Negishi coupling strategy of a repetitive two-step method for oligoarene synthesis

Article abstract of DOI:10.1016/j.tetlet.2006.06.048

A novel repetitive two-step method for oligoarene synthesis, based on Negishi cross-coupling of zinciophenoxides or zinciopyridinoxides with aryl triflates and subsequent triflation of the hydroxy group, was developed. Reaction conditions were optimized for the preparation of the arylzinc compounds and the palladium-catalyzed cross-coupling step.

Full text of DOI:10.1016/j.tetlet.2006.06.048

Tetrahedron Letters 47 (2006) 5927–5931
Negishi coupling strategy of a repetitive two-step method
for oligoarene synthesis
Haruka Shimizu and Kei Manabe*
RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan
Received 10 May 2006; revised 7 June 2006; accepted 8 June 2006
Available online 27 June 2006
Abstract—A novel repetitive two-step method for oligoarene synthesis, based on Negishi cross-coupling of zinciophenoxides or
zinciopyridinoxides with aryl triflates and subsequent triflation of the hydroxy group, was developed. Reaction conditions were
optimized for the preparation of the arylzinc compounds and the palladium-catalyzed cross-coupling step.
Ó 2006 Elsevier Ltd. All rights reserved.
We have recently reported on a synthetic method of
multifunctionalized oligoarenes,1,2 which can serve as
useful molecules in various research areas that involve
self-assembling molecules,3,4 biologically active com-
pounds,5 and enzyme mimics.6 The repetitive two-step
methodology features the Suzuki–Miyaura coupling7
of hydroxyphenylboronic acids or their derivatives as
the key carbon–carbon bond-forming step (Fig. 1a).
(a) Repetitive method based on Suzuki—Miyaura coupling
FGn+1
FGn
FGn FGn+1
OH
FGn FGn+1
OTf
X2B
OH
R
OTf
R
R
Suzuki—Miyaura
coupling
triflation
FG = functional group
repetition
FGn FGn+1 FGn+2 FGn+3 FGn+4
R
multifunctionalized oligoarene
(b) Repetitive method based on Negishi coupling
FGn+1
repetition
FGn FGn+1
OTf
FGn
FGn FGn+1
OH
XZn
OM
zinciophenoxide
R
R
OTf
R
Negishi
triflation
coupling
Figure 1. Repetitive two-step method for multifunctionalized oligoarene synthesis.
Keywords: Negishi coupling; Oligoarene; Palladium; Lithiation; Zinciophenoxide.
*
Corresponding author. Tel.: +81 48 467 9394; fax: +81 48 462 4662; e-mail: keimanabe@riken.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.048

5928
H. Shimizu, K. Manabe / Tetrahedron Letters 47 (2006) 5927–5931
subsequent transmetalation with zinc salts (3 and 4).
Correspondingly, an effective procedure for the Negishi
coupling step, as shown in Scheme 1, can be proposed.
Br
Br
Li
RLi
RLi
HO
LiO
LiO
1
2
3
ZnCl2
To determine the reaction conditions for the dilithiation
of bromophenols, deuteration experiments were carried
out, some of which are listed in Table 1. In the presence
of a functional group having an acidic hydrogen, the
lithium–halogen exchange is often problematic due to
the proton transfer from the starting molecule to the ini-
tially formed dilithiated species during the dropwise
addition of the alkyllithium.12 Although a combination
of a metal hydride (such as NaH) and an alkyllithium
has been widely used to circumvent this problem, we
first investigated the preparation of dilithiated species
using only the alkyllithium for experimental simplicity.
ArOTf
Ar
ZnX
Pd catalyst
HO
MO
5
4
X = Cl, Br, OR'
M = Li, Zn
Scheme 1. Reaction plan for Negishi coupling of zinciophenoxides.
Repetition of the cross-coupling step and subsequent tri-
flation of the hydroxy group were shown to afford the
multifunctionalized oligoarenes with high efficiency.
Although the Suzuki–Miyaura coupling methodology
can be applied to the synthesis of various oligoarenes,
there are limitations, such as the difficulty in preparing
some functionalized boronic acids—for example, 2-pyri-
dineboronic acids are known to hydrolyze rapidly.8
Thus, to widen our repetitive two-step methodology
for the synthesis of various oligoarenes, we investigated
the use of an alternative cross-coupling step. Herein, we
report the repetitive two-step method for oligoarene
synthesis that features, as the key cross-coupling step,
Negishi coupling9 of an arylzinc species that contains
an oxido group (Fig. 1b), specifically, phenylzincs (zinc-
iophenoxides) and pyridylzincs (zinciopyridinoxides).
The results of the dilithiation and subsequent deutera-
tion of various bromophenols and bromopyridinols
revealed that the substrates can be classified into three
groups. The first group can be exemplified by 3-bromo-
phenol (8). Previous reports13 on the dilithiation of 8
with t-BuLi describe conditions requiring fairly large
volumes of the solvent (THF) (Table 1, entry 1). Under
concentrated conditions, however, a significant degree
of protonation was observed (entry 2). In contrast, for-
tunately, after screening various reaction conditions, our
results show that, even under concentrated conditions,
the use of t-BuLi in ether can afford high yield with high
ratio between 6 and 7 (entry 4). This improvement by
changing the solvents can be attributed to slow Li–Br
exchange in ether compared with the diffusion rate of
the added t-BuLi. The use of t-BuLi in ether was also
favorable for other substrates of the first group, such
as 11–13 (Chart 1). The second group can be exemplified
by 4-bromophenol (9). In contrast to the first group, the
use of t-BuLi in ether resulted in low yields (entries 6
Although Negishi coupling of arylzinc compounds10 has
been widely used to construct Csp2 –Csp2 bonds, examples
of the coupling reaction involving zinciophenoxides
have been limited.11 The most convenient method in
preparing zinciophenoxides is presumably via dilithia-
tion of halophenols, such as bromophenols (1–3), and
Table 1. Deuteration experiments
X
Br
1) conditions
X
D
X
H
2) CD3OD
HO
HO
HO
+
3) aqueous work up
R
R
R
X = CH or N
6
7
Entry
Substrate
Conditions
Yield (%)a
89
>99
96
95
6:7a
1
2
3
4
t-BuLi, THF(15 mL/mmol), ꢀ78 °C, 5 minb
97:3
65:35
83:17
>99:1
t-BuLi, THF (2 mL/mmol), ꢀ78 °C, 5 minb
HO
Br
NaH, THF (2 mL/mmol), rt, 30 min then t-BuLi, ꢀ78 °C, 1 hc
t-BuLi, Et2O (2 mL/mmol), ꢀ78 °C, 5 minb
8
5
6
7
8
t-BuLi, THF (2 mL/mmol), ꢀ78 °C, 5 minb
t-BuLi, Et2O (2 mL/mmol), ꢀ78 °C, 5 minb
t-BuLi, Et2O (2 mL/mmol), ꢀ78 °C, 1 hb
94
46
59
97
80:20
92:8
86:14
87:13
Br
Br
HO
t-BuLi, Et2O (1 mL/mmol), ꢀ78 °C, 5 min then THF (1 mL/mmol), 30 minb
t-BuLi, Et2O (1 mL/mmol), ꢀ78 °C, 5 min then THF (1 mL/mmol), 1 hb
9
9
55
93
80:20
82:18
N
HO
10
NaH, THF (2 mL/mmol), rt, 30 min then t-BuLi, ꢀ78 °C, 1 hc
10
a Determined by 1H NMR.
b 3.4 equiv of t-BuLi was used.
c 1.05 equiv of NaH and 2.1 equiv of t-BuLi were used.

H. Shimizu, K. Manabe / Tetrahedron Letters 47 (2006) 5927–5931
5929
Br
F
Br
Br
PCy2
Oi-Pr i-Pr
PCy2
i-Pr MeO
PCy2
OMe
OH
HO
F
OH
i-PrO
11
12
MeO
HO
13
Br
Br
18
20
i-Pr
19
OH
15
OMe
14
PCy2
NMe2
PCy2
PCy2
Pt-Bu2
N
OH
Br
N
Br
OH
21
22
23
24
16
17
Chart 2.
Chart 1.
and 7) probably due to extremely low solubility of the
corresponding lithiated species in ether. However, satis-
factory results were obtained by the addition of THF
following the treatment with t-BuLi in ether (entry 8).
The sequential addition of the two solvents (ether and
THF) is critical for the substrates of the second group,
which includes 9, 14, and 15. Substrates that did not give
satisfactory results under either conditions, as men-
tioned above, constitute the third group, which includes
10, 16, and 17. For this group, the reaction requires a
combination of NaH and t-BuLi (entry 10).
model substrate) that was prepared by dilithiation of
8, followed by transmetalation with ZnCl2. Recently,
Buchwald et al. reported that biphenylphosphine 18
(Chart 2) can serve as an extremely effective ligand for
Pd-catalyzed Negishi coupling of arylzincs with aryl
chlorides and bromides.14 Using this catalytic system,
the desired product was obtained at 45 °C in a high yield
(Table 2, entry 1). As a note, an increase in the amount
of ZnCl2 required a longer reaction time (entry 2).
Since ligand 18 might not be the best ligand for our sys-
tem, we screened various phosphine ligands. Based on
the screening studies (entries 3–13), the activity of 1915
seemed to be higher than that of 18, according to TLC
analysis. Thus, we next compared the activity of 18 with
To optimize the conditions for the carbon–carbon bond-
forming step, the Negishi coupling reaction was investi-
gated using p-tolyl triflate and zinciophenoxide (as a
Table 2. Optimization of Negishi coupling step
8 (1.5 equiv)
t-BuLi (5.1 equiv), Et2O, —78 °C;
ZnCl2 (1.5 equiv), THF, —78 °C to rt;
concentrated
Pd cat.
ligand
OTf
OH
+
XZn
OM
THF
(1 equiv)
Entry
Pd cat. (mol %)
Ligand (mol %)
Temperature (°C)
Time
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd2(dba)3 (0.5)
Pd(OAc)2 (1)
18 (2)
18 (2)
19 (2)
20 (2)
21 (2)
22 (2)
23 (2)
24 (2)
DPPF (1)
PCy2Ph (2)
PCy3 (2)
P(o-tol)3 (2)
PPh3 (2)
18 (2)
19 (2)
19 (2)
19 (1.2)
19 (0.6)
19 (0.12)
45
45
45
45
45
45
45
45
45
45
45
45
45
rt
2 h
17 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
10 min
10 min
20 min
20 min
2 h
92
92
96
89
92
92
90
70
87
10
0
0
9
5
95
95
95
91
24
rt
rt
rt
rt
Pd(OAc)2 (1)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.1)
rt
24 h

5930
H. Shimizu, K. Manabe / Tetrahedron Letters 47 (2006) 5927–5931
Table 3. Negishi coupling of various substrates
X
Br
(1.5 equiv) X = CH or N
OH
R
lithiation conditions;
ZnCl2 (1.5 equiv), THF, —78 °C to rt;
concentrated
Pd(OAc)2 (x mol%)
X
X
ligand (1.2x mol%)
Ar
OH
XZn
OM
ArOTf
+
THF
R
R
(1 equiv)
Entry
ArOTf
BrAr0
Lithiation conditionsa
Pd(OAc)2 (mol %)
Ligand
Temperature (°C)b
Time (h)b
Yield (%)
1
2
3
4
5
6
7
8
9
9
B
A
A
A
B
B
C
C
C
1
1
1
1
2
1
2
2
2
19
19
19
19
19
19
23
23
23
rt
1
2
2
1
1
2
1
2
1
92
80
80
84
83
70
78
78
75
11
12
13
14
15
10
16
17
45
45
rt
45
rt
60
60
60
OTf
OTf
10
8
A
2
19
45
20
94
a (A) t-BuLi (5.1 equiv), Et2O, ꢀ78 °C, 30 min. (B) t-BuLi (5.1 equiv), Et2O, ꢀ78 °C, 5 min, then THF, 30 min. (C) NaH (1.58 equiv), THF, rt,
30 min, then t-BuLi (3.15 equiv), ꢀ78 °C, 1 h.
b Temperature and reaction time for the Pd-catalyzed cross-coupling step.
Pd(OAc)2
(1 mol%)
(entries 7–9). Interestingly, a bulky triflate (2,6-dimeth-
ylphenyl triflate) also gave the coupling product in a
high yield (entry 10).
a
19 (1.2 mol%)
+
+
XZn
XZn
OM
OM
OTf
OTf
THF
rt, 6 h
Subsequently, our Negishi coupling strategy was applied
towards the synthesis of oligoarenes. As shown in
Scheme 2, trimers were readily synthesized from the
corresponding triflates and the zinciophenoxide (derived
from 8). In spite of the bulky ortho-aryl group of the tri-
flates, high yields of the products were obtained. Again,
the use of 23 as the ligand was favorable for the pyridyl-
containing substrate.
HO
HO
91%
N
Pd(OAc)2
(1 mol%)
N
a
23 (1.2 mol%)
THF
60 °C, 1 h
76%
As shown in Scheme 3, our Negishi coupling strategy
was also used for the facile synthesis of a pentamer. In
each triflation step, purification of the triflated product
was unnecessary—the crude mixture obtained after
work up was directly used for the next Negishi coupling
step to give the coupling product in a high yield.
Scheme 2. aPrepared by the same procedure as shown in Table 2.
that of 19 at room temperature and found that 19 was
indeed much more active than 18 (entry 14 vs 15). It is
noteworthy that, even at room temperature, the reaction
proceeded rapidly to give the product in excellent yields.
The use of Pd(OAc)2 instead of Pd2(dba)3 was also
found to be effective (entry 16), and the amount of the
ligand can be reduced to 1.2 mol % (entry 17). As
expected, lower loading of the catalyst led to significant
retardation of the coupling reaction (entries 18 and
19).
In summary, a repetitive two-step method for oligoarene
synthesis based on Negishi coupling strategy was devel-
oped. For the preparation of zinciophenoxides and zin-
ciopyridinoxides, the selection of appropriate conditions
for the lithiation of bromophenols and bromopyridinols
is crucial. In the Pd-catalyzed cross-coupling step, 19
was found to be an effective ligand for most substrates,
whereas 23 was favorable for pyridyl-containing
substrates. The availability of this Negishi coupling
strategy, in addition to the Suzuki–Miyaura coupling
strategy reported previously,1,2 provides access to the
synthesis of various multifunctionalized oligoarenes.
Further studies to develop functional molecules based
on these strategies are currently underway.
As shown in Table 3, the reaction conditions were suc-
cessfully applied to various zinciophenoxides and zincio-
pyridinoxides. Although higher temperatures were
required in some cases, the products were obtained in
good yields. Interestingly, 2316 was found to be the most
effective ligand for the less reactive zinciopyridinoxides

H. Shimizu, K. Manabe / Tetrahedron Letters 47 (2006) 5927–5931
5931
a
XZn
Pd(OAc)2
OM
Tf2O
(1 mol%)
pyridine
19 (1.2 mol%)
OH
OH
CH2Cl2
0 °C
THF
rt, 1 h
20 min
89% (2 steps)
a
XZn
OM
Pd(OAc)2
Tf2O
(1 mol%)
pyridine
19 (1.2 mol%)
OH
CH2Cl2
0 °C
THF
rt, 3 h
20 min
94% (2 steps)
a
XZn
OM
Pd(OAc)2
Tf2O
(1 mol%)
pyridine
19 (1.2 mol%)
OH
CH2Cl2
0 °C
THF
rt, 2 h
20 min
83% (2 steps)
Scheme 3. aPrepared by the same procedure as shown in Table 2.
method based on Negishi coupling of silyloxyphenylzincs
was developed to prepare terphenyl derivatives.
6. Cram, D. J.; Lam, P. Y.-S.; Ho, S. P. J. Am. Chem. Soc.
1986, 108, 839.
7. Suzuki, A.; Brown, H. C. Organic Synthesis via Boranes.
In Suzuki Coupling; Aldrich Chemical Company: Milwau-
kee, 2003; Vol. 3.
Acknowledgments
We thank MEXT (Grant-in-Aid for Scientific Research)
for financial support.
Supplementary data
8. Tyrrell, E.; Brookes, P. Synthesis 2004, 469.
9. Negishi, E.-i. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-i., Ed.; John Wiley &
Sons Ltd: New York, 2002, Chapter III.2.
10. A review on organozinc compounds for organic synthesis:
Organozinc Reagents: A Practical Approach; Knochel, P.,
Jones, P., Eds.; Oxford University Press: Oxford, 1999.
11. Merlic, C. A.; Roberts, W. M. Tetrahedron Lett. 1993, 34,
7379.
Experimental procedures and spectral data of the prod-
ucts. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2006.06.048.
References and notes
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