2-Pyridyl and 3-pyridylzinc bromides: direct preparation and coupling reaction

Article abstract of DOI:10.1016/j.tet.2010.02.061

A facile synthetic approach to the direct preparation of 2-pyridyl and 3-pyridylzinc bromides has been demonstrated using Rieke zinc with 2-bromopyridine and 3-bromopyridine, respectively. A variety of different electrophiles have been coupled with the resulting organozinc reagents to give the corresponding cross-coupling products in moderate to good yields.

Full text of DOI:10.1016/j.tet.2010.02.061

Tetrahedron 66 (2010) 3135–3146
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
2-Pyridyl and 3-pyridylzinc bromides: direct preparation and coupling reaction
*
Seung-Hoi Kim, Reuben D. Rieke
Rieke Metals, Inc., 1001 Kingbird Rd. Lincoln NE 68521, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 January 2010
Received in revised form 15 February 2010
Accepted 16 February 2010
Available online 21 February 2010
A facile synthetic approach to the direct preparation of 2-pyridyl and 3-pyridylzinc bromides has been
demonstrated using Rieke zinc with 2-bromopyridine and 3-bromopyridine, respectively. A variety of
different electrophiles have been coupled with the resulting organozinc reagents to give the corre-
sponding cross-coupling products in moderate to good yields.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
a limited number of studies have been reported on the preparation
of 3-pyridylmetallic halides. 3-Pyridylmagnesium,15 3-pyr-
Heterocyclic compounds, which contain a pyridine ring are
frequently found in natural products. Accordingly, they are of
special interest in pharmaceutical, agrochemical, and medicinal
chemistry.1 Also, a number of pyridine derivatives have been used
in material chemistry.2 Bipyridine groups are found to be a key
element in antibiotics such as caerulomycins and collismycins.
Another example is pyridylpyrimidines, which are used as fungi-
cides as well as tyrosine kinase inhibitors.3 In addition, pyridine-
containing oligomers are frequently found in liquid crystals.4
As described above, the pyridine moiety has played a very
significant role in a wide range of organic compounds. Consequently,
new practical synthetic approaches for introducing a pyridine ring
into complex organic molecule are of high value. To this end, prepa-
ration of pyridyl derivatives are mostly performed by transition
metal-catalyzed cross-coupling reactions of pyridylmetallic reagents.
However, the preparation of electron-deficient pyridinyl organome-
tallic reagents has been a challenging subject mainly because of some
difficulties such as instability and formation of by-products.
idylzinc,16 3–pyridylindium17 halides, and Suzuki reagents18 are the
most widely used reagents for the preparation of pyridine-
containing compounds. Lithiation of 3-halopyridine followed by
transmetallation with appropriate metals (Mg, Zn, In) afforded the
corresponding 3-pyridylmetallic halides. However, this route has
limitations such as cryogenic conditions, several side reactions and
limited functional group tolerance.19 Very few studies have been
reported on the direct synthesis of 3-pyridylmetallic halide
reagents. Most of these reports included the treatment of 3-iodo or
3-bromopyridine with highly active metals.20 Also, the subsequent
coupling reactions were carried out with limited electrophiles.
Interestingly, in our continuing study on the preparation and
application of organozinc reagents, we found that 2-pyridylzinc
bromide and 3-pyridylzinc bromide were easily prepared by
treatment of 2-bromopyridine and 3-bromopyridine with active
zinc under mild conditions, respectively. Significantly, the resulting
organozinc reagents were found to react with a variety of different
electrophiles with/without transition metal catalysts affording the
coupling products in good yields.
Most of the 2-pyridyl derivatives have been prepared using the
Suzuki,5 Stille,6 Grignard,7 and Negishi8 coupling reactions in the
presence of a transition metal catalyst. Among these, the Suzuki
coupling reaction is the most intensively studied and a very
extensive work has been developed.9 Recently, several outstanding
studies on the direct arylation of pyridine have been reported to
2. Results and discussion
In general, the preparation of 2-pyridyl organometallics is mostly
performed by lithiation of 2-halopyridine at cryogenic conditions
followed by transmetallation with an appropriate metal halide. As
mentioned above, this procedure causes some limitations on the use
of the 2-pyridyl organometallics. In our study, readily available
2-bromopyridine was treated at rt with active zinc prepared by the
Rieke Method.21 The oxidative addition of the active zinc to carbon–
bromine bond was completed in an hour at refluxing temperature to
give rise to the corresponding 2-pyridylzinc bromide (P1).
avoid these inevitable difficulties. For examples, Rh(I)10 and Au(I)11
-
catalyzed arylation of pyridines, Pd-catalyzed arylation of pyridine
N-oxide with unactivated arenes12 and haloarenes13 have been
developed. Also, the direct arylation of pyridine N-oxide by
Grignard reagents was reported.14
Even though there are many examples of the preparation of
2-pyridylmetallic halides from the reaction of halopyridines,
In order to investigate the reactivity of the 2-pyridylzinc bromide,
it was treated with benzoyl chlorides. As summarized in Table 1, the
coupling ketone products were obtained in moderate yields. It should
* Corresponding author.
E-mail address: sales@riekemetals.com (R.D. Rieke).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.061

3136
S.-H. Kim, R.D. Rieke / Tetrahedron 66 (2010) 3135–3146
Table 1
carbonyl chlorides were also coupled with 2-pyridylzinc bromide
resulting in the formation of the ketones (2c and 2d, Table 2) in 42%
and 63% yields.
With these results in hand, we also explored the Pd-catalyzed
C–C bond forming reaction of P1. Even though 2-pyridylaryl de-
rivatives were successfully prepared via the aforementioned direct
arylation methods, relatively harsh conditions (excess amount of
reactant, high temperature, protection/deprotection step and ad-
dition of additives) were required.
Prior to the Pd-catalyzed coupling reaction with a variety of aryl
halides, a preliminary test was performed using Pd(0)-catalyst to
find out any effect of substitutents on the C–C bond forming re-
actions. Several different types of 2-pyridylzinc bromides (P1–P6,
Table 3) were coupled with 3-iodothiophene in the presence of
1 mol % of Pd(PPh3)4 in THF at rt and the results are summarized in
Table 1. In general, good yields (entries 1, 3, and 4, Table 3) were
obtained from using 2-pyridylzinc bromide (P1), 4-methyl-2-pyr-
idylzinc bromide (P3), and 5-methyl-2-pyridylzinc bromide (P4).
Reactions with 3-methyl-2-pyridylzinc bromide (P2), 6-methyl-2-
pyridylzinc bromide (P5), and 6-methoxy-2-pyridylzinc bromide
(P6) resulted in moderate yields (entries 2, 5, and 6, Table 3).
Coupling reaction of 2-pyridylzinc bromide (P1) with benzoyl chloridesa
O
ZnBr
+
COCl
FG
rt
FG
N
THF
N
1a - 1j
P1 (1.0eq)
(0.8eq)
Entry
FG
Product
Yieldb(%)
1
2
3
4
5
6
7
8
9
2-F
2-F (1a)
65
52
45
47
36
54
50
64
40
47
3-F
3-F (1b)
2-Br (1c)
4-Br (1d)
4-I (1e)
2-Br
4-Br
4-I
3-CN
4-CN
4-Me
3-CN (1f)
4-CN (1g)
4-Me (1h)
3,4-(OMe)2
4-NO2
3,4-(OMe)2 (1i)
4-NO2 (1j)
10
a
No catalyst was used.
Isolated yield(based on electrophile).
b
be emphasized that the coupling reaction with acid chlorides de-
scribed in Table 1 was carried out in the absence of any transition
metal catalyst under mild conditions. Generally, a copper catalyst is
widely used for the coupling reactions of organozinc reagents.22
Halobenzoyl chlorides were easily coupled with 2-pyridylzinc bro-
mide (P1) at rt to give the corresponding ketones (1a, 1b, 1c, 1d, and
1e, Table 1) in moderate yields. Both benzoyl chlorides containing an
electron-withdrawing group (CN and NO2) and an electron-donating
group (Me and MeO) also successfully afforded the corresponding
ketones (1f, 1g, 1h, and 1i, Table 1). Even with nitrobenzoyl chloride,
ketone (1j, Table 1) was obtained in moderate yield. According to GC–
MS analysis of the reaction mixture, a major by-product was the
couplingproductobtainedfromthereactionofacidchloridewithTHF.
More results obtained from the catalyst-free coupling reactions
are shown in Table 2. Treatment of P1 with chloronicotinoyl chlo-
rides (entries 1 and 2, Table 2) at rt for 3 h provided the corre-
sponding ketones (2a, and 2b) in 62% and 53%, respectively. Alkyl
Table 3
Study of substitutent effect
X
I
X
1% Pd[P(Ph)3]4
THF/rt/24h
+
N
S
N
ZnBr
X: H, CH3
1.0eq
S
0.8eq
Entry
X
Product, X
Yielda(%)
1
2
3
4
5
6
H(P1)
H (3a)
85
58
77
79
57
54
3-CH3(P2)
4-CH3(P3)
5-CH3(P4)
6-CH3(P5)
6-OCH3(P6)
3-CH3 (3b)
4-CH3 (3c)
5-CH3 (3d)
6-CH3 (3e)
6-OCH3 (3f)
a
Isolated yield (based on 3-iodothiophene).
Table 2
Coupling reaction of P1 with acid chloridesa
An additional study was carried out to investigate the steric
effect on cross-coupling reaction using 2-pyridylzinc bromides (P2
and P4). As shown in Table 4, the steric hindrance (76% vs 89%, 51%
vs 84% isolated yield) was clearly observed from the coupling re-
actions with 5-bromofuran-2-carboxylic acid ethyl ester and 5-
bromothiophen-2-carboxylic acid ethyl ester (entries 1 vs 2 and 3
vs 4, Table 4), respectively. The results clearly demonstrate that the
steric bulk around the reaction site reduces the coupling ability of
the corresponding organozinc reagents.
O
ZnBr
rt
Ar
Acid
+
Chloride
N
N
THF
(0.8eq)
2a- 2d
P1 (1.0eq)
Entry
1
Acid chloride
Product
Cl
Yieldb(%)
62
O
COCl
Table 4
N
2a
Steric effect on cross-coupling reaction
N
Cl
N
X
1 mol%
+
O
Br
CO2Et
Product
Y
(0.8eq)
COCl
N
(1.0 eq)
ZnBr
Pd[P(Ph)3]4
THF/rt/24h
2
3
53
2b
4a - 4d
Y : O, S
Cl
N
N
X : 3-Me(P2)
5-Me(P4)
N
Cl
O
Entry
RZnBr
Y
Product
Yield(%)a
COCl
42
63
2c
X
N
1
2
P2
P4
X; 3-Me(4a) 76
X; 5-Me(4b) 89
O
O
S
CO2Et
CO2Et
N
O
COCl
3
4
P2
P4
X; 3-Me(4c) 51
X; 5-Me(4d) 84
4
X
2d
S
N
N
a
No catalyst used.
Isolated yield(based on electrophile).
b
a
Isolated (based on electrophile).

S.-H. Kim, R.D. Rieke / Tetrahedron 66 (2010) 3135–3146
3137
Table 6
With the preliminary results, we expanded this methodology to
Coupling reactions of P2–P6 with heteroaryl halides
the coupling reactions with a variety of haloaromatic compounds.
The results are described in Table 5. Interestingly, the mild condi-
tions worked well to complete the coupling reactions of 2-pyr-
idylzinc bromide (P1). As shown in Table 5, several different types
of functionalized aryl halides and heteroaryl halides were coupled
with P1 in the presence of 1 mol % of Pd[P(Ph)3]4 at rt in THF.
Functionalized iodobenzenes were first treated with 2-pyridylzinc
bromide and the coupling products (5a–5d) were obtained in good
to excellent yields (entries 1–4, Table 5). Mono-substituted thio-
phene was also easily coupled with 2-pyridylzinc bromide to give
rise to 2-(20-pyridyl)thiophene (5e) in 68%. Di- and tri-substituted
thiophenes (entries 6 and 7, Table 5) were also good coupling
partners to give interesting thiophene derivatives (5f and 5g) in
high yields. The coupling reaction with a furane derivative resulted
in the formation of 5h in an excellent yield (entry 8, Table 5).
Entry RZnBr Electrophilea Conditionsb
Product
Yieldc
(%)
CH3
S
C6H13
6a
Br
1
2
3
P2
P3
P3
A
B
B
41
N
I
Br
S
C6H13
CH3
N
6b
60
40
S
Br
S
N
N
N
CH3
6c
Br
N
N
Table 5
Pd-catalyzed coupling of P1 with arylhalide
a
ZnBr
H3C
Ar(HetAr)
Ar-X
or
Pd[P(PPh)3]4
THF/rt
+
4
5
6
P4
P4
P6
A
A
A
64
51
47
6d
N
S
S
Br
Cl
N
HetAr-I
Cl
Br
S
N
(1.0 eq)
P1
(0.8eq)
5a - 5h
H3C
Entry
Electrophile
Time
24 h
24 h
Product
Yieldb
(%)
6e
Br
Br
S
N
Cl
5a
1
2
81
88
I
Cl
S
N
6f
I
N
H3CO
N
S
H3C
CH3
CN
5b
N
I
CN
7d
P4
P5
C
C
68
23
N
S
6g
Br
Br
S
OMe
5c
3
4
24 h
68
90
I
OMe
N
CH3
N
CH3
C6H13
Br
OMe
OMe
N
6h
8d
S
Br
4 h
I
5d
S
N
C6H13
OMe
OMe
a
0.8 equiv of electrophile used otherwise mentioned.
A: Pd[P(Ph)3]4/rt/24 h B: Pd[P(Ph)3]4/rt/72 h C: Pd[P(Ph)3]2Cl2/reflux/24 h.
Isolated yield (based on electrophile).
b
c
5e
5
6
24 h
24 h
68
89
S
Br
S
d
N
2.2 equiv of organozinc used.
C6H13
C6H13
Moderate yields (60% and 40%) were obtained from these reactions.
Significantly, another selective C–C bond forming reaction was
achieved from the coupling reaction with symmetrically di-
substituted thiophene, 2,5-dibromothiophene (entry 5, Table 6),
affording 6e, which could be used for further application. Even
though slightly different reaction conditions (Pd-II catalyst and
refluxing temperature) were applied to carry out the coupling re-
actions with dibromothiophenes, symmetrically disubstituted
thiophene derivatives (6g and 6h) were easily prepared by its
twofold reaction (entries 7 and 8, Table 6). These types of linear
oligomers are important materials for optoelectronic device
applications.23
Br
S
I
Br
S
5f
N
S
Br
7
8
24 h
3 h
80
91
S
N
OMe
OMe
5g
CO2Et
5h
O
Br
CO2Et
O
N
aPerformed with 1 mol %
b
Isolated yield(based on electrophile).
As described in many previous reports, bipyridine units are very
important futures for many natural products as well as many
molecules used in material chemistry.24 Significantly, this struc-
tural future can be readily prepared utilizing 2-pyridylzinc bro-
mides. As described in Table 7, not only symmetrical 2,20-bipyridine
(7a) but several different types of unsymmetrical 2,20-bipyridines
(7b–7h) were prepared in moderate yields. Again, the coupling
reaction was completed in the presence of 1 mol % Pd[P(Ph)3]4 in
THF at rt and, in general, 3-methyl-2-pyridylzinc bromide (P2) and
6-methoxy-2-pyridylzinc bromide (P6) produced 2,20-bipyridines,
More interesting materials were prepared by the coupling re-
action of various 2-pyridylzinc bromides with halo heterocyclic
derivatives and the results are summarized in Table 6. A selective
C–C bond forming reaction occurred in the reactions with 2-bromo-
3-hexyl-5-iodothiophene and 2-bromo-5-chlorothiophene giving
6a and 6d in 41% and 64% isolated yield, respectively (entries 1 and
4, Table 6). A slightly longer reaction time was required to complete
the coupling reaction with 2-bromothiazole and 2-bromoquinoline
with 4-methyl-2-pyridylzinc bromide (P3) (entries 2 and 3, Table 6).

3138
S.-H. Kim, R.D. Rieke / Tetrahedron 66 (2010) 3135–3146
Table 7
Br
CO2Me
A
Preparation of 2,20-bipyridinesa
1% Pd[P(Ph)3]4
THF/reflux/24h
+
ZnBr
MeO
N
ZnBr
THF
N
(0.8eq)
Z
+
N
(1.0eq)
rt/24h
Z
P6
X
N
N
Y
N
X
H
N
(1.0eq)
(0.8eq)
7a - 7h
CO2Me
MeO
N
Entry
1
X
Y
I
Z
Product
Yieldb (%)
60
N
N
s1a
64%
O
H(P1)
H(P1)
H(P1)
H
Cytisine
N
N
7a
7b
ZnBr
1% Pd[P(Ph)3]4
B
2
3
Br
I
6-Me
5-Br
65
72
+
N
N
N
THF/rt/24h
Br
N
CH3
Me
Br
(0.8eq)
(1.0eq)
P1
OCH3
N
N
7c
N
N
N
R
N
4
H(P1)
Br
I
6-OMe
5-Br
53
30
75
63
CH3
N
N
65%
s1b
7d
OMe
Br
Caerulomycines
CH3
Scheme 1. Preparation of intermediates.
5
3-Me(P2)
4-Me(P3)
5-Me(P4)
the cross-coupling reactions of 2-pyridylzinc bromides with hal-
oaromatic compounds containing relatively acidic protons. To this
end, haloaromatic amines, phenols, and alcohols are reasonable
candidates as coupling reactants. By utilizing this strategy,
2-substituted aminophenyl and hydroxyphenyl pyridines have
been successfully prepared under mild conditions.
N
N
7e
H3C
6c
Br
I
5-Me
5-Br
CH3
N
N
7f
Since Pd(II)-catalysts along with an appropriate ligand have been
used in the coupling reactions of organozinc reagents with haloar-
omatic amines and alcohols,25 it seemed reasonable to try these
conditions in our study. The coupling reactions worked well with 2-
pyridylzinc bromide (1a) and the results are summarized in Table 8.
The reaction of P1 with 4-iodoaniline in the presence of 1 mol %
Pd(OAc)2 and 2 mol % SPhos gave rise to the cross-coupling product,
8a, in 90% isolated yield (entry 1, Table 8). Two more reactions,
methyl substituted 2-pyridylzinc bromide (P3) with 4-iodoaniline
and P1 with 4-bromoaniline resulted in relatively low yields (en-
tries 2 and 3, Table 8). However, a significantly improved yield was
obtained by the simple change of reaction temperature (entry 4,
Table 8). An elevated reaction temperature also worked well for the
reaction of P3 with 3-iodoaniline leading 8c in 85% isolated yield
(entry 5, Table 8). As described in the previous report,25a we also
found that the presence of an extra ligand (SPhos) was critical for
the completion of the coupling reaction.
H3C
Br
7
N
N
7g
8c
6-OMe(P6)
Br
6-Me
26
N
N
MeO
CH3
7h
a
Performed in the presence of 1 mol % of Pd[P(Ph)3]4.
Isolated yield (based on electrophile).
Carried out for 72 h at rt.
b
c
7e and 7h, in low yields (entries 5 and 8, Table 7). It should be
emphasized that the preparation of bipyridines using readily
available 2-pyridylzinc bromides (P1–P6) could be a very practical
approach because considerable effort has been directed toward the
preparation of unsymmetrical 2,20-bipyridines.
As aforementioned, some of natural products have bipyridine
unit in their structure. Therefore, we also tried to make an in-
termediate, which could be utilized for the preparation of the
natural product. Scheme 1 shows two examples. 2,3-Bipyridine
(s1a) was prepared by the coupling reaction of P6 with 5-bromo-
nicotinic acid methyl ester in the presence of Pd(PPh3)4 in THF at
refluxing temperature affording the coupling product in 64% iso-
lated yield (route A, Scheme 1). Under the similar conditions, 2,20-
bipyridine (s1b) was achieved in moderate yield (65%) by Pd(0)-
catalyzed cross-coupling reaction of P1 (route B, Scheme 1). As
depicted in Scheme 1, further manipulation of s1a and s1b would
result in the formation of the natural products.
Including our study, most of the electrophiles used in afore-
mentioned transition metal-catalyzed cross-coupling reactions of
2-pyridylmetallics contain relatively non-reactive functional
groups toward organometallics, such as ester, ketone, nitrile, hal-
ogen, and ether. For the preparation of a variety of 2-pyridyl de-
rivatives, highly functionalized electrophiles are necessary as the
coupling partner in the reactions. Therefore, we have performed
At this point, even though similar conditions with the previous
work25a were used, it should be emphasized that a more practical
procedure, especially for the large scale synthesis, has been dem-
onstrated in our study. For example, the organozinc solution was
added into the flask containing Pd(II)-catalyst, ligand (SPhos), and
electrophile at a steady-stream rate at rt. However, in the previous
report, a very slow addition of organozinc reagent into the reaction
flask was crucial in order to obtain high yields.26
As mentioned above, the extra ligand (SPhos) was necessary
when using the Pd(II)-catalysts for the coupling reactions in our
study and others. From an economic point of view as well as ease of
work-up, a ligand-free reaction condition would be highly benefi-
cial. Thus, with the preliminary results (entries 1–5, Table 8) in
hand, we have investigated the SPhos-free Pd-catalyzed coupling
reactions of 2-pyridylzinc bromides with haloanilines. The re-
actions were performed by employing a Pd(0)-catalyst and the
results are summarized in Table 8 (entries 6–10). Significantly, the
Pd(0)-catalyzed coupling reactions were not affected by the pres-
ence of acidic protons (NH2).27

S.-H. Kim, R.D. Rieke / Tetrahedron 66 (2010) 3135–3146
3139
Table 8
Table 9
Coupling reaction with haloaromatic amines
Coupling reaction with haloaromatic alcohols
conditions
conditions
THF
X
NH2
X
+
Y
X
+
Haloalcohol
0.5eq
Ar OH
9a - 9g
THF/reflux/24h
N
ZnBr
NH2
Y : I, Br
0.8eq
N
1.0 eq
ZnBr
X
N
N
X : H, CH3, MeO
1.0 eq
Entry X
Alcohol
Conditionsa
Product
Yieldb
(%)
Entry
1
X
Y
Conditionsa
Product
Yieldb (%)
90
I
NH2
NH2
H(P1)
4-I
A
1
H(P1)
A
95
N
N
N
OH
OH
8a
9a
OH
OH
H3C
I
2
4-CH3(P3) 4-I
A
50
8b
2
3
H(P1)
A
A
80
25
N
9b
3
4
H(P1)
H(P1)
4-Br
4-Br
A
B
8a
8a
50
89
OH
I
OH
H(P1)
N
H3C
NH2
9c
8c
5
6
7
4-CH3(P3) 3-I
B
C
C
85
89
64
CH3
N
I
4
5
6
4-CH3(P3)
H(P1)
A
54
H(P1)
H(P1)
4-I
3-I
8a
N
OH
OH
NH2
OH
9d
8d
Br
A
B
0c
86
9a
N
H2N
8
9
H(P1)
2-I
C
74
8e
Br
N
H(P1)
B
A
92
60
N
OH
OH
9e
CH3
3-CH3(P2) 4-I
D
8f 68
Br
NH2
7
8
6-CH3(P5)
N
H3C
N
OH
OH
9f
NH2
8g
10
6-OMe(P6) 4-Br
D
Tracec
N
Br
OH
N
OH
OCH3
MeO
H(P1)
A
65
OCH3
a
A: 1% Pd(OAc)2/2% SPhos/rt/24 h B: 1% Pd(OAc)2/2% SPhos/reflux/24 h C: 1%
Pd[P(Ph)3]4/rt/24 h D: 1% Pd[P(Ph)3]4/reflux/24 h.
9g
a
b
c
b
A: 1% Pd[P(Ph)3]4 B: 1% Pd(OAc)2/2% SPhos.
Isolated yield (based on alcohol).
No coupling observed by GC.
Isolated yield (based on aniline).
By GC–MS.
c
The reaction of P1 with 4-iodoaniline in the presence of 1 mol %
Pd[P(Ph)3]4 provided 2-(4-aminophenyl)pyridine (8a) with similar
results (89% isolated yield, entry 6, Table 8). 3-Iodoaniline and
2-iodoaniline were also coupled with P1 under the same conditions
(condition C, Table 8) affording the aminophenyl pyridines (8d and
8e) in 64% and 74% isolated yields, respectively (entries 7 and 8,
Table 8). Another successful coupling reaction (entry 9, Table 8) was
achieved from a sterically hindered 3-methyl-2-pyridylzinc bro-
mide (P2), resulting in 68% isolated yield with the formation of 8f.
Unfortunately, no satisfactory coupling reaction occurred with
4-bromoaniline using the Pd(0)-catalyst (entry 10, Table 8). With
the results obtained from the coupling reactions with haloaromatic
amines, it can be concluded that Pd(0)-catalyzed reaction of
2-pyridylzinc bromides works effectively with iodoaromatic amines
and also the relatively more reactive bromoaromatic amines.
Another interesting reaction of 2-pyridylzinc bromides would be
the coupling reaction with phenols or alcohols, which also have an
acidic proton. Encouraged by the results described above, the cou-
pling reactions with iodophenols were carried out in the presence of
Pd(0)-catalyst. As shown in Table 9, 4-iodophenol and 3-iodophenol
were coupled with P1 affording the corresponding hydroxyphenyl
pyridine products (9a and 9b) in excellent yields (entries 1 and 2,
Table 9). A slightly disappointing result (25%) was obtained from
2-iodophenol (entry 3, Table 9). The reason is not clear, but it is
presumably because the coupling was next to the hydroxy group. A
similar outcome has also been reported in another study.26 In the
caseofbromophenolicalcohols, nocoupling reactiontook placewith
the Pd(0)-catalyst. Instead, the Pd(II)-catalyst was more efficient for
the coupling reaction. 4-Bromophenol and 6-bromo-2-naphthol
were nicely coupled with P1 resulting in the coupling products (9a
and 9e) in 86% and 92% (entries 5 and 6, Table 9). Unlike the reactions
with bromophenols, it is of interest that the coupling products (9f
and 9g) of P5 and P1 were efficiently achieved from the Pd(0)-
catalyzed reactions with 4-bromobenzyl alcohol and 3-bromo-5-
methoxybenzyl alcohol (entries 7 and 8, Table 9), respectively.
Interestingly, unsymmetrical amino-bipyridines were produced
from the coupling reactions of 2-pyridylzinc bromides with halo-
genated aminopyridines under the conditions used above. As
shown in Scheme 2, 2-amino-5-iodopyridine reacted with P1 to
afford 2,3-bipyridine (s2a) in 59% isolated yield in the presence of
1 mol % of Pd[P(Ph)3]4 catalyst (route A, Scheme 2). However, in the
case of 2-amino-5-bromo-pyridine, the Pd(II)-catalyst was more
efficient for the coupling reaction and the reaction proceeded
smoothly to give 2,3-bipyridine (s2b) in 37% yield (route B, Scheme
2). It is of interest that the bipyridyl amines can be used as in-
termediates for the synthesis of highly functionalized molecules
after transformation of the amino group to a halogen.28

3140
S.-H. Kim, R.D. Rieke / Tetrahedron 66 (2010) 3135–3146
Table 10
A
B
C
Pd-catalyzed coupling Reactions of 3-pyridylzinc bromide (P7)
I
1% Pd[P(Ph)3]4
N
ZnBr
+
ZnBr
Pd[P(Ph)3]4
THF
THF/reflux/24h
59%
Ar
+
Electrophile
N
N
NH2
N
N
NH2
s2a
N
N
P1,1.0eq
0.8eq
CH3
Entry
1
Electrophilea
Conditionsb
rt/1 h
Product
Yieldc (%)
65
CH3
Br
1% Pd(OAc)2
N
+
2 % SPhos
THF/reflux/24h
CN
10a
a
I
CN
N
ZnBr
N
NH2
OH
NH2
OH
N
s2b
P3,1.0eq
37%
0.8eq
1% Pd[P(Ph)3]4
OCH3
10b
+
2
b
OCH3
rt/1 h
rt/1 h
rt/24 h
rt/24 h
rt/1 h
rt/1 h
rt/1 h
rt/48 h
81
63
63
32
71
62
71
86
I
N
N
N
ZnBr
Br
N
THF/reflux/24h
51%
N
s2c
P1,1.0eq
0.5eq
OCH3
OCH3
Scheme 2. Preparation of amino and hydroxyl bipyridines.
I
3
c
10c
N
N
OCH3
Br
OCH3
Br
Treatment of 2-pyridylzinc bromide (P1) with a halopyridine
bearing a hydroxyl group provided another functionalized bipyr-
idine. Interestingly, the relatively reactive bromopyridyl alcohol,
2-bromo-5-hydroxypyridine, was coupled with P1 using Pd(0)-
catalyst. As a result, the corresponding hydroxyl 2,20-bipyridine
(s2c) was obtained in 51% isolated yield (route C, Scheme 2). The
hydroxyl group on 2,20-bipyridine can also be converted to halogen
to make halobipyridines by using several different methods.29
As mentioned earlier, direct preparation of 3-pyridylzinc reagents
has been another challenging subject in organometallic chemistry. In
our continuing study of heterocyclic organozinc reagents,30 it has
been found that Rieke zinc in the presence of certain additives ex-
hibits a very high reactivity to 3-bromopyridine. The corresponding
3-pyridylzinc bromide was easily prepared by the direct insertion of
active zinc to 3-bromopyridine and the resulting 3-pyridylzinc bro-
mide was successfully applied to the cross-coupling reaction with
a variety of electrophiles under mild conditions.
The first attempt to synthesize 3-pyriylzinc bromide from the
direct reaction of active zinc and 3-bromopyridine in THF at rt and
refluxing temperature resulted in low conversion (70%) to the
organozinc reagent. Almost the same result was obtained from an
extended reaction time (reflux/24 h). However, a dramatic im-
provement in the oxidative addition of active zinc has been ach-
ieved by adding 10–20 mol % of lithium chloride to the reaction
mixture. Even though the role of lithium chloride has not been
totally explained, more than 99% conversion of 3-bromopyridine to
3-pyridylzinc bromide was obtained in 2 h at refluxing temperature
in THF. As was pointed out in 1989,21 the rate limiting step in the
oxidative addition is electron transfer. Accordingly, this process will
be accelerated by the presence of alkali salts, which are generated
in the reduction process of forming the active metals or additional
salts can be added to the reaction mixture.22b
F
10d
4
d
I
F
I
5
e
10e
N
H3CS
H3CS
I
10f
6
f
N
N
N
I
Br
Br
10g
7
g
N
N
N
I
8
h
10h
S
N
S
S
9
i
10i
Br
S
N
N
Br
10j
10
j
rt/48 h
rt/12 h
29
38
N
N
Br
Br
O
O
O
11
k
10k
Ph
O
Ph
N
a
0.8 equiv of electrophile used.
1 mol % of Pd[P(Ph)3]4 used.
Isolated yield(based on electrophile).
b
c
In order to confirm the formation of 3-pyridylzinc bromide, the
resulting organozinc reagent was first treated with iodine affording
90% 3-iodopyridine and 3% pyridine. Next, the resulting 3-pyr-
idylzinc bromide (P7) was added to a variety of different electro-
philes to give the corresponding coupling products in moderate to
good yields. The results are summarized in Table 10. Palladium
catalyzed cross-coupling reactions with aryl iodides (a–c, Table 10)
were completed in 1 h at rt to give 3-pyridylbenzene derivatives
(10a, 10b, and 10c) in good yields (entries 1–3, Table 10). A longer
reaction time was required with aryl iodides (d and e), bearing
a substitutent in the 2-position (entries 4 and 5, Table 10). This is
probably due to steric hindrance. With this result in hand, hetero-
aryl iodides (f–h) were also coupled with 3-pyridylzinc bromide
affording the heteroaryls (10f–10h) in good yields. Coupling re-
actions with heteroaryl bromides (i and j) needed also a longer
reaction time and afforded the coupling product (10i and 10j, Table
10) in 86% and 29% isolated yields, respectively. As shown in entries
4 and 7 in Table 10, the carbon–iodine bond was selectively reacted
in coupling reactions with the organozinc reagent (P7) for carbon–
carbon bond formation under the conditions used here. Even
though a low yield was obtained from 2,6-dibromopyridine (j), the
coupling product (10j) bearing a bromine atom can serve as
a valuable intermediate for the preparation of a variety of materials.
Interestingly, it was also possible to obtain an aromatic ketone (10k)
in moderate yield from the reaction of P7 with benzoic acid anhy-
dride in the presence of palladium (0) catalyst.
To expand the application of 3-pyridylzinc bromide, several
other copper-catalyzed coupling reactions were also investigated
and the results are summarized in Table 11. SN20-type reactions
have been tried with allyl halides affording the resulting products
(11a and 11b, Table 11) in moderate to good yields. In the presence
of TMSCl, silyl enol ether (11c, Table 2) was obtained from the
conjugate addition intermediate. Like other general organozinc

S.-H. Kim, R.D. Rieke / Tetrahedron 66 (2010) 3135–3146
3141
Table 11
Table 12
Copper-catalyzed coupling reaction of P7
Preparation of quinoline and isoquinoline derivatives via heteroarylzinc reagent
Entry Organozinc Electrophilea Conditionsb
Product
Yieldc (%)
ZnBr
CuI
+
Electrophile
Product
THF
N
CN
ZnBr
CN
Pd[P(Ph)3]4
rt/1 h
1
2
70
Entry
1
Electrophilea
Conditionsb
0 ꢀC/10 min
Product
Yieldc (%)
71
N
Q1
12a
I
N
Br
N
ZnBr
11a
Pd[P(Ph)3]4
rt/1 h
N
65
N
Q1
N
I
N
Cl
Cl
N
2
3
0 ꢀC/10 min
50
48
12b
Cl
11b
S
ZnBr
I
3
4
Pd[P(Ph)3]4 rt/1 h
Pd[P(Ph)3]4 rt/1 h
53
37
TMSCl/0 ꢀCwrt
N
Q1
O
N
S
N
OSiMe3
11c
12c
ZnBr
O
N
COCl
4
5
6
0 ꢀCwrt/12 h
0 ꢀCwrt/12 h
0 ꢀCwrt/12 h
0 ꢀCwrt/12 h
50
69
38
50
N
N
I
N
N
N
Q2
10k
12d
O
CH3
COCl
COCl
ZnBr
N
CH3
5
CuId 0 ꢀCwrt/1 h
35
Cl
11d
N
Q2
O
12e
a
b
c
0.8 equiv of electrophile used.
1 mol % Pd-catalyst used.
Isolated yield(based on electrophile).
10 mol % used.
11e
N
d
O
COCl
S
7
The first approach included the reaction of 3-pyridylzinc bro-
N
S
11f
mide (P7) with 4-iodoaniline in the presence of 1% of Pd(OAc)2
along with 2% of SPhos in THF (enty1, Table 13). The coupling re-
action was completed at rt in 30 min affording 4-pyridin-3-yl-
phenylamine (13a) in 80% isolated yield. Even though a little longer
reaction time was required, the coupling product (13a) was also
obtained in good yield from the reaction with 4-bromoaniline un-
der the same conditions (entry 2, Table 13). Interestingly, trace
amounts of the coupling product was detected by GC from the re-
action with 4-iodophenol using the same conditions (entry 3, Table
a
0.8eq of electrophile used.
10 mol % CuI used.
Isolated yield(based on electrophile).
b
c
reagents, 3-pyridylzinc bromide (P7) was successfully used for the
copper-catalyzed synthesis of ketone compounds. As shown in
Table 11, 10 mol % of CuI promoted the coupling reaction with P7 to
give the ketones (10k, 11d–11f, Table 11) in moderate yields under
the conditions described in Table 11.
This study was expanded to several analogues of 3-bromopyr-
idine. As described in Table 12, 3-bromoquinoline and 3-bromoi-
soquinoline were treated with active zinc along with 20 mol % of
lithium chloride. It was found that the oxidative addition of active
zinc was completed in 2 h at refluxing temperature to give the cor-
responding organozinc reagents (Q1 and Q2). The subsequent cou-
pling reactions of Q1 were performed with aryl iodide (entry 1, Table
12) and heteroaryl iodides (entries 2 and 3, Table 12) in the presence
of palladium catalyst affording the corresponding products (12a–
12c) in moderate to good isolated yields. Entries 4 and 5 in Table 12
showed the results of the coupling reactions of Q2 with heteroaryl
iodide and allyl chloride. From these reactions, more new heteroaryl
compounds (12d–12e, Table 12) were obtained in moderate yields.
Sincewe obtained successful results from the coupling reaction of
2-pyridylzinc bromides with aromatic haloamines and alcohols, we
also demonstrated the same strategy for the coupling reaction of the
3-pyridylzinc bromides. It was found that the readily available 3-
pyridylzinc bromide was easily coupled with haloaromatic com-
pounds bearing relatively acidic protons under mild conditions
affording the corresponding cross-coupling products in the moder-
ate to excellent yields. Of primary interest, we report the general
procedure for the transition metal-catalyzed cross-coupling re-
actions of 3-pyridylzinc bromides with haloanilines and halophenols
providing 3-(aminophenyl)pyridines and 3-(hydroxyphenyl) pyri-
dines. The results also include the preparation of quinoline and iso-
quinoline derivatives as well as other pyridine derivatives.
Table 13
Preliminary test for the coupling reaction of P7
conditions
ZnBr
+
Halide
Product
N
THF
Entry
1
Halidea
Conditions
Product
Yieldb
(%)
1% Pd(OAc)2 2%
SPhos rt/30 min
NH2
80
I
NH2
N
13a
1% Pd(OAc)2 2%
SPhos rt/3 days
2
3
13a
80
Br
I
NH2
OH
1% Pd(OAc)2 2%
SPhos rt/24 h
13a
Tracec
O
O
Br
1% Pd(OAc)2 2%
SPhos rt/24 h
4
5
44
O
O
O
O
13b
N
Br
Br
1% Pd(OAc)2 rt/3 days
Pd(PPh3)4 rt/24 h
13b
Tracec
6
13b
0c
O
O
a
0.8 equiv of amine, 0.5 equiv of alcohol used.
Isolated (based on halide).
Monitored by GC.
b
c

3142
S.-H. Kim, R.D. Rieke / Tetrahedron 66 (2010) 3135–3146
13). A protected bromophenol gave rise to the coupling product
(13b) in moderate yield under the same conditions (entry 4, Table
13). The critical role of an extra ligand (SPhos) for the completion
of the coupling reaction was also noticed. Trace amounts of product
formation was detected in the absence of SPhos (entry 5, Table 13).
It was also found that a Pd(0)-catalyst was not effective for the
coupling with a protected bromophenol (entry 6, Table 13).
Even though the conditions used in the preliminary tests
worked well, an extra ligand(SPhos)-free reaction condition would
be more interesting. Thus, once again, the SPhos-free Pd-catalyzed
coupling reactions of 3-pyridylzinc bromides with haloanilines
were carried out. This was accomplished by using 1 mol % of
Pd(PPh3)4 without any extra additives and the corresponding
coupling products were obtained in moderate to excellent yields.
The results are summarized in Table 14. As observed in the coupling
reaction of 2-pyridylzinc bromide (P1) with haloaromatic amine,
no significant effect of the presence of acidic protons was observed
from the study of P7.
isolated yield (entry 1, Table 14). 3-Iodoaniline and 2-iodoaniline
were also coupled with P7 under the same conditions (at rt for
1.0 h) affording the aminophenyl pyridines (14a and 14b) in 85%
and 61% isolated yield, respectively (entries 2 and 3, Table 14).
However, even at an elevated temperature, a low yield of 13a was
obtained from the coupling reaction using 4-bromoaniline (entry 4,
Table 14). With the results obtained from the simple 3-pyridylzinc
bromide, we also expanded this reaction conditions to the wide
range of functionalized 3-pyridylzinc reagents. All of these 3-pyr-
idylzinc bromides were easily prepared under the same conditions
used for the preparation of P7. For the sterically hindered 4-methyl-
3-pyridylzinc bromide (P8), a slightly severe condition (refluxing
for 6 h) was required to complete the coupling, resulting in the
formation of 14c in 48% isolated yield (entry 5, Table 14). However,
the reaction with 2-methyl-5-pyridylzinc bromide (P10) provided
the coupling product (14d) in a good yield (entry 6, Table 14). In-
terestingly, excellent results were achieved from the coupling re-
actions using chlorine substituted 3-pyridylzinc reagents. As shown
in Table 14, a 92% isolated yield of 14e and 14f was obtained from
both reactions of 2-chloro-3-pyridylzinc bromide (P11) and
2-chloro-5-pyridylzinc bromide (P12) after 3 h stirring at rt (entries
7 and 8, Table 14). Unfortunately, no satisfactory coupling reaction
occurred with 2-methoxy-5-pyridylzinc bromide (P13) using the
Pd(0)-catalyst (entry 9, Table 14). Similar results were also obtained
from the reaction with iodophenol (entry 10, Table 8). From the
The coupling reactions were easily accomplished by the addi-
tion of 3-pyridylzinc bromide into the mixture of haloaniline and
Pd(0)-catalyst in THF. The organozinc solution was added into the
reaction flask in one portion via a syringe at rt. The lack of a large
heat of reaction should be a useful feature for large scale synthesis.
The reaction of P7 with 4-iodoaniline in the presence of 1 mol %
Pd(PPh3)4 provided 4-pyridin-3-yl-phenylamine (13a) in 86%
Table 14
Preparation of aminophenylpyridines
X
1 % Pd(PPh3)4
ZnBr
+
Aniline
Product
THF
N
X : H, CH3, Cl, OMe
Entry
RZnX
Aniline
Conditions
rt/1 h
Product
Yielda
(%)
ZnBr
NH2
1
2
3
4
5
6
7
8
13a
86
85
61
15
48
85
92
92
0b
I
NH2
N
N
P7
NH2
I
P7
rt/1 h
14a
NH2
N
H2N
I
P7
rt/1 h
14b
NH2
N
P7
Reflux/24 h
Reflux/6 h
rt/1 h
13a
Br
NH2
CH3
CH3
14c
I
I
I
I
I
NH2
NH2
NH2
NH2
NH2
ZnBr
P8
NH2
N
N
N
H3
C
ZnBr
H3C
NH2
14d
N
N
P10
NH2
ZnBr
rt/3 h
14e
N
Cl P11
Cl
Cl
ZnBr
Cl
NH2
14f
rt/3 h
N
N
P12
H3CO
ZnBr
H3CO
NH2
9
Reflux/24 h
N
N
P13
a
Isolated yield (based on amine).
No reaction. Starting materials were recovered (confirmed by GC and GC–MS).
b

S.-H. Kim, R.D. Rieke / Tetrahedron 66 (2010) 3135–3146
3143
Table 16
results described above, it can be concluded that Pd(0)-catalyzed
Preparation of quinoline and isoquinoline derivatives
coupling reactions of 3-pyridylzinc bromides work effectively
with iodoanilines under mild conditions.
Entry
RZnX
Halide
Conditions
Product
Yielda
(%)
Another interesting reaction of 3-pyridylzinc bromide would be
the coupling reaction with phenols, which also have an even more
acidic proton.27 Encouraged by the results achieved from the re-
action with haloanilines, the coupling reactions with iodophenols
were carried out using Pd(0)-catalyst. As shown in Table 15,
2.0 equiv of organozinc reagent were reacted with halophenols at
refluxing temperature in the presence of 1 mol % of Pd(PPh3)4 in
THF. In the case of P7, even though the coupling reaction with
iodophenol worked fairly at rt, increasing the reaction temperature
worked more effectively to complete the coupling reaction.
Therefore, all of the coupling reactions with halophenols in this
study were conducted at refluxing temperature for 12 h. 4-Iodo-
phenol was coupled with P7 affording the corresponding 3-(4-
hydroxyphenyl) pyridine (15a) in excellent yields (entry 1, Table
15). A slightly disappointing result (49%) was obtained from 3-
iodophenol (entry 2, Table 15). Unlike the reaction with 4-bro-
moaniline, treatment of P7 with 4-bromophenol gave rise to the
product 15a in moderate yield (entry 3, Table 15). More coupling
reactions of methyl and chlorine substituted 3-pyridylzinc bro-
mides (P10, P11, and P12) were also performed with 4-iodophenol.
The reactions occurred successfully to result in good yields (81%,
entry 4, Table 15) to moderate yields (61% and 60%, entries 5 and 6,
Table 15, respectively). Again, no coupling product was obtained
from 2-methoxy-5-pyridylzinc bromide (P13).
I
ZnBr
NH2
N
1% Pd(PPh3)4
THF/rt/3.0 h
Q1
1
89
NH2
1.0 equiv
0.8 equiv
N
16a
I
ZnBr
OH
N
1% Pd(PPh3)4
THF/rt/12 h
Q1
2
3
64
90
0b
OH
1.0 equiv
0.5 equiv
N
16b
I
ZnBr
OH
N
1% Pd(PPh3)4
THF/rt/3 h
Q2
OH
0.5 equiv
16c
1.0 equiv
N
I
ZnBr
N
N
1% Pd(PPh3)4
THF/reflux/24 h
Q2
4
d
NH2
1.0 equiv
0.8 equiv
a
Isolated yield (based on halide).
b
No reaction. Starting materials were recovered (confirmed by GC and GC–MS).
easily by using the previously mentioned procedure. Subsequent
coupling reactions of 3-quinolinylzinc bromide with 4-iodoaniline
and4-iodophenolaffordedthecorrespondingproducts(16a and16b,
Table 16) in 89% and 64% isolated yield, respectively. The coupling
reaction of 4-isoquinolinylzinc bromide (Q2) with 4-iodophenol was
carried out at rt for 3 h to give the product (16c) in excellent yield
(entry 3, Table 16). Unfortunately, coupling of 5-pyrimidinylzinc
bromide showed no product at all (entry 4, Table 16).
Further application of this practical synthetic approach has been
performed by the coupling reaction with different types of alcohols.
2-Methoxy-5-bromobenzyl alcohol and 6-bromo-2-naphthol were
nicely coupled with P7 under the reaction conditions given in
Scheme 3 resulting in the coupling products (s3a and s3b) in 48%
and 81% yield, respectively (routes A and B, Scheme 3). In-
terestingly, unsymmetrical amino-bipyridines were produced from
the coupling reactions of P7 with 2-amino-6-bromopyridine (route
C, Scheme 3). It was accomplished by the reaction of P7 with 2-
amino-6-bromopyridine in the presence of 1 mol % of Pd(PPh3)4 in
THF at refluxing temperature for 12 h affording 2,3-bipyridine (s3c)
in 65% isolated yield. It is of interest that the resulting product (s3c)
can be utilized for further applications after transformation of the
amino group to a halogen.28
Table 15
Preparation of hydroxyphenylpyridines
X
Y
1 % Pd(PPh3)4
THF/reflux/12h
ZnBr
+
OH
Product
N
X : H, CH3, Cl, OMe
Entry
1
RZnX
Y
Product
Yielda (%)
OH
ZnBr
4-I
90
N
N
P7
15a
OH
2
3
4
P7
P7
3-I
49
40
81
N
15b
4-Br
4-I
15a
H3C
ZnBr
H3C
OH
N
N
15c
P10
ZnBr
OH
5
6
4-I
4-I
61
60
N
N
Cl
Cl
P11
15d
Cl
OH
Cl
ZnBr
P12
N
N
15e
OCH3
A
Br
OH
H3CO
ZnBr
P13
Isolated yield (based on alcohol).
OH
1 % Pd(PPh3)4
THF/reflux/12h
46%
0b
H3CO
OH
7
4-I
P7
N
+
N
s3a
OCH3
1.0eq
N
0.5eq
a
OH
b
B
Carried out at refluxing temperature for 24 h. No reaction. Starting materials
were recovered (confirmed by GC and GC–MS).
Br
1 % Pd(PPh3)4
THF/reflux/12h
81%
P7
+
1.0eq
OH
s3b
0.5eq
N
Since the coupling reactions of 3-pyridylzinc bromides provided
very positive results of preparing highly functionalized pyridine
derivatives, this study was applied to several analogues of 3-bro-
mopyridine. The results are described in Table 16. Quinolinylzinc
bromide (Q1) and isoquinolinylzinc bromide (Q2) were prepared
C
1 % Pd(PPh3)4
THF/reflux/12h
65%
P7
+
N
NH2
Br
N
0.8eq
NH2
1.0eq
N
s3c
Scheme 3.

3144
S.-H. Kim, R.D. Rieke / Tetrahedron 66 (2010) 3135–3146
3. Conclusions
4.5. Pd-catalyzed coupling reaction with 4-iodoanisol (10b)
We have demonstrated a practical synthetic route for the
preparation of 2-pyridyl and 3-pyridyl derivatives. It has been ac-
complished by utilizing a simple coupling reaction of readily
available 2-pyridylzinc bromides and 3-pyridylzinc bromides,
which were prepared via the direct insertion of active zinc to the
corresponding bromopyridines. The subsequent coupling reactions
with a variety of different electrophiles have been performed under
mild conditions affording the coupling products.
In a 50 mL round-bottomed flask, Pd[P(Ph)3]4 (0.10 g, 1 mol %)
was placed. Next, 20 mL of 0.5 M solution of 3-pyridylzinc bromide
(P7) in THF was added into the flask at rt. 4-Iodoanisol (1.80 g,
8 mmol) dissolved in 10 mL of THF was added via a syringe. The
resulting mixturewas stirred at rt for 1.0 h. Quenchedwith saturated
NH4Cl solution, then extracted with ethyl acetate (30 mLꢁ3). Com-
bined organics were washed with saturated NaHCO3 solution and
brine, then dried over anhydrous MgSO4. A flash column chroma-
tography (20% EtOAc/80% Heptane) gave 1.20 g of 10b as a light
yellow solid in 81% isolated. Mp¼56–58 ꢀC; IR (thin film) 2972,1605,
4. Experimental
4.1. General
1516,1248,1020 cmꢂ1; 1H NMR (CDCl3, 500 MHz):
d 8.84 (s,1H), 8.56
(m, 1H), 7.85 (m, 1H), 7.55 (d, 2H, J¼10 Hz), 7.36 (m, 1H), 7.04 (d, 2H,
J¼10 Hz), 3.88 (s, 3H); 13C NMR (CDCl3, 125 MHz):
d 159.75, 148.03,
147.91, 136.25, 133.86, 130.27, 128.24, 123.51, 114.55, 55.39; HRMS
(EI) calculated for C12H11NO 185.0841, found 185.0844.
All reactions were carried out under an argon atmosphere with
dry solvent and vacuum line was employed for all manipulations of
air-sensitive compounds. Commercially available reagents were
used without further purification. Active zinc was prepared by lit-
erature procedure.21 Column chromatography was carried out on
silica gel. 1H NMR spectra were recorded on 300 MHz, 400 MHz
and/or 500 MHz in CDCl3 and 13C NMR spectra was recorded on
75 MHz, 100 MHz and/or 125 MHz in CDCl3, THF-d8 or DMSO-d6
using TMS as internal standard.
4.6. Preparation of bipyridines
In a 50 mL round-bottomed flask, Pd[P(Ph)3]4 (0.10 g, 1 mol %)
and 5-bromo-2-iodoaniline (2.26 g, 8 mmol) were placed. Next,
20 mL of 3-pyridylzinc bromide (P7) (0.5 M in THF, 10 mmol) was
added via a syringe. The resulting mixture was allowed to stir at rt
for 1 h. Quenched with saturated NH4Cl solution, then extracted
with ethyl acetate (30 mLꢁ3). Combined organics were washed
with saturated Na2S2O3 solution and brine, then dried over anhy-
drous MgSO4. Flash chromatography on silica gel (20% EtOAc/80%
Heptane) gave 1.17 g of 5-bromo-2,30-bipyridine (10g) as a beige
solid in 62% isolated yield. Mp¼75–76 ꢀC; IR (thin film) 3039, 2931,
4.2. Preparation of 2-pyridylzinc bromide (P1)
A 250 mL RBF was charged with active zinc(9.81 g, 150 mmol) in
100 mL of THF. 2-Bromopyridine (15.8 g, 100 mmol) was then
added into the flask via a cannula while being stirred at rt. After the
addition was completed, the resulting mixture was allowed to stir
at refluxing temperature. The oxidative addition was monitored by
GC analysis of the reaction mixture. After being settled down
overnight, the supernatant was transferred into a 500 mL bottle
and then diluted with fresh THF to 200 mL.
1578, 1465, 1415, 1005 cmꢂ1 1H NMR (CDCl3, 500 MHz):
; d 9.18 (s,
1H), 8.78 (s, 1H), 8.67 (d, 1H, J¼20 Hz), 8.30 (d, 1H, J¼20 Hz), 7.92 (d,
1H, J¼20 Hz), 7.66 (d, 1H, J¼30 Hz), 7.42 (d, 1H, J¼25 Hz); 13C NMR
(CDCl3, 125 MHz):
d 153.23, 151.18, 150.30, 148.05, 139.57, 134.16,
133.76, 123.66, 121.60, 120.22; HRMS (EI) calculated for C10H7BrN2
235.9772, found 235.9777.
4.7. Pd-catalyzed coupling reactions with haloanilines
4.3. Preparation of 3-pyridylzinc bromide (P7)
In a 50 mL round-bottomed flask, Pd[P(Ph)3]4 (0.10 g, 1 mol %)
and 4-iodoaniline (1.75 g, 8 mmol) were placed. Next, 20 mL of
3-pyridylzinc bromide (P7) (0.5 M in THF, 10 mmol) was added via
a syringe. The resulting mixture was stirred at rt for 1 h. Quenched
with saturated NH4Cl solution, then extracted with ethyl acetate
(30 mLꢁ3). Combined organics were washed with saturated
Na2S2O3 solution and brine, then dried over anhydrous MgSO4.
Flash chromatography on silica gel (30% EtOAc/70% Heptane) gave
1.17 g of 3-(4-aminophenyl)pyridine (13a) as a beige solid in 86%
isolated yield. Mp¼114–116 ꢀC; IR (thin film) 3405, 3307, 3171,
An oven-dried 100 mL round-bottomed flask was charged with
3.3 g of active zinc (50 mmol) in 30 mL of THF and 0.2 g of lithium
chloride (20 mol %) under the positive pressure of argon gas. 3.9 g
of 3-Bromopyridine (25 mmol) was added into the solution of ac-
tive zinc at rt. The resulting mixture was then stirred at refluxing
temperature for 2 h. Cooled down to rt and settled down overnight.
Then the supernatant was used for the subsequent coupling
reactions.
4.4. General procedure for copper-free coupling reactions
1640, 1601, 1281 cmꢂ1 1H NMR (CDCl3, 400 MHz):
; d 8.81 (s, 1H),
8.51 (d, 1H, J¼5 Hz), 7.81 (m, 1H), 7.41 (d, 2H, J¼5 Hz), 7.32 (m, 1H),
In a 50 mL round-bottomed flask, isobutyryl chloride (1.27 g,
12 mmol) and 10 mL of THF were placed. Next, 20 mL of 0.5 M so-
lution of 2-pyridylzinc bromide (P1) in THF (10 mmol) was added
into the reaction flask via a syringe. The resulting mixture was
stirred at rt for 4 h. The reaction was monitored by GC analysis.
Quenched with saturated NH4Cl solution, then extracted with ether
(30 mLꢁ3). Combined organics were washed with saturated
NaHCO3 solution and brine, then dried over anhydrous MgSO4. A
vacuum distillation gave 0.94 g of 2-methyl-1-pyridin-2-yl-
propan-1-one (2d) as colorless oil in 63% isolated yield. 1H NMR
6.79 (d, 2H, J¼5 Hz), 3.81 (br s, 2H); 13C NMR (CDCl3, 100 MHz):
d
147.90, 147.60, 146.81, 136.74, 133.64, 128.23, 128.03, 123.65,
115.69; HRMS (EI) calculated for C11H10N2 170.0844, found
170.0843.
4.8. Pd-catalyzed coupling reactions with halophenols
In a 50 mL round-bottomed flask, Pd[P(Ph)3]4 (0.10 g, 1 mol %)
and 4-iodophenol (1.10 g, 5 mmol) were placed. Next, 20 mL of
2-pyridylzinc bromide (P1) (0.5 M in THF, 10 mmol) was added via
a syringe. The resulting mixture was heated to reflux for 24 h while
being stirred. Cooled down to rt and quenched with saturated
NH4Cl solution, then extracted with ethyl acetate (30 mLꢁ3).
Combined organics were washed with saturated Na2S2O3 solution
and brine, then dried over anhydrous MgSO4. Flash
(CDCl3, 500 MHz)
d
8.64 (d, 1H, J¼5 Hz), 8.01 (d, 1H, J¼5 Hz), 7.81 (t,
1H, J¼5 Hz), 7.42 (dd, 1H, J¼5 Hz), 4.08 (q, 1H, J¼5 Hz), 1.18 (d, 6H,
J¼5 Hz); 13C NMR (CDCl3, 125 MHz)
d 205.81, 153.01, 148.99, 137.03,
127.00, 122.55, 34.32, 18.78; GC–MS (EI, rel ratio): 149 (Mþ, 31), 106
(36), 79 (100), 51 (44).

S.-H. Kim, R.D. Rieke / Tetrahedron 66 (2010) 3135–3146
3145
chromatography on silica gel (10% EtOAc/90% Heptane) gave 0.80 g
of 4-pyridin-3-yl-phenol (9a) as a white solid in 95% isolated yield.
Mp¼159–160 ꢀC; IR (thin film) 3358 (br), 2975, 2893, 1593, 1467,
temperature for 1.0 h, quenched with saturated NH4Cl solution.
Then, extracted with ethyl acetate (30 mLꢁ3). Combined organics
were washed with 7% NH4OH solution and brine, then dried over
anhydrous MgSO4. Flash chromatography on silica gel (20% EtOAc/
80% Heptane) gave 0.57 g of 4-(2-methyl-allyl)-isoquinoline (12e)
as a beige solid in 35% isolated yield. Mp¼59–61 ꢀC; IR (thin film)
2967, 2933, 2362, 1620, 1582, 1445, 1390, 1231, 896 cmꢂ1; 1H NMR
1270, 1182 cmꢂ1 1H NMR (CDCl3/DMSO-d6, 500 MHz):
; d 9.09 (s,
1H), 8.52 (d,1H, J¼5 Hz), 7.75 (d, 2H, J¼10 Hz), 7.60 (m, 2H), 7.05 (m,
1H), 6.83 (d, 2H, J¼10 Hz); 13C NMR (CDCl3/DMSO-d6, 125 MHz):
d
158.43, 157.32, 149.26, 136.66, 130.52, 128.11, 121.12, 119.63,
115.80; HRMS (EI) calculated for C11H9NO 171.0684, found 171.0691.
(CDCl3, 500 MHz):
7.69 (t, 1H, J¼5 Hz), 7.59 (t, 1H, J¼5 Hz), 4.88 (s, 1H), 4.63 (s, 1H),
3.72 (s, 2H), 1.78 (s, 3H); 13C NMR (CDCl3, 125 MHz):
151.89,
d
9.16 (s, 1H), 8.39 (s, 1H), 7.97 (dd, 2H, J¼5 Hz),
4.9. Copper-catalyzed SN2 addition reactions
d
143.96, 143.91,135.36, 130.32, 128.99,128.78,128.32, 127.04,123.65,
112.88; HRMS (EI) calculated for C13H13N 183.1048, found 183.1054.
In a 100 mL round-bottomed flask, CuI (0.50 g,10 mol %) and LiCl
(0.20 g, 20 mol %) were placed. Next, 50 mL of 3-pyridylzinc bro-
mide (P7) (0.5 M in THF, 25 mmol) was added via a syringe. Cooled
down to 0 ꢀC using an ice-bath. 4.0 g (25 mmol) of 3-Bromocyclo-
hexene was added via a syringe while being stirred in the ice-bath.
After being stirred at 0 ꢀC, quenched with saturated NH4Cl solution,
then extracted with ethyl ether (30 mLꢁ3). Combined organics
were washed with 7% NH4OH solution and brine, then dried over
anhydrous MgSO4. Flash chromatography on silica gel (50% Ether/
50% Pentane) gave 2.50 g of 3-cyclohex-2-enyl-pyridine (11a) as
a yellow oil in 71% isolated yield. IR (thin film) 3020, 2928, 1670,
Supplementary data
Copies of 1H, 13C NMR data. Supplementary data associated with
this article can be found in the online version, at doi:10.1016/
j.tet.2010.02.061.
References and notes
1573,1422, 713 cmꢂ1; 1H NMR (CDCl3, 500 MHz):
d 8.48 (s,1H), 8.44
1. For recent examples, (a) Denton, T. T.; Zhang, X.; Cashman, J. R. J. Med. Chem.
2005, 48, 224; (b) Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. J. Org.
Chem. 2005, 70, 5840; (c) Yang, C.-G.; Huang, H.; Jiang, B. Curr. Org. Chem. 2004,
8, 1691; (d) Che, D.; Wegge, T.; Stubbs, M. T.; Seitz, G.; Meier, H.; Methfessel, C.
J. Med. Chem. 2001, 44, 47.
2. (a) Trecourt, F.; Gervais, B.; Mallet, M.; Queguiner, G. J. Org. Chem. 1996, 61, 1673;
(b) Trecourt, F.; Gervais, B.; Mongin, O.; Le Gal, C.; Mongin, F.; Queguiner, G.
J. Org. Chem. 1998, 63, 2892.
(m, 1H), 7.51 (m, 1H), 7.22 (m, 1H), 5.94 (m, 1H), 5.66 (q, 1H,
J¼20 Hz), 3.42 (m, 1H), 2.09 (m, 2H), 2.02 (m, 1H), 1.72 (m, 1H), 1.64
(m, 1H), 1.55 (m, 1H); 13C NMR (CDCl3, 125 MHz):
d 149.60, 147.49,
141.67, 135.08, 129.38, 128.72, 123.25, 39.30, 32.35, 24.85, 20.85;
HRMS (EI) calculated for C11H13N 159.1048, found 159.1050.
3. (a) Hargreaves, S. L.; Pilkington, B. L.; Russell, S. E.; Worthington, P. A. Tetrahedron
Lett. 2000, 41, 1653; (b) Zimmermann, J.; Buchdunger, E.; Mett, H.; Meyer, T.;
Lydon, N. B. Bioorg. Med. Chem. Lett. 1997, 7, 187; (c) Zimmermann, J.; Buch-
dunger, E.; Mett, H.; Meyer, T.; Lydon, N. B. Bioorg. Med. Chem. Lett. 1996, 6, 1221.
4. Getmanenko, Y. A.; Twieg, R. J. J. Org. Chem. 2008, 73, 830.
5. For recent examples, see: (a) Deng, J. Z.; Paone, D. V.; Ginnetti, A. T.; Kurihara,
H.; Dreher, S. D.; Weissman, S. A.; Stauffer, S. R.; Burgey, C. S. Org. Lett. 2009, 11,
345; (b) Yang, D. X.; Colletti, S. L.; Wu, K.; Song, M.; Li, G. Y.; Shen, H. C. Org. Lett.
2009, 11, 381; (c) Voisin-Chiret, A. S.; Bouillon, A.; Burzicki, G.; Celant, M.;
Legay, R.; El-Kashef, H.; Rault, S. Tetrahedron 2009, 65, 607; (d) Hodgson, P. B.;
Salingue, F. H. Tetrahedron Lett. 2004, 45, 685.
6. (a) Schwab, P. F. H.; Fleischer, F.; Michl, J. J. Org. Chem. 2002, 67, 443; (b) Zhang,
N.; Thomas, L.; Wu, B. J. Org. Chem. 2001, 66, 1500; (c) Schubert, U. C.; Es-
chbaumer, C.; Heller, M. Org. Lett. 2000, 2, 3373; (d) Gronowitz, S.; Bjork, P.;
Malm, J.; Hornfeldt, A.-B. J. Organomet. Chem. 1993, 460, 127.
7. (a) Sugimoto, O.; Yamada, S.; Tanji, K. J. Org. Chem. 2003, 68, 2054; (b) Song, J. J.;
Yee, N. K.; Tan, Z.; Xu, J.; Kapadia, S. R.; Senanayake, C. H. Org. Lett. 2004, 6,
4905; (c) Duan, X.-F.; Ma, Z.-Q.; Zhang, F.; Zhang, Z.-B. J. Org. Chem. 2009, 74,
939.
4.10. Pd-catalyzed bimolecular coupling reactions
In a 50 mL round-bottomed flask, bis(triphenylphosphine)-
palladium (II) dichloride, Pd[P(Ph)3]2Cl2 (0.50 g) was placed. Next,
25 mL of 5-methyl-2-pyridylzinc bromide (P4) (0.5 M in THF,
12.5 mmol) was added via a syringe. 1.21 g (5.0 mmol) of 2,5-
Dibromothiophene was added into the flask. The resulting mixture
was heated to reflux for 24 h while being stirred. Cooled down to rt
and quenched with saturated NH4Cl solution, then extracted with
ethyl acetate (30 mLꢁ3). Combined organics were washed with
saturated Na2S2O3 solution and brine, then dried over anhydrous
Na2SO4. Flash chromatography on silica gel (10% EtOAc/90% Hep-
tane) gave 0.90 g of 2,5-di(5-methylpyridin-2-yl)thiophene (6g) as
a yellow solid in 68% isolated yield. Mp¼dec at 170 ꢀC; IR (thin film)
2975, 2928, 1596, 1470, 1378, 1292, 808 cmꢂ1
500 MHz):
13C NMR (CDCl3, 125 MHz):
;
1H NMR (CDCl3,
8.43 (m, 2H), 7.58 (m, 4H), 7.51 (m, 2H), 2.27 (s, 6H);
149.99, 145.48, 137.19, 131.66, 129.97,
8. (a) Savage, S. A.; Smith, A. P.; Fraser, C. L. J. Org. Chem. 1998, 63, 10048; (b) Fang,
Y.-Q.; Hanan, G. S. Synlett 2003, 852; (c) Lutzen, A.; Hapke, M.; Staats, H.;
Bunzen, J. Eur. J. Org. Chem. 2003, 3948.
9. Billingsley, K. L.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 4695.
10. Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008,
130, 14926.
d
d
125.01, 118.55, 18.32; HRMS (EI) calculated for C16H14N2S 266.0878,
found 266.0879.
11. Li, M.; Hua, R. Tetrahedron Lett. 2009, 50, 1478.
12. Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254.
13. Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020.
14. Andersson, H.; Almqvist, F.; Olsson, R. Org. Lett. 2007, 9, 1335.
15. (a) Furukawa, N.; Shibutani, T.; Fujihara, H. Tetrahedron Lett. 1987, 28, 5845; (b)
Berillon, L.; Lepretre, A.; Turck, A.; Ple, N.; Queguiner, G.; Cahiez, G.; Knochel, P.
Synlett 1998, 1359; (c) Trecourt, F.; Breton, G.; Mongin, F.; Marsais, F.; Que-
guiner, G. Tetrahedron Lett. 1999, 40, 4339; (d) Abarbri, M.; Dehmel, F.; Knochel,
P. Tetrahedron Lett. 1999, 40, 7449; (e) Abarbri, M.; Thibonnet, J.; Berillon, L.;
Dehmel, F.; Rottlander, M.; Knochel, P. J. Org. Chem. 2000, 65, 4618; (f) Trecourt,
F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.; Queguiner, G. Tetrahedron
2000, 56, 1349; (g) Dumouchel, S.; Mongin, F.; Trecourt, F.; Queguiner, G.
Tetrahedron Lett. 2003, 44, 3887.
4.11. Preparation of quinolinylzinc reagents and subsequent
coupling reactions
Preparation of quinolinylzinc bromide:
A 250 mL round-
bottomed flask was charged with active zinc (2.70 g, 41 mmol) in
30 mL of THF and lithium chloride (0.23 g, 20 mol %) under an
argon atmosphere. 5.70 g (27.5 mmol) of 3-Bromoquinoline (or
3-bromoisoquinoline) was added into the solution of active zinc at
rt. The resulting mixture was then stirred at refluxing temperature
for 2 h. Cooled down to rt and settled overnight. Then the super-
natant was used for the subsequent coupling reactions.
Coupling reaction: In a 50 mL round-bottomed flask, CuI (0.19 g,
10 mol %) and LiCl (0.08 g, 20 mol %) were placed. Next, 20 mL of
3-isoquionolinyl bromide (Q2) (0.5 M in THF, 10 mmol) was added
via a syringe. Cooled down to 0 ꢀC using an ice-bath. 0.80 g
(9 mmol) of 3-chloro-2-methylpropene was added via a syringe
while being stirred in the ice-bath. After being stirred at ambient
16. Simkovsky, N. M.; Ermann, M.; Roberts, S. M.; Parry, D. M.; Baxter, A. D. J. Chem.
Soc., Perkin Trans. 1 2002, 1847.
17. (a) Font-Sanchis, E.; Cespedes-Guirao, F. J.; Sastre-Santos, A.; Fernandez-Lazaro,
F. J. Org. Chem. 2007, 72, 3589; (b) Lee, P. H.; Seomoon, D.; Lee, K. Org. Lett. 2005,
7, 343; (c) Chen, Y.-H.; Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 7648.
18. (a) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem. 2009, 74, 973; (b)
Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358; (c) Thompson,
A. E.; Hughes, G.; Batsanov, A. S.; Bryce, M. R.; Parry, P. R.; Tarbit, B. J. Org. Chem.
2005, 70, 388; (d) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Cai, D.;
Larsen, R. D.; Reider, P. J. J. Org. Chem. 2002, 67, 5394; (e) Cai, D.; Larsen, R. D.;
Reider, P. J. Tetrahedron Lett. 2002, 43, 4285.

3146
S.-H. Kim, R.D. Rieke / Tetrahedron 66 (2010) 3135–3146
19. For the side reaction of lithiation of 3-halopyridines, see; (a) Mallet, M.;
Branger, G.; Marsais, F.; Queguiner, G. J. Organomet. Chem. 1990, 382, 319 and
also see; Ref. 15c and 15f.
20. (a) Sakamoto, T,; Kondo, Y.; Murata, N.; Yamanaka, H. Tetrahedron 1993, 49,
9713; (b) Sakamoto, T.; Kondo, Y.; Murata, N.; Yamanaka, H. Tetrahedron Lett.
1992, 33, 5373; (c) Pryor, L.; Kiessling, A. Am. J. Undergrad. Res. 2002, 1, 25; (d)
Bell, A. S.; Roberts, D. A.; Ruddock, K. S. Synthesis 1987, 843; (e) Sugimoto, O.;
Yamada, S.; Tanji, K. Tetrahedron Lett. 2002, 43, 3355.
(c) Jiang, B.; Wang, Q.-F.; Yang, C.-G.; Xu, M. Tetrahedron Lett. 2001, 42, 4083; (d)
For an example of the coupling reaction of 2-pyridylzinc bromide with
bromoaromatic amine, see; Charifson, P. S.; Grillot, A.-L.; Grossman, T. H.;
Parsons, J. D.; Badia, M.; Bellon, S.; Deininger, D. D.; Drumm, J. E.; Gross, C. H.;
LeTiran, A.; Liao, Y.; Mani, N.; Nicolau, D. P.; Perola, E.; Ronkin, S.; Shannon, D.;
Swenson, L. L.; Tang, Q.; Tessier, P. R.; Tian, S.-K.; Trudeau, M.; Wang, T.; Wei, Y.;
Zhang, H.; Stamos, D. J. Med. Chem. 2005, 51, 5243.
26. Manolikakes, G.; Hernandez, C. M.; Schade, M. A.; Metzger, A.; Knochel, P. J. Org.
Chem. 2008, 73, 8422 Slow cannulation (over 90 min) of organozinc (2.4 mmol)
via syringe pump was required.
27. pKa values; range between 15–20 for phenols, 20–30 for anilines, source from
http://www.chem.wisc.edu/areas/reich/pkatable/index.htm
21. Rieke, R. D. Science 1989, 246, 1260.
22. For examples, (a) Rieke, R. D.; Hanson, M. V. Tetrahedron 1997, 53, 1925; (b)
Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 6040.
23. For review; Mitsche, U.; Bauerle, P. J. Mater. Chem. 2000, 10, 1471 See also; Ref. 4.
24. For a review, see: Kaes, C.; Katz, M.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553
and see also Ref. 6c cited therein.
28. (a) Eweiss, N. F.; Katritzky, A. R.; Nie, P. L.; Ramsden, C. R. Synthesis 1997, 634;
(b) Boyer, J. H.; McCane, D. I.; McCarville, W. J.; Tweedie, A. T. J. Am. Chem. Soc.
1953, 75, 5298.
25. (a) Manolikakes, G.; Schade, M. A.; Hernandez, C. M.; Mayr, H.; Knochel, P. Org.
Lett. 2008, 10, 2765 For scattered examples of Suzuki coupling, see: (b) Parry, P.
A.; Wang, C.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B. J. Org. Chem. 2002, 67, 7541;
29. (a) Kato, Y.; Okada, S.; Tomimoto, K.; Mase, T. Tetrahedron Lett. 2001, 42, 4849;
(b) Sugimoto, O.; Mori, M.; Tanji, K.-I. Tetrahedron Lett. 1999, 40, 7477.
30. Kim, S.-H.; Rieke, R. D. Tetrahedron Lett. 2009, 50, 5329.