Preparation of 5-brominated and 5,5′-dibrominated 2,2′-bipyridines and 2,2′-bipyrimidines

Article abstract of DOI:10.1021/jo010707j

Efficient syntheses of 5-brominated and 5,5′-dibrominated 2,2′-bipyridines and 2,2′-bipyrimidines, useful for the preparation of metal-complexing molecular rods, have been developed. 5-Bromo-2,2-bipyridine, 5-bromo-5′-n-butyl-2,2′-bipyridine, and 5-bromo-5′-n-hexyl-2,2′-bipyridine were obtained by Stille coupling of 2,5-dibromopyridine with 2-trimethylstannylpyridine or the requisite 5-alkyl-2-trimethylstannylpyridine, obtained via regioselective zincation of a 3-alkylpyridine. BF3 complex in the less hindered of the two reactive positions with lithium di-tert-butyl-(2,2,6,6-tetramethyl-piperidino)zincate. 5,5′-Dibromo-2,2′-bipyridine was obtained by the reductive symmetric coupling of 2,5-dibromopyridine with hexa-n-butyldistannane. The yields of these coupling reactions ranged from 70 to 90%. 5-Bromo- and 5,5′-dibromo-2,2′-bipyrimidines were obtained in yields of 30 and 15%, respectively, by bromination of 2,2′-bipyrimidine, prepared from 2-chloropyrimidine in 80% yield by an improved reductive symmetric coupling procedure.

Full text of DOI:10.1021/jo010707j

J . Org. Chem. 2002, 67, 443-449
443
P r ep a r a tion of 5-Br om in a ted a n d 5,5′-Dibr om in a ted
2,2′-Bip yr id in es a n d 2,2′-Bip yr im id in es
Peter F. H. Schwab, Frank Fleischer, and J osef Michl*
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215
michl@eefus.colorado.edu
Received J uly 16, 2001
Efficient syntheses of 5-brominated and 5,5′-dibrominated 2,2′-bipyridines and 2,2′-bipyrimidines,
useful for the preparation of metal-complexing molecular rods, have been developed. 5-Bromo-2,2′-
bipyridine, 5-bromo-5′-n-butyl-2,2′-bipyridine, and 5-bromo-5′-n-hexyl-2,2′-bipyridine were obtained
by Stille coupling of 2,5-dibromopyridine with 2-trimethylstannylpyridine or the requisite 5-alkyl-
2-trimethylstannylpyridine, obtained via regioselective zincation of a 3-alkylpyridine‚BF3 complex
in the less hindered of the two reactive positions with lithium di-tert-butyl-(2,2,6,6-tetramethyl-
piperidino)zincate. 5,5′-Dibromo-2,2′-bipyridine was obtained by the reductive symmetric coupling
of 2,5-dibromopyridine with hexa-n-butyldistannane. The yields of these coupling reactions ranged
from 70 to 90%. 5-Bromo- and 5,5′-dibromo-2,2′-bipyrimidines were obtained in yields of 30 and
15%, respectively, by bromination of 2,2′-bipyrimidine, prepared from 2-chloropyrimidine in 80%
yield by an improved reductive symmetric coupling procedure.
Sch em e 1
In tr od u ction
In connection with the synthesis of rigid-rod molecules1
containing pyridine and pyrimidine modules, we needed
to use 5-brominated and 5,5′-dibrominated 2,2′-bipyri-
dines and 2,2′-bipyrimidines as starting materials. Al-
though the brominated bipyridine derivatives have been
long known, they were mostly obtained by direct bromi-
nation under harsh conditions and in low yield. We now
report improved access to these building blocks, including
new 5-bromo-2,2′-bipyridines that carry solubilizing alkyl
chains. Very little was known about brominated bipy-
rimidines; we were able to obtain two of them by direct
bromination in low yield.
Sch em e 2
Ch a r t 1
Resu lts a n d Discu ssion
5-Br om in a ted a n d 5,5′-Dibr om in a ted 2,2′-Bip yr -
id in es (Sch em es 1 a n d 2). The best reported synthesis
of 5-bromo-2,2′-bipyridine (1) is the reaction of the 2,2′-
bipyridine (2) dihydrobromide with neat bromine de-
scribed by Ziessel and Romero.2 However, we share the
experience of others3 who obtained very poor results
when following the published procedure. The reaction is
run in a pressurized vessel at 180 °C for 3 days. This
makes it difficult to monitor, and the harsh conditions
cause extensive degradation and formation of many
brominated derivatives. We varied the conditions, but the
major product was always 5,5-dibromo-2,2′-bipyridine (3),
isolated in a poor overall yield. We concluded that a more
efficient method to produce 5-bromo-2,2′-bipyridine (1)
would be useful.
tivity toward oxidative addition in a Pd-catalytic cycle
of a Stille-type coupling reaction.4-8 Indeed, when treated
with 2-trimethylstannylpyridine9 (5) in the presence of
Pd(0)(PPh3)4 at 130 °C, 4 reacted almost exclusively at
the 2-position, yielding the desired product 1 cleanly
It seemed to us that the two bromine substituents in
2,5-dibromopyridine (4) would exhibit differential reac-
(4) Yamamoto, Y.; Azuma, Y.; Mitoh, H. Synthesis 1986, 564.
(5) Malm, J .; Bjoerk, P.; Gronowitz, S.; Hoernfeldt, A. B. Tetrahedron
Lett. 1992, 33, 2199.
* To whom correspondence should be addressed. Fax: 303-492-0799.
(1) Schwab, P. F. H.; Levin, M. D.; Michl, J . Chem. Rev. 1999, 99,
1863.
(2) Romero, F. M.; Ziessel, R. Tetrahedron Lett. 1995, 36, 6471.
(3) Henze, O.; Lehmann, U.; Schlu¨ter, A. D. Synthesis 1999, 683.
(6) Zoltewicz, J . A.; Cruskie, M. P., J r. Tetrahedron 1995, 51, 11393.
(7) Yamamoto, Y.; Tanaka, T.; Yagi, M.; Inamoto, M. Heterocycles
1996, 42, 189.
(8) Fallapour, R.-A. Synthesis 2000, 1665.
(9) Yamamoto, Y.; Yanagi, A. Heterocycles 1981, 16, 1161.
10.1021/jo010707j CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/03/2002

444 J . Org. Chem., Vol. 67, No. 2, 2002
Schwab et al.
(Scheme 1). The stannylated pyridine 5 was prepared
from 2-bromopyridine in high yield by lithiation and
transmetalation, following a procedure published10 for the
synthesis of 2-tributylstannylpyridine. When 4 was used
in slight excess relative to 5, no significant byproducts
were formed. Excess 4 was easily separated from the
crude reaction mixture by sublimation.
A small amount of 5,5′-dibromo-2,2′-bipyridine (3) was
also formed, indicating that a symmetrical coupling of 4
takes place in the presence of an organotin compound
and a Pd(0) catalyst. The bipyridine 3 is a valuable
building block and has seen considerable use as a module
in supramolecular architecture,11,12 and several syntheses
have been published. Burstall first obtained 3 in 193813
by direct bromination of 2,2′-bipyridine hydrobromide
salts in a stream of bromine gas, but as mentioned above,
even the latest variation of the direct bromination
procedure2 only yields a mixture of monobromo and
dibromo derivatives and suffers from harsh conditions
and the uncontrolled nature of the reaction. A high-
temperature Ullmann coupling of 4 is also known,14 but
all of these procedures either are lengthy or suffer from
low yields.
We have therefore examined the observed side reaction
in more detail and found that about 50 mol % hexa-n-
butyldistannane and a catalytic amount of Pd(0) give
superior results (Scheme 2). Other trimethyltin com-
pounds were active but less effective. At lower reactant
ratios, the reaction proceeded much more slowly. No
major side products were formed, and even though the
reaction was rather slow, it was possible to run it on a 5
g scale. In principle, the reaction can be stopped before
it has run to completion because the starting material
can be easily recovered from the crude product mixture
by sublimation. The dibromo derivative 3 was purified
by flash chromatography and crystallization and obtained
in a yield of about 80%. Overall, the method is vastly
superior to the direct bromination procedure and should
be applicable to the synthesis of other symmetrical 5,5′-
disubstituted bipyridine derivatives.
5-Br om o-5′-n -bu tylbip yr id in e. A. 5-n -Bu tyl-2-tr i-
m eth ylsta n n ylp yr id in e (6). The C-alkylation of pyri-
dine derivatives has been a frequently encountered
challenge in organic synthesis, as these compounds are
a part of many natural products, pharmaceuticals, and
ligands.15-18 Even though a few substitution reactions on
halogenated pyridines have been reported for the intro-
duction of alkyl groups, all of them suffer from limited
applicability.19-22 Coupling reactions with organolithium
compounds23 and organocuprates24 are restricted to very
few systems; coupling with Wittig reagents18 and the
Ullmann25 reaction occur only with reactive halides or
under very harsh conditions, and nickel- or palladium-
catalyzed reactions are often accompanied by elimination
reactions on the alkylorganometallic reagents and the
reduction of the aryl halide.
Since it appeared to be the most direct route, we
started with 3 and attempted to substitute one of the
bromines with a n-butyl substituent using two recent
transition-metal-based methods15,22 for the alkylation of
heterocycles. Both produced the desired product in a very
low yield and gave mostly the reduction products 1 and
2,2′-bipyridine (2), presumably because 2,2-bipyridine
interferes with the coupling reaction by binding the
metal; interference by metal ions has been reported in
similar cases.26
We concluded that 3 was not a promising starting
material and decided to prepare a 2-halo-5-alkylpyridine,
stannylate it at position 2, and run a Stille-type coupling
with 2,5-dibromopyridine, taking advantage of the dif-
ferential bromine reactivity described above. Several
routes to 2-halo-5-alkylpyridines appeared feasible. We
did not use 5-alkyl-2-pyridones because none with longer
alkyl chains are commercially available and chose the
deprotonation of 2-alkylpyridines as the most direct path.
3-n-Butylpyridine (7) is commercial, and other 3-alkyl-
pyridines can be easily synthesized on a large scale in
one step. Although a number of literature procedures
were available for the deprotonation of pyridines27-31 and
pyridine-N-oxides,32,33 the selective deprotonation of one
of the two R-positions was not known. As we needed to
deprotonate exclusively at position 6, we searched for an
encumbered base to take advantage of the steric hin-
drance provided by the alkyl group. Our first choice,
lithium 2,2,6,6-tetramethylpiperidide (LiTMP),34 reacts
with trimethylstannyl chloride, and thus a large excess
of both the base and the trapping electrophile was
necessary to achieve a ∼50% yield of 6 by 1H NMR.
Attempted separation of the product from the reagents
resulted in the loss of the SnMe3 group. Our second
choice, the uncharged and sterically very hindered phos-
phazene base P4-tert-butyl (8) developed by Schwesing-
(20) (a) Pridgen, L. N. J . Heterocycl. Chem. 1980, 17, 1289. (b)
Pridgen, L. N. J . Heterocycl. Chem. 1975, 12, 443.
(21) Thorsett, E. D.; Stermitz, F. R. J . Heterocycl. Chem. 1973, 10,
243.
(22) Tamao, K.; Kodama, S.; Nakajima, I.; Kumada, M.; Minato, A.;
Suzuki, K. Tetrahedron 1982, 38, 3347.
(23) For example, see: Hay, J . V.; Wolfe, J . F. J . Am. Chem. Soc.
1975, 97, 3702.
(24) (a) Posner, G. H. Org. React. 1975, 22, 253. (b) Manhas, M. S.;
Sharma, S. D. J . Heterocycl. Chem. 1971, 8, 1051.
(25) Fanta, P. E. Synthesis 1974, 9.
(26) Grosshenny, V.; Romero, F. M.; Ziessel, R. J . Org. Chem. 1997,
62, 1491.
(27) Marsais, F.; Breant, P.; Ginguene, A.; Queguiner, G. J . Orga-
nomet. Chem. 1981, 216, 139.
(28) Taylor, S. L.; Lee, D. Y.; Martin, J . C. J . Org. Chem. 1983, 48,
4156.
(29) Kessar, S. V.; Singh, P.; Singh, K. N.; Dutt, M. J . Chem. Soc.,
Chem. Commun. 1991, 570.
(10) Peters, D.; Ho¨rnfeldt, A.-B.; Gronowitz, S. J . Heterocycl. Chem.
1990, 27, 2165.
(11) (a) Suffert, J .; Ziessel, R. Tetrahedron Lett. 1991, 32, 757. (b)
Grosshenny, V.; Ziessel, R. Tetrahedron Lett. 1992, 33, 8075. (c)
Grosshenny, V.; Ziessel, R. J . Chem. Soc., Dalton Trans. 1993, 817.
(d) Benniston, A. C.; Grosshenny, V.; Harriman, A.; Ziessel, R. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1884. (e) Grosshenny, V.; Harriman,
A.; Ziessel, R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2705.
(12) (a) Khatyr, A.; Ziessel, R. J . Org. Chem. 2000, 65, 7814. (b)
Khatyr, A.; Ziessel, R. Tetrahedron Lett. 2000, 41, 3837. (c) Harriman,
A.; Hissler, M.; Khatyr, A.; Ziessel, R. Chem. Commun. 1999, 735.
(13) Burstall, F. H. J . Chem. Soc. 1938, 1662.
(30) Gros, P.; Fort, Y.; Caube´re, P. J . Chem. Soc., Perkin Trans. 1
1997, 3597.
(31) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J . Am. Chem.
Soc. 1999, 121, 3539.
(14) Case, F. H. J . Am. Chem. Soc. 1946, 68, 2574.
(15) Bell, T. W.; Hu, L.-Y.; Patel, S. V. J . Org. Chem. 1987, 52, 3847.
(16) Schultz, A. G.; Flood, L.; Springer, J . P. J . Org. Chem. 1986,
51, 838.
(17) Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223.
(18) Taylor, E. C.; Martin, S. F. J . Am. Chem. Soc. 1974, 96, 8095.
(19) Negishi, E.; Luo, F.-T.; Frisbee, R.; Matsushita, H. Heterocycles
1982, 18, 117.
(32) Tagawa, Y.; Hama, K.; Goto, Y.; Hamana, M. Heterocycles 1995,
40, 809.
(33) Mongin, O.; Rocca, P.; Thomas-dit-Dumont, L.; Tre´court, F.;
Marsais, F.; Godard, A.; Que´guiner, G. J . Chem. Soc., Perkin Trans. 1
1995, 2503.
(34) Turck, A.; Ple´, N.; Tallon, V.; Que´guiner, G. Tetrahedron 1995,
51, 13045.

Brominated 2,2′-Bipyridines and 2,2′-Bipyrimidines
J . Org. Chem., Vol. 67, No. 2, 2002 445
Sch em e 3
Sch em e 4
er,35 did not react with trimethylstannyl chloride at room
temperature, permitting us to add the base to the
pyridine derivative in the presence of the trapping agent.
However, 8 failed to deprotonate the pyridine, and no
reaction was observed.
We next attempted to increase the acidity of the
hydrogen in position 6. 3-n-Butylpyridine-N-oxide was
deprotonated by 8 at position 6, and we were able to
capture the anion with trimethylstannyl chloride to
obtain the stannylated pyridine-N-oxide 9. However, we
were subsequently unable to reduce the N-oxide without
losing the C-Sn bond at the same time. Since 9 failed to
couple with 4, we abandoned this approach.
the base was employed. However, with 2 equiv of TMP-
zincate, we observed a clean conversion of the starting
material to 13 (Scheme 4). The alternative structure, 3-n-
butyl-2-iodopyridine (14), was excluded by NOE NMR:
irradiation of the benzylic methylene protons enhances
the signals of two ring protons, H4 and H6, and irradia-
tion of H6 only enhances the signals of the benzylic
protons and the methylene protons next to them. Com-
pound 13 appeared to be stable in solution as judged by
1H NMR, but upon evaporation of the solvent, it turned
dark orange, indicating partial decomposition. We were
unable to isolate it pure in neat form.
When trimethylstannyl chloride was used instead of
iodine as the trapping agent, only one product was formed
Inspired by a report by Kessar et al.,29 who used the
easily formed and easily hydrolyzed BF3 complex to
activate the pyridine ring and synthesize R-pyridyl
alcohols, and by a study32 describing a deprotonation of
pyridine‚BF3 complexes with LiTMP/TMEDA, we then
attempted to deprotonate under these conditions and trap
the anion with iodine to obtain a more stable product that
could be converted to the desired trimethylstannyl de-
rivative in a subsequent step. However, after hydrolysis,
this reaction yielded an iodo-5,5′-di-n-butyl-2,2′-bipyri-
1
and the H NMR spectrum clearly showed a singlet in
the region where the resonance of the proton located next
to the ring nitrogen is expected. However, the separation
of 2-trimethylstannyl-5-n-butylpyridine (6) from the zin-
cate and its further purification proved to be difficult
because of its low stability, and it is preferable to obtain
the trimethylstannyl derivative 6 by metal-halogen
exchange from the purified iodo compound 13 (Scheme
4). The use of diethyl ether as the solvent gave better
results than the use of THF. A solution in xylenes is
easier to store for an extended period than the neat
compound.
B. Cou p lin g of 6 a n d 4 (Sch em e 1). Stille-type
coupling of 6 and 4 to 5-bromo-5′-n-butylbipyridine (15)
was accomplished by applying the procedure described
above for 2-trimethylstannylpyridine; however, the yield
was lower, and a considerable amount of 3 was isolated
along with 3-n-butylpyridine (7). Clearly, 4 was depleted
due to symmetric coupling and the unreacted 6 decom-
posed during the workup. No coupling through bromine
in position 5 was observed, even when there was no 4
left in the reaction mixture. When excess 4 was used,
the yield of 15 improved to a value similar to that
observed above in the absence of the butyl group. 5,5′-
Dibromobipyridine (3) was still formed in a considerable
amount but could be separated by column chromatogra-
phy, and excess 4 was easily recovered by sublimation.
The comparison of the 1H and 13C NMR spectra with
those of 4 gave conclusive evidence of the structure and
therefore indirectly confirmed the structural assignment
of 13 in the previous step as well.
1
dine, most likely the 3-iodo isomer 10 judging by the H
NMR spectrum (Scheme 3). Formation of 2,2′-bipyridine
from pyridine was previously reported by Gros et al.30
after treatment with BuLi/LiDMEA and by Tagawa et
al.32 after treatment with LiTMP, but Tagawa’s group
claimed that this reaction could be suppressed when
the pyridine‚BF3 complex was used in the presence of
TMEDA. However, in our case, deprotonation of the 3-n-
butylpyridine‚BF3 complex (11) at position 6 was appar-
ently followed by a nucleophilic attack by the resulting
anion on the 6 position of another molecule of the
pyridine‚BF3 complex. The remaining base then probably
deprotonated the resulting 5,5′-dibutyl-2,2′-bipyridine at
position 3, and the resulting anion was finally trapped
with I2. Indeed, Zoltewicz and Dill36 recently reported an
ortho lithiation of 2,2′- and 2,4′-bipyridines with LiTMP
followed by quenching with various electrophiles, and
among the compounds they obtained was 3-iodo-2,2′-
bipyridine.
We finally turned to a new base, lithium di-tert-butyl-
(2,2,6,6-tetramethylpiperidino)zincate (TMP-zincate, 12),
useful for the chemoselectively directed ortho metalation
of alkyl benzoates and direct R-metalation of π-deficient
aza-aromatics.33,37 This base permits a conversion of
pyridine to 2-iodopyridine in 76% yield. When we applied
the procedure to 7, we obtained a product mixture whose
1H NMR suggested the presence of 50% starting material
and several monoiodinated isomers but only about 5%
of the expected 5-n-butyl-2-iodopyridine (13). When we
activated positions 2 and 6 by using the 3-n-butylpyridine‚
BF3 complex 11, there was no reaction when 1 equiv of
5-Br om o-5′-n -h exylbip yr id in e. The treatment of
3-n-hexylpyridine (16) with 2 equiv of the TMP-zincate
base, followed by quenching with iodine, yielded a single
product characterized as 5-hexyl-2-iodopyridine (17) by
1
comparison of its H and 13C NMR spectra with those of
13. When the progress of the reaction was followed closely
by 1H NMR, the formation and disappearance of an
intermediate became obvious. This species has a sym-
metrical peak pattern in the aromatic region and a
shifted peak with a changed splitting pattern for the
benzylic protons on the hexyl chain. We did not investi-
gate this intermediate further, but its appearance sug-
gests that the reaction is more complex than a mere
deprotonation followed by electrophile trapping. Product
(35) Schwesinger, R.; Willaredt, J .; Schlemper, H.; Keller, M.;
Schmitt, D.; Fritz, H. Chem. Ber. 1994, 127, 2435.
(36) Zoltewicz, J . A.; Dill, C. D. Tetrahedron 1996, 52, 14469.
(37) Kondo, Y.; Fujinami, M.; Uchiyama, M.; Sakamoto, T. J . Chem.
Soc., Perkin Trans. 1 1997, 799.

446 J . Org. Chem., Vol. 67, No. 2, 2002
Schwab et al.
Sch em e 5
uct since bromine had to be used in excess in order to
ensure a reasonable reaction rate. Milder bromination
agents such as NBS did not yield any brominated
products. Fortunately, the separation of 21 from 22 was
facile because the latter is poorly soluble in most organic
solvents. A saturated solution of the mixture in chloro-
form contained an ∼95:5 mixture of 21 and 22, easily
separated by flash chromatography, while the residual
solid consisted solely of 22.
17 was stable in solution but decomposed slightly when
neat. As a result, attempts to obtain an elemental
analysis were unsuccessful, but the HRMS clearly proved
the composition.
The iodine was cleanly exchanged to form 5-n-hexyl-
2-trimethylstannylpyridine (18) by halogen-metal ex-
change using BuLi and transmetalation with trimethyl-
stannyl chloride at -78 °C in diethyl ether (Scheme 4).
Again, we did not isolate the trimethylstannyl derivative
18 in pure form due to its inherent instability; we simply
separated the inorganic salts formed in the reaction by
precipitation and transferred the compound in dry xy-
lenes for reaction with 4 under Pd(0) catalysis to yield
the desired 5-bromo-5′-n-hexylbipyridine (19) in good
yield (Scheme 1). It was again necessary to use an excess
of 4 in order to compensate for the loss due to symmetric
coupling.
Con clu sion
We have developed efficient syntheses of 5-brominated
and 5,5′-dibrominated bipyridine and of 5′-n-butyl- and
5′-n-hexyl-substituted 5-bromobipyridine. We also report
low-yield but still practical syntheses of 5-brominated and
5,5′-dibrominated bipyrimidine. These compounds are
useful for the synthesis of rodlike heterocyclic structures.
In the process, we have found a procedure for selective
deprotonation of 3-n-alkylpyridines at position 6 with
lithium di-tert-butyl-(2,2,6,6-tetramethylpiperidino)zin-
cate (23) as a mild bulky base.
5-Br om in a ted a n d 5,5′-Dibr om in a ted 2,2′-Bip y-
r im id in es (Sch em e 5). Since bromination of 2,2′-bipy-
rimidine (20) is expected38 to occur in the desired po-
sitions, we decided to try this admittedly harsh procedure
first. We also considered the synthesis of 5-bromo-2,2′-
bipyrimidine (21) and 5,5′-dibromo-2,2′-bipyrimidine (22)
by a coupling similar to that shown for 1 and 3 in
Schemes 1 and 2, respectively, but were discouraged by
the reported39 instability of the starting 2,5-dibromopy-
rimidine. The possible alternative, 2-iodo-5-bromopyrim-
idine,39 requires a rather elaborate synthesis itself. For
the direct bromination, simple access to 2,2′-bipyrimidine
(20) in large amounts was clearly essential. To run the
reaction on a multigram scale, we found it necessary to
adjust the procedure published by Nasielski et al.,40
which is based on reductive coupling of 2-chloropyrimi-
dine, in the following three respects. (i) The starting
2-chloropyrimidine was sublimed immediately prior to
use. (ii) A half equivalent of the nickel reagent with
respect to the product was used. This amount is most
likely required because the nickel ion is deactivated when
it is complexed to two bipyrimidine units. (iii) In the
workup of the reaction, EDTA disodium salt was added
to the aqueous layer and 20 was recovered by repeated
extractions with chloroform. This ligand was necessary
since the metal complexes of 20 are very water soluble
and could not be extracted into an organic layer. With
these modifications, the yield of 20 exceeds 80% when
the reaction is run on a multigram scale.
Exp er im en ta l Section
All reactions were carried out under an argon atmosphere
with dry solvent, freshly distilled under anhydrous conditions
unless otherwise noted. Standard Schlenk and vacuum line
techniques were employed for all manipulations of air- or
moisture-sensitive compounds. Yields refer to isolated, chro-
matographically and spectroscopically homogeneous materials,
unless otherwise stated.
Melting points were determined with a Laboratory Devices
MEL-TEMP II apparatus and are uncorrected. 1H and 13C
NMR spectra were acquired with a Varian Unity Inova 500
spectrometer and referenced to residual 1H and 13C present
in deuterated solvents. All NMR spectra were recorded at room
temperature. IR spectra were recorded with a Nicolet Avatar
320 FT-IR spectrometer. GC MS spectra were measured with
an HP GC/MS 5988A instrument with a fused silica capillary
column (cross-linked 5% phenyl methyl silicone). EI+MS
spectra were measured with
a VG 7070 EQ-HF Hybrid
Tandem Mass spectrometer. FAB measurements were con-
ducted with a Fisons Instruments VG autospec instrument.
ESI spectra were acquired with a Hewlett-Packard 59987A
Electrospray instrument connected to a HP 5989B Mass
Spectrometer. Elemental Analyses were performed by Desert
Analytics, Tucson, AZ, and Galbraith Laboratories, Knoxville,
TN.
2,5-Dibromopyridine and 2-chloropyrimidine were pur-
chased from Aldrich and sublimed prior to use. 2-Bromopyri-
dine, 3-bromopyridine, and 3-n-butylpyridine were purchased
from Aldrich and distilled from CaH2 prior to use. t-BuLi,
n-BuLi, 2,2,6,6-tetramethylpiperidine, ZnCl2, Me3SnCl, and
Pd(PPh3)4 were purchased from Aldrich and used without
further purification. THF, diethyl ether, and hydrocarbon
solvents were dried by distillation from sodium metal.
5-Br om o-2,2′-bip yr id in e (1).2 2,5-Dibromopyridine (4, 12.3
g, 0.052 mol) was charged into a flask, evacuated, and put
under argon. The 2-trimethylstannylpyridine (5, 11.5 g, 0.047
mol) obtained as described below was transferred under argon
with dry m-xylene (100 mL), and argon gas was bubbled
through the solution for 1 h. Then, Pd(PPh3)4 (0.547 g, 1 mol
%) was added from a tip tube, and the reaction mixture was
heated while stirring for 12 h at 120 °C and poured into 2 M
NaOH. The phases were separated, and the aqueous layer was
extracted with toluene (2 × 25 mL). The combined organic
phases were dried over Na2SO4 and evaporated under reduced
pressure. The solid crude product was chromatographed
(alumina, 5:1 hexanes/ethyl acetate), and 1 was isolated as a
white crystalline powder: 8.61 g (78%); mp 73 °C (lit.2 74-75
The bromination step was accomplished by heating 20
with bromine in nitrobenzene to 135 °C. Unfortunately,
at this temperature, considerable degradation of the
starting material was observed and the yield of the
reaction was rather low, but there was no reaction at
lower temperatures. Even when we tried to favor the
formation of the singly brominated product 21, 5,5′-
dibromo-2,2′-bipyrimidine (22) was a substantial byprod-
(38) Advances in Organobromine Chemistry I, Industrial Chemistry
Library, ; Desmurs, J .-R., Gerard, B., Eds.; Elsevier: Amsterdam, 1991;
Vol. 3.
(39) Goodby, J . W.; Hird, M.; Lewis, R. A.; Toyne, K. J . J . Chem.
Soc., Chem. Commun. 1996, 2719.
(40) Nasielski, J .; Standaert, A.; Nasielski-Hinkins, R. Synth. Com-
mun. 1991, 21, 901.
1
°C); H NMR (CDCl3, 300 MHz) δ 7.29 (ddd, J ) 7.4 Hz, J )

Brominated 2,2′-Bipyridines and 2,2′-Bipyrimidines
J . Org. Chem., Vol. 67, No. 2, 2002 447
4.8 Hz, J ) 1.0 Hz, 1 H, H5′), 7.79 (td, J ) 7.4 Hz, J ) 1.8 Hz,
1 H, H4′), 7.90 (dd, J ) 2.4 Hz, J ) 8.5 Hz, 1 H, H4), 8.29 (d,
J ) 8.5 Hz, 1 H, H3′), 8.34 (d, J ) 8.5 Hz, 1 H, H3), 8.64 (dt,
J ) 4.8 Hz, J ) 1.0 Hz, 1 H, H6′), 8.69 (d, J ) 2.4 Hz, 1 H,
H6). Romero and Ziessel2 reported a 13C NMR spectrum with
only 9 signals; our data reveal the expected 10 peaks: 13C {1H}
NMR (CDCl3, 124 MHz) δ 120.92 (Cbipy), 121.09 (Cbipy-Br),
122.29 (Cbipy), 123.96 (Cbipy), 136.97 (Cbipy), 139.45 (Cbipy), 149.21
(Cbipy), 150.15 (Cbipy), 154.58 (Cbipy), 155.13 (Cbipy).
mL). The combined organic layers were dried over Na2SO4,
and the solvents were evaporated. The crude product mixture
was separated by PTLC (silica, 5:1 hexanes/ethyl acetate).
Some unreacted 7 was also recovered (15 mg, 10%), but the
main product isolated was 5,5′-dibutyl-3-iodo-2,2′-bipyridine
as a yellow-orange oil (10, 137 mg, 69%): 1H NMR (CDCl3,
300 MHz) δ 0.80 (t, 3 H, J ) 7.3 Hz), 0.87 (t, 3 H, J ) 7.3 Hz),
1.25 (m, 2 H), 1.35 (m, 2 H), 1.47 (m, 2 H), 1.61 (m, 2 H), 2.64
(t, 2 H, J ) 7.7 Hz), 2.82 (t, 2 H, J ) 7.7 Hz), 7.57 (d, 1 H,
J ) 2.1 Hz), 7.62 (d, 1 H, J ) 8.1 Hz), 7.92 (d, 1 H, J ) 2.1
Hz), 8.45 (s, 1 H), 8.67 (d, 1 H, J ) 2.1 Hz); 13C {1H} NMR
(CDCl3, 124 MHz) δ 13.69 (CH3-), 13.79 (CH3-), 22.12
(-CH2-), 22.39 (-CH2-), 31.94 (-CH2-), 32.47 (-CH2-),
32.79 (-CH2-pyr), 33.11 (-CH2-pyr), 92.67 (C-I), 123.56
(Cpyr-H), 136.39 (Cpyr-H), 137.24 (Cpyr-H), 139.31 (Cpyr-H),
146.05 (Cpyr-H), 148.63 (Cpyr-H), 152.33 (Cpyr-H), 155.09
(Cpyr-H), 155.55 (Cpyr-H); MS (EI+) m/z (rel intensity) 394
([M]+, 45), 365 ([M - C2H5]+, 100), 351 ([M - C3H7]+, 15), 322
(5), 308 (3), 267 ([M - I]+, 4), 238 (6), 195 (5), 128 ([I]+, 3), 77
(2); IR (KBr) 634, 750, 789, 848, 866, 888, 901, 931, 1026, 1039,
1079, 1109, 1130, 1155, 1193, 1259, 1305, 1378, 1431, 1463,
1485, 1531, 1568, 1595, 2857, 2928, 2956, 3031; HRMS calcd
394.0906, found 394.0921.
5,5-Dibr om o-2,2′-bip yr id in e (3).2 2,5-Dibromopyridine (4,
1.00 g, 4.33 mmol) was charged into a flask, evacuated, and
put under argon. Anhydrous m-xylene (35 mL) was added from
a syringe, followed by hexa-n-butyldistannane (1.18 mL, 50
mol %). Argon was bubbled through the stirred solution for 1
h before Pd(PPh3)4 (0.117 g, 0.101 mmol) was added from a
tip tube. The reaction mixture was heated to 130 °C for 3 days
until all starting material was consumed and poured into
aqueous EDTA (1 M, 25 mL). After the mixture was stirred
for 15 min, the phases were separated. The aqueous phase was
extracted with chloroform (3 × 50 mL), and the combined
organic phases were dried over Na2SO4. After evaporation of
the solvents, the crude product was flash chromatographed
(alumina, 5:1 hexanes/ethyl acetate), yielding 5,5-dibromo-2,2′-
1
bipyridine (3) as a white solid (95% by H NMR, 0.52 g, 78%).
5-n -Bu tyl-2-iod op yr id in e (13). Freshly distilled 3-n-bu-
tylpyridine (7, 2.5 g, 0.0185 mol) was rinsed into a flask with
dry ether (25 mL) and cooled to 0 °C under stirring. BF3
etherate (2.5 mL, 0.019 mol) was added dropwise, and the
mixture was stirred at 0 °C for 2 h. In the meantime, ZnCl2
(0.5 M in THF, 67.2 mL) was placed in a separate flask and
cooled to -78 °C under stirring. Under argon, t-BuLi (1.7 M
in pentane, 58 mL, 0.0983 mol) was added dropwise but
rapidly, and the clear, yellow reaction mixture was slowly
warmed to room temperature and stirred for 15 min before
recooling to -78 °C. In a third flask, 2,2,6,6-tetramethylpi-
peridine (6.9 mL, 0.0407 mol) was put under argon and cooled
to 0 °C. Under stirring, n-BuLi (1.6 M in hexanes, 26.0 mL)
was added dropwise, and the reaction mixture was stirred for
30 min before warming up to room temperature. After 30 min,
the flask was cooled to -78 °C under continued stirring and
the di-tert-butylzinc solution was added slowly through a
cannula over 20 min. The mixture was stirred vigorously until
all solids were dissolved, yielding a clear, yellow solution. The
solution was stirred for 30 min at -78 °C before warming to
room temperature for 15 min. After the solution was recooled
to -78 °C, the ether solution of the pyridine‚BF3 complex was
added through a cannula in small portions. The reaction
mixture turned orange immediately and then brown. The
reaction mixture was stirred for 2 h at -78 °C at which time
the color had turned to dark red. In a fourth flask, freshly
sublimed iodine (18.8 g, 0.074 mol) was placed under argon,
dissolved in dry diethyl ether (100 mL), and cooled to 0 °C.
The solution was added to the pyridinium zincate through a
cannula over 5 min. Then, the reaction mixture was slowly
warmed to room temperature overnight and poured into a
saturated aqueous solution of sodium sulfite (100 mL). Fol-
lowing vigorous mixing, the two layers were separated and
the aqueous layer was extracted with diethyl ether (3 × 50
mL). The combined organic layers were washed once more with
sodium sulfite solution (2 × 50 mL), and after drying over Na2-
SO4, the organic solvents were evaporated under reduced
pressure. The crude product was chromatographed (alumina,
10:1 hexanes/ethyl acetate), and 13 was recovered as a
The product 3 was further purified by PTLC (alumina, 8:1
hexanes/ethyl acetate) and obtained as colorless plates after
recrystallization from chloroform: mp 201 °C (lit.2 205 °C);
1H NMR (CDCl3, 300 MHz) δ 7.91 (dd, J ) 2.4 Hz, J ) 8.5 Hz,
2 H, H4), 8.26 (d, J ) 8.5 Hz, 2 H, H3), 8.68 (d, J ) 2.4 Hz, 2
H, H6).
2-Tr im eth ylsta n n ylp yr id in e (5).9 Freshly distilled 2-bro-
mopyridine (8.5 g, 5.2 mL, 0.053 mol) was charged into a flask,
evacuated, and put under argon. Dry diethyl ether (100 mL)
was added from a syringe under stirring, and the solution was
cooled to -78 °C in a dry ice/acetone bath. n-BuLi (2.0 M in
cyclohexane, 29 mL, 0.058 mol) was added dropwise from a
syringe, and the reaction mixture was stirred for 2 h under
continued cooling. Then, trimethylstannyl chloride (1.0 M in
THF, 58 mL, 0.058 mol) was added dropwise from a syringe.
After 3 h, the reaction mixture was allowed to warm slowly to
room temperature overnight. The solvents were evaporated
directly from the reaction flask under reduced pressure. Dry
hexanes (100 mL) were added from a syringe, and the slurry
was stirred for 10 min. Following filtration through a frit under
argon, the hexanes were evaporated under reduced pressure
and the crude product (5, 11.5 g, 88%, 96% purity by 1H NMR)
was used in the next step without further purification: 1H
NMR (CDCl3, 500 MHz) δ 0.33 (s, 9 H, J SnH ) 27 Hz, SnCH3),
7.12 (ddd, 1 H, J ) 6.1 Hz, J ) 4.8 Hz, J ) 1.5 Hz, H5), 7.42
(dt, 1 H, J ) 6.9 Hz, J ) 0.9 Hz, H3), 7.50 (td, 1 H, J ) 6.9
Hz, J ) 1.5 Hz, H4), 8.72 (dt, 1 H, J ) 4.8 Hz, J ) 0.9 Hz,
H6).9
5,5′-Dibu tyl-3-iod o-2,2′-bip yr id in e (10). Freshly distilled,
dry 3-n-butylpyridine (7,135 mg, 0.001 mol) was transferred
by a syringe to a two-neck flask filled with argon. Under
stirring, dry diethyl ether (10 mL) was added from a syringe
and the clear, colorless solution was cooled to 0 °C. Then, BF3
etherate (0.125 mL, 0.001 mol) was added dropwise and the
reaction mixture was stirred at 0 °C for 30 min. In a second
flask, freshly distilled 2,2,6,6-tetramethylpiperidine (0.186 mL,
0.0011 mol) was stirred under argon and cooled to 0 °C in an
ice bath. n-BuLi (2 M in cyclohexane, 0.6 mL, 0.0012 mol) was
added dropwise from a syringe, and the reaction mixture was
stirred for 20 min before the solution was warmed to room
temperature. Dry THF (15 mL) was added from a syringe
along with TMEDA (0.098 mL, 0.0012 mol). The yellow, clear
solution was stirred for 15 min and transferred to a syringe.
Then, the solution containing the pyridine‚BF3 complex was
cooled to -78 °C and the base was added dropwise. The orange-
red solution was stirred for 20 min before freshly sublimed
iodine (550 mg, 0.002 mol) dissolved in diethyl ether (10 mL)
was added via cannula. After stirring for an additional 2 h
below -30 °C, the reaction mixture was poured into aqueous
Na2SO3 and shaken vigorously. The phases were separated,
and the aqueous layer was extracted with chloroform (3 × 15
1
yellowish oil: 3.8 g (79%, 98% purity by 1H NMR); H NMR
(CDCl3, 500 MHz) δ 0.87 (t, J ) 7.3 Hz, 3 H, CH3), 1.30 (m, 2
H, CH2-CH3), 1.52 (m, 2 H, CH2), 2.49 (t, J ) 7.7 Hz, 2 H,
Cpyr-CH2), 7.10 (dd, J ) 8.1 Hz, J ) 2.5 Hz, 1 H, Cpyr-H),
7.56 (d, J ) 8.1 Hz, 1 H, Cpyr-H), 8.25 (d, J ) 2.5 Hz, 1 H,
Cpyr-H); 13C {1H} NMR (CDCl3, 124 MHz) δ 13.73 (CH3-CH2),
22.05 (CH2), 31.94 (CH2), 32.94 (CH2-Cpyr), 114.40 (Cpyr-I),
134.27 (Cpyr), 137.59 (Cpyr), 137.80 (Cpyr), 150.88 (Cpyr); IR
(NaCl) 513, 622, 641, 729, 788, 818, 833, 934, 1019, 1070, 1128,
1210, 1377, 1451, 1552, 1575, 2858, 2929, 2956, 3034 cm-1
MS (EI+) m/z (rel intensity) 261 ([M]+, 35), 218 ([M - C3H7]+,
;

448 J . Org. Chem., Vol. 67, No. 2, 2002
Schwab et al.
12), 167 (3), 149 (13), 134 ([M - I]+, 100), 91 ([M - C3H7I]+,
25), 77 (16), 69 (20), 55 (30); HRMS calcd 261.0015, found
261.0020.
were filtered off and washed thoroughly with diethyl ether (500
mL). The filtrate was washed with NH4OH (14% in water,
2 × 200 mL), and the aqueous layer was extracted with diethyl
ether (3 × 100 mL). The organic phases were combined, dried
over Na2SO4, and concentrated under reduced pressure. The
organic layer was extracted with 2 M HCl (4 × 50 mL). The
aqueous phases were combined and basified with concentrated
NaOH under stirring and cooling with ice. The solution was
transferred to a separatory funnel and extracted with diethyl
ether (4 × 100 mL). The organic layers were combined and
dried over Na2SO4, and the solvent was evaporated under
reduced pressure. The crude liquid was fractionally distilled,
and 3-n-hexylpyridine (16) was collected as a colorless liquid
with a sweet fragrance: 6.2 g, (30%); bp 73 °C at 0.5 Torr; 1H
NMR (CDCl3, 500 MHz) δ 0.85 (t, J ) 7.3 Hz, 3 H, CH3), 1.28
(m, 6 H, C3H6-CH3), 1.59 (m, 2 H, CH2), 2.57 (t, J ) 7.7 Hz,
2 H, Cpyr-CH2), 7.16 (dd, J ) 8.1 Hz, J ) 2.3 Hz, 1 H, H5),
7.45 (dt, 1 H, J ) 8.1 Hz, J ) 2.1 Hz, H4), 8.39 (dd, 1 H, J )
7.7 Hz, J ) 2.1 Hz, H6), 8.41 (s, 1 H, H2).41
5-n -Hexyl-2-iod op yr id in e (17). Freshly distilled 3-n-hex-
ylpyridine (16, 3.02 g, 0.0185 mol) was rinsed into a flask with
dry diethyl ether (25 mL) and cooled to 0 °C under stirring.
BF3 etherate (2.5 mL, 0.019 mol) was added dropwise, and the
mixture was stirred at 0 °C for 2 h.
In the meantime, ZnCl2 (0.5 M in THF, 67.2 mL) was put
in a separate flask and cooled to -78 °C under stirring. t-BuLi
(1.7 M in pentane, 58 mL, 0.098 mol) was added dropwise but
rapidly, and the clear, yellow reaction mixture was slowly
warmed to room temperature and stirred for 15 min before
being recooled to -78 °C.
5-n -Bu tyl-5′-br om o-2,2′-bip yr id in e (15). 5-n-Butyl-2-iodo-
pyridine (13, 2.8 g, 0.0107 mol) was charged into a flask, kept
under vacuum for 20 min, and put under argon. Dry diethyl
ether (100 mL) was added from a syringe, and the solution
was transferred to a two-neck flask through a cannula. The
solution was stirred and cooled to -78 °C with a dry ice/acetone
bath. n-BuLi (2.0 M in cyclohexane, 5.75 mL, 0.0115 mol) was
added dropwise while the color changed from yellow to orange
and finally red when the addition was complete. After stirring
for 1 h, the reaction mixture turned brown. Trimethylstannyl
chloride (1 M in THF, 13 mL, 0.013 mol) was added dropwise
from a syringe, and the solution was allowed to warm to room
temperature overnight. The diethyl ether and THF were
evaporated directly from the reaction flask under reduced
pressure. Dry hexanes (50 mL) were added through a syringe,
and the slurry was stirred for 30 min at room temperature.
The white precipitate was filtered off through a frit under
argon, and the hexanes were evaporated from the filtrate
under vacuum, leaving a brown viscous liquid (3.18 g, 99%,
94% purity by 1H NMR). Dry xylenes were added, and the
crude 5-n-butyl-2-trimethylstannylpyridine (6) was used in the
next step: 1H NMR (CDCl3, 500 MHz) δ 0.31 (s, 9 H, J SnH
27 Hz, SnCH3), 0.90 (t, J ) 7.3 Hz, 3 H, CH3), 1.34 (m, 2 H,
)
CH2-CH3), 1.56 (m, 2 H, CH2), 2.54 (t, J ) 7.7 Hz, 2 H, Cpyr
-
CH2), 7.33 (m, 2 H, H4, H5), 8.57 (s, 1 H, H2); 13C {1H} NMR
(CDCl3, 124 MHz) δ 13.85 (CH3-CH2), 22.22 (CH2), 32.76
(CH2), 33.27 (CH2-Cpyr), 131.18 (Cpyr), 133.58 (Cpyr), 136.46
(Cpyr), 151.01 (Cpyr), 169.51 (Cpyr-SnMe3).
In a third flask, 2,2,6,6-tetramethylpiperidine (6.9 mL, 0.041
mol) was put under argon and cooled to 0 °C. Under stirring,
n-BuLi (1.6 M in hexanes, 26.0 mL) was added dropwise, and
the reaction mixture was stirred for 30 min before warming
up to room temperature. After 30 min, the flask was cooled to
-78 °C under continued stirring and the di-tert-butylzinc
solution was added slowly through a cannula over 20 min. The
mixture was stirred vigorously until all solids were dissolved,
yielding a clear, yellow solution. The solution was stirred for
30 min at -78 °C before warming to room temperature for 15
min. After the solution was recooled to -78 °C, the ethereal
solution of the pyridine‚BF3 complex was added through a
cannula in small portions. The reaction mixture turned orange
immediately and then brown. It was stirred for 3 h at -78 °C,
at which time the color had turned to dark red.
In a fourth flask, freshly sublimed iodine (18.8 g, 0.074 mol)
was placed under argon, dissolved in 100 mL of dry THF, and
cooled to -78 °C. The pyridinium zincate solution was then
slowly added under vigorous stirring. After slowly warming
to room temperature, the reaction mixture was stirred over-
night. Then, the solution was poured into a saturated aqueous
solution of sodium sulfite (100 mL). Following vigorous mixing,
the two layers were separated and the aqueous layer was
extracted with diethyl ether (3 × 100 mL). The combined
organic layers were washed once more with sodium sulfite
solution (2 × 50 mL), and after drying over Na2SO4, the organic
solvents were evaporated under reduced pressure. The crude
product was subsequently chromatographed (alumina, 10:1
hexanes/ethyl acetate), and 5-n-hexyl-2-iodopyridine (17) was
recovered as an orange oil: 4.2 g (78%, 96% purity by 1H
NMR); 1H NMR (CDCl3, 500 MHz) δ 0.89 (t, J ) 7.3 Hz, 3 H,
CH3), 1.28 (m, 6 H, C3H6-CH3), 1.58 (m, 2 H, CH2), 2.55 (t,
J ) 7.7 Hz, 2 H, Cpyr-CH2), 7.14 (dd, J ) 8.1 Hz, J ) 2.3 Hz,
1 H, Cpyr-H), 7.60 (d, J ) 8.1 Hz, 1 H, Cpyr-H), 8.19 (d, J )
2.5 Hz, 1 H, Cpyr-H); 13C {1H} NMR (CDCl3, 124 MHz) δ 13.99
(CH3-CH2), 22.47 (CH2), 28.64 (CH2), 30.81 (CH2), 31.46 (CH2),
32.25 (CH2-Cpyr), 114.41 (Cpyr-I), 134.27 (Cpyr), 137.63 (Cpyr),
137.79 (Cpyr), 150.89 (Cpyr); IR (NaCl) 405, 422, 449, 455, 463,
489, 601, 623, 643, 731, 790, 817, 924, 1020, 1071, 1128, 1211,
1377, 1452, 1552, 1575, 2856, 2928, 2955, 3034 cm-1; MS (EI+)
m/z (rel intensity) 289 ([M]+, 55), 250 (13), 218 ([M - C5H11]+,
17), 162 ([M - I]+, 100), 149 (8), 128 (18), 91 ([M - C5H11I]+,
25), 77 (16), 69 (20), 55 (30); HRMS calcd 289.0328, found
289.0324.
2,5-Dibromopyridine (4, 3.02 g, 0.0128 mol) was charged into
a flask, evacuated, and put under argon. The crude 6 prepared
above (3.18 g, 0.0107 mol) in dry xylenes (75 mL) was added
through a cannula, and argon gas was bubbled through the
solution for 2 h. Then, Pd(PPh3)4 (400 mg, 0.346 mmol) was
added from a tip tube. The reaction mixture was stirred at
120 °C for 16 h and subsequently poured into 2 M NaOH (50
mL) saturated with ETDA. The two layers were separated,
and the aqueous layer was extracted with diethyl ether (3 ×
50 mL). The combined organic layers were dried over Na2SO4,
and the solvents were evaporated under reduced pressure. The
crude product was chromatographed (alumina, 15:1 hexanes/
ethyl acetate) and 5-bromo-5′-n-butyl-2,2′-bipyridine (15) was
1
recovered as a colorless oil: 2.45 g, (79%); H NMR (CDCl3,
500 MHz) δ 0.92 (t, J ) 7.3 Hz, 3 H), 1.35 (m, 2 H), 1.62 (m,
2 H), 2.64 (t, J ) 7.8 Hz, 2 H), 7.58 (dd, J ) 7.8 Hz, J ) 2.2
Hz, 1 H), 7.88 (dd, J ) 8.5 Hz, J ) 2.4 Hz, 1 H), 8.25 (dd, J )
8.5 Hz, J ) 2.2 Hz, 2 H), 8.46 (s, 1 H), 8.68 (s, 1H); 13C {1H}
NMR (CDCl3, 124 MHz) δ 13.85 (CH3-CH2), 22.20 (CH2), 32.57
(CH2), 33.16 (CH2-Cpyr), 120.59 (Cbipy), 120.68 (Cbipy), 122.06
(Cbipy), 136.86 (Cbipy), 138.66 (Cbipy-Cbu), 139.41 (Cbipy), 149.39
(Cbipy), 150.10 (Cbipy), 152.82 (Cbipy), 154.81 (Cbipy); IR (NaCl)
633, 649, 735, 836, 920, 1005, 1025, 1056, 1090, 1130, 1242,
1269, 1364, 1399, 1454, 1545, 1565, 1594, 2858, 2930, 2957,
3003, 3043 cm-1; MS (EI+) m/z (rel intensity) 290 ([M]+, 75),
275 ([M -CH3]+, 3), 261 ([M - C2H5]+, 10), 247 ([M - C3H7]+,
100), 234 (3), 220 (7), 181 (4), 168 (9), 154 (3), 141 (25), 115
(5), 77 (5), 55 (5); HRMS calcd 290.0419, found 290.0428. Anal.
Calcd for C14H15N2Br: C, 57.75; H, 5.19; N, 9.62. Found: C,
58.00; H, 5.24; N, 9.53.
3-n -Hexylp yr id in e (16).41 Into a 2 L three-neck flask was
placed CuBr (71.7 g, 0.5 mol) under argon, and dry THF (500
mL) was added. The suspension was cooled to -78 °C, and
n-hexylmagnesium bromide (2 M in diethyl ether, 500 mL, 1.0
mol) was added dropwise over 1 h under mechanical stirring.
After additional stirring for 30 min, freshly distilled 3-bro-
mopyridine (19.8 g, 0.125 mol) was added dropwise from a
syringe. The reaction mixture was kept at -78 °C for 30 min,
warmed to -25 °C, and then stirred overnight. After the
mixture was warmed to room temperature, the black solids
(41) Tereshko, A. B.; Tarasevich, V. A.; Kozlov, N. G. Zh. Org. Khim.
1995, 31, 289.

Brominated 2,2′-Bipyridines and 2,2′-Bipyrimidines
J . Org. Chem., Vol. 67, No. 2, 2002 449
5-Br om o-5′-n -h exyl-2,2′-bip yr id in e (19). 5-n-Hexyl-2-io-
dopyridine (17, 3.2 g, 0.011 mol) was charged into a flask, kept
under vacuum for 20 min, and put under argon. Dry diethyl
ether (100 mL) was added from a syringe, and the solution
was transferred to a two-neck flask through a cannula. The
solution was stirred and cooled to -78 °C with a dry ice/acetone
bath. n-BuLi (2.0 M in cyclohexane, 5.75 mL, 0.012 mol) was
added dropwise while the color changed from yellow to orange
and finally to red when the addition was complete. The
reaction mixture was stirred for 2 h and gradually turned
brown. Then, trimethylstannyl chloride (1 M in THF, 13 mL,
0.013 mol) was added dropwise from a syringe and the solution
was allowed to warm to room temperature overnight. The
diethyl ether and THF were evaporated directly from the
reaction flask under reduced pressure. Dry hexanes (50 mL)
were added through a syringe, and the slurry was stirred for
30 min at room temperature. The white precipitate was filtered
off through a frit under argon, and the hexanes were evapo-
rated from the filtrate under vacuum, leaving a brown viscous
Torr, 60 °C) 2-chloropyrimidine (40 g, 0.35 mol) was added
through a funnel under argon and the solution turned darker.
It was stirred vigorously for 1 h at room temperature, heated
to 50 °C for 50 h, and filtered through Celite. After being
washed with chloroform, the filtrate was evaporated under
reduced pressure. The dark green crude solid was suspended
in a solution of EDTA (150 g) in aqueous NH3 (400 mL, 7%).
The aqueous layer was extracted with diethyl ether (3 × 200
mL) and subsequently with chloroform (8 × 150 mL). The
organic solvents were dried over Na2SO4 and evaporated under
reduced pressure. The ether extract contained almost pure
triphenylphosphine. The chloroform extract yielded 20 as a
yellow solid, which was recrystallized from ethanol as off-white
1
plates: 22.5 g (82%), mp 112 °C (lit.42 113-115 °C); H NMR
(CDCl3, 300 MHz) δ 7.44 (t, 4 H, J ) 5.1 Hz, H4, H6), 9.02 (d,
2 H, J ) 5.1 Hz, H5).
5-Br om o-2,2′-bip yr im id in e (21). 2,2′-Bipyrimidine (20, 8
g, 0.051 mol) was placed in a two-neck flask, evacuated, and
put under argon. Freshly distilled nitrobenzene (125 mL) was
added from a syringe, and the solution was stirred at room
temperature until the solid was dissolved. Bromine (10 mL,
3.12 g, 0.19 mol) was added from a pipet, and the reaction
mixture was stirred at 135 °C for 48 h. Most of the nitroben-
zene (100 mL) was then evaporated under reduced pressure,
and the remaining solution was poured into saturated aqueous
Na2SO3. After vigorous mixing, the layers were separated and
the aqueous layer was extracted with chloroform (3 × 50 mL).
The organic phases were combined and washed with aqueous
ammonia (2 M, 1 × 50 mL). After the combined phases were
dried over Na2SO4, the solvents were evaporated under
reduced pressure. The dark brown residue was flash chro-
matographed (alumina, 1:2 hexane/chloroform). The recovered
off-white crude product mixture was washed with chloroform,
leaving most of the 5,5′-dibromo-2,2′-bipyrimidine (22) undis-
solved, and then chromatographed (silica, chloroform) to obtain
5-bromo-2,2′-bipyrimidine (21) as a white solid, which crystal-
lized from chloroform as large colorless prisms: 3.7 g, (30%)
1
liquid (3.38 g, 95%, purity 94% by H NMR). Dry xylenes were
added, and the crude 5-n-hexyl-2-trimethylstannylpyridine
(18) was used without further purification in the next step:
1H NMR (CDCl3, 500 MHz) δ 0.31 (s, 9 H, J SnH ) 27 Hz,
SnCH3), 0.85 (t, J ) 7.3 Hz, 3 H, CH3), 1.28 (m, 6 H, C3H6-
CH3), 1.58 (m, 2 H, CH2), 2.55 (t, J ) 7.7 Hz, 2 H, Cpyr-CH2),
7.33 (m, 2 H, H4, H5), 8.57 (s, 1 H, H2).
2,5-Dibromopyridine (4, 4.05 g, 0.0171 mol) was charged into
a 250 mL three-neck flask, evacuated, and put under argon.
Through a cannula, the crude 18 (3.38 g, 0.0104 mol) dissolved
in anhydrous m-xylene (100 mL) was added under stirring.
Argon gas was bubbled through the solution for 1 h, and
Pd(PPh3)4 (165 mg, 1.25 mol %) was added from a tip tube.
The reaction mixture was stirred at 110 °C for 32 h and poured
into EDTA (1 M in water, 50 mL) to which NH4OH (concen-
trated, 5 mL) had been added. The layers were mixed vigor-
ously and then separated. The aqueous layer was extracted
with diethyl ether (3 × 100 mL). The combined organic phases
were dried over Na2SO4, and the solvents were evaporated
under reduced pressure. The crude product was flash chro-
matographed (alumina), first with hexanes to elute the excess
4, and then with 10:1 hexanes/ethyl acetate to elute the
5-bromo-5′-n-hexyl-2,2′-bipyridine (19) contaminated with 5,5′-
dibromo-2,2′-bipyridine (3) and a small amount of 2,5-dibro-
mopyridine. Compound 4 was sublimed off (0.5 Torr, 75 °C).
The two products were crudely separated in a centrifuge (3200
rpm). Finally, 19 was purified by column chromatography
(silica, 25:1 hexanes/ethyl acetate) and obtained as a colorless
oil that crystallized as a white solid upon standing at room
1
mp 215 °C; H NMR (CDCl3, 500 MHz) δ 7.39 (t, J ) 4.9 Hz,
1 H, C5′bipyrim-H), 9.00 (d, J ) 4.9 Hz, 2 H, C4′bipyrim-H), 9.04
(s, 2 H, C4bipyrim-H); 13C {1H} NMR (CDCl3, 126 MHz) δ 121.56
(C5′), 121.64 (C5), 158.08 (C4′, C6′), 158.70 (C4, C6), 160.14
(C2′), 161.61 (C2); IR (KBr) 431, 642, 705, 764, 807, 837, 925,
991, 1010, 1107, 1138, 1243, 1369, 1384, 1403, 1533, 1562,
2612, 3038 cm-1; MS (EI+) m/z (rel intensity) 236 (bromine
cluster center, isotope pattern fits the calculated cluster for
M, 100), 211 (bromine cluster center, 10), 183 (25), 130 (40),
105 (30), 79 (10), 52 (20); HRMS calcd 235.9698, found
235.9708. Anal. Calcd for C8H5N4Br: C, 40.53; H, 2.13.
Found: C, 40.68; H, 2.06.
1
temperature: 2.32 g (72%); mp 28 °C; H NMR (CDCl3, 500
MHz) δ 0.86 (t, J ) 6.9 Hz, 3 H), 1.29 (m, 6 H), 1.62 (m, 2 H),
2.64 (t, J ) 7.5 Hz, 2 H), 7.60 (dd, J ) 7.0 Hz, J ) 2.2 Hz, 1
H), 7.89 (dd, J ) 8.5 Hz, J ) 2.4 Hz, 1 H), 8.25 (dd, J ) 8.5
Hz, J ) 4.6 Hz, 2 H), 8.46 (d, J ) 1.8 Hz, 1 H), 8.67 (d, J ) 2.4
Hz, 1H); 13C {1H} NMR (CDCl3, 124 MHz) δ 14.05 (CH3-CH2),
22.56 (CH2), 28.79 (CH2), 31.01 (CH2), 31.60 (CH2), 32.87
(CH2-Cpyr), 120.59 (Cbipy), 120.67 (Cbipy), 122.05 (Cbipy-Br),
136.85 (Cbipy), 138.70 (Cbipy-Chex), 139.41 (Cbipy), 149.41 (Cbipy),
150.10 (Cbipy), 152.84 (Cbipy), 154.83 (Cbipy); IR (KBr) 466, 491,
634, 657, 721, 736, 754, 787, 828, 921, 1004, 1020, 1056, 1089,
1128, 1183, 1225, 1355, 1367, 1384, 1427, 1453, 1544, 1565,
1592, 2854, 2925, 2958, 3045 cm-1; MS (EI+) m/z (rel intensity)
318 ([M]+, 55), 303 ([M -CH3]+, 2), 289 ([M - C2H5]+, 5), 275
([M - C3H7]+, 7), 261 ([M - C4H9]+, 15), 247 ([M - C5H11]+,
100), 219 (7), 183 (4), 168 (15), 154 (5), 141 (25), 115 5), 77 (5),
55 (5); HRMS calcd 318.0732, found 318.0720. Anal. Calcd for
5,5′-Dibr om o-2,2′-bip yr im id in e (22). Compound 22 was
recrystallized from chloroform/benzene as colorless plates: 2.2
g (14%), mp 325 °C (subl.); 1H NMR (CDCl3, 500 MHz) δ 9.02
(s, 4 H); 13C {1H} NMR (CDCl3, 124 MHz) δ 121.82 (C5), 158.83
(C4), 159.69 (C2); IR (KBr) 446, 641, 732, 758, 931, 1009, 1089,
1138, 1221, 1237, 1362, 1385, 1412, 1439, 1525, 1542, 1614,
1866, 1994, 3018, 3066 cm-1; MS (EI+) m/z (rel intensity) 316
(bromine isotope pattern fits the calculated pattern for M,
100), 236 ([M - Br]+, 10), 208 (20), 183 (15), 158 ([M -
C4N2H2Br]+, 5), 156 ([M - 2Br]+, 5), 130 (3), 104 (10), 77 (5),
52 (9); HRMS calcd 313.8803, found 313.8801. Anal. Calcd for
C8H4N4Br2: C, 30.41; H, 1.28; N, 17.73. Found: C, 30.48; H,
1.36; N, 17.50.
Ack n ow led gm en t. This work was supported by the
USARO (DAAG-55-98-1-0310). P.F.H.S. is grateful to
the Institute of International Exchange and the Ger-
manistic Society of America for a Quadrille Scholarship
and the CU Graduate School for a Graduate School
Fellowship. J oanna J . Brown is acknowlegded for her
help with the synthesis of 5,5′-dibromobipyridine.
C
16H19N2Br: C, 60.20; H, 6.00; N, 8.77. Found: C, 60.44; H,
6.18; N, 8.70.
2,2-Bip yr im id in e (20).40 Dry DMF (1.7 L) was degassed
by bubbling argon gas through a frit into the stirred liquid
overnight. Triphenylphosphine (91.7 g, 0.35 mol), NiCl2‚H2O
(20.8 g, 0.088 mol), and zinc powder (11.4 g, 0.175 mol) were
put under vacuum for 20 min and then added to the solution
under argon. Under vigorous stirring at room temperature,
the heterogeneous solution turned first red after a few minutes
and then gradually brownish. After 1 h, freshly sublimed (0.5
J O010707J
(42) Musgrave, T. R.; Westcott, P. A. Org. Synth. 1972, 52, 1799.