5-Bromo-2-pyridylzinc reagent; Direct preparation and its coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2010.11.041

A facile synthetic route to the direct preparation of 5-bromo-2-pyridylzinc iodide has been developed. Treatment of 5-bromo-2-iodopyridine with active zinc gave rise to the selective oxidative addition to C-I bond under mild conditions. The resulting orga

Full text of DOI:10.1016/j.tetlet.2010.11.041

Tetrahedron Letters 52 (2011) 244–247
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5-Bromo-2-pyridylzinc reagent; direct preparation and its coupling reactions
Reuben D. Rieke a, Seung-Hoi Kim b,
⇑
a Rieke Metals, Inc., 1001 Kingbird Rd. Lincoln, NE 68521, USA
b Department of Chemistry, Dankook University, 29 Anseo, Cheonan 330-714, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthetic route to the direct preparation of 5-bromo-2-pyridylzinc iodide has been developed.
Treatment of 5-bromo-2-iodopyridine with active zinc gave rise to the selective oxidative addition to
C–I bond under mild conditions. The resulting organozinc iodide has been used in the variety of coupling
reactions affording the corresponding cross-coupling product.
Received 17 September 2010
Revised 26 October 2010
Accepted 4 November 2010
Available online 27 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The use of pyridine-containing compounds has frequently ap-
peared in a wide range of chemistry, such as natural product syn-
thesis, pharmaceutical chemistry, and material science.1 Many of
the 2-pyridyl derivatives have been prepared using the Suzuki,2
Stille,3 Grignard,4 and Negishi5 coupling reactions in the presence
of a transition metal catalyst.
In spite of these intensive studies on the preparation and appli-
cation of metalated-pyridine reagents, a very limited number of
procedures have been reported using a selective metallation of
dihalopyridines.
As described above, several methods have been performed to
make Grignard-type of pyridylmetallic reagents using 2,5-dihalo-
pyridines. However, to our best knowledge, the preparation of
the corresponding pyridylzinc reagent was not reported. We herein
would like to report a practical procedure for the preparation of 5-
bromo-2-pyridylzinc iodide and subsequent coupling reactions.
Interestingly, in our continuing study on the preparation and
application of organozinc reagents, it was found that 5-bromo-2-
pyridylzinc iodide (I) was easily prepared using 5-bromo-2-iodo-
pyridine and active zinc. It is of importance that the reaction
proceeded via a selective oxidative addition of active zinc at the
C(2)-position of pyridine under mild conditions. The resulting
organozinc reagent (I) was treated with a variety of different elec-
trophiles with/without any transition metal catalyst affording the
coupling products.
Especially, 5-bromo-2-metalated pyridine has received
considerable attention in the pharmaceutical chemistry. To
this end, several efforts have been performed by lithiation of
2,5-dibromopyridine. However, the preparation of stable pyridyl
organometallics has been typically considered
a problematic
subject mainly because of its instability and the formation of by-
products.6 Along with this stability issue, selective lithiation of
2,5-dibromopyridine was a big challenging subject. As described
in previous reports,7 the lithiation of 2,5-dibromopyridine oc-
curred at the C(5)-position even at cryogenic conditions (n-BuLi,
ꢀ100 °C). Wang et al. reported that 5-bromo-2-lithiopyridine re-
sulted from the C(2)-selective lithiation of 2,5-dibromopyridine
was obtained using n-BuLi under very low concentration (0.017–
0.085 M) at cold temperature (ꢀ78 °C). However, the selectivity
was highly dependent on the reaction conditions.8 Magnesium–
halogen exchange using 2,5-dibromopyridine with i-PrMgCl9 or
n-Bu3MgLi10 was also reported. Again, metallation at the C(5)
was exclusively observed. Recently, Song et al. reported the
synthesis of 5-bromopyridyl-2-magnesium chloride utilizing
metal–halogen exchange method. Metallation took place selec-
tively at the C(2)-position resulting in the formation of the corre-
sponding Grignard reagent.4b
The selective oxidative addition of the active zinc to carbon–
iodine bond was completed at room temperature resulting in the
formation of the corresponding 5-bromo-2-pyridylzinc iodide (I).
According to GC–MS analysis of the reaction aliquot, more than
99% conversion into the corresponding organozinc reagent (I)
was detected (Scheme 1).
Prior to the application of this organozinc (I) in the C–C bond
forming reactions, the resulting 5-bromo-2-pyridylzinc iodide
was treated with iodine to confirm the formation of organozinc re-
agent. The result showed the formation of 5-bromo-2-iodopyridine
(85%), 3-bromopyridine (2%), and unidentified products by GC.
Therefore, it could be concluded that the corresponding
5-bromo-2-pyridylzinc iodide was successfully prepared under
the reaction conditions used in this study.
Br
Br
2.0 eq Zn*
THF
0ºC ~ rt/ 2 h
N
ZnI
N
I
I
⇑
Corresponding author.
E-mail address: kimsemail@dankook.ac.kr (S.-H. Kim).
Scheme 1. Preparation of 5-bromo-2-pyridylzinc iodide (I).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.041

R. D. Rieke, S.-H. Kim / Tetrahedron Letters 52 (2011) 244–247
245
Table 1
Coupling reaction of I with aryl iodides
Br
1 % Pd(PPh3)4
THF
+
ArI
Product
N
ZnI
1.0 eq
2.0 eq
Entry
1
ArI
Conditions
rt/24 h
Product
Yield (%)a
I
Br
94
75
70
N
N
N
1a
CN
I
I
CN
Br
Br
Br
2
3
Reflux/1 h
rt/24 h
1b
OCH3
OCH3
Br
1c
I
I
Br
4
5
6
rt/24 h
rt/24 h
rt/24 h
78
79
69
N
N
N
1d
F
F
Br
Br
S
1e
S
NH2
I
NH2
1f
NH2
NH2
I
I
Br
Br
7
8
rt/24 h
73
N
N
1g
rt–reflux/24 h
Pd(OAc)2/SPhos
0b
0b
OH
OH
a
Isolated yield (based on ArI).
20% conversion by GC/GC–MS, no isolated product.
b
In order to investigate the reactivity of this new organozinc re-
2a in 30% isolated yield (Table 2, entry 1). Interestingly, slightly
higher yield (2b, 46%) was obtained from the reaction with the
corresponding furan derivative (Table 2, entry 2) under the same
conditions. 5-Bromofuran-2-carbaldehyde was also coupled with
I at rt and resulted in the formation of 5-(5-bromopyridin-2-yl)fur-
an-2-carbaldehyde 2c in 78% yields (Table 2, entry 3).
agent (I), it was treated with aryl iodides first in the presence of a
catalytic amount of Pd(PPh3)4. As summarized in Table 1, most of
the coupling reactions were performed at room temperature and
the corresponding compounds were obtained in good to excellent
yields. A simple iodobenzene reacted with I under the conditions
depicted in Table 1. Interestingly, the coupling product 1a was ob-
tained in excellent yield (94%, Table 1, entry 1). In the case of 4-
iodobenzonitrile containing an electro-withdrawing group (CN),
an elevated temperature was more effective to complete the cou-
pling reaction (Table 1, entry 2). Coupling reactions of I with other
iodoaromatics containing an electron-donating group (OCH3) and
halogen (Br, F) also gave rise to the coupling products 1c and 1d
in 70% and 78% isolated yields (Table 1, entries 3 and 4), respec-
tively. Heteroaryl iodide was also a good coupling partner for the
Table 2
Coupling reaction with aryl bromides
Br
1 % Pd(PPh3)4
THF
+
ArBr
Product
N
ZnI
1.0 eq
Entry ArBr
Conditions Product
Yield
(%)a
preparation of 2-heteroayl-substituted pyridine derivatives.
A
Br
good result (1e, 79% yield) was obtained from the coupling reaction
with 3-iodothiophene (Table 1, entry 5). It is of significance that
the reaction conditions used for aforementioned coupling reactions
worked well for the coupling reaction with aryl iodides containing
an acidic proton. For example, coupling products, 1f and 1g, were
successfully achieved from the coupling reactions with 3-aminoi-
odobenzene and 4-aminoiodobenzene (Table 1, entries 6 and 7),
respectively.11 Unfortunately, no reaction took place with iodophe-
nol even with Pd(OAc)2/SPhos (Table 1, entry 8).12
More results were obtained from the Pd(0)-catalyzed coupling
reactions with bromoaromatic compounds. As shown in Table 2,
treatment of I with functionalized aromatic (0.5 equiv of ethyl
5-bromothiophene-2-carboxylate) provided the coupling product
Br
CO2Et
CO2Et
CHO
S
S
O
O
1
Reflux/2 h
30
46
78
CO2Et
N
0.5 eq
2a
Br
Br
Br
O
2
Reflux/2 h
rt/24 h
CO2Et
N
N
0.8 eq
2b
Br
O
3
CHO
0.8 eq
2c
a
Isolated yield (based on ArI).

246
R. D. Rieke, S.-H. Kim / Tetrahedron Letters 52 (2011) 244–247
Br
Br
S
N
N
3a
61%
Br
Br
S
Pd(PPh3)2Cl2
0.3 eq
THF/reflux/24 h
COCl
0.8 eq
Br
0.8 eq
O
X
Br
Br
N
X: H, 2-F
THF/rt
no catalyst
N
ZnI
CuI/LiCl
THF/rt/20 min
71%
N
Br
X
3e
X: H (24%),3b
2-F (29%),3c
I
Pd(PPh3)4
0.5 eq
Br
N
reflux/2 h
81%
NH2
NH2
N
N
3d
Scheme 2. More examples of coupling reaction.
Several different types of coupling reactions of 5-bromo-2-
References and notes
pyridylzinc iodide (I) have been investigated and the results are
summarized in Scheme 2. Not only Pd-catalyzed coupling reaction
but copper-catalyzed coupling reaction was accomplished. As
described in Scheme 2, Pd(0) catalyst worked for the coupling reac-
tion with 2-amino-5-iodopyridine to give an unsymmetrical 2,3-
bipyridine (3d) in 81% yield under mild conditions. This result is
significant because considerable effort has been directed toward
the preparation of unsymmetrical bipyridines.13
1. For recent examples, see: (a) Carey, J. S.; Laffan, D.; Thomson, C.; Wiliams, M. T.
Org. Biomol. Chem. 2006, 4, 2337; (b) Bagley, M. C.; Glover, C.; Merritt, E. A.
Synlett 2007, 2459; (c) Fang, A. G.; Mello, J. V.; Finney, N. S. Org. Lett. 2003, 5,
967.
2. 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.
In the presence of Pd(II) catalyst, symmetrically substituted
thiophene derivative (3a) was obtained in moderate yield. The cou-
pling reaction was carried out with 0.3 equiv of 2,5-dibromothio-
phene at refluxing temperature for 24 h. This kind of product
could be utilized for further application in material chemistry. A
typical copper-catalyzed SN20-reaction was also successfully
accomplished. Coupling reaction of I with 3-bromo-2-methylpro-
pene gave rise to product 3e in 71% at room temperature in 20 min.
Transition metal catalyst-free coupling reactions with acid chlo-
rides were also carried out under mild conditions in this study.14
Even though low yields were obtained, a copper-free coupling
reaction with benzoyl chlorides provided the corresponding ke-
tones (3b and 3c) in 24% and 29% isolated yields, respectively.
In conclusion, a practical synthetic route for the preparation of
2-substituted-5-bromopyridine derivatives has been demon-
strated.15 It has been accomplished by utilizing a simple coupling
reaction of a stable 5-bromo-2-pyridylzinc iodide (I), which was
prepared via the direct insertion of active zinc to 5-bromo-2-iodo-
pyridine. The subsequent coupling reactions with a variety of dif-
ferent electrophiles have been carried out under mild conditions.
More applications of the organozinc reagent are currently under
way.
3. (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.;
Eschbaumer, C.; Heller, M. Org. Lett. 2000, 2, 3373; (d) Gronowitz, S.; Bjork, P.;
Malm, J.; Hornfeldt, A.-B. J. Organomet. Chem. 1993, 460, 127.
4. (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.
5. (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) Trecourt, F.; Gervais, B.; Mallet, M.;
Queguiner, G. J. Org. Chem. 1996, 61, 1673; (d) Lutzen, A.; Hapke, M.; Staats, H.;
Bunzen, J. Eur. J. Org. Chem. 2003, 3948.
6. For general examples of the coupling reactions of pyridylmetallics, see: Li, J. J.;
Gribble, G. W. Palladium in Heterocyclic Chemistry, 2nd ed.; ELSEVIER, 2006.
7. (a) Romero-Salguero, F. J.; Lehn, J.-M. Tetrahedron Lett. 1999, 40, 859; (b)
Parham, W. E.; Piccirlli, R. M. J. Org. Chem. 1977, 42, 257; Preparation of 2-
bromo-5-pyridylboronic acid via lithiation of 2,5-dibromopyridine, see: (c)
Parry, P. R.; Wang, C.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B. J. Org. Chem. 2002,
67, 7541; (d) Bouillon, A.; Lancelot, J.-C.; Collot, V.; Bovy, P. R.; Rault, S.
Tetrahedron 2002, 58, 2885.
8. Wang, X.; Rabbat, P.; O’Shea, P.; Tillyer, R.; Grabowski, E. J.; Reider, P. J.
Tetrahedron Lett. 2000, 41, 4335.
9. Trecourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.; Queguiner, G.
Tetrahedron Lett. 1999, 40, 4339.
10. (a) Mase, T.; Houpis, I. N.; Akao, A.; Dorziotis, I. K.; Hoang, T.; Iida, T.; Itoh, T.;
Kamei, K.; Kato, S.; Kato, Y.; Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.; Maligres,
P.; Monila, A.; Nemoto, T.; Okada, S.; Reamer, R.; Song, J. Z.; Tschaen, D.; Wada,
T.; Zewge, D.; Volante, R. P.; Reider, P. J.; Tomimoto, K. J. Org. Chem. 2001, 66,
6775; (b) Iida, T.; Wada, T.; Tomimoto, K.; Mase, T. Tetrahedron Lett. 2001, 42,
4841.
11. A recent example of coupling reaction with aminopyridine, see; Thompson, A.
E.; Hughes, G.; Batsanov, A. S.; Bryce, M. R.; Parry, P. R.; Tarbit, B. J. Org. Chem.
2005, 70, 388.
Supplementary data
Supplementary data (experimental procedures and copies of 1H,
13C NMR data) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2010.11.041.
12. pKa values (in DMSO); range between 10 and 19 for phenols, 20–30 for anilines,
source from http://www.chem.wisc.edu/areas/reich/pkatable/index.htm.

R. D. Rieke, S.-H. Kim / Tetrahedron Letters 52 (2011) 244–247
247
13. For a review, see: Kaes, C.; Katz, M.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553.
and see also:3c references cited therein.
iodopyridine (0.55 g, 2.5 mmol) were placed. Next, 10 mL (5 mmol) of 0.5 M
solution of 5-bromo-2-pyridylzinc iodide (I) in THF was added into the flask at
room temperature. After being stirred at room temperature for 6 h, the
reaction mixture was heated to reflux for 2 h to complete the reaction. Cooled
the mixture down to room temperature. Quenched with saturated NH4Cl
solution, then extracted with ethyl acetate (30 mL ꢁ 3). Combined organics
were washed with saturated Na2S2O3 solution and brine. Dried over anhydrous
MgSO4. A flash column chromatography (50% EtOAc/50% heptane) gave 0.51 g
of 3d as an off-white solid in 81% isolated. 1H NMR (CDCl3/DMSO-d6, 500 MHz):
d 8.64 (s, 1H), 8.61 (s, 1H), 8.01 (d, J = 5 Hz, 1H), 7.82 (d, J = 10 Hz, 1H), 7.56 (d,
J = 5 Hz, 1H), 6.60 (d, J = 10 Hz, 1H), 5.69 (s, 2H); 13C NMR (CDCl3/DMSO-d6,
125 MHz): d 159.17, 153.18, 149.34, 145.99, 138.32, 134.70, 122.12, 119.12,
116.92, 107.38.
14. For other example, see: Kim, S. H.; Rieke, R. D. Tetrahedron Lett. 2009, 50, 5329.
15. (a) Preparation of 5-bromo-2-pyridylzinc iodide (I): An oven-dried 100 mL
round-bottomed flask equipped with stir bar and inlet valve was placed under
an argon atmosphere. Next, Rieke zinc (0.5 M in THF, 33 mL, 50 mmol) was
added via a syringe and then cooled the flask down in an ice-bath. 5-Bromo-2-
iodopyridine (7.1 g, 25 mmol) dissolved in 20 mL of THF was cannulated into
the flask while being stirred. After the addition was completed, the flask was
allowed to warm up gradually, and then stirred at ambient temperature for 2 h.
After settled down overnight, the supernatant was used for the subsequent
coupling reactions. (b) A representative procedure of coupling reaction; In a
25 mL round-bottomed flask, Pd[P(Ph)3]4 (0.06 g, 1 mol %) and 2-amino-5-