupling reaction of 1 with arylboronic esters 2 to 5
Entry
Substrates
R1
R2
R3
Products
Solvent
THF
Benzene
Benzene
Benzene
ClCH2CH2Cl
THF
Time (h)
Yield %
1
2
3
4
5
6
7
8
2
3
4
5
5
5
5
5
5
5
5
5
5
H
H
H
H
H
H
H
9
10
11
12
12
12
12
12
12
12
12
12
12
6
30
30
97
97
99
96
81.5
72
70
69
65
65
62.5
47
OMe
OPr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
90±100
90±100
90±100
90±100
90±100
90±100
90±100
90±100
90±100
90±100
DMFa
DME
1,4-dioxane
C6H12
CH3CN
C6H5CH3
CCl4
9
10
11
12
13
16
a Reaction run at 1108C.

H. Chaumeil et al. / Tetrahedron 56 (2000) 9655±9662
Table 2. In¯uence of base amount on the yield of the reaction Table 3. Effect of different bases on the cross-coupling reaction
9657
Base (mol. equiv.)
Time (h)
Yields %
Entry
Base
Yield %
2.12
0.53
0.28
120
120
168
94
96
54
1
2
3
4
5
6
7
Tl2CO3
TlOH
TlOEt
TlOAc
PbO
96
19a
7.5b
0
16
0
PbCO3
Bi2O2CO3
0
addition, the promotion of the coupling reaction of alkyl-
boronic esters with 1-alkenyl and aryl halides in the
presence of thallium salts in a mixture THF/H2O.13 Thal-
lium (I) is thought to remove halide as TlX, producing
PdOH species that accelerates the transmetalation.14
However, Sniekus et al., in 1994, reported that Tl2CO3
was inef®cient for the coupling of arylboronate esters with
an aryl iodide in THF.15 We found that he coupling reaction
of 1 with 5 in benzene readily proceeded using Tl2CO3 but
failed using other thallium salts (entries 2±4). Using TlOH,
the main product resulted in the reduction of 1 (entry 2).
Suzuki et al. has already described such a reduction during
the cross coupling reaction of (E)-1-hexenylborane with
(E)-b-styrylbromide.2a
8
9
Ag2CO3
Cs2CO3
Na2CO3
Ag2O
Ag3PO4
K3PO4
Ba(OH)2,H2O
BaO
NaOMe
NaOH
AgOAc
HuÈnig'base
NaOC6H5
KOC6H5
NaO±(4-tBu±C6H4)
NaO±(4-CH3±C6H4)
NaO±(2-CH3±C6H4)
NaO±(3-CH3±C6H4)
NaO±(4-Cl±C6H4)
NaO±(2-Cl±C6H4)
NaO±(3-NO2±C6H4)
NaO±(4-NO2±C6H4)
NaO±(2-NO2±C6H4)
CsOC6H5
97
46
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
67c
9
6
5
5
60d
27
0
0
80
79
80
80
63.5
60.5
62
10
20
5
Pb(II) as PbO and PbCO3, Bi(III) as Bi2O2CO3 have the
same d10s2 con®guration as Tl(I) salts. Therefore, the use
of these salts seemed to be particularly attractive. Unfortu-
nately, the coupling reaction proceeded, at best, only in very
low yields (entries 5 to 7).
0
60
22
LiOC6H5
Since Chang et al. described that, using carbonates as base,
the cross-coupling reaction rate were strongly dependent of
the nature of the cation,16 we tried Ag2CO3, Cs2CO3 and
Na2CO3 (entries 8±10). The excellent yield achieved with
the former should be emphasized. It is consistent with the
literature, indicating that the reductive elimination of halide
is enhanced when a sparingly soluble salt is formed.12
a Presence of 45% 4-methoxybenzoic acid methylester.
b Presence of 43% 4-methoxybenzoic acid ethylester.
c Presence of 13% 4-methoxybenzoic acid methylester.
d Presence of 22% 4-methoxybenzoic acid methylester.
already claimed that, for boronic acids, a base of suf®cient
strength was needed to form the boronate anion, allowing,
therefore, the transmetalation step to occur.2c The major
in¯uence of pH, in cross coupling reactions, has also been
demonstrated in detail.18 Charette et al. recommended
strong base for the cross-coupling of boronate esters with
iodocyclopropane.19 It's worth noting that ethoxide,
methoxide and hydroxide are commonly used for the Suzuki
coupling reaction of arylboronic acids.1f
In literature, couplings of hindered boronic esters were often
promoted by K3PO4 in DMF.7b,15,17 (In our hands, we
obtained under these conditions a 60% yield.) In benzene
at re¯ux, K3PO4 and Ag3PO4 were ineffective (entries
12±13).
Ba(OH)2 both in benzene and DME was used in sterically
demanding coupling reactions and good yields of product
were often obtained1e,1i,7b (see, however, Ref. 16). Unfortu-
nately, the coupling reaction of 1 with 5 in benzene proceed
with only 5% yield (entry 14).
We concentrated then on the use of phenoxides: sodium
phenoxide having been already successfully tested by
Suzuki for the cross coupling of (Z)1-hexylboranes with
(E)-b-styrylbromide.2a Phenoxides are cheap and easy to
prepare. The results indicated that the use of sodium or
potassium phenoxide, sodium p-tBu- or p-methyl-
phenoxides led to the desired biaryl compound in good
Our experiments clearly highlight the importance of both
the nature of the cation and the strength of the base in the
course of the cross-coupling reaction. Smith et al. have
Scheme 2.

9658
H. Chaumeil et al. / Tetrahedron 56 (2000) 9655±9662
Table 4. In¯uence of the reaction time on the cross-coupling reaction
Base
Time(h)
Yield %
Tl2CO3
Tl2CO3
Tl2CO3
Tl2CO3
PhONa
PhONa
PhONa
PhONa
PhONa
PhONa
PhONa
PhONa
21
30
48
100
24
48
50
70
72
79
87
36
50
88.5
96
7.5
10
21
29
43
47
80
80
118
yields (entries 20 to 23), while phenates of weaker basicity
were less effective (entries 28 to 30). Compared to the
p-isomers the use of sterically hindered ortho-substituted
phenoxides gave lower yields suggesting that the trans-
metalation step was sensitive to the steric hindrance of the
base (entries 24, 27, 30). Replacement of Tl2CO3 by sodium
phenoxide required a longer reaction time (Table 4). This
could be explained by differences in the nucleophilicities of
the bases which can delay the transmetalation step.
benzoic acid methylester was observed and unchanged ester
6 was recovered.
Attempts to couple 1 either with 5,5-dimethyl-2-(2,4,6-
trimethoxyphenyl)-1,3,2-dioxaborinane 7 or with 5,5-
dimethyl-2-(2,4,6-triisopropoxyphenyl)-1,3,2-dioxaborinane
8 failed, leading only to deboronated derivatives. Moreover,
the coupling reaction of 5 with iodomesitylene gave no
reaction which was expected according to previous Suzuki's
results.7b
Eventually, at this stage, our study clearly emphasizes the
use of sodium or potassium phenoxides as ef®cient,
convenient, cheap and non-toxic bases for a successful
coupling reaction.
Using Ag2CO3 as a base, the cross-coupling reaction of 5,5-
dimethyl-2-(2-formylphenyl)-1,3,2-dioxaborinane with iodo-
mesitylene gave 30.5% yield of the expected biaryl product,
whereas using sodium phenoxide as base, it gave only 3%
yield. These low yields of cross-coupling were not
unexpected since the 2-formyl group is known to accelerate
the rate of protonolysis.8a,8b However, Suzuki et al. reported
a 73% yield in coupling the 2-(2-formylphenyl)-1,3,2-
dioxaborinane with iodomesitylene.7b
Nature and amount of catalyst
A great variety of palladium (0) catalysts has been
commonly used for cross-coupling reactions between aryl-
boronic acids and arylhalides.1f,1n Our attempts to replace
Pd(PPh3)4 in the coupling reaction of 1 with 5 by of other
palladium catalyst were unsuccessful (Table 5). The cross-
coupling reaction with Pd(OAc)2 gave a reaction mixture
contaminated by Pd(0). This suggest that triphenyl-
phosphine reduces the divalent palladium from the complex
Pd(OAc)2(PPh3)4 as Jutand et al. reported.20
Table 5. In¯uence of nature and amount of catalysts on the cross-coupling
reaction
The minimum amount of Pd(PPh3)4 required to complete the
reaction in four days was 0.06 equiv.
Catalysts
Catalyst (mol equiv.)
Yield %
Besides, the addition of triphenylphosphine to the catalyst
had a negative effect on the reaction. With Pd(PPh3)4
(0.06 equiv.), the yield dropped from 80% to 30% in the
presence of 0.12 equiv. of PPh3 and from 45% to 37% in
the case of PdCl2(dppf). This phosphine inhibition in Suzuki
aryl±aryl coupling between boronic acids and aryl halides
has already been observed by Wallow and Novak.18a
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd/C
Pd/alumine
Pd/BaSO4
Pd(Oac)2
0.007
0.01
0.03
0.044
0.06
0.1
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
25
35
52.5
65.5
80
80
10
0
0
9
45
42
48
26.5
25.5
More hindered boronic esters
PdCl2dppfa
PdCl2dppbb
PdCl2dpppc
PdCl2(CH3CN)2
PdCl2(C6H4CN)2
The coupling reaction of 1 with di-n-butyl 2,4,6-triiso-
propylphenylboronate 6 using Tl2CO3 and Pd(PPh3)4 in
benzene at re¯ux, i.e. our initial conditions affording an
almost quantitative yield for 5, led to a much lower yield
in coupling product 13 (11%). No further evolution could be
observed after seven days. The reduction of 1 to 4-methoxy-
a dppf: 1,10 bis(diphenylphosphino)ferrocene.
b dppb: 1,10 bis(diphenylphosphino)butane.
c dppp: 1,10 bis(diphenylphosphino)propane.

H. Chaumeil et al. / Tetrahedron 56 (2000) 9655±9662
9659
Conclusion
2-Methoxyphenylboronic acid.32 A solution of 2-bromo-
anisole (5 g, 26.7 mmol) in 50 ml of THF and a solution of
n-butyllithium in hexane (1.6 M, 20 ml, 1.2 equiv.) were
added simultaneously with vigorous stirring at 2908C
under N2 to 50 ml of THF. After 15 min at 2908C, trimethyl
borate (6 ml, 2 equiv.) was rapidly added. The reaction
mixture was stirred at 2908C for 1 h and at room tempera-
ture for an extra 1 h. The solvents were concentrated in
vacuo. The colourless oil was poured into a mixture of ice
and water (1:1). The mixture was acidi®ed with HCl to pH
5±6 and extracted with Et2O. The combined extracts were
dried over MgSO4 and concentrated in vacuo. The crude
material was crystallised from n-hexane (2.4 g, 67%).
mpˆ1008C. IR (KBr): 3500±3250, 3060±2960, 2830,
1595, 1570, 1480, 1460, 1340, 1160, 1105, 1090, 1050,
Although numerous examples of Suzuki cross-couplings to
form hindered biphenyls from aryl iodides or bromides have
been reported.8c,7d,15,17,21 Unfortunately, these reactions are
often problematic. As for us, we coupled in high yields
sterically hindered boronic esters with 3-iodo-4-methoxy-
benzoic acid methylester using 0.06 equiv. of Pd(PPh3)4 as
catalyst. Sodium phenoxide proved to be an ef®cient base
and silver carbonate was a useful alternative to the toxic
thallium carbonate. As it could be expected, we did not
succeed in synthesising ortho±ortho0 tetrasubstituted
biaryls.
1
1020, 770, 750. H NMR: 3.8 (3H, s), 6.7 (2H, s), 6.8±7.1
Experimental
(2H, m), 7.4 (1H, ddd), 7.9 (1H, dd). Anal. calcd for
C7H9BO3 (151.96): C 55.33%, H 5.97%; found: C
55.57%, H 5.96%.
General
Et2O, THF, toluene and benzene were freshly distilled from
sodium/benzophenone, CCl4, cyclohexane and dichloro-
ethane from P2O5, CH3CN from CaH2 and TMEDA from
KOH. A freshly opened DMF bottle was used. Residual
water content has been measured with a Bizot and Constant
apparatus. 1H NMR (60 or 250 MHz) and 13C NMR
(62.9 MHz) spectra were measured in CDCl3. Micro-
analyses were performed by the `Service Central d'Analyse
du C.N.R.S.'.
2-Isopropoxyphenylboronic acid.33 This was prepared
according to the procedure used for 2-methoxyphenylboronic
acid, starting from 1-bromo-2-isopropoxybenzene34 (5 g,
23 mmol), n-butyllithium (1.6 M, 17.23 ml, 1.2 equiv.)
and trimethyl borate (5.17 ml, 2 equiv.). After crystallisa-
tion in hexane, the desired product was obtained as a colour-
less solid (2.93 g, 70%). mpˆ40±418C. IR (KBr): 3500±
3300, 3060±2870, 1595, 1570, 1470, 1440, 1400±1330,
1
1215, 1015, 950, 750. H NMR: 1.4 (6H, d, Jˆ6 Hz), 4.71
(1H, sept., Jˆ6 Hz), 6.75 (2H, s), 6.8±7.1 (2H, m), 7.4 (1H,
ddd, Jˆ8; 7; 3 Hz), 7.9 (1H, dd, Jˆ7; 2 Hz). Anal. calcd for
C9H13BO3 (180.01): C 60.05%, H 7.28%; found: C 60.06%,
H 7.37%.
Halides compounds
3-Iodo-4-methoxybenzoic acid methyl ester 1 and mono-
iodomesitylene were prepared according to the literature.22,23
7a
2,4,6-Trimethoxyphenylboronic acid. To a solution of
Palladium complexes
1,3,5-trimethoxybenzene (6.72 g, 40 mmol.) in 40 ml Et2O,
at 258C, under N2, were added with vigorous stirring, 6 ml
of TMEDA and n-butyllithium in hexane (1.6 M, 30 ml,
1.2 equiv.). After 20 min, the mixture was cooled to
2788C and 30 ml of THF was slowly added. Then,
trimethyl borate was added (9 ml, 2 equiv.). The reaction
mixture was stirred at 2788C for 1 h and, then, 15 h at
room temperature. The solvents were concentrated in
vacuo. The colourless oil was dropped into a mixture of
ice and water (1:1). The mixture was acidi®ed with HCl
2 N to pH 5±6. This aqueous solution was extracted three
times with chloroform. The combined extracts were dried
over MgSO4 and concentrated in vacuo. The crude material
was treated with Et2O and crystallised. The desired product
was obtained as a colourless solid (5g, 60%). mpˆ107±
1098C (mpˆ1098C7a). IR (KBr): 3540±3420, 3020±2900,
2840, 1605, 1575, 1465, 1410, 1340, 1290, 1220, 1205,
Pd/C, Pd/alumina, Pd/BaSO4 and Pd(OAc)2 were purchased
from Fluka. The reported procedures were used to prepare
Pd(PPh3)4,24 PdCl2(C6H5CN)2 and PdCl2(CH3CN)2,25
PdCl2(dppf), PdCl2(dppb), PdCl2(dppp).26
Bases
Lithium phenoxide, potassium phenoxide and the different
sodium phenoxides were prepared according to
literature.27,28
Cesium phenoxide. A sealed tube slightly notched contain-
ing cesium (1.99 g, 14.9 mmol) was ®tted under N2 in a
P.V.C. tube. The sealed tube was broken and the pieces
were quickly dropped into a solution of phenol (1.71 g,
18.1 mmol) in 25 ml of anhydrous hexane. The mixture
was allowed to react under N2. The pieces of glass were
discarded. The solvent was evaporated and the resulting
solid was heated at 608C under vacuum (1 Torr) overnight
to remove the traces of solvent and the excess of phenol.
1
1120, 810, 755. H NMR: 3.87 (3H, s), 3.9 (6H, s), 6.17
(2H, s), 7.00 (2H, s).
2,4,6-Triisopropylphenylboronic acid. This was prepared
according to the procedure used for 2,4,6-trimethoxy-
phenylboronic acid starting from 1-bromo-2,4,6-triiso-
propylbenzene35 (6 g, 21 mmol), n-butyllithium (1.6 M,
15.75 ml, 1.2 equiv.) and trimethyl borate (4.72 ml,
2 equiv.). A yellow oil was obtained and was heated at
re¯ux with 50 ml of water at 08C; After crystallisation
from hexane, the desired product was obtained as a
Boronic acids
We obtained, according to the literature procedures, the
phenylboronic acid,29 the mesityleneboronic acid30 and
2-formylbenzene boronic acid.31

9660
H. Chaumeil et al. / Tetrahedron 56 (2000) 9655±9662
colourless solid (3 g, 57%). mpˆ159±1618C. IR (KBr):
(2.5 g, 13.9 mmol) and 2,2-dimethyl-1,3-propanediol. After
6 h at re¯ux, the desired product was isolated as a colourless
oil (2.75 g, 86%). IR (®lm): 3070±2890, 1600, 1575, 1480,
1440, 1415, 1380, 1335, 1315, 1240, 1135, 1110, 950, 755.
1H NMR: 1.0 (6H, s), 1.3 (6H, d, Jˆ6 Hz), 3.7 (4H, s), 4.4
(1H, sept., Jˆ6 Hz), 6.75 (1H, m), 6.91 (1H, m), 7.25 (1H,
ddd, Jˆ7; 6; 2 Hz), 7.55 (1H, dd, Jˆ8; 2 Hz). Anal. calcd
for C14H21BO3 (248.13): C 67.77%, H 8.53%; found C
67.35%, H 8.79%.
3450±3200, 2980±2870, 1605, 1460, 1400±1250, 1055,
1
1025, 870. H NMR: 1.24 (6H, d, Jˆ6.8 Hz), 1.27 (12H,
d, Jˆ6.8 Hz), 2.9 (3H, m), 4.67 (2H, s), 7 (2H, s). Anal.
calcd for C15H25BO2 (248.18): C 72.60%, H 10.15%; found:
C 72,67%, H 10.13%.
2,4,6-Triiosopropoxyphenylboronic acid. This was
prepared according to the procedure used for 2,4,6-
trimethoxyphenylboronic acid starting from 1,3,5-triiso-
propoxybenzene (6.5 g, 26 mmol), n-butyllithium (1.6 M,
19.5 ml, 1.2 equiv.) and trimethyl borate (5.85 ml,
2 equiv.). After crystallisation from hexane, the desired
product was isolated as colourless solid (5.6 g,
5,5-Dimethyl-2-(2,4,6-trimethylphenyl)-1,3,2-dioxabori-
nane 5. This was prepared from 2,4,6-trimethylphenylboro-
nic acid (1 g, 6.1 mmol) and 2,2-dimethyl-1,3-propanediol.
After 6 h at re¯ux and evaporation, the desired product was
crystallized from water and isolated as a colourless solid
(900 mg, 64%). mpˆ39±408C. IR (KBr): 2960±2870,
1610, 1470, 1425, 1410, 1370, 1320, 1290, 1240, 1165,
1
73%).mpˆ648C (mpˆ64±658C36), H NMR: 1.35 (6H, d,
Jˆ6 Hz), 1.38 (12H, d, Jˆ6 Hz), 4.56 (3H, sept., Jˆ6 Hz),
6.08 (2H, s), 7.36 (2H, s).
1
1105, 845. H NMR: 1.1 (6H, s), 2.25 (3H, s), 2.37 (6H,
s), 3.79 (4H, s), 6.78 (2H, s). Anal. calcd for C14H21BO2
(232.13) C 72.44%, H 9.12%; found C 72.80%, H 9.34%.
Boronic esters
Dibutyl 2,4,6-triisopropylphenylboronate 6. 2,4,6-Triiso-
propylphenylboronic acid (500 mg, 2.02 mmol) in solution
in 35 ml of n-butanol was stirred at re¯ux for one day
according to the literature.37 The evaporation under reduced
pressure of the excess of alcohol yielded the desired product
as a colourless oil (674 mg, 93%). IR (KBr): 2960±2860,
5,5-Dimethyl-2-(2,4,6-trimethoxyphenyl)-1,3,2-dioxa-
borinane 7. This was prepared from 2,4,6-trimethoxy-
phenylboronic acid (1 g, 4.7 mmol) and 2,2-dimethyl-1,3-
propanediol. After 9 h at re¯ux and evaporation, the desired
product was crystallized from Et2O and isolated as a colour-
less solid (990 mg, 75%). mpˆ99±1018C. IR (KBr): 3000±
2880, 2835, 1600, 1580, 1475, 1450, 1405, 1310, 1285,
1250, 1220, 1200, 1150, 1130, 810. H NMR: 1.1 (6H, s),
3.8 (13H, s), 6.1 (2H, s). Anal. calcd for C14H21BO5
(280.13): C 60.03%, H 7.56%; found C 59.88%, H 7.56%.
1
1605, 1460, 1405, 1360±1260, 870. H NMR: 1.03 (6H,
Jˆ7.2 Hz), 1.37 (18H, d, Jˆ6.7 Hz), 3.94 (4H, t,
Jˆ6.35 Hz), 7.06 (2H, s). Anal. calcd for C23H41BO2
(360.39): C 76.65%, H 11.47%; found C 76.40%, H
11.32%.
1
5,5-Dimethyl-2-(2,4,6-triisopropoxyphenyl)-1,3,2-dioxa-
borinane 8. This was prepared from 2,4,6-triisopropoxy-
phenylboronic acid (1 g, 3.4 mmol) and 2,2-dimethyl-1,3-
propanediol. After 8 h at re¯ux and evaporation, the desired
product was crystallized from hexane and isolated as a
colourless solid (1.06 g, 80%). mpˆ48±498C. IR (KBr):
2970±2860, 1595, 1570, 1475, 1420, 1370, 1330, 1320,
General procedure for 2 to 5 and 7 to 8
In a ¯ask equipped with a Dean±Stark apparatus and a
condenser, boronic acid and 2,2-dimethyl-1,3-propanediol
(1.2 equiv.) in THF (40 ml/g of boronic acid) was stirred at
re¯ux. Evaporation under reduced pressure yield the crude
boronic ester.38
1
1290, 1110, 1025. H NMR: 1.08 (6H, s), 1.28 (18H, d,
Jˆ6 Hz), 3.72 (4H, s), 4.44 (3H, sept, Jˆ6 Hz), 6.03 (2H,
s). Anal. calcd for C20H33BO5 (364.29) C 65.94%, H 9.13%;
found C 65.53%, H 9.22%.
5,5-Dimethyl-phenyl-1,3,2-dioxaborinane 2. This was
prepared from phenylboronic acid (750 mg, 6.1 mmol)
and 2,2-dimethyl-1,3-propanediol. After 4 h at re¯ux and
evaporation, the crude material was cooled at 2108C and
the desired product was isolated as a colourless solid
(951 mg, 82%). mpˆ628C (mpˆ628C36). IR (KBr): 3060,
2960±2860, 1600, 1475, 1435, 1410, 1340±1285, 1250,
5,5-Dimethyl-2-(2-formylphenyl)-1,3,2-dioxaborinane.
This was prepared from 2-formylbenzeneboronic acid39
(500 mg, 3.3 mmol) and 2,2-dimethyl-1,3-propanediol.
After 24 h at re¯ux and evaporation, the desired product
was crystallized from hexane and isolated as a colourless
solid (725 mg, 99%). mpˆ122.68C. IR (KBr): 2932, 1694,
1478, 1415, 1303, 1247, 1133.1H NMR: 1.08 (6H, s), 3.82
(4H, s), 7.50±7.60 (2H, m), 7.8 (1H, dd, Jˆ8.5; 1.55 Hz),
7.91 (1H, dd, Jˆ7.77; 1.72 Hz), 10.46 (1H,s). 13C NMR:
21.9 (2q), 31.75 (s), 72.54 (2t), 128.34 (d), 129.91 (d),
132.96 (d), 133.84 (s), 134.28 (d), 140.83 (s), 194.96 (d).
1
1130, 760, 695. H NMR: 1.0 (6H, s), 3.7 (4H, s), 7.2±
7.45 (3H, m), 7.7±7,9 (2H, m).
5,5-Dimethyl-2-(2-methoxyphenyl)-1,3,2-dioxaborinane
3. This was prepared from 2-methoxyphenylboronic acid
(1 g, 6.58 mmol) and 2,2-dimethyl-1,3-propanediol. After
5 h at re¯ux and evaporation, the desired product was crys-
tallised from hexane and isolated as a colourless solid
(1.23 g, 86%). mpˆ418C. IR(KBr): 3000±2890, 1600,
1
1485, 1475, 1430, 1340±1240, 1130, 1100, 1020, 770. H
Coupling reaction
NMR: 1.05 (6H, s), 3.75 (4H, s), 3.8 (3H, s), 6.8±7.7 (4H,
m). Anal. calcd for C12H17BO3 (220.08): C 65.49%, H
7.79%; found C 64.92%, H 8.12%.
General procedure. In a ¯ask equipped with a Dean±Stark
apparatus and a condenser, 3-iodo-4-methoxybenzoic acid
methylester 1 (100 mg, 0.34 mmol.), arylboronic ester
(1.1 equiv.), catalyst (0.06 equiv.) and base (1.1 equiv.)
were suspended in 20±25 ml of solvent and were stirred at
5,5-Dimethyl-2-(2-isopropoxyphenyl)-1,3,2-dioxaborinane
4. This was prepared from 2-isopropoxyphenylboronic acid

H. Chaumeil et al. / Tetrahedron 56 (2000) 9655±9662
9661
re¯ux under N2 for 90±100 h. The suspension was ®ltered
through Celite and a solution of HCl 2N was added to the
®ltrate with stirring. The organic layer was washed with
water. The aqueous layers were extracted twice with
CH2Cl2. The organic phases were then washed with brine,
dried over MgSO4 and concentrated in vacuo. The coupling
product 9±13 was isolated by chromatography on silicagel
(petroleum ether/ethyl acetate) and further crystallised from
ethanol.
(q), 24.24 (q), 30.65 (2d), 34.19 (d), 51.85 (q), 55.46 (q),
109.97 (d), 120.61 (2d), 122.22 (s), 129.37 (s), 130.63 (d),
132.00 (s), 133.16 (d), 146.67 (2s), 148.02 (s), 167.00 (s).
Detection of a CO2 emission
The coupling reaction of 1 and 2 was carried out as
previously described, however using 700 mg (2.4 mmol)
of iodoaromatic 1. A slow stream of N2 was intermittently
passed through the reaction vessel to a wash bottle contain-
ing lime water. After 4 days of reaction, 32 mg (0.32 mmol
i.e. 27% of the theoretical amount) of calcium carbonate
could be recovered by centrifugation of the lime water.
When a similar experiment was run without Pd(Ph3)4, no
coupling reaction could be observed and less than 1 mg of
CaCO3 was formed. Therefore, we have not attempted by
further experiments to quantitatively recover the CO2
formed during the coupling reaction.
Methyl 6-methoxybiphenyl-3-carboxylate 9. Mpˆ908C.
IR (KBr): 3060±2950, 2840, 1710, 1600, 1460, 1435,
1310, 1230, 1140, 1015, 770, 725. H NMR: 3.87 (3H, s),
1
3.89 (3H, s), 7.3±7.55 (5H, m), 7.00 (1H, d, Jˆ9.2 Hz), 8.01
(1H, d, Jˆ2.2 Hz), 8.03 (1H, dd, Jˆ9.2; 2.2 Hz). 13C NMR:
51.92 (q), 55.77 (q), 110.6 (d), 122.7 (s), 127.35 (d), 128.09
(2d), 129.52 (2d), 130.61 (s), 130.76 (d), 132.45 (d), 137.54
(s), 160.20 (s), 166.89 (s). Anal. calcd for C15H14O3
(242.28): C 74.36%, H 5.82%; found: C 74.18%, H 5.98%.
Methyl 6,20-dimethoxybiphenyl-3-carboxylate 10. Mpˆ
938C. IR (KBr): 3040±2940, 2840, 1710, 1610, 1590,
1460, 1430, 1310, 1295, 1240, 1135, 1115, 1030, 1015,
Acknowledgements
Thanks to the Centre National de la Recherche Scienti®que
(UPRES-A 7015) for ®nancial support. We are grateful to
Professor J.-P. Fleury for helpful discussions and to
G. Sinquin, an undergraduate student, who worked with
dedication during the early stages of this project. We also
gratefully acknowledge the help of Dr P. Bisseret and Dr A.
Defoin for valuable comments and suggestions especially
during the preparation of the manuscript.
1
770, 745. H NMR: 3.76 (3H, s), 3.82 (3H, s), 3.87 (3H,
s), 6.97 (1H, d, Jˆ8.7 Hz), 6.99±7.05 (2H, m), 7.22 (1H, dd,
Jˆ7.5; 1.8 Hz), 7.35 (1H, ddd, Jˆ7.5; 7.6; 1.8 Hz), 7.94
(1H, d, Jˆ2.2 Hz), 8.04 (1H, dd, Jˆ8.7; 2.2 Hz). 13C
NMR: 51 (q), 55.69 (q), 55.81 (q), 110.33 (d), 111.07 (d),
120.41(d), 122.22 (s), 126.84 (s), 127.8 (s), 129.02 (s),
130.87 (s), 131.31 (d), 133.08 (d), 157.02 (s), 160.87 (s),
166.97 (s). Anal. calcd for C16H16O4 (272.30): C 70.58%, H
5.92%; found: C 70.50%, H 5.94%.
References
Methyl 6-methoxy-20-isopropoxybiphenyl-3-carboxylate
11. Mpˆ1068C. IR (KBr): 3000±2900, 2830, 1705, 1605,
1590, 1480, 1445, 1295, 1240, 1110, 1025, 1010, 950, 760.
1H NMR: 1.17 (6H, d, Jˆ6 Hz), 3.84 (3H, s), 3.9 (3H, s),
4.42 (1H, sept, Jˆ6 Hz), 6.93±7.2 (2H, m), 6.95 (1H, d,
Jˆ8.6 Hz), 7.21±7.33 (2H, m), 7.94 (1H, d, Jˆ2.2 Hz),
8.04 (1H, dd, Jˆ8.6; 2.2 Hz). 13C NMR: 22.03 (2 q),
51.79 (q), 55.59 (q), 70.55 (d), 109.99 (d), 114.25 (d),
120.38 (d), 122.03 (s), 128.22 (s), 128.26 (s), 128.79 (d),
130.64 (s), 131.47 (s), 133.21 (d), 155.46 (s), 160.88 (s),
167.07 (s). Anal. calcd for C18H20O4 (300.36): C 71.98%, H
6.71%; found: C 72.04%, H 6.60%.
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1710, 1600, 1440, 1260, 1240, 1020, 780, 640. H NMR:
1.99 (6H, s), 2.35 (3H, s), 3.82 (3H, s), 3.89 (3H,s), 6.96
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