Base effect and inhibition of catalytic activity in palladium-catalyzed N-heteroarylation of pyrazoles with 2,6-dibromopyridine

Article abstract of DOI:10.1021/om0501576

Using the catalytic system Pd(OAc)₂/PPh₃, coupling of 2,6-dibromopyridine (1) and pyrazoles (2) in a molar ratio of 1:2:base = 1:2.4:2.5 afforded the monosubstituted compounds 3 as the major products when KOtBu was used as the base. Without using the catalyst or using NaOtBu as the base the disubstituted compounds 4 were formed as the major products in yields up to 93%. Reactions of 1 and 2 in a molar ratio of 1:2:base = 1:1:1 selectively produced compounds 3 in yields up to 82% when KOtBu was used as the base. The complex from the reaction of 3 and Pd(OAc)₂ did not undergo further reaction with 1 to form 4 in the presence of a base. The base effect and inhibition of catalytic activity for Pd(OAc)₂ are discussed.

Full text of DOI:10.1021/om0501576

Organometallics 2005, 24, 2959-2963
2959
Base Effect and Inhibition of Catalytic Activity in
Palladium-Catalyzed N-Heteroarylation of Pyrazoles
with 2,6-Dibromopyridine
†
,†
†
,‡
Xiaojiao Sun, Zhengkun Yu,* Sizhong Wu, and Wen-Jing Xiao*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road,
Dalian, Liaoning 116023, People’s Republic of China, and The Key Laboratory of Pesticide
and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal
University, 152 Luoyu Road, Wuhan, Hubei 430007, People’s Republic of China
Received March 4, 2005
Using the catalytic system Pd(OAc)
pyrazoles (2) in a molar ratio of 1:2:base ) 1:2.4:2.5 afforded the monosubstituted compounds
as the major products when KOtBu was used as the base. Without using the catalyst or
2 3
/PPh , coupling of 2,6-dibromopyridine (1) and
3
using NaOtBu as the base the disubstituted compounds 4 were formed as the major products
in yields up to 93%. Reactions of 1 and 2 in a molar ratio of 1:2:base ) 1:1:1 selectively
produced compounds 3 in yields up to 82% when KOtBu was used as the base. The complex
from the reaction of 3 and Pd(OAc) did not undergo further reaction with 1 to form 4 in the
2
presence of a base. The base effect and inhibition of catalytic activity for Pd(OAc)
discussed.
2
are
Introduction
bromides has exhibited promising synthetic routes to
C-N bond formation.7 Both palladium- and copper -
catalyzed cross-coupling of N-H-containing heterocycles
with aryl halides, affording N-arylated heterocyclic
compounds, has been only moderately successful in
some cases. Copper-diamine-catalyzed N-arylation of
pyrazoles with aryl bromides or iodides was reported
,8
9
10
Development of new ligands bearing donor atoms
other than phosphorus, particularly nitrogen-containing
heterocyclic ligands, has been arousing more and more
interest in the fields of coordination chemistry, transi-
tion metal-based homogeneous catalysis, and organic
synthesis. Phosphine ancillary ligands are often sus-
ceptible to undergo degradation such as P-C bond
cleavage, oxidation to phosphine oxides, and ortho-
metalation, during the reaction or under storage condi-
tions. Organometallic complexes containing nitrogen
donor ligands usually exhibit high reactivities.1 Re-
cently, planar tridentate nitrogen donor (N3) ligands
10b
to afford N-aryl pyrazoles. Palladium-catalyzed ami-
11
nation of 1 with amines has been known. Pyrazole (2a)
and 3,5-dimethylpyrazole (2c) have usually been used
10b,11
to test the relevant synthetic methodology.
During
the course of our study on pyrazolyl-based ligands, we
investigated synthesis of compounds 4 in the presence
of a base with or without a catalyst. Herein, we report
catalytic synthesis of ligands 4, the base effect, and
inhibition of catalytic activity in palladium-catalyzed
N-heteroarylation of pyrazoles with 2,6-dibromopyridine
in the presence of a base.
2
such as 2,2′:6′,2′′-terpyridines (terpy) A, 2,6-bis(imino)-
3
pyridines B, and 2,6-bis(oxazolinyl)pyridines (Pybox)
4
C have been well documented (Scheme 1). However,
one new family of pseudo N3 ligands, i.e., 2,6-bis-
(
pyrazol-1-yl)pyridines (4), have not been paid consider-
able attention, and only a few relevant reports were
(
6) (a) Blaho, J. K.; Kruger, K. T.; Goldsby, K. A. Inorg. Chem. 1989,
8, 4314. (b) Jameson, D. L.; Goldsby, K. A. J. Org. Chem. 1990, 55,
4992. (c) Watson, A. A.; House, D. A.; Steel, P. J. J. Org. Chem. 1991,
6, 4072.
2
5
published over the last two decades. Ligands of type 4
5
were prepared by reactions of 2,6-dibromopyridine (1)
(
7) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
with the potassium or sodium salts of pyrazoles under
Int. Ed. Engl. 1995, 34, 1348. (b) Louie, J.; Hartwig, J. F. Tetrahedron
Lett. 1995, 36, 3609.
6
harsh conditions. Buchwald-Hartwig amination of aryl
(
8) For reviews and accounts on the Buchwald-Hartwig reactions,
see: (a) Bara n˜ ano, D.; Mann, G.; Hartwig, J. F. Curr. Org. Chem. 1997,
1, 287. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805. (c) Frost, C. G.; Mendonca, P. J. Chem.
Soc., Perkin Trans. 1 1998, 2615. (d) Hartwig, J. F. Angew. Chem.,
Int. Ed. 1998, 37, 2046. (e) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 125. (f) Hartwig, J. F. In Modern Amination Methods;
Ricci, A., Ed.; Wiley-VCH: Weinheim, Germany, 2000. (g) Muci, A.
R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (h) Prim, D.;
Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58,
2041.
(9) (a) Mann, G.; Hartwig, J. F.; Driver, M. S.; Fernandez-Rivas, C.
J. Am. Chem. Soc. 1998, 120, 827. (b) Hartwig, J. F.; Kawatsura, M.;
Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem.
1999, 64, 5575. (c) Old, D. W.; Harris, M. C.; Buchwald, S. L. Org.
Lett. 2000, 2, 1403.
*
Corresponding
authors.
E-mail:
zkyu@dicp.ac.cn;
wxiao@mail.ccnu.edu.cn.
†
Dalian Institute of Chemical Physics.
The Key Laboratory of Pesticide and Chemical Biology.
‡
(
1) Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994,
3
3, 497-526.
(
2) (a) Hagfeldt, A.; Gr a¨ tzel, M. Acc. Chem. Res. 2000, 33, 269. (b)
Hofmeier, H.; Schubert, U. S. Chem. Soc. Rev. 2004, 33, 373.
3) Bianchini, C.; Giambastiani, G.; Guerrero, I. R.; Meli, A.;
Passaglia, E.; Gragnoli, T. Organometallics 2004, 23, 6087.
4) (a) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2003, 103,
119. (b) Suga, H.; Inoue, K.; Inoue, S.; Kakehi, A.; Shiro, M. J. Org.
Chem. 2005, 70, 47.
5) (a) Bassel, C. A.; See, R. F.; Jameson, D. L.; Churchill, M. R.;
(
(
3
(
Takeuchi, K. J. J. Chem. Soc., Dalton Trans. 1991, 2801-2805. (b)
Bassel, C. A.; See, R. F.; Jameson, D. L.; Churchill, M. R.; Takeuchi,
K. J. J. Chem. Soc., Dalton Trans. 1993, 1563-1576. (c) Beach, N. J.;
Spivak, G. J. Inorg. Chim. Acta 2003, 343, 244-252.
(10) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J.
Am. Chem. Soc. 2001, 123, 7727. (b) Antilla, J. C.; Baskin, J. M.;
Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578.
(11) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240.
1
0.1021/om0501576 CCC: $30.25 © 2005 American Chemical Society
Publication on Web 04/30/2005

2960 Organometallics, Vol. 24, No. 12, 2005
Sun et al.
Scheme 1.
3 3
N and Pseudo N Ligands
Scheme 2. Pyrazoles 2a-h
Table 1. Reactions of 1 and 2 in a 1:2.4 Molar
a
Ratio
KOtBu
NaOtBu
run pyrazole
yield (%)c
yield (%)c
1b
2
2a
2b
2c
2d
2e
2f
3a, 29 (46) 4a, 69 (54) 3a, none
3b, 64 (36)d 4b, 35 (62) 3b, <1
4a, 86 (93)
4b, 86 (85)
b
3
3c, 57 (37) 4c, 35 (54) 3c, 20 (16) 4c, 63 (72)
3d, 58 (40) 4d, 30 (59) 3d, 25 (22) 4d, 62 (64)
b
4
5
6
7
8
3e, 66 (43) 4e, 25 (55) 3e, 13 (7)
3f, 65 (58) 4f, 30 (42) 3f, 37 (28) 4f, 60 (56)
4e, 76 (79)
2g
2h
3g, 29 (33) 4g, none
3h, none 4h, none
3g, 8 (11)
3h, none
4g, none
4h, none
a
Reaction conditions: 1, 2.0 mmol; 2, 4.8 mmol; base, 5.0 mmol;
Pd(OAc)2, 10 mol %; PPh3, 20 mol %; dioxane, 10.0 mL; 102 °C,
Figure 1. Yields of 3 and 4 from the reactions of 1 and 2
in a 1:2.4 molar ratio using KOtBu as the base. Pyrazole:
b
c
4
8 h. Pd(OAc)2, 5 mol %; PPh3, 10 mol %. Isolated yields based
1-2a, 2-2b, 3-2c, 4-2d, 5-2e, 6-2f, 7-2g, 8-2h.
on 1, and data in parentheses are the product yields without using
Pd(OAc)2/PPh3. d Determined as a 4:1 mixture of two regioisomers
(
2-bromo-6-(3-methylpyrazol-1-yl)pyridine/2-bromo-6-(5-methylpyra-
the most sterically hindered pyrazoles 2g and 2h, the
monosubstituted product 3h and the disubstituted
products 4g and 4h were not formed, and only the less
sterically hindered 2-bromo-6-(3,5-diphenylpyrazol-1-
yl)pyridine (3g) was obtained in a yield as low as 29%
(Table 1, runs 7, 8). Under harsh conditions, i.e., using
potassium salts of pyrazoles, 110-130 °C in diglyme for
4 days, reactions of 1 and the potassium salts of 2a and
2c afforded 2,6-bis(pyrazol-1-yl)pyridine (4a) and 2,6-
bis(3,5-dimethylpyrazol-1-yl)pyridine (4c) in 85% and
1
zol-1-yl)pyridine) by HNMR.
Results and Discussion
To achieve our objectives, Pd(OAc)2-catalyzed reac-
tions of 1 and pyrazoles (2a-h) were systematically
investigated in the presence of a base, i.e., KOtBu or
NaOtBu. Pyrazole (2a) and substituted pyrazoles (2b-
h) were used in the reactions (Scheme 2). We intended
to synthesize 2,6-bis(pyrazol-1-yl)pyridines (4) from the
reactions of 1 and an excess of 2 (>2.0 equiv), i.e., in a
molar ratio of 1:2.4:2.5 for 1, 2, and KOtBu in dioxane
at 102 °C. Using 5-10 mol % Pd(OAc)2 as the catalyst
and 10-20 mol % PPh3 as the ligand, the reaction
mixture was stirred under a nitrogen atmosphere for
5
77% yields, respectively. Without using the catalyst,
the same reactions using KOtBu as the base gave
compounds 4 as the major products (Table 1, runs 1-5,
Figure 1b) except in the case of 2f (Table 1, run 6), and
for pyrazoles 2g and 2h, the results are similar to those
using Pd(OAc)2 as the catalyst (Table 1, runs 7, 8). It is
noted that the catalyst inhibited formation of the
disubstituted products, i.e., 4, except in the case using
pyrazole 2a (Table 1, run 1).
When the base NaOtBu was employed with a molar
ratio of 1:2:base ) 1:2.4:2.5 under the same reaction
conditions, compounds 4 were obtained as the major
products in 56-93% yields with or without using the
catalyst (Table 1). Compounds 4 were formed in yields
much higher than those using KOtBu as the base,
revealing that a stronger base improves formation of
4
8 h and followed by purification with column chroma-
tography on silica gel. In the case of 2a, compound 4a
was obtained as the major product in 69% yield and the
monosubstituted product, i.e., 2-bromo-6-(pyrazol-1-yl)-
pyridine (3a), was collected as the minor product in 29%
yield (Table 1, run 1). However, in the cases using the
substituted pyrazoles, i.e., 2b-g, compounds of type 3
were formed in yields up to 66% as the major products
(
Table 1, runs 2-7, and Figure 1a). Steric hindrance
from the substituent(s) on the corresponding pyrazolyl
rings is 2a < 2b < 2c < 2d < 2e < 2f < 2g < 2h. For

Pd-Catalyzed N-Heteroarylation of Pyrazoles
Organometallics, Vol. 24, No. 12, 2005 2961
Table 2. Reactions of 1 and 2 in a 1:1 Molar Ratioa
Scheme 3. Complex 5
KOtBu
NaOtBu
run pyrazole
yield (%)c
yield (%)c
1b
2
2a
2b
2c
2d
2e
2f
3a, 73 (73) 4a, 2 (5) 3a, 54 (52) 4a, 30 (28)
3b, 76 (66) 4b, <1
3c, 68 (69) 4c, <1
3d, 54 (57) 4d, <1
3e, 43 (59) 4e, <1
3f, 76 (82) 4f, <1
3b, 46 (42) 4b, 3 (6)
3c, 42 (45) 4c, 4 (5)
3d, 39 (46) 4d, 2 (6)
3e, 31 (55) 4e, 3 (8)
3f, 70 (74) 4f, 3 (9)
b
3
b
4
5
6
7
8
improved the formation of the disubstituted products 4
in the reactions of 1 and 2 in a molar ratio 1:2.4 (Table
2g
2h
3g, 11 (19) 4g, none 3g, 14 (16) 4g, none
3h, none 4h, none 3h, none 4h, none
1
), while a relatively weak base, i.e., KOtBu, prompted
production of the monosubstituted products 3 in the
reactions of 1 and 2 in a molar ratio 1:1 (Table 2). Use
of Pd(OAc)2 as the catalyst inhibited further reaction
of 3 with 2 to form 4 in the presence of KOtBu (Table
1). Possible formation of complexes 5 (Scheme 3) de-
creases coordination of N-H of 2, and C-Br of 3, to the
metal center and led to increase of the steric hindrance
around the C-Br bond, reducing the reactivity of 3 to
form 4 by nucleophilic attack of the pyrazolate anion
on the C-Br bond or by catalytic coupling. For com-
parison, two experiments were carried out (see the
Experimental Section) to demonstrate inhibition of the
a
Reaction conditions: 1, 2.0 mmol; 2, 2.0 mmol; base, 2.0 mmol;
Pd(OAc)2, 10 mol %; PPh3, 20 mol %; dioxane, 10.0 mL; 102 °C,
b
c
4
8 h. Pd(OAc)2, 5 mol %; PPh3, 10 mol %. Isolated yields based
on 1, and data in parentheses are the product yields without using
Pd(OAc)2/PPh3.
the disubstituted products. In the presence of the
catalyst, a considerable amount (0-37%) of 3 was
obtained as well (Table 1, runs 3-7). In most cases,
without using the catalyst, compounds 4 were formed
in yields higher than those reactions using the catalyst
(
Table 1). Compounds 3h, 4g, and 4h were not formed
in any case due to steric hindrance of the substituents.
It is also noted that using much weaker bases such as
Cs2CO3, K3PO4, or K2CO3 led only to the monosubsti-
tuted product, i.e., 3c, in yields less than 40% in the
reactions of 2c and 1.
catalytic activity for Pd(OAc) . Using KOtBu as the base,
2
reaction of 3e and 2e in a 1:1 molar ratio gave the
disubstituted product 4e in 72% yield. However, under
the same conditions, the complex from the reaction of
3e and Pd(OAc) hardly underwent coupling with 2e to
2
For the reactions of 1 with pyrazoles in a 1:1:1 molar
ratio for 1, 2, and KOtBu using Pd(OAc)2 as the catalyst,
-bromo-6-(pyrazol-1-yl)pyridines (3) were selectively
form 4e. These results reveal that the catalyst inhibited
further coupling of 3 with 2 to form the final product 4.
2
formed in yields up to 76% (Table 2, runs 1-7), and the
disubstituted products, i.e., 4, were hardly formed. The
highly sterically hindered pyrazoles 2g and 2h showed
only very low or no reactivity to form 3 (Table 2, runs
Conclusions
In conclusion, the stronger base NaOtBu prompted
formation of the disubstituted products, i.e., 2,6-bis-
pyrazol-1-yl)pyridines, from the reactions of 2,6-dibro-
mopyridine and pyrazoles (>2.0 equiv), while the base
KOtBu prompted formation of the monosubstituted
products, i.e., 2-bromo-6-(pyrazol-1-yl)pyridines. The
catalyst Pd(OAc)2 inhibited further coupling of 2-bromo-
-(pyrazol-1-yl)pyridines with pyrazoles in the presence
of a base. The present work has offered a general route
to 2,6-bis(pyrazol-1-yl)pyridine and 2-bromo-6-(pyrazol-
(
7
, 8). With the catalyst, in the case using 2b as the
substrate, a product of type 3, i.e., 3b, was produced in
6% yield, but in other cases, using the catalyst, yields
of 3 were lower than those without using the catalyst
up to 82% yield, Table 2). The inhibition effect of
catalyst was also observed; that is, the presence of Pd-
OAc)2 inhibited the formation of both 3 and 4 except
7
(
6
(
in the case using 2b (Table 2). Using the stronger base
NaOtBu under the same conditions lower yields of 3
were obtained as compared to the reactions using
KOtBu as the base, and small amounts of the disubsti-
tuted products 4 were produced (Table 2). Only in the
cases of 2a and 2b were yields of 3a and 3b in the
presence of Pd(OAc)2 a little bit higher (54% and 46%,
respectively) than those without using the catalyst. In
other cases, the presence of the catalyst also inhibited
formation of both the products 3 and 4. CuI as the
catalyst in the 1:2.4 or 1:1 molar ratio reactions of 1
and 2 showed only very poor catalytic activity, and the
reactions afforded 3c in 10-30% yields in the presence
1
-yl)pyridine derivatives.
Experimental Section
General Considerations. All the reactions were carried
out under a nitrogen atmosphere with a drybox and standard
1
13
1
Schlenk techniques. H and C{ H} NMR spectra were
recorded on a Bruker DRX-400 spectrometer. Elemental
analysis was achieved by the Analysis Center, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences.
Pyrazole and substituted pyrazoles were commercially avail-
1
3
14
able or prepared as reported. 3,4,5-Trimethylpyrazole and
1
5
3
,5-dimethyl-4-benzylpyrazole were synthesized by known
procedures.
8
of a typical base for amination, e.g., K3PO4, and 1,2-
Representative Procedure for the Preparation of 3
and 4. A 50 mL Schlenk flask was charged with 2,6-dibro-
mopyridine, 1 (0.474 g, 2.0 mmol), 3,5-dimethylpyrazole, 2c
1
0b
diaminocyclohexane.
During the reaction both coordination of the N-H of
pyrazoles and C-Br of 1 or 3 to the metal center led to
catalytic coupling of 1 and 2, and further 3 and 2,
forming 3 and/or 4, and competitive deprotonation of
the N-H of pyrazoles by the base generated pyrazolate
anions, which attacked 1 and/or 3, affording 3 and/or
(
2
0.461 g, 4.8 mmol), KOtBu (0.561 g, 5.0 mmol), Pd(OAc) (22.5
(12) Meyers, C.; Maes, B. U. W.; Loones, K. T. J.; Bal, G.; Lemire,
G. L. F.; Dommisse, R. A. J. Org. Chem. 2004, 69, 6010.
13) Elguero, J.; Gonzalez, E.; Jacquier, R. Bull. Soc. Chim. Fr. 1968,
(
707.
(
(
14) Chamber, D.; Denny, W. A. J. Org. Chem. 1985, 50, 4736.
4
, respectively. A base effect was observed in the
palladium-catalyzed amination of aryl iodides. In our
15) Jeffery, J. C.; Kurek, S. S.; McCleverty, J. A.; Psillakis, E.;
12
Richardson, R. M.; Ward, M. D.; Wlodarczyk, A. J. Chem. Soc., Dalton
Trans. 1994, 2559.
case, NaOtBu, which behaved stronger than NaOtBu,

2962 Organometallics, Vol. 24, No. 12, 2005
Sun et al.
mg, 0.1 mmol), and PPh
3
(52.4 mg, 0.2 mmol). With stirring
8.09. Anal. Calcd for C11
Found: C, 49.64; H, 4.54; 18.79.
H
12BrN
3
: C, 49.34; H, 4.50; N, 18.33.
10 mL of dioxane was introduced. The flask was placed in an
oil bath preheated at 102 °C, and the mixture was stirred at
the refluxing temperature for 2 days. After cooling to ambient
temperature, the reaction mixture was diluted with ethyl
acetate (10 mL) and filtered through Celite, and all the
volatiles were removed under reduced pressure. Purification
by column chromatography (silica gel, ethyl acetate/petroleum
ether (v/v, 20:1-10:1)) afforded 2-bromo-6-(3,5-dimethylpyra-
zol-1-yl)pyridine, 3c (0.287 g, 57%), and 2,6-bis(3,5-dimeth-
ylpyrazol-1-yl)pyridine, 4c (0.187 g, 35%).
Synthesis of 2,6-Bis(3,5-dimethyl-4-benzylpyrazol-1-
yl)pyridine (4e) from the Reaction of 2-Bromo-6-(3,5-
dimethyl-4-benzylpyrazol-1-yl)pyridine (3e) and 3,5-
Dimethyl-4-benzylpyrazole (2e). A mixture of 3e (0.343 g,
2
,6-Bis(3,4,5-trimethylpyrazol-1-yl)pyridine (4d): white
1
3
solid, mp 114 °C. H NMR (400 MHz, CDCl ): δ 7.85 (t, 1H),
7
1
3
1
.63 (d, 2H), 2.51 (s, 6H), 2.26 (s, 6H), 1.97 (s, 6H). C{ H}
NMR (400 MHz, CDCl ): δ 151.70, 149.65, 140.44, 137.47,
3
15.10, 113.32, 12.54, 12.21, 8.16. Anal. Calcd for C17H N :
21 5
C, 68.87; H, 7.02; N, 23.24. Found: C, 69.12; H, 7.17; N, 23.71.
1
1.0 mmol), 2e (0.187 g, 1.0 mmol), KOtBu (0.113 g, 1.0 mmol),
and dioxane (8 mL) was stirred at 102 °C for 2 days. A workup
procedure the same as the above-mentioned gave a liquid
residue. Purification by column chromatography (silica gel,
ethyl acetate/petroleum ether (v/v, 20:1-10:1)) afforded 4e as
a pale yellow liquid (0.323 g, 72%).
Reaction of the Complex of 2-Bromo-6-(3,5-dimethyl-
2-Bromo-6-(3,5-dimethyl-4-benzylpyrazol-1-yl)pyri-
1
4
3
-benzylpyrazol-1-yl)pyridine (3e) and Pd(OAc)
,5-Dimethyl-4-benzylpyrazole (2e) in the Presence of
(0.224 g, 1.0 mmol), 3e (0.341
g, 1.0 mmol), and 10 mL of dioxane was refluxed at 102 °C for
.5 h until 3e was completely consumed by TLC determination.
2
with
dine (3e): white solid, mp 60 °C. H NMR (400 MHz,
CDCl ): δ 7.86 (d), 7.60 (t), and 7.17 (d) (1:1:1 H, pyridyl CH),
3
KOtBu. A mixture of Pd(OAc)
2
7.29 and 7.15 (m each, 3:2 H, phenyl CH), 3.81 (s, 2H), 2.63
1
3
1
(s, 3H), 2.19 (s, 3H). C{ H} NMR (400 MHz, CDCl ):
3
δ
5
153.39, 150.47, 140.32, 139.19, 138.95, 128.58, 128.20, 126.16,
124.18, 119.07, 113.75, 29.22, 13.10, 12.48. Anal. Calcd for
C H BrN : C, 59.29; H, 4.66; N, 12.36. Found: C, 59.66; H,
Thus 5e was presumably formed. To the mixture were suc-
cessively added 2e (0.186 g, 1.0 mmol) and KOtBu (0.113 g,
.0 mmol), and the mixture was further stirred at 102 °C for
days. Formation of palladiun black was observed during the
1
7
16
3
1
2
4.71; N, 12.28.
reaction. A trace amount of 4e was detected in the reaction
mixture by TLC on silica gel. Workup by the procedure
described above did not afford a measurable amount of 4e.
2
,6-Bis(3,5-dimethyl-4-benzylpyrazol-1-yl)pyridine
1
(
4e): yellow liquid. H NMR (400 MHz, CDCl
and 7.71 (d, 2H) (pyridyl CH), 7.29 and 7.17 (m each, 4:6 H,
phenyl CH), 3.81 (s, 4H), 2.55 (s, 6H), 2.21 (s, 6H). C{ H}
3
): δ 7.89 (t, 1H)
1
3
1
2
-Bromo-6-(3-methylpyrazol-1-yl)pyridine (3b): white
NMR (400 MHz, CDCl ): δ 151.73, 149.95, 140.60, 140.41,
3
1
solid, mp 52 °C. H NMR (400 MHz, CDCl
3
): δ 8.41 (br, 1H),
138.33, 128.62, 128.25, 126.18, 118.39, 113.78, 29.37, 12.75,
12.48. Anal. Calcd for C H N : C, 76.31; H, 6.64; N, 14.86.
7
3
1
.86 (d, 1H), 7.61 (t, 1H), 7.29 (d, 1H), 6.26 (br, 1H), 2.38 (s,
2
9
29
5
1
3
1
H). C{ H} NMR (400 MHz, CDCl
40.65, 139.95, 128.31, 124.64, 110.54, 108.60, 13.99. Anal.
BrN : C, 45.49; H, 3.36; N, 18.48. Found: C,
5.40; H, 3.39; N, 17.65.
3
): δ 152.53, 151.46,
Found: C, 77.82; H, 6.53; N, 15.65.
Calcd for C
9
H
8
3
4
2
-Bromo-6-(5-methyl-3-phenylpyrazol-1-yl)pyridine (3f):
1
white solid, mp 95 °C. H NMR (400 MHz, CDCl
3
): δ 8.04 (d),
7
.65 (t), and 7.33 (d) (1:1:1 H, pyridyl CH), 7.88, 7.44 and 7.36
2
,6-Bis(3-methylpyrazol-1-yl)pyridine (4b): white solid,
13
(
{
1
1
m each, 2:2:1 H, phenyl CH), 6.53 (s, 1H), 2.76 (s, 3H). C-
1
mp 74 °C. H NMR (400 MHz, CDCl
(
(
1
2
3
): δ 8.44 (d, 2H), 7.85
1
H} NMR (400 MHz, CDCl
40.45, 138.94, 132.74, 128.77, 128.49, 126.04, 124.73, 114.03,
07.07, 15.09. Anal. Calcd for C15 : C, 57.37; H, 3.89;
3
): δ 153.26, 152.36, 143.03,
1
3
1
m, 1H), 7.73 (m, 2H), 6.27 (d, 2H), 2.39 (s, 6H). C{ H} NMR
400 MHz, CDCl ): δ 152.11, 150.06, 141.25, 127.78, 108.55,
08.22, 14.03. Anal. Calcd for C13 : C, 65.18; H, 5.43; N,
9.54. Found: C, 65.25; H, 5.48; N, 29.27.
3
H
12BrN
3
13 5
H N
N, 13.40. Found: C, 57.34; H, 3.85; N, 13.37.
2
-Bromo-6-(3,4,5-trimethylpyrazol-1-yl)pyridine (3d):
2,6-Bis(5-methyl-3-phenylpyrazol-1-yl)pyridine(4f): white
1
1
white solid, mp 89 °C. H NMR (400 MHz, CDCl
3
): δ 7.80 (d,
solid, mp 146 °C. H NMR (400 MHz, CDCl
3
): δ 7.98 and 7.36
1
(m each, 1:2 H, pyridyl CH), 7.91 and 7.45 (m each, 6:4 H,
1
3
1
13
1
(
s, 3H). C{ H} NMR (400 MHz, CDCl
40.27, 138.92, 138.34, 123.96, 115.85, 113.57, 12.93, 12.27,
phenyl CH), 6.57 (s, 2H), 2.72 (s, 6H). C{ H} NMR (400 MHz,
CDCl ): δ 152.30, 151.65, 141.95, 140.81, 132.99, 128.81,
1
3

Pd-Catalyzed N-Heteroarylation of Pyrazoles
Organometallics, Vol. 24, No. 12, 2005 2963
3
MHz, CDCl ): δ 153.02, 152.19, 145.80, 140.22, 139.50, 132.59,
1
28.38, 126.00, 114.59, 106.47, 14.53. Anal. Calcd for C25
: C, 76.01; H, 5.69; N, 17.39. Found: C, 76.70; H, 5.41; N,
7.89.
H
21
-
N
5
131.10, 129.14, 128.80, 128.58, 128.50, 128.16, 126.15, 116.35,
107.32. Anal. Calcd for C20 : C, 63.12; H, 3.75; N, 11.02.
1
H14BrN
3
Found: C, 63.84; H, 3.79; N, 11.17.
Acknowledgment. We are grateful to the “Hundred
Talented Program” Funding of the Chinese Academy of
Sciences and National Science Foundation of China
(Grant No. 20406020) for support of this research.
Supporting Information Available: NMR spectra for
compounds 3b, 3d-g, 4b, and 4d-f. This material is available
free of charge via the Internet at http://pubs.acs.org.
2
-Bromo-6-(3,5-diphenylpyrazol-1-yl)pyridine(3g): white
1
solid, mp 120 °C. H NMR (400 MHz, CDCl
3
): δ 7.95, 7.46,
and 7.38 (m each, 2:2:6 H, phenyl CH), 7.70 (d), 7.61 (t), and
.37 (d) (1:1:1 H, pyridyl CH), 6.83 (s, 1 H). C{ H} NMR (400
13
1
7
OM0501576