Pd-Catalyzed Cross-Coupling Reaction of Alkyl Tosylates and Bromides with Grignard Reagents in the Presence of 1,3-Butadiene

Article abstract of DOI:10.1246/cl.2003.890

A new method for cross-coupling reaction of alkyl tosylates and bromides with Grignard reagents has been developed by the use of Pd(acac)₂ or PdCl₂ as the catalyst. Addition of 1,3-butadiene is essential to afford good yields of coupling products. This reaction proceeds efficiently at room temperature using primary and secondary alkyl and aryl Grignard reagents.

Full text of DOI:10.1246/cl.2003.890

890
Chemistry Letters Vol.32, No.10 (2003)
Pd-Catalyzed Cross-Coupling Reaction of Alkyl Tosylates and Bromides
with Grignard Reagents in the Presence of 1,3-Butadiene
Jun Terao, Yoshitaka Naitoh, Hitoshi Kuniyasu, and Nobuaki Kambeꢀ
Department of Molecular Chemistry & Science and Technology Center for Atoms, Molecules and Ions Control,
Graduate School of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871
(Received July 1, 2003;CL-030587)
A new method for cross-coupling reaction of alkyl tosylates
Table 1. Pd-catalyzed cross-coupling of n-C7H15OTs with
PhMgBra
and bromides with Grignard reagents has been developed by the
use of Pd(acac)2 or PdCl2 as the catalyst. Addition of 1,3-buta-
diene is essential to afford good yields of coupling products.
This reaction proceeds efficiently at room temperature using
primary and secondary alkyl and aryl Grignard reagents.
GC yield/%
Ph-n-Hep Heptane Heptenes
b
Entry Catalyst
Additive
none
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
1
2
3
4
5
6
85
9
3
14
5
0
17
43
25
10
5
20
10
27
Palladium catalyzes cross-coupling reaction of aryl and al-
kenyl halides with a variety of organometallic reagents provid-
ing extremely useful and straightforward methods for C–C bond
formation in organic synthesis.1 These reactions proceed via ox-
idative addition of organic halides to Pd(0) followed by trans-
metallation and reductive elimination. Until quite recently, it
was considered that alkyl halides are difficult to adapt to this
cross-coupling reaction due to the slow oxidative addition of al-
kyl halides to Pd(0) and the facile ꢀ-elimination from the alkyl-
palladium intermediates.2 Fu et al. recently established Pd-cat-
alyzed cross-coupling reaction of alkyl halides with various
organometallic reagents, such as organoboranes,3 alkenyltins,4
and arylsilanes5 by the use of bulky trialkylphosphines as addi-
tives. We have developed independently a unique Ni-catalyzed
cross-coupling reaction between alkyl electrophiles (Alkyl–X;
X = F, Cl, Br, and OTs) and Grignard reagents (R–MgX0; R
= alkyl and aryl) in the presence of 1,3-butadienes (Eq 1)6 dem-
onstrating that this reaction proceeds by a new mechanism in-
volving bis-allylnickelate complexes7 as the key intermediates.
4
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
PdCl2
12
8
Ph
22
26
18
7
Ph
7
8
1,5-cyclooctadiene 16
14
14
3
p-F-C6H4
2
9
<1
60
5
Ph
Et
10
11
<1
<1
5
PdCl2(PPh3)2
14
PdCl2(dppe)
12
3
<1
0
<1
4
Ni(acac)2
NiCl2
70
68
2
13
14
15
4
<1
0
PtCl2
0
aConditions: n-C7H15OTs (2 mmol), PhMgBr (1.5 equiv, 0.9 M
in THF, 3.3 mL), 3 mol% catalyst, additive (0.5 equiv, 1 mmol,
cat. NiCl2
Alkyl−X
R−MgX′
Alkyl−R
(1)
+
b
0.3 M), 25 ꢁC, 3 h. A mixture of 1-heptene and 2-heptenes.
1,3-butadienes
R = alkyl, aryl
X = F, Cl, Br, OTs
10), whereas palladium complexes bearing phosphine ligands,
such as PdCl2(PPh3)2 and PdCl2(dppe) did not show catalytic
activity (Entries 11 and 12). Under the same conditions,
Ni(acac)2 and NiCl2 also catalyzed this reaction but slightly less
effectively than Pd(acac)2 (Entry 1 vs Entries 13 and 14). PtCl2
was ineffective (Entry 15).
We intended to apply this methodology to Pd chemistry
since Pd can promote more superior and convenient reactions
than the corresponding Ni-catalyzed system in many instances.8
We disclose herein Pd-catalyzed cross-coupling reaction of al-
kyl tosylates and bromides with Grignard reagents using 1,3-bu-
tadiene as an additive.
Results of Pd-catalyzed cross-coupling reaction using some
other reagents are shown in Table 2. Alkyl–alkyl cross-coupling
has been achieved efficiently using n-BuMgCl (Entry 1). Use of
alkyl bromides and secondary alkyl Grignard reagent also af-
forded corresponding coupling products in good yields (Entries
2 and 3). When NiCl2 was used under identical conditions as
Entries 1–3, excellent results were obtained in the case of pri-
mary alkyl Grignard reagents, whereas less activity was ob-
served for secondary alkyl Grignard reagent than in the case
of Pd. Cl and Br substituents on aromatic rings tolerate in these
reactions (Entries 4 and 5). When 6-bromo-1-phenyl-1-hexene
was employed, 1-phenyl-1-decene was obtained as the sole cou-
pling product in 77% yield (Entry 6). No formation of the cy-
For example, a reaction of n-heptyl tosylate (2 mmol) with
phenylmagnesium bromide (1.5 equiv.) in the presence of 1,3-
butadiene (0.5 equiv.) and Pd(acac)2 (0.03 equiv., 0.06 mmol)
at 25 ꢁC for 3 h gave n-heptylbenzene in 85% yield along with
3% yield of heptane (Table 1, Entry 1). In the absence of 1,3-
butadiene, the coupling product was obtained in only 9% yield
and heptane and heptenes were formed as major products in
14% and 17% yields, respectively (Entry 2). Isoprene and 1,3-
pentadiene are less effective under the same conditions (Entries
3 and 4). 2,3-Dimethyl-1,3-butadiene, 1,4-diphenyl-1,3-buta-
diene, 1,5-cyclooctadiene, 4-fluorostyrene, and phenylethylace-
tylene did not promote this coupling reaction (Entries 5–9).
PdCl2 also afforded coupling product in good yield (Entry
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.10 (2003)
Table 2. Pd-catalyzed cross-coupling of alkyl tosylates and bromides with Grignard reagents
891
Pd(acac)2
/mol %
1,3-Butadiene
/mol %
Entr
1
R−X
R'-MgX'
Product
n-C10H22
n-C11H24
Yield/%a
n-Bu-MgCl
1
1
30 (0.19 M)
93
n-Hex-OTs
n-Oct-Br
n-Hep-OTs
(>99)c
30 (0.19 M)
86
(>99)c
n-Pr-MgCl
s-Bu-MgCl
n-Bu-MgCl
2
1
3
3
1
71
(45)c
30 (0.20 M)
3
4
Br
Br
b
100 (0.62 M)
71
OTs
n-Bu
Cl
MgBr
n-Hep
Cl
50 (0.30 M)
30 (0.19 M)
96
n-Hep-OTs
5
6
77b
n-Bu-MgCl
Br
n-Bu
b
c
aGC yield unless otherwise stated. Isolated yield. NiCl2 was used instead of Pd(acac)2.
clized product in this reaction suggests that carbon radicals are
not involved as intermediates.9
chemoselectivities in favor of tosylates against bromides and
chlorides. For the reaction of aryl and sec-alkyl Grignard re-
agents, better yields were attained by the use of Pd than Ni cat-
alyst. A detailed study of the mechanism of this reaction is cur-
rently under investigation.
Under the same conditions, 1-chlorooctane was sluggish.
This result prompted us to examine the reaction of 6-chloro-
hexyl tosylate and site selective cross-coupling was achieved
to give 1 in 86% yield (Eq 2). This is in large contrast to the
reaction using NiCl2, where dialkylated product 2 was obtained
in 13% yield. When 6-bromo-hexyl tosylate was employed,
Pd catalyst also showed high chemoselectivity in favor of
cross-coupling at the tosylate site whereas Ni was non-selective
(Eq 3).
This research was supported financially in part by a grant
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan and by Frontier Research Center. We thank
the Instrumental Analysis Center, Faculty of Engineering, Osa-
ka University, for HRMS measurement and elemental analysis.
cat. (1 mol %)
1,3-butadiene (0.3 mmol)
References and Notes
OTs
EtMgBr
+
Cl
1
For the history and recent development of transition metal catalyzed
cross-coupling reactions, see: International Symposium on 30 years
of the Cross-coupling Reaction, K. Tamao, T. Hiyama, and E.
Niegishi, J. Organomet. Chem., 653, 1 (2002).
THF (1.7 mL), rt, 1 h
1 mmol
1.5 mmol
(2)
Et
Et
+
Cl
Et
2
1
2
For recent articles and a review of transition metal catalyzed cross-
Pd(acac)2
NiCl2
86%
87%
0%
13%
´
coupling reactions using alkyl halides, see: a) D. J. Cardenas, Angew.
Chem., Int. Ed., 38, 3018 (1999). b) D. J. Cardenas, Angew. Chem.,
´
Int. Ed., 42, 384 (2003). c) T.-Y. Luh, M.-K. Leung, and K.-T. Wong,
Chem. Rev., 100, 3187 (2000).
cat. (3 mol %)
1,3-butadiene (0.5 mmol)
OTs
PhMgBr
+
Br
3
a) M. R. Netherton, C. Dai, K. Neuschutz, and G. C. Fu, J. Am. Chem.
¨
THF (1.7 mL), rt, 3 h
1 mmol
1.5 mmol
Soc., 123, 10099 (2001). b) J. H. Kirchhoff, C. Dai, and G. C. Fu, An-
gew. Chem., Int. Ed., 41, 1945 (2002). c) M. R. Netherton and G. C.
Fu, Angew. Chem., Int. Ed., 41, 3910 (2002). d) J. H. Kirchhoff, M. R.
Netherton, I. D. Hills, and G. C. Fu, J. Am. Chem. Soc., 124, 13662
(2002).
K. Menzel and G. C. Fu, J. Am. Chem. Soc., 125, 3718 (2003).
J.-Y. Lee and G. C. Fu, J. Am. Chem. Soc., 125, 5616 (2003).
a) J. Terao, H. Watanabe, A. Ikumi, H. Kuniyasu, and N. Kambe, J.
Am. Chem. Soc., 124, 4222 (2002). b) J. Terao, A. Ikumi, H.
Kuniyasu, and N. Kambe, J. Am. Chem. Soc., 125, 5646 (2003).
The bis-allylnickelate complexes can be trapped with chlorosilanes to
give silylated dienes, see: J. Terao, A. Oda, A. Ikumi, A. Nakamura,
H. Kuniyasu, and N. Kambe, Angew. Chem., Int. Ed., 42, 3412 (2003).
‘‘Metal-catalyzed Cross-coupling Reactions,’’ ed. by F. Diederich and
P. J. Stang, Wiley-VCH, New York (1998).
(3)
Ph
Ph
+
Br
Ph
3
4
Pd(acac)2
NiCl2
69%
27%
8%
20%
4
5
6
As for the reaction mechanisms of this Pd-catalyzed cross-
coupling, we would like to propose a possible pathway where
bis-allylpalladium complexes10 play important roles as active
catalytic species as the case of our Ni-catalyzed reaction. How-
ever no experimental information is available at the moment
about the mechanism and alternative pathways might not be
ruled out.
In conclusion, we revealed Pd-catalyzed alkyl–alkyl and al-
kyl–aryl cross-coupling reaction of alkyl tosylates and bromides
with primary and secondary alkyl and aryl Grignard reagents by
the use of 1,3-butadiene as an additive. Pd catalyst shows higher
7
8
9
Formation of carbon radicals was suggested in Pd-catalyzed cross-
coupling reaction using alkyl iodides, see: T. Ishiyama, S. Abe, N.
Miyaura, and A. Suzuki, Chem. Lett., 1992, 691.
10 P. W. Jolly, Angew. Chem., Int. Ed., 24, 283 (1985).
Published on the web (Advance View) September 1, 2003;DOI 10.1246/cl.2003.890