Palladium-catalyzed selective cross-coupling between 2-bromopyridines and aryl bromides

Full text of DOI:10.1021/jo005682n

1500
J . Org. Chem. 2001, 66, 1500-1502
bromides using hexamethylditin catalyzed by palladium-
P a lla d iu m -Ca ta lyzed Selective
(0). An intramolecular version of this reaction, a cross-
coupling between 2-bromopyridines and aryl bromides in
the same molecule, is known in the literature.10,11 Here,
however, selectivity is not an issue. For the intermolecu-
lar coupling, the level of selectivity depends on the
reactivity difference between 2-bromopyridines and aryl
bromides. Tilley et al.12 showed that 2,5-dibromopyridine
underwent a regioselective palladium-catalyzed coupling
reaction with terminal acetylenes and arylzinc halides
to provide the corresponding 2-alkynyl-5-bromo- and
2-aryl-5-bromopyridines. The result suggests that the
bromide at the 2-position in 2,5-dibromopyridine is
significantly more reactive in palladium-catalyzed cou-
pling reactions than the 5-bromide. This result was
further reinforced by the work done by Kelly et al.13 in
the reactivity studies of pyridines doubly substituted with
bromine and triflate. It was found that regardless of the
leaving group the 2-position was more reactive than the
3-position of the pyridine in a palladium-catalyzed cou-
pling reaction.
Cr oss-Cou p lin g betw een 2-Br om op yr id in es
a n d Ar yl Br om id es
Nan Zhang,* Lincy Thomas,1 and Biqi Wu
Chemical Sciences, Wyeth-Ayerst Research,
Pearl River, New York 10965
zhangn@war.wyeth.com
Received October 13, 2000
Palladium-catalyzed coupling reactions between two
aromatic groups, such as the Stille coupling,2 are widely
utilized in organic synthesis. Intermolecular coupling of
2-halopyridines to other aryl halides has attracted con-
siderable interest. Most methods involve a stepwise
process in which anions are generated from one aryl
halide either through bromo-lithium exchange with
n-butyllithium3 or tert-butyllithium4-6 or Grignard reac-
tion with magnesium metal.6,7 The anions formed are
thus quenched with trialkyltin halides to form arylstan-
nanes3 or exchanged with zinc chloride to form arylzinc
halides.4-6 The arylstannanes or arylzinc halides are then
coupled with the other aryl halide catalyzed by palladium
to form the cross-coupled products. Many functional
groups are not tolerated during anion generation.
Two one-pot selective cross-coupling procedures be-
tween 2-pyridyl and aryl groups have been reported. The
first selective cross-coupling8 was reported between equal
molar amounts of 2-pyridyl triflate and a variety of aryl
bromides in the presence of 1 equiv of hexamethylditin
catalyzed by palladium. The cross-coupled 2-aryl-
pyridines were obtained in 35-68% yields. Another
selective cross-coupling was an electrochemical process9
in which a nickel-catalyzed electroreduction of a one to
one mixture of aryl halides and either 2-chloro- or
2-bromopyridine provided 2-arylpyridines in 30-80%
yields. For both processes, the selectivity originated from
different reactivity of the two starting materials. How-
ever, for both methods, no substituent was present on
the 2-pyridyl ring.
On the basis of these results, we took advantage of the
high reactivity of 2-bromopyridines and studied their
coupling reaction with aryl bromides. We now report a
selective, one-pot cross-coupling between 2-bromo-
pyridines and aryl bromides in the presence of 1 equiv
of hexamethylditin catalyzed by palladium. 2-Bromo-
pyridine derivatives are commercially available or can
be readily made. The method is promising toward ap-
plications in combinatorial synthesis, and a variety of
electron-withdrawing substituents are tolerated on the
pyridyl ring. The isolated yields of cross-coupled products
after column chromatography are shown in Table 1.
Coupling of 2-bromopyridine and phenyl bromide
(entry a) gave a 45% yield of the desired cross-coupled
product, 2-phenylpyridine, together with trace quantities
of homo-coupled products, biphenyl and 2,2′-bipyridyl.
The coupling of 2-bromopyridine and 3-bromopyridine
yielded predominantly cross-coupled product (entry b),
in agreement with the observation that the 2-pyridyl
position is more reactive. The reactions of 6-bromonico-
tinaldehyde (entry c) and 6-bromo-2-pyridinecarbalde-
hyde (entry d) were subjected to extensive product
distribution analysis. 1H NMR analysis of the crude
reaction mixtures revealed that the ratios of the desired
cross-coupled product to the homo-coupled bipyridyl
dialdehyde were 6.5:1 and 4:1, respectively. In addition,
a small quantity of biphenyl was also isolated (<15%
mole of the cross-coupled products). The reaction of
2-bromonicotinaldehyde (entry h) gave a much lower
As a part of our ongoing effort in a combinatorial
approach to couple 2-pyridyl groups with a variety of
substituents to aryl groups also with a variety of sub-
stituents, we developed a one-pot, selective intermolecu-
lar cross-coupling between 2-bromopyridines and aryl
(1) Summer Intern from Rutgers University College of Pharmacy,
Piscataway, NJ 08854.
(2) For reviews, see: Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986,
25, 508.
(3) Groenedaal, L.; Frechet, J . M. J . J . Org. Chem. 1998, 63, 5675.
(4) Cooper, K.; Fray, M. J .; Parry, M. J .; Richardson, K.; Steele, J .
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J ackson, W. T.; Marder, P.; Palkowitz, J . A.; Roman, C. R.; Saussy, D.
L.; Schmittling, E. A.; Silbaugh, S. A.; Spaethe, S. M.; Stengle, P. W.;
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(13) Kelly, T. R.; Lang, F. J . Org. Chem. 1996, 61, 4623.
10.1021/jo005682n CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/24/2001

Notes
J . Org. Chem., Vol. 66, No. 4, 2001 1501
Ta ble 1. Cr oss-Cou p lin g betw een 2-Br om op yr id in es a n d Ar yl Br om id es
a
b
Isolated yield. Incomplete reaction. c Tris(dibenzylidineacetone)dipalladium(0) and tri-tert-butylphosphine were used instead of
tetrakis(triphenylphosphine)palladium(0).
yield, probably due to steric hindrance. The desired cross-
coupled product was obtained in 25% yield, together with
a substantial quantity of biphenyl and some unreacted
2-bromonicotinaldehyde.
tetrakis(triphenylphosphine)palladium(0). To our delight,
no major byproduct was observed under these modified
conditions (entries p-r). The desired products were
obtained as the major products, albeit in moderate yields.
We then studied coupling reactions between 6-bro-
monicotinonitrile or 6-bromonicotinaldehyde with sub-
stituted phenyl bromides (entries i-r). The general trend
is that the yields are higher when phenyl bromide is
substituted with electron-withdrawing groups (entries
j-o). This is expected because electron-withdrawing
groups make the aryl bromide more electron-deficient
and thus facilitate the oxidative addition to Pd(0). For
phenyl bromides substituted with electron-donating groups
(3- and 4-bromoanisole and 4-bromotoluene), the desired
coupled products were obtained in much lower yields
(31-40%). A byproduct, 6-phenylnicotinonitrile, was
isolated in substantial quantity (10-40%). This byprod-
uct, not observed in other reactions, probably was formed
due to internal aryl exchange14,15 with triphenylphos-
phine ligand as a result of the low reactivity of the
electron-rich phenyl bromides. We successfully elimi-
nated this byproduct by using tris(dibenzylidineacetone)-
dipalladium(0) and tri-tert-butylphosphine16 instead of
In conclusion, we have demonstrated a selective, one-
pot intermolecular cross-coupling reaction between 2-bro-
mopyridines and aryl bromides using hexamethylditin
and palladium catalyst. 2-Bromopyridine derivatives are
commercially available or can be readily made. The
desired phenylpyridines can be easily separated from the
homo-coupled products, the main side products. The
method is promising toward applications in combinatorial
synthesis, and the desired cross-coupled products can be
obtained in moderate to good yields.
Exp er im en ta l Section
Gen er a l. All reactions were conducted under a nitrogen
atmosphere with magnetic stirring. All reagents and solvents
were commercial grade. Column chromatography was performed
on Baker silica gel (40 µm). Melting points are uncorrected. NMR
spectra were recorded in CDCl3 at 400 MHz for 1H with TMS
as the internal standard and at 100 MHz for 13C with the solvent
as the internal standard. Electrospray mass spectra were
recorded on Micromass Platform or Micromass Quattro. Electron
impact mass spectra were recorded by ionization at 70 eV.
6-Br om on icotin on itr ile (1e). 6-Chloronicotinonitrile (1.38
g, 10 mmol) was heated at 145 °C in phosphorus tribromide (15
mL) for 32 h. After cooling, the mixture was concentrated in
vacuo. To the residue was added phosphorus tribromide (15 mL),
(14) Sakamoto, M.; Shimizu, I.; Yamamoto, A. Chem. Lett. 1995,
1101.
(15) Kwong, F. Y.; Chan, K. S. Organometallics 2000, 19, 2058.
(16) For the use of tris(dibenzylidineacetone)dipalladium(0) and tri-
tert-butylphosphine in Stille coupling, see: Littke, A. F.; Fu, G. C.
Angew. Chem., Int. Ed. 1999, 38, 2411.

1502 J . Org. Chem., Vol. 66, No. 4, 2001
Notes
and the mixture was heated at 145 °C for another 32 h. After
cooling, the mixture was concentrated in vacuo, and an ice-
water mixture (50 mL) was added. Sodium bicarbonate was
added to neutralize the mixture, and the product was extracted
with ethyl acetate (3 × 50 mL). The combined organic extracts
were washed with brine and dried over magnesium sulfate. The
solvent was removed in vacuo, and the residue was chromato-
graphed (hexanes-ethyl acetate) to give 1.49 g (81%) of 6-bro-
monicotinonitrile as a white solid: mp 116-118 °C. 1H NMR
(400 MHz, CDCl3) δ 7.66 (d, J ) 11.0 Hz, 1H), 7.80 (dd, J ) 3.1,
11.0 Hz, 1H), 8.67 (d, J ) 3.1 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 109.2, 115.7, 128.7, 140.7, 146.6, 152.8. Electrospray
MS m/z 183.0, 185.0 (M + H+). Anal. Calcd for C6H3BrN2: C,
39.38; H, 1.65; N, 15.31. Found: C, 39.22; H, 1.82; N, 15.17.
Gen er a l P r oced u r e of th e Cr oss-Cou p lin g. A mixture of
2-bromopyridine 1 (1 mmol), aryl bromide 2 (1 mmol), tetrakis-
(triphenylphosphine)palladium(0) (110 mg, 0.1 mmol), and hexa-
methylditin (327 mg, 1 mmol) in anhydrous 1,4-dioxane (10 mL)
was refluxed under nitrogen for 18 h. The starting 2-bromo-
pyridine was totally consumed as shown by TLC and mass
spectroscopic analysis. The reaction time was not optimized. For
entries p-r, tris(dibenzylidineacetone)dipalladium(0) (61 mg,
0.05 mmol) and tri-tert-butylphosphine (61 mg, 0.3 mmol) were
used instead of tetrakis(triphenylphosphine)palladium(0). The
solvent was removed, and the residue was then separated using
flash column chromatography over silica gel eluting typically
with hexanes-ethyl acetate, providing the coupled product 3.
Yields are given in Table 1. Compounds 3a -3h are known in
the literature.17-23
6-(2-Na p h th yl)n icotin on itr ile (3i): mp 165-167 °C. 1H
NMR (400 MHz, CDCl3) δ 7.57 (m, 2H), 7.90 (m, 1H), 8.01 (m,
4H), 8.15 (dd, J ) 1.8, 8.4 Hz, 1H), 8.56 (d, J ) 1.3 Hz, 1H),
9.00 (dd, J ) 0.9, 2.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
107.8, 117.0, 120.2, 124.1, 126.8, 127.5, 127.7, 127.8, 128.9, 129.0,
133.3, 134.3, 134.6, 139.9, 152.5, 160.4. Electrospray MS m/z
231.1 (M + H+). Anal. Calcd for C16H10N2: C, 83.46; H, 4.38; N,
12.17. Found: C, 83.14; H, 4.75; N, 12.20.
Ack n ow led gm en t. The authors wish to thank Wy-
eth-Ayerst Research management for the support of the
Summer Intern Program. We are very grateful to
Professor Michael J ung (UCLA) for helpful discussions
and suggestions.
Su p p or tin g In for m a tion Ava ila ble: Full characteriza-
tion data for compounds 3j-3r . This material is available free
of charge via the Internet at http://pubs.acs.org.
J O005682N
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