Negishi coupling of 2-pyridylzinc bromide-paradigm shift in cross-coupling chemistry?

Article abstract of DOI:10.1016/j.tetlet.2009.11.036

The efficient cross-coupling of 2-pyridylzinc bromide with functionalized aryl halides has been accomplished by a simple and highly efficient protocol. To the best of our knowledge, we report the first shelf life study of 2-pyridylzinc bromide which confirms the excellent stability of this compound and underlines the synthetic value of organozinc reagents in the cross-coupling reactions of sensitive heterocyclic nucleophiles on academic and commercial scale.

Full text of DOI:10.1016/j.tetlet.2009.11.036

Tetrahedron Letters 51 (2010) 357–359
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Negishi coupling of 2-pyridylzinc bromide—paradigm shift in
cross-coupling chemistry?
Brian M. Coleridge, Charles S. Bello, David H. Ellenberger, Andreas Leitner *
BASF Corporation, 1424 Mars-Evans-City Road, Evans City, PA 16033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficient cross-coupling of 2-pyridylzinc bromide with functionalized aryl halides has been accom-
plished by a simple and highly efficient protocol. To the best of our knowledge, we report the first shelf
life study of 2-pyridylzinc bromide which confirms the excellent stability of this compound and under-
lines the synthetic value of organozinc reagents in the cross-coupling reactions of sensitive heterocyclic
nucleophiles on academic and commercial scale.
Received 18 September 2009
Revised 26 October 2009
Accepted 9 November 2009
Available online 13 November 2009
Ó 2009 Published by Elsevier Ltd.
The introduction of a 2-pyridyl moiety by cross-coupling reac-
tions into functionalized organic molecules displays a challenging
and important transformation in organic synthesis. Several phar-
maceutically relevant molecules, agrochemicals, and natural prod-
ucts contain 2-pyridyl scaffolds.1 Despite the groundbreaking
discoveries in the field of transition metal-catalyzed carbon–car-
bon bond forming reactions, the scope for cross-coupling of 2-pyr-
idyl-nucleophiles is still limited.2 The reason for this
methodological lag is based on the fact, that 2-pyridyl nucleophiles
often suffer from low stability, short shelf life or have to be gener-
overall yield was 27%. The applied catalyst system consisting of
Pd (dba) , SPhos, and Cu(OAc) in the presence of K CO in DMF/
IPA at 100 °C provides the desired cross-coupling products in good
2
3
2
2
3
yields up to 79%. Since organozinc halides were introduced by
9
10
Negishi for cross-coupling applications in the 1970s, his group,
1
1
12
13
14
Knochel, Rieke, Fu, Buchwald and others have developed
very powerful procedures to open this technology to a broad vari-
ety of applications. Recently, Kappe described two examples for the
cross-coupling of 2-pyridylzinc chloride with aryl chlorides in the
presence of Pd
2
dba
3
/Bu
3
PÁHBF
4
as a catalyst under microwave con-
3
,4
15
ated under elaborate reaction conditions at low temperatures. To
circumvent unstable organometallic intermediates, novel direct
arylation reactions of pyridine derivatives with aryl halides and
unactivated arenes have been reported.4
ditions in good yields. Although pyridylzinc halides have been
used in organic synthesis, to the best of our knowledge, no stability
data of 2-pyridylzinc halides is available and cross-coupling reac-
16
tions with this nucleophile are under-represented.
Furthermore, several research groups made important progress
to accomplish Suzuki reactions of 2-pyridyl nucleophiles. Buch-
In order to evaluate the potential of 2-pyridylzinc halide nucle-
ophiles for organic synthesis and in particular for Negishi cross-
coupling reactions in more detail, we started our studies with
5
wald reported a new cross-coupling reaction of lithium triisopro-
6
pyl-2-pyridylborates with aryl bromides and aryl chlorides. The
borate was synthesized in two steps from the corresponding 2-bro-
mopyridine by lithium-halogen exchange and reaction of the orga-
nometallic intermediate with triisopropylborate. The novel
protocol employs air stable phosphine oxide ligands in combina-
Table 1
Catalyst screening
catalyst
I
NO2
+
NO
2
tion with Pd
2
(dba)
3
as a pre-catalyst. Although yields are high,
THF
N
ZnBr
N
the lithium triisopropyl-2-pyridylborates were described as some-
what air-sensitive. Likewise, Li and Shen reported cross-coupling
reactions of 2-pyridylboronic esters with aryl bromides using pal-
ladium phosphine chloride and oxide catalysts under Suzuki condi-
1
0 mmol
15 mmol
Entry
Catalyst
Mol %
Time (h)
Temp (°C)
Conversion % (GC)
1
2
3
4
5
6
7
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh3)4
PEPPSI
3
3
3
3
)
)
)
)
4
4
4
4
2.5
1.0
0.1
0.01
0.1
2.5
2.5
24
24
24
24
24
24
24
rt
rt
rt
rt
65
rt
rt
98
100
25
1.4
97
95
0
7
tions. The method requires careful optimization of the applied
base and gives the desired biaryl in moderate to good yields. Burk
and coworkers developed an elegant approach to generate an air
stable MIDA-protected 2-pyridyl boronate derivative.8 However,
the synthesis of the 2-pyridyl MIDA boronate is difficult and the
Pd (dba)
2 3
O
O
H
P
5
*
Corresponding author. Tel.: +1 724 538 1334; fax: +1 724 538 1 258.
O
E-mail address: Andreas.Leitner@basf.com (A. Leitner).
0
040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.11.036

3
58
B. M. Coleridge et al. / Tetrahedron Letters 51 (2010) 357–359
Table 2
Stability and reactivity study
transformation and without further optimization of reaction condi-
tions, conversions >95% were obtained in the first trials (Table 1,
entries 1–3).
F3C
2
.5% Pd(PPh3)4
THF
+
CF
3
3
At reflux, a catalyst loading of 0.1% Pd(PPh )4, which correlates
N
ZnBr
N
Br
to a useful technical turn over number of 1000, gave a conversion
of 97% in 24 h. PEPPSI showed a comparable high reactivity to
6
5°, 1h
Entry
Storage time (month at room temperature)
Conversion % (GC)
1
7
Pd(PPh
on Pd (dba)
was recently used by several groups for the cross-coupling of aryl
3
)
4
(Table 1, entry 6). An in situ catalyst system based
1
2
0
>99
>99
2
3
in presence of a pinacolephospholane ligand, which
12
1
8
chlorides, showed no conversion (Table 1, entry 7).
As depicted in Table 2, 2-pyridylzinc bromide turned out to be
very stable as a solution in THF under nitrogen. The cross-coupling
with a newly synthesized reagent (0.98 mol/l) and an aged com-
pound (12 month at room temperature) of the same batch showed
no significant difference in reactivity and full conversion of 4-bro-
mobenzotrifluoride was obtained within 1 h in both cases.
Zn*
Rieke Zn
N
Br
THF
N
ZnBr
>
95% yield
Scheme 1.
Most important, insignificant amounts of decomposition prod-
ucts in the aged material were detected by gas chromatography.
To the best of our knowledge, this is the first report about the
Pd (PPh3)
2
4
19
.5 mol%
long-term stability of a 2-pyridylzinc reagent. As compared to
Ar-X +
X = Br, I
other nucleophiles, 2-pyridylzinc bromide can be prepared by the
N
ZnBr
THF
N
Ar
1
2
6
5°C
Rieke technology in one step. This pathway provides the product
solution in THF (IM) with yields >95% and prevents a multistep
synthesis (see Scheme 1).
1
4
1 examples
3-93 % yield
Scheme 2.
We were able to produce 2-pyridylzinc bromide on multi-kilo-
gram scale by this process.
Having these promising stability data and the convenient one-
step synthesis with a high yield in hand, we evaluated the scope
of the Negishi coupling with 2-pyridylzinc bromide in more detail
to get comprehensive information about the value of this technol-
the conversion of 4-iodonitrobenzene in the presence of 1.5 equiv
of 2-pyridylzinc bromide and different palladium pre-catalysts in
THF (Table 1). Pd(PPh ) emerged as an excellent catalyst for this
3 4
Table 3
c
Palladium-catalyzed cross-coupling reactions of aryl halides with 2-pyridylzinc bromide
Entry
1
Substrate
Catalystb (mol %)
Reaction time (h)/temperature (°C)
Product
Yielda (%)
>90 (GC)
O
O
Br
2.5%
16/65
N
O
O
2
3
Br
Br
2.5%
2.5%
16/65
16/65
98 (GC)
91
OEt
N
N
N
OEt
CN
CN
CN
4
5
2.5%
2.5%
16/65
24/65
93
66
CN
Br
CN
Br
NC
N
S
S
N
6
7
Br
2.5%
2.5%
1/65
1/65
43
60
N
N
O
H
O
H
Br
N
N
N
N
I
NO2
NO2
8
9
2.5%
2.5%
2.5%
1/65
4/65
4/65
88
85
82
Br
Br
OCH3
OCH3
1
0
a
b
c
Isolated yields unless stated otherwise. Reactions conducted in THF on 10 mmol scale.
Catalyst loadings are not optimized.
2
-Pyridylzinc bromide was prepared as 1 M solution in THF by BASF.

B. M. Coleridge et al. / Tetrahedron Letters 51 (2010) 357–359
359
ogy (Scheme 2). As outlined in Table 3, aryl bromides and -iodides
bearing functional groups like an enolizable methyl ketone, ester,
nitrile, aldehyde, and ether or nitro group undergo Negishi cross-
coupling in high conversions and yields in the presence of
Pd(PPh ) . No broad catalyst or additive screening was required
3 4
to accomplish these results. The substitution pattern of the aryl ha-
lide had no significant impact on the reaction rate. For example, 2-,
coupling reactions with pyridine derivatives see: (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
.
Novel approaches to introduce 2-pyridine scaffolds by direct arylation see: (a)
Campeau, L.-C.; Stuart, D. R.; Leclerc, J.; Bertrand-Laperle, M.; Villemure, E.;
Sun, H.-Y.; Lasserre, S.; Guimond, N.; Lecavallier, M.; Fagnou, K. J. Am. Chem. Soc.
2009, 131, 3291–3306; (b) Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J.
A. J. Am. Chem. Soc. 2008, 130, 14926; (c) Li, M.; Hua, R. Tetrahedron Lett. 1999,
3
-, and 4-bromo benzonitrile were coupled with comparable high
reaction rates providing the final product in isolated yields up to
3% (Table 3, entries 3–5). 2-Bromo-thiazole was converted into
5
0, 1478–1481; (d) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130,
254–9256.
5. For a review see: Hapke, M.; Brandt, L.; Lützen, A. Chem. Soc. Rev. 2008, 37,
782–2797.
9
9
2
the cross-coupling product within 1 h reaction time and the prod-
uct was isolated in 43% yield (Table 3, entry 6). Electron neutral
bromobenzene as well as the electron rich 4-bromo-anisol pro-
vided the biaryl product in 85% and 82% isolated yields (Table 3,
6
7
.
.
Billingsley, K. L.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 4695–4698.
Yang, D. X.; Colletti, S. L.; Wu, K.; Song, M.; Li, G. Y.; Shen, H. C. Org. Lett. 2009,
11, 381–384; See also: Deng, J. Z.; Paone, D. V.; Ginnetti, A. T.; Kurihara, H.;
Dreher, S. D.; Weissmann, S. A.; Stauffer, S. R.; Burgey, C. S. Org. Lett. 2009, 11,
345–347.
2
0
entries 9 and 10).
8
.
Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961–6963.
In summary, we have demonstrated the high value of 2-pyridyl-
zinc nucleophiles for cross-coupling chemistry. The excellent
stability of 2-pyridylzinc bromide, the tolerance to sensitive-
functional groups and its simple one step, high yield synthesis
can lead to a paradigm shift in the cross-coupling of this important
nucleophile. Apart from stability data, we demonstrated the appli-
cation in cross-coupling reactions of aryl bromides and iodides.
The developed Negishi cross-coupling protocol does not require
careful optimization of reaction conditions, additives, and catalysts
for the selected substrate scope. Currently we are working on the
extension of this technology to aryl chlorides which will be re-
ported in due course.
9. King, A. O.; Negishi, E.; Villani, F. J., Jr.; Silveira, A., Jr. J. Org. Chem. 1978, 43,
358–360.
1
0. (a) Negishi, E.; Hu, Q.; Huang, Z.; Wang, G.; Yin, N. Palladium- or Nickel-
Catalyzed Cross-Coupling Reactions with Organozincs and Related
Organometals. In Chemistry of Organozinc Compounds, Wiley, 2006; (Pt.1), pp
457–553.; (b) Negishi, E. Bull. Chem. Soc. Jpn. 2007, 80, 233–257; (c) Negishi, E.;
Huang, Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori, H. Acc. Chem. Res. 2008, 41,
1474–1485.
1
1. (a) Knochel, P.; Leuser, H.; Gong, L.; Perrone, S.; Kneisel, F. Functionalized
Organozinc Compounds. In Chemistry of Organozinc Compounds; Rappoport, Z.,
Marek, I., Eds.; John Wiley & Sons Ltd: Chichester, UK, 2006; pp 287–393 (Pt.
1); (b) Manolikakes, G.; Dong, Z.; Mayr, H.; Li, J.; Knochel, P. Chem. Eur. J. 2009,
1
5, 1324–1328; (c) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 6040–6044.
1
1
1
1
2. (a) Rieke, R. D. Science 1989, 246, 1260; (b) Rieke, R. D. Aldrichim. Acta 2000, 33,
52–60.
3. (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176–4211; (b) Fu, G. C.
Acc. Chem. Res. 2008, 41, 1555–1564.
4. (a) Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 7532–7533; (b) Milne, J.
E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028–13032.
5. Walla, P.; Kappe, C. O. Chem. Commun. 2004, 564–565.
Acknowledgments
The authors are grateful to BASF Corporation for releasing this
manuscript for publication. In particular we would like to thank
Dr. Karl Matos and Dr. Elizabeth R. Burkhardt for very productive
chemistry discussions.
16. During the preparation of this manuscript, the following publication on this
topic appeared: Kim, S.-H.; Rieke, R. D. Tetrahedron Lett. 2009, 50, 5329–
5331. No information about the stability of 2-pyridylzinc bromide was
provided.
1
7. (a) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass, G. A.; Lough,
A.; Hopkinson, A. C.; Organ, M. G. Chem. Eur. J. 2006, 12, 4743; (b) Organ, M. G.;
Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Valente, C. Eur.
J. Chem. 2006, 12, 4749; (c) Sase, S.; Jaric, M.; Metzger, A.; Malakhov, V.;
Knochel, P. J. Org. Chem. 2008, 73, 7380–7382.
References and notes
1
.
(a) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006,
, 2337; (b) Richards, C. M.; Gillespie, R. J.; Williamson, D. S.; Jordan, A. M.; Fink,
A.; Knight, A. R.; Sellwood, D. M.; Misra, A. Bioorg. Med. Chem. Lett. 2006, 16,
993–5997; (c) Pérec-Balado, C.; Willemsens, D.; Ormerod, D.; Aelterman, W.;
4
1
8. For selected examples of phosphine oxides ligands cross-coupling chemistry
see: (a) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513–1516; (b) Lerebours, R.;
Camacho-Soto, A.; Wolf, C. J. Org. Chem. 2005, 70, 8601–8604; (c) Ackermann,
L.; Born, R.; Spatz, J. H.; Meyer, D. Angew. Chem., Int. Ed. 2005, 44, 7216–7219.
9. For information about the thermal stability of cyclopropylzinc bromide see:
Coleridge, B. M.; Bello, C. S.; Leitner, A. Tetrahedron Lett. 2009, 50, 4475–4477.
0. General procedure: 4-(2-pyridyl)nitrobenzene (Table 2, entry 8). In a glove box,
5
Mertens, N. Org. Process Res. Dev. 2007, 11, 237–240; (d) Meyers, K. M.; Kim, N.;
Mendez-Andino, J. L.; Hu, X. E.; Mumin, R. N.; Klopfenstein, S. R.; Wos, J. A.;
Mitchell, M. C.; Paris, J. L.; Ackley, D. J.; Holbert, K.; Mittelstadt, S. W.; Reizes, O.
Bioorg. Med. Chem. Lett. 2007, 17, 814–818; (e) Salama, I.; Hocke, C.; Utz, W.;
Prante, O.; Boeckler, F.; Huebner, H.; Kuwert, T.; Gmeiner, P. J. Med. Chem. 2007,
1
2
Pd(PPh
3 4
) (0.29 g, 0.25 mmol), 4-iodonitrobenzene (2.49 g, 10 mmol), and THF
50, 489–500.
(
3 mL) were filled into a 50 mL 2-necked round-bottomed flask with magnetic
2
.
(a) For general recent cross coupling reviews see: Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Meijere, A., Eds.; Wiley-VCH: Weinheim,
stir bar. The mixture was stirred for 0.5 h at room temperature resulting in a
yellow-orange slurry. Next, 2-pyridylzinc bromide (15 mL, 15 mmol 1 M
solution in THF) was added by syringe and the flask was sealed with rubber
septa. The reaction mixture was heated at 65 °C for 1 h. The resulting blood-red
to black solution was cooled to room temperature, and aqueous HCl was added
2
2
004; (b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev.
002, 102, 1359–1469; (c) Miyaura, N. Cross-Coupling Reactions. A Practical
Guide; Miyaura, N., Ed.; Topics in Current Chemistry; Springer: Berlin, 2002;
Vol. 219, pp. 11–59; (d) Corbet, J.; Mignani, G. Chem. Rev. 2006, 106, 2651–
(
3.0 M; 10 mL). Aqueous NaOH (25 wt %, 10 ml) was added followed by an
extraction of the product with Et
(3 Â 30 mL), washed with 10 mL of
saturated aqueous KCl, dried over MgSO , and concentrated, resulting in a light
2
710; (e) Knochel, P.; Calaza, M. I.; Hupe, E. Carbon–carbon Bond-forming
2
O
Reactions Mediated by Organozinc Reagents, 2nd ed.. In Metal-Catalyzed Cross-
Coupling Reactions; De Meijere, A., Diederich, F., Eds.; Wiley-VCH Verlag GmbH
4
brown solid. The solid was dissolved in THF and recrystallized from cold
hexane. Vacuum filtration furnished 1.88 g (88%) of the title compound as a
&
Co. KgaA: Weinheim, Germany, 2004; 2, pp 619–670; (f) Knochel, P.; Leuser,
H.; Gong, L.; Perrone, S.; Kneisel, F. Functionalized Organozinc Compounds. In
Chemistry of Organozinc Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley &
Sons Ltd: Chichester, UK, 2006; pp 287–393 (Pt. 1); (g) Suzuki, A. J. Organomet.
Chem. 1999, 576, 147–168; (h) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
tan-colored powder. 1H NMR (CDCl
, 300 MHz): 8.76 (d, 1H, J = 4.95 Hz), 8.33
3
13
(
(
1
d, 2H, J = 8.98 Hz), 8.19 (H, J = 9.01 Hz), 7.82 (m, 2H), 7.35 (m, 1H). C NMR
CDCl 75 MHz) 155.1, 150.3, 148.4, 145.5, 137.4, 127.9, 124.2, 123.8,
21.5.Compound is also described in the following publication: Prasad, A. S.
B.; Stevenson, T. M.; Citineni, J. R.; Nyzam, V.; Knochel, P. Tetrahedron 1997, 53,
237–7254.
3
,
2
457–2483.
3
.
(a) Trécourt, F.; Breton, G.; Bonnet, V. ; Mongin, F. ; Marsais, F. ; Quéguiner, G.
Tetrahedron 2000, 56, 1349–1360. and references cited therein. (b) For Stille
7