Tetraphosphine/palladium catalysed Suzuki cross-coupling reactions of aryl halides with alkylboronic acids

Article abstract of DOI:10.1016/j.tet.2004.03.009

Through the use of [PdCl(C₃H₅)]₂/cis,cis, cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane as a catalyst, a range of aryl bromides and chlorides undergoes Suzuki cross-coupling with alkylboronic acids in good yields. Several alkyl substituents such as ethyl, n-butyl, n-octyl, isobutyl or 2,2-dimethylpropyl on the alkylboronic acids have been successfully used. The functional group tolerance on the aryl halide is remarkable; substituents such as fluoro, methyl, methoxy, acetyl, formyl, benzoyl, nitro or nitrile are tolerated. Furthermore, this catalyst can be used at low loading, even for reactions of sterically hindered aryl bromides.

Full text of DOI:10.1016/j.tet.2004.03.009

Tetrahedron 60 (2004) 3813–3818
Tetraphosphine/palladium catalysed Suzuki cross-coupling
reactions of aryl halides with alkylboronic acids
*
Isabelle Kondolff, Henri Doucet and Maurice Santelli
*
` ´ ´ ´ ˆ
Laboratoire de Synthese Organique associe au CNRS UMR 6180, Faculte des Sciences de Saint Jerome,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
Received 17 December 2003; revised 9 February 2004; accepted 3 March 2004
Abstract—Through the use of [PdCl(C3H5)]2/cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane as a catalyst, a range of
aryl bromides and chlorides undergoes Suzuki cross-coupling with alkylboronic acids in good yields. Several alkyl substituents such as ethyl,
n-butyl, n-octyl, isobutyl or 2,2-dimethylpropyl on the alkylboronic acids have been successfully used. The functional group tolerance on the
aryl halide is remarkable; substituents such as fluoro, methyl, methoxy, acetyl, formyl, benzoyl, nitro or nitrile are tolerated. Furthermore,
this catalyst can be used at low loading, even for reactions of sterically hindered aryl bromides.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
simple primary alkylboronic acids are still subject to
significant improvement.
Arylalkane derivatives are important building blocks in
organic synthesis and their preparation is an important
industrial goal. The palladium-catalysed so-called Suzuki
cross-coupling reaction is a powerful method for the
synthesis of these arylalkane compounds.1 Organoboron
reagents exhibit greater functional group compatibility than
organozinc or Grignard reagents. However, the procedure
suffers generally from high catalyst loading due to the fast
decomposition of the catalyst.2 In recent years, several
thermally stable palladium catalysts have been successfully
used for Suzuki reactions,3 but the results which have been
described with these catalysts, were generally obtained for
In order to find more efficient palladium catalysts, we have
prepared the tetrapodal4 phosphine ligand, Tedicyp5 (Fig. 1).
We have reported recently several results obtained in allylic
substitution,5 Heck,6 Sonogashira reactions7 and Suzuki
cross-coupling8 using Tedicyp as ligand. For example,
a TON (turnover number) of 96000000 for the reaction of
4-bromobenzophenone with benzeneboronic acid had been
obtained.8b We also reported some results for Suzuki cross-
coupling reaction using Tedicyp ligand with sterically
hindered aryl bromides,8d heteroaryl bromides,8c aryl
chlorides,8e vinylhalides,8g benzylhalides8h and with a
variety of arylboronic acids.8f Here, in order to further
establish the requirements for a successful Suzuki cross-
coupling reaction, we wish to report on the reaction of
alkylboronic acids with a variety of arylhalides using
Tedicyp as the ligand.
the coupling of arylboronic acids. With alkylboronic acids
2b,c
most of the results were described with Pd(PPh3)4
or
PdCl2/dppf.2a,d,e For example, Molander et al. have reported
that PdCl2/dppf is an efficient catalyst for the cross-coupling
of 2-phenylethylboronic acid with several arylbromides.2h
Good results have also been reported recently by Hartwig
et al. and by Najera et al.2f,g They described that a sterically
hindered ferrocenyl dialkylphosphine palladium complex
and an oxime-derived palladacycle led to efficient catalysts
for the reaction of n-butylboronic acid with aryl halides.
However, to our knowledge, low-catalyst loading Suzuki
cross-coupling reactions with alkylboronic acids have not
been described. Thus, an effective method using high
substrate/catalyst ratios for the successful coupling of
Figure 1.
2. Results and discussion
For this study, based on previous results,8 xylene was
chosen as the solvent and potassium carbonate as the base
(Scheme 1). The reactions were performed at 130 8C under
argon in the presence of a ratio 1/2 of [Pd(C3H5)Cl]2/
Tedicyp as catalyst.
Keywords: Catalysis; Palladium; Tetraphosphine; Alkylboronic acids; Aryl
halides.
*
Corresponding authors. Tel.: þ33-4-91-28-84-16; fax: þ33-4-91-98-38-
65 (H.D.); tel.: þ33-4-91-28-88-25 (M.S.);
First, we have investigated the Suzuki cross-coupling
e-mail addresses: henri.doucet@univ.u-3mrs.fr; m.santelli@univ.u-3mrs.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.009

3814
I. Kondolff et al. / Tetrahedron 60 (2004) 3813–3818
Scheme 1.
reactions of n-butylboronic acid with several para- and
ortho-substituted arylbromides. The results presented in the
Table 1 disclose a strong influence of the substituents on
the aryl bromide on the reaction rate. The reaction with
n-butylboronic acid can be performed with as little as 0.01%
catalyst. Electron-withdrawing groups in the aryl bromide
support the Suzuki reaction, while electron-donation groups
are unfavourable. Turnover numbers of 8000–14,000 can
be achieved with this catalyst for activated substrates such
as 4-bromoacetophenone, 4-bromobenzaldehyde, 4-bromo-
benzophenone, 4-bromobenzonitrile and 4-bromonitro-
benzene (Table 1, entries 1–10). With the deactivated
arylbromides: 4-bromoanisole and 4-t-butylbromobenzene
lower TONs of 820 and 1000 were obtained (Table 1,
entries 11 and 12). Then, we tried to evaluate the importance
of the presence of one ortho substituent on the arylbromide
on the reaction rate. We observed that the coupling of
2-bromoacetophenone, 2-bromobenzaldehyde, 2-bromo-
benzonitrile or 1-bromonaphthalene with n-butylboronic
acid in the presence of 0.1 or 0.01% catalyst led to the
alkylaryl adducts in TONs of 1000–3800 (Table 1, entries
13–21). Next, we tried to evaluate the difference of reaction
rate between mono- and di-ortho-substituted arylbromides,
and we observed that even very hindered aryl bromides
could be coupled efficiently with n-butylboronic acid. For
example, with 9-bromoanthracene and 1-bromo-2,4,6-tri-
isopropylbenzene high conversions were obtained. The
presence of 0.1 and 1% catalyst was necessary for these
reactions showing a significant effect of the ortho-
substituents of the aryl bromide on the reaction rate
(Table 1, entries 22 and 23).
In our previous researches on the coupling of phenylboronic
acid with these aryl bromides much higher reaction rates
had been observed with this catalyst.8b In order to obtain
more information on the rate-limiting step of this reaction,
we performed a competitive reaction using an equimolar
mixture of phenylboronic acid (20 mmol) and n-butyl-
boronic acid (20 mmol) with 4-bromoacetophenone
(10 mmol) in the presence of 0.1% catalyst. After one
Table 1. Palladium-Tedicyp catalysed Suzuki cross-coupling reactions with n-butylboronic acid (Scheme 1)
Entry
Aryl halide
Ratio substrate/catalyst
Product number
Yield (%)a
1
2
3
4
5
6
7
8
4-Bromoacetophenone
4-Bromoacetophenone
4-Bromobenzaldehyde
4-Bromobenzaldehyde
4-Bromobenzophenone
4-Bromobenzophenone
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Nitrobromobenzene
4-Nitrobromobenzene
4-Bromoanisole
4-t-Butylbromobenzene
2-Bromoacetophenone
2-Bromoacetophenone
2-Bromobenzaldehyde
2-Bromobenzaldehyde
2-Bromobenzonitrile
2-Bromobenzonitrile
2-Nitrobromobenzene
2-Bromobiphenyl
1000
10,000
1000
10,000
10,000
100,000
1000
10,000
1000
10,000
1000
1000
1000
10,000
1000
10,000
1000
10,000
1000
1000
1000
1000
100
1
1
2
2
3
3
4
4
5
5
6
7
8
8
9
9
10
10
11
12
13
14
15
16
16
4
4
1
5
5
17
17
(92) 100
90
(85) 100
92
(94) 100
14
(90) 100
100
(82) 100
100
(73) 82
(84) 100
(78) 85
38
(84) 100
35
(91) 100
28
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
(83) 100
(92) 100
(93) 100
(91) 100
(88) 100
(80) 100
88
1-Bromonaphthalene
9-Bromoanthracene
2,4,6-Triisopropylbromobenzene
3-Bromoquinoline
1000
10,000
50
100
50
50
100
100
250
3-Bromoquinoline
4-Chlorobenzonitrile
4-Chlorobenzonitrile
4-Chloroacetophenone
4-Chloronitrobenzene
4-Chloronitrobenzene
2-Chloroquinoline
(78) 100
65
(58) 69
(74) 100
97
(72) 100b
77b
2-Chloroquinoline
Conditions: Pd-tedicyp catalyst, ArX (1 equiv.), n-butylboronic acid (2 equiv.), K2CO3 (2 equiv.), xylene, 130 8C, 20 h, GC or NMR yields.
Yields in parentheses are isolated.
a
b
The formation of 2,20-biquinoline was also observed.

I. Kondolff et al. / Tetrahedron 60 (2004) 3813–3818
3815
hour, the conversion was complete and we only observed
the formation of the coupling product with phenylboronic
acid. An other competitive reaction using an equimolar
mixture of 4-bromoacetophenone (10 mmol) and 2,4,6-tri-
isopropylbromobenzene (10 mmol) with n-butylboronic
acid (5 mmol) in the presence of 0.1% catalyst was also
perfomed. This reaction led after five hours to a mixture of
coupling adducts 1 and 15 in a ratio 97:3. The respective
rates of these reactions suggest that, in the presence of
this catalyst, the rate-determining step of the reaction is
not the oxidative addition of the arylbromide. The rate-
determining step of this reaction seems to be the trans-
metallation of the alkylboronic acid with the palladium
centre or the C–C bond formation from the Pd-aryl-alkyl
intermediate.
presence of ethyl- or 2,2-dimethylpropaneboronic acids
lower TONs were obtained (Table 2, entries 12–14 and
30–32).
We also studied the coupling of bromopyridines with
n-octylboronic acid. As expected,8c we observed higher
TONs for the coupling of b- and g-substituted bromo-
pyridines (1000) (Table 2, entries 10 and 11) than with the
a-substituted 2-bromopyridine (100) (Table 2, entry 9).
In summary, we have established that the Tedicyp-
palladium system is not limited to Suzuki reactions of
arylboronic acids; alkylboronic acids are also efficiently
coupled. Lower TONs are obtained than for the coupling
with arylboronic acids, but the reaction with alkylboronic
acids can be performed with as little as 0.01% catalyst with
a wide variety of arylbromides. This catalyst seems to be
much more efficient than the complexes formed with
triphenylphosphine ligand. Due to the high price of palla-
dium, the practical advantage of such low catalyst loadings
can become increasingly important for industrial processes.
These alkylboronic acids are thermally, air-, and moisture-
stable. Moreover, some of them are commercially available.
This is a practical advantage of the Suzuki reaction, relative
to the other coupling processes. A wide range of functions
such as methoxy, fluoro, acetyl, formyl, benzoyl, nitro or
nitrile on the arylbromide are tolerated. As expected, the
steric hindrance of the arylbromide has an important effect
on the reaction rates.
Then, we studied the reaction in the presence of aryl
chlorides (Table 1, entries 26–32). We observed that this
system is not very active for such compounds: the reactions
were performed in the presence of 0.4–2% catalyst. For
these substrates, a tetraphosphine electronically similar to
P(t-Bu)3 should lead to better results.
Finally, we have investigated the Suzuki reaction of eight
other alkylboronic acids (Table 2). In the presence of
n-propyl-, 2-methylpropyl-, 3-methylbutyl-, (cyclohexyl)-
methyl-, 2-phenylethyl- or n-octylboronic acids, very
similar results to those observed with n-butylboronic acid
were obtained (Table 2, entries 1–8 and 15–29). In the
Table 2. Palladium-Tedicyp catalysed Suzuki cross-coupling reactions with various alkylboronic acids (Scheme 1)
Entry
Aryl bromide
Alkylboronic acid
Ratio substrate/catalyst
Product number
Yield (%)a
1
2
3
4
5
6
7
8
4-Bromoacetophenone
4-Bromobenzaldehyde
4-Fluorobromobenzene
4-Fluorobromobenzene
2-Bromoanisole
n-Octylboronic acid
n-Octylboronic acid
n-Octylboronic acid
n-Octylboronic acid
n-Octylboronic acid
n-Octylboronic acid
n-Octylboronic acid
n-Octylboronic acid
n-Octylboronic acid
n-Octylboronic acid
n-Octylboronic acid
n-Ethylboronic acid
n-Ethylboronic acid
n-Ethylboronic acid
n-Propylboronic acid
3-Methylbutylboronic acid
3-Methylbutylboronic acid
3-Methylbutylboronic acid
2-Methylpropylboronic acid
2-Methylpropylboronic acid
2-Methylpropylboronic acid
2-Methylpropylboronic acid
2-Methylpropylboronic acid
(Cyclohexyl)methylboronic acid
(Cyclohexyl)methylboronic acid
(Cyclohexyl)methylboronic acid
(Cyclohexyl)methylboronic acid
2-Phenylethylboronic acid
2-Phenylethylboronic acid
2,2-Dimethylpropylboronic acid
2,2-Dimethylpropylboronic acid
2,2-Dimethylpropylboronic acid
10,000
10,000
250
1000
250
1000
250
1000
100
18
19
20
20
21
21
22
22
23
24
25
26
26
27
28
29
30
30
31
31
32
32
33
34
34
35
35
36
36
37
37
38
(93) 100
(74) 78
(95) 100
41
(82) 100
48
2-Bromoanisole
2,4,6-Trimethylbromobenzene
2,4,6-Trimethylbromobenzene
2-Bromopyridine
3-Bromopyridine
4-Bromopyridine
(82) 100
55
9
(52) 100b
(87) 100
(80) 100
(89) 100
63
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
1000
1000
250
4-Bromoacetophenone
4-Bromoacetophenone
2-Bromobenzaldehyde
4-Bromoacetophenone
4-Bromoacetophenone
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Bromoacetophenone
4-Bromoacetophenone
2-Bromoacetophenone
2-Bromoacetophenone
4-tButylbromobenzene
4-Bromoacetophenone
4-Bromoacetophenone
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Bromoacetophenone
4-Bromoacetophenone
4-Bromoacetophenone
4-Bromoacetophenone
4-Bromobenzaldehyde
1000
1000
10,000
10,000
1000
10,000
1000
10,000
1000
10,000
1000
1000
10,000
1000
10,000
1000
10,000
250
(58) 64
(74) 81
(92) 100
(94) 100
100
(91) 99
42
(92) 100
41
(75) 78
(95) 100
74
(92) 100
67
(94) 100
93
(79) 100
95
(77) 90
1000
250
Conditions: Pd-tedicyp catalyst, ArBr (1 equiv.), alkylboronic acid (2 equiv.), K2CO3 (2 equiv.), xylene, 130 8C, 20 h, GC or NMR yields.
Yields in parentheses are isolated.
a
b
The formation of 2,20-bipyridine was also observed.

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I. Kondolff et al. / Tetrahedron 60 (2004) 3813–3818
3. Experimental
(1.82 g, 10 mmol) and n-butylboronic acid (2.04 g,
20 mmol), product 4 was obtained in 90% (1.43 g) yield.
3.1. General remarks
3.3.5. 4-n-Butylnitrobenzene 5. From 4-bromonitroben-
zene (2.02 g, 10 mmol) and n-butylboronic acid (2.04 g,
20 mmol), product 5 was obtained in 82% (1.47 g) yield. 1H
NMR (300 MHz, CDCl3) d 8.14 (d, 2H, J¼8.7 Hz), 7.35 (d,
2H, J¼8.7 Hz), 2.70 (t, 2H, J¼7.8 Hz), 1.60 (m, 2H), 1.36
(m, 2H), 0.92 (t, 3H, J¼7.2 Hz).
All reactions were run under argon in Schlenk tubes using
vacuum lines. Xylene analytical grade was not distilled
before use. Some of the aryl halides were distilled before
use. Potassium carbonate (99þ) was used without drying.
Alkenylboronic acids were prepared according to reported
procedures by addition of 2 equiv. of B(OMe)3 to alkenyl-
magnesium bromide solutions in THF at 290 8C, then the
solution was allowed to room temperature, poured on ice,
extracted with ether, dried (MgSO4) and evaporated. The
reactions were followed by GC and NMR for high boiling
point substrates and by GC for low boiling point substrates.
GC/MS was recorded with a Varian Saturn 2100T spectro-
meter. 1H spectrum were recorded with a Bruker 300 MHz
spectrometer in CDCl3 solutions. Chemical shift are
reported in ppm relative to CDCl3 (7.25). Flash chroma-
tography were performed on silica gel (230–400 mesh) GC
and NMR yields in the tables are conversions of the aryl
3.3.6. 4-n-Butylanisole 6. From 4-bromoanisole (1.87 g,
10 mmol) and n-butylboronic acid (2.04 g, 20 mmol),
1
product 6 was obtained in 73% (1.20 g) yield. H NMR
(300 MHz, CDCl3) d 7.10 (d, 2H, J¼8.5 Hz), 6.83 (d, 2H,
J¼8.5 Hz), 3.80 (s, 3H), 2.58 (t, 2H, J¼7.8 Hz), 1.58 (m,
2H), 1.33 (m, 2H), 0.92 (t, 3H, J¼7.2 Hz).
3.3.7. 1-n-Butyl-4-t-butylbenzene 7. From 4-t-butylbromo-
benzene (2.13 g, 10 mmol) and n-butylboronic acid (2.04 g,
20 mmol), product 7 was obtained in 84% (1.60 g) yield.
1H NMR (300 MHz, CDCl3) d 7.30 (d, 2H, J¼8.1 Hz), 7.13
(d, 2H, J¼8.1 Hz), 2.58 (t, 2H, J¼7.8 Hz), 1.59 (m, 2H),
1.35 (m, 2H), 1.32 (s, 9H), 0.92 (t, 3H, J¼7.2 Hz).
1
halides into the products calculated with GC and H NMR
spectrum of the crude mixtures.
3.2. General procedure
3.3.8. 2-n-Butylacetophenone 8. From 2-bromoacetophe-
none (1.99 g, 10 mmol) and n-butylboronic acid (2.04 g,
20 mmol), product 8 was obtained in 52% (0.92 g) yield.
1H NMR (300 MHz, CDCl3) d 7.60 (d, 1H, J¼7.7 Hz),
7.40–7.15 (m, 3H), 2.83 (t, 2H, J¼7.8 Hz), 2.63 (s, 3H),
1.54 (m, 2H), 1.40 (m, 2H), 0.91 (t, 3H, J¼7.2 Hz).
The reaction of the arylhalide (10 mmol), alkylboronic acid
(20 mmol) and K2CO3 (2.76 g, 20 mmol) at 130 8C during
20 h in anhydrous xylene (20 mL) in the presence of
cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclo-
pentane/[PdCl(C3H5)]2 complex under argon affords the
corresponding adduct after extraction with ether, evapo-
ration and filtration on silica gel (pentane/ether).
3.3.9. 2-n-Butylbenzaldehyde 9. From 2-bromobenzalde-
hyde (1.85 g, 10 mmol) and n-butylboronic acid (2.04 g,
20 mmol), product 9 was obtained in 84% (1.37 g) yield. 1H
NMR (300 MHz, CDCl3) d 10.29 (s, 1H), 7.82 (d, 1H, J¼
7.8 Hz), 7.49 (t, 1H, J¼7.6 Hz), 7.34 (t, 1H, J¼7.6 Hz), 7.26
(d, 1H, J¼7.8 Hz), 3.02 (t, 2H, J¼7.8 Hz), 1.59 (m, 2H),
1.40 (m, 2H), 0.93 (t, 3H, J¼7.2 Hz).
3.3. Preparation of the Pd-Tedicyp catalyst
An over-dried 40-mL Schlenk tube equipped with a
magnetic stirring bar under argon atmosphere, was charged
with [Pd(h3-C3H5)Cl]2 (30 mg, 81 mmol) and Tedicyp
(140 mg, 162 mmol). 10 mL of anhydrous THF were
added, then the solution was stirred at room temperature
for 10 min and the THF was evaporated. The appropriate
catalyst concentration was obtained by successive dilutions.
31P NMR (162 MHz, CDCl3) d 25 (w¼80 Hz), 19.4 (w¼
110 Hz).
3.3.10. 2-n-Butylbenzonitrile 10. From 2-bromobenzo-
nitrile (1.82 g, 10 mmol) and n-butylboronic acid (2.04 g,
20 mmol), product 10 was obtained in 91% (1.45 g) yield.
1H NMR (300 MHz, CDCl3) d 7.59 (d, 1H, J¼7.5 Hz), 7.49
(t, 1H, J¼7.5 Hz), 7.30 (d, 1H, J¼7.5 Hz), 7.26 (t, 1H, J¼
7.7 Hz), 2.83 (t, 2H, J¼7.8 Hz), 1.65 (m, 2H), 1.40 (m, 2H),
0.93 (t, 3H, J¼7.2 Hz).
3.3.1. 4-n-Butylacetophenone 1. From 4-bromoaceto-
phenone (1.99 g, 10 mmol) and n-butylboronic acid (2.04 g,
20 mmol), product 1 was obtained in 92% (1.62 g) yield.
3.3.11. 2-n-Butylnitrobenzene 11. From 2-bromonitro-
benzene (2.02 g, 10 mmol), and n-butylboronic acid (2.04 g,
20 mmol), product 11 was obtained in 83% (1.48 g) yield.
1H NMR (300 MHz, CDCl3) d 7.85 (d, 1H, J¼8.3 Hz), 7.49
(t, 1H, J¼7.7 Hz), 7.31 (m, 2H), 2.87 (t, 2H, J¼7.8 Hz),
1.61 (m, 2H), 1.36 (m, 2H), 0.92 (t, 3H, J¼7.2 Hz).
3.3.2. 4-n-Butylbenzaldehyde 2. From 4-bromobenzalde-
hyde (1.85 g, 10 mmol) and n-butylboronic acid (2.04 g,
20 mmol), product 2 was obtained in 85% (1.38 g) yield.
3.3.3. 4-n-Butylbenzophenone 3. From 4-bromobenzophe-
none (2.61 g, 10 mmol) and n-butylboronic acid (2.04 g,
20 mmol), product 3 was obtained in 94% (2.24 g) yield. 1H
NMR (300 MHz, CDCl3) d 7.78 (d, 2H, J¼8.2 Hz), 7.73 (d,
2H, J¼8.2 Hz), 7.56 (t, 1H, J¼7.6 Hz), 7.46 (t, 2H, J¼
7.6 Hz), 7.27 (d, 2H, J¼8.2 Hz), 2.69 (t, 2H, J¼7.8 Hz),
1.61 (m, 2H), 1.36 (m, 2H), 0.94 (t, 3H, J¼7.2 Hz).
3.3.12. 2-n-Butylbiphenyl 12. From 2-bromobiphenyl
(2.33 g, 10 mmol) and n-butylboronic acid (2.04 g,
20 mmol), product 12 was obtained in 92% (1.93 g) yield.
1H NMR (300 MHz, CDCl3) d 7.60–7.10 (m, 9H), 2.76
(t, 2H, J¼7.8 Hz), 1.66 (m, 2H), 1.39 (m, 2H), 0.97 (t, 3H,
J¼7.2 Hz).
3.3.13. 1-n-Butylnaphthalene 13. From 1-bromonaphtha-
lene (2.07 g, 10 mmol) and n-butylboronic acid (2.04 g,
3.3.4. 4-n-Butylbenzonitrile 4. From 4-bromobenzonitrile

I. Kondolff et al. / Tetrahedron 60 (2004) 3813–3818
3817
20 mmol), product 13 was obtained in 93% (1.71 g) yield.
1H NMR (300 MHz, CDCl3) d 8.06 (d, 1H, J¼8.1 Hz), 7.86
(d, 1H, J¼7.9 Hz), 7.71 (d, 1H, J¼7.9 Hz), 7.55–7.30 (m,
4H), 3.09 (t, 2H, J¼7.8 Hz), 1.76 (m, 2H), 1.49 (m, 2H),
0.99 (t, 3H, J¼7.2 Hz).
3.3.22. 1-n-Octyl-2,4,6-trimethylbenzene 22. From 2,4,6-
trimethylbromobenzene (1.99 g, 10 mmol) and n-octyl-
boronic acid (3.16 g, 20 mmol), product 22 was obtained
in 82% (1.90 g) yield. 1H NMR (300 MHz, CDCl3) d
6.82 (s, 2H), 2.56 (t, 2H, J¼7.5 Hz), 2.28 (s, 6H), 2.24
(s, 3H), 1.55 (m, 2H), 1.27 (m, 10H), 0.89 (t, 3H, J¼
7.2 Hz).
3.3.14. 9-n-Butylanthracene 14. From 9-bromoanthracene
(2.57 g, 10 mmol) and n-butylboronic acid (2.04 g,
20 mmol), product 14 was obtained in 91% (2.13 g) yield.
1H NMR (300 MHz, CDCl3) d 8.32 (s, 1H), 8.27 (d, 2H,
J¼8.1 Hz), 8.00 (d, 2H, J¼7.7 Hz), 7.47 (m, 4H), 3.60
(t, 2H, J¼7.8 Hz), 1.81 (m, 2H), 1.61 (m, 2H), 1.03 (t, 3H,
J¼7.2 Hz).
3.3.23. 2-n-Octylpyridine 23. From 2-bromopyridine
(1.58 g, 10 mmol) and n-octylboronic acid (3.16 g,
20 mmol), product 23 was obtained in 52% (0.99 g) yield.
1H NMR (300 MHz, CDCl3) d 8.53 (d, 1H, J¼5.0 Hz), 7.60
(t, 1H, J¼7.8 Hz), 7.10 (m, 2H), 2.80 (t, 2H, J¼7.5 Hz),
1.70 (m, 2H), 1.27 (m, 10H), 0.88 (t, 3H, J¼7.2 Hz).
3.3.15. 1-n-Butyl-2,4,6-triisopropylbenzene 15. From
2,4,6-triisopropylbromobenzene (2.83 g, 10 mmol) and
n-butylboronic acid (2.04 g, 20 mmol), product 15 was
3.3.24. 3-n-Octylpyridine 24. From 3-bromopyridine
(1.58 g, 10 mmol) and n-octylboronic acid (3.16 g,
20 mmol), product 24 was obtained in 87% (1.66 g) yield.
1H NMR (300 MHz, CDCl3) d 8.40 (m, 2H), 7.46 (d, 1H,
J¼7.8 Hz), 7.16 (dd, 1H, J¼7.5, 4.7 Hz), 2.58 (t, 2H,
J¼7.5 Hz), 1.57 (m, 2H), 1.28 (m, 10H), 0.86 (t, 3H,
J¼7.2 Hz).
1
obtained in 88% (2.29 g) yield. Colourless oil; H NMR
(300 MHz, CDCl3) d 6.97 (s, 2H), 3.16 (sept., 2H, J¼
6.8 Hz), 2.85 (sept., 1H, J¼6.9 Hz), 2.61 (t, 2H, J¼7.8 Hz),
1.45 (m, 4H), 1.25 (d, 6H, J¼6.9 Hz), 1.24 (d, 12H, J¼
6.9 Hz), 0.97 (t, 3H, J¼7.3 Hz); MS (EI, 70 eV): Calcd
260.2. Found 260 (34%) (Mþ). C19H32 (260.46): Calcd C
87.62, H 13.38. Found C 87.29, H 13.28.
3.3.25. 4-n-Octylpyridine 25. From 4-bromopyridine
(1.58 g, 10 mmol) and n-octylboronic acid (3.16 g,
20 mmol), product 25 was obtained in 80% (1.53 g) yield.
1H NMR (300 MHz, CDCl3) d 8.59 (d, 2H, J¼6.0 Hz), 7.22
(d, 2H, J¼6.0 Hz), 2.69 (t, 2H, J¼7.5 Hz), 1.66 (m, 2H),
1.33 (m, 10H), 0.94 (t, 3H, J¼7.2 Hz).
3.3.16. 3-n-Butylquinoline 16. From 3-bromoquinoline
(2.08 g, 10 mmol) and n-butylboronic acid (2.04 g,
20 mmol), product 16 was obtained in 80% (1.48 g) yield.
1H NMR (300 MHz, CDCl3) d 8.76 (d, 1H, J¼2.3 Hz), 8.10
(d, 1H, J¼8.5 Hz), 7.90 (s, 1H), 7.75 (d, 1H, J¼8.5 Hz),
7.60 (t, 1H, J¼8.5 Hz), 7.50 (t, 1H, J¼8.5 Hz), 2.78 (t, 2H,
J¼7.8 Hz), 1.69 (m, 2H), 1.38 (m, 2H), 0.94 (t, 3H,
J¼7.2 Hz).
3.3.26. 4-Ethylacetophenone 26. From 4-bromoaceto-
phenone (1.99 g, 10 mmol) and ethylboronic acid (1.48 g,
20 mmol), product 26 was obtained in 89% (1.32 g) yield.
3.3.17. 2-n-Butylquinoline 17. From 2-chloroquinoline
(1.63 g, 10 mmol) and n-butylboronic acid (2.04 g,
20 mmol), product 17 was obtained in 72% (1.33 g) yield.
1H NMR (300 MHz, CDCl3) d 8.05 (m, 2H), 7.76 (d, 1H,
J¼7.0 Hz), 7.67 (t, 1H, J¼7.9 Hz), 7.47 (t, 1H, J¼7.9 Hz),
7.28 (d, 1H, J¼7.0 Hz), 2.97 (t, 2H, J¼7.8 Hz), 1.76 (m,
2H), 1.40 (m, 2H), 0.96 (t, 3H, J¼7.2 Hz).
3.3.27. 2-Ethylbenzaldehyde 27. From 2-bromobenzalde-
hyde (1.85 g, 10 mmol) and ethylboronic acid (1.48 g,
20 mmol), product 27 was obtained in 58% (0.78 g) yield.
3.3.28. 4-n-Propylacetophenone 28. From 4-bromoaceto-
phenone (1.99 g, 10 mmol) and n-propylboronic acid
(1.76 g, 20 mmol), product 28 was obtained in 74%
(1.20 g) yield.
3.3.18. 4-n-Octylacetophenone 18. From 4-bromoaceto-
phenone (1.99 g, 10 mmol) and n-octylboronic acid (3.16 g,
20 mmol), product 18 was obtained in 93% (2.16 g) yield.
3.3.29. 4-(3-Methylbutyl)acetophenone 29. From 4-bromo-
acetophenone (1.99 g, 10 mmol) and 3-methylbutylboronic
acid (2.32 g, 20 mmol), product 29 was obtained in 92%
1
3.3.19. 4-n-Octylbenzaldehyde 19. From 4-bromobenzal-
dehyde (1.85 g, 10 mmol) and n-octylboronic acid (3.16 g,
20 mmol), product 19 was obtained in 74% (1.61 g) yield.
(1.75 g) yield. H NMR (300 MHz, CDCl3) d 7.87 (d, 2H,
J¼8.3 Hz), 7.26 (d, 2H, J¼8.3 Hz), 2.66 (t, 2H, J¼7.7 Hz),
2.57 (s, 3H), 2.52 (m, 3H), 0.93 (d, 6H, J¼6.4 Hz).
3.3.20. 4-n-Octylfluorobenzene 20. From 4-bromofluoro-
benzene (1.75 g, 10 mmol) and n-octylboronic acid (3.16 g,
20 mmol), product 20 was obtained in 95% (1.97 g) yield.
1H NMR (300 MHz, CDCl3) d 7.14 (dd, 2H, J¼8.5, 5.5 Hz),
6.97 (dd, 2H, J¼8.5, 8.5 Hz), 2.59 (t, 2H, J¼7.5 Hz), 1.60
(m, 2H), 1.29 (m, 10H), 0.90 (t, 3H, J¼7.2 Hz).
3.3.30. 4-(3-Methylbutyl)benzonitrile 30. From 4-bromo-
benzonitrile (1.82 g, 10 mmol) and 3-methylbutylboronic
acid (2.32 g, 20 mmol), product 30 was obtained in 94%
1
(1.63 g) yield. H NMR (300 MHz, CDCl3) d 7.54 (d, 2H,
J¼8.3 Hz), 7.26 (d, 2H, J¼8.3 Hz), 2.65 (t, 2H, J¼7.7 Hz),
2.52 (m, 3H), 0.93 (d, 6H, J¼6.4 Hz).
3.3.21. 2-n-Octylanisole 21. From 2-bromoanisole (1.87 g,
10 mmol) and n-octylboronic acid (3.16 g, 20 mmol),
product 21 was obtained in 82% (1.81 g) yield. H NMR
(300 MHz, CDCl3) d 7.15 (m, 2H), 6.90 (t, 1H, J¼7.5 Hz),
6.84 (d, 1H, J¼8.3 Hz), 3.82 (s, 3H), 2.61 (t, 2H, J¼7.5 Hz),
1.58 (m, 2H), 1.30 (m, 10H), 0.89 (t, 3H, J¼7.2 Hz).
3.3.31. 4-(2-Methylpropyl)acetophenone 31. From 4-bro-
moacetophenone (1.99 g, 10 mmol) and 2-methylpropyl-
boronic acid (2.04 g, 20 mmol), product 31 was obtained in
91% (1.60 g) yield.
1
3.3.32. 2-(2-Methylpropyl)acetophenone 32. From

3818
I. Kondolff et al. / Tetrahedron 60 (2004) 3813–3818
2-bromoacetophenone (1.99 g, 10 mmol) and 2-methylpro-
pylboronic acid (2.04 g, 20 mmol), product 32 was obtained
68266-59-1; 35, 98446-82-3; 36, 785-78-4; 37, 52380-60-6;
38, 52986-52-4.
1
in 46% (0.81 g) yield. H NMR (300 MHz, CDCl3) d 7.60
(d, 1H, J¼7.7 Hz), 7.42–7.15 (m, 3H), 2.74 (d, 2H, J¼
6.2 Hz), 2.56 (s, 3H), 1.80 (m, 1H), 0.91 (d, 6H, J¼6.4 Hz).
Acknowledgements
`
I. K. is grateful to the Ministere de la Recherche for a grant.
We thank CNRS and the ‘Conseil General des Bouches-du-
ˆ
Rhone, Fr’ for financial support.
3.3.33. 4-(2-Methylpropyl)-t-butylbenzene 33. From
4-t-butylbromobenzene (2.13 g, 10 mmol) and 2-methyl-
propylboronic acid (2.04 g, 20 mmol), product 33 was
obtained in 75% (1.43 g) yield. 1H NMR (300 MHz, CDCl3)
d 7.28 (d, 2H, J¼8.3 Hz), 7.06 (d, 2H, J¼8.3 Hz), 2.43
(d, 2H, J¼7.1 Hz), 1.89 (m, 1H), 1.30 (s, 9H), 0.92 (d, 6H,
J¼6.4 Hz).
´ ´
References and notes
1. For reviews on the palladium-catalysed Suzuki cross-coupling
reactions see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(c) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
3009. (d) Suzuki, A. J. Organomet. Chem. 2002, 653, 83.
(e) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4177.
3.3.34. 4-(Cyclohexyl)methylacetophenone 34. From
4-bromoacetophenone (1.99 g, 10 mmol) and (cyclohexyl)-
methylboronic acid (2.84 g, 20 mmol), product 34 was
obtained in 95% (2.05 g) yield. 1H NMR (300 MHz, CDCl3)
d 7.85 (d, 2H, J¼8.2 Hz), 7.21 (d, 2H, J¼8.2 Hz), 2.57
(s, 3H), 2.52 (d, 2H, J¼7.0 Hz), 1.75–0.75 (m, 11H).
2. For examples of Suzuki reactions with alkylboron derivatives:
(a) Miyaura, N.; Ishiyama, T.; Ishikawa, M.; Suzuki, A.
Tetrahedron Lett. 1986, 27, 6369. (b) Rivera, I.; Colberg, J.;
Soderquist, J. Tetrahedron Lett. 1992, 33, 6919. (c) Wright,
S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem. 1994, 59,
6095. (d) Guiles, J. W.; Johnson, S. G.; Murray, W. V. J. Org.
Chem. 1996, 61, 5169. (e) Zou, G.; Reddy, K.; Falck, J. R.
Tetrahedron Lett. 2001, 42, 7213. (f) Botella, L.; Najera, C.
J. Organomet. Chem. 2002, 663, 46. (g) Kataoka, N.; Shelby,
Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553.
(h) Molander, G. A.; Yun, C.-S. Tetrahedron 2002, 58, 1465.
3.3.35. 4-(Cyclohexyl)methylbenzonitrile 35. From 4-bro-
mobenzonitrile (1.82 g, 10 mmol) and (cyclohexyl)methyl-
boronic acid (2.84 g, 20 mmol), product 35 was obtained
1
in 92% (1.83 g) yield. H NMR (300 MHz, CDCl3) d 7.54
(d, 2H, J¼8.1 Hz), 7.22 (d, 2H, J¼8.1 Hz), 2.53 (d, 2H,
J¼7.0 Hz), 1.75–0.75 (m, 11H).
3.3.36. 1-Phenyl-2-(4-acetylphenyl)ethane 36. From
4-bromoacetophenone (1.99 g, 10 mmol) and 2-phenyl-
ethylboronic acid (3.00 g, 20 mmol), product 36 was
obtained in 94% (2.11 g) yield. 1H NMR (300 MHz,
CDCl3) d 7.90 (d, 2H, J¼8.1 Hz), 7.35–7.15 (m, 7H),
2.99 (m, 4H), 2.61 (s, 3H).
¨
3. (a) Beller, M.; Fischer, H.; Herrmann, W. A.; Ofele, K.;
Brossmer, C. Angew. Chem., Int. Ed. Engl. 1995, 34, 1848.
(b) Albisson, D. A.; Bedford, R. B.; Lawrence, S. E.; Scully,
P. N. Chem. Commun. 1998, 2095. (c) Weissman, H.; Milstein,
D. Chem. Commun. 1999, 1901. (d) Wolfe, J.; Buchwald, S.
Angew. Chem., Int. Ed. Engl. 1999, 38, 2413. (e) Wolfe, J.;
Singer, R.; Yang, B.; Buchwald, S. J. Am. Chem. Soc. 1999,
121, 9550.
3.3.37. 4-(2,2-Dimethylpropyl)acetophenone 37. From
4-bromoacetophenone (1.99 g, 10 mmol) and 2,2-dimethyl-
propylboronic acid (2.32 g, 20 mmol), product 37 was
obtained in 79% (1.50 g) yield. 1H NMR (300 MHz, CDCl3)
d 7.85 (d, 2H, J¼8.1 Hz), 7.20 (d, 2H, J¼8.1 Hz), 2.57 (s,
3H), 2.54 (s, 2H), 0.90 (s, 9H).
4. For a review on the synthesis of polypodal diphenylphosphine
ligands, see: Laurenti, D.; Santelli, M. Org. Prep. Proc. Int.
1999, 31, 245.
3.3.38. 4-(2,2-Dimethylpropyl)benzaldehyde 38. From
4-bromobenzaldehyde (1.85 g, 10 mmol) and 2,2-dimethyl-
propylboronic acid (2.32 g, 20 mmol), product 38 was
obtained in 77% (1.36 g) yield. 1H NMR (300 MHz, CDCl3)
d 10.01 (s, 1H), 7.82 (d, 2H, J¼8.3 Hz), 7.32 (d, 2H, J¼
8.3 Hz), 2.61 (s, 2H), 0.97 (s, 9H).
`
5. Laurenti, D.; Feuerstein, M.; Pepe, G.; Doucet, H.; Santelli, M.
J. Org. Chem. 2001, 66, 1633.
6. Feuerstein, M.; Doucet, H.; Santelli, M. J. Org. Chem. 2001, 66,
5923.
7. Feuerstein, M.; Berthiol, F.; Doucet, H.; Santelli, M. Org.
Biomol. Chem. 2003, 2235.
8. (a) Feuerstein, M.; Laurenti, D.; Bougeant, C.; Doucet, H.;
Santelli, M. Chem. Commun. 2001, 325. (b) Feuerstein, M.;
Laurenti, D.; Doucet, H.; Santelli, M. Synthesis 2001, 2320.
(c) Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron Lett.
2001, 42, 5659. (d) Feuerstein, M.; Doucet, H.; Santelli, M.
Tetrahedron Lett. 2001, 42, 6667. (e) Feuerstein, M.; Doucet,
H.; Santelli, M. Synlett 2001, 1458. (f) Feuerstein, M.; Berthiol,
F.; Doucet, H.; Santelli, M. Synlett 2002, 1807. (g) Berthiol, F.;
Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2003, 1091.
(h) Chahen, L.; Doucet, H.; Santelli, M. Synlett 2003, 1668.
Registry no.: 1, 37920-25-5; 2, 1200-14-2; 3, 55363-57-0; 4,
20651-73-4; 5, 20651-75-6; 6, 8272-84-9; 7, 14011-00-8; 8,
58632-85-2; 9, 59059-42-6; 10, 57775-05-0; 11, 7137-55-5;
12, 54532-97-7; 13, 1634-09-9; 14, 1498-69-7; 16, 59321-
68-5; 17, 5058-19-5; 18, 10541-56-7; 19, 49763-66-8; 20,
28593-20-6; 21, 20056-59-1; 22, 207114-16-7; 23, 33841-
61-1; 24, 58069-37-7; 25, 40089-91-6; 26, 937-30-4; 27,
22927-13-5; 28, 2932-65-2; 29, 65189-85-7; 30, 7089736;
31, 38861-78-8; 32, 100585-54-4; 33, 68018-45-1; 34,