Synthesis of carbo- and heterobiaryls by intermolecular radical addition of aryl bromides onto aromatic solvents

Article abstract of DOI:10.1016/j.tet.2004.05.038

Tris(trimethylsilyl)silane (TTMSS) and azabisisobutyronitrile (AIBN) promoted the intermolecular arylation of aryl and heteroaryl bromides onto aromatic solvents under thermal conditions via a radical pathway.

Full text of DOI:10.1016/j.tet.2004.05.038

Tetrahedron 60 (2004) 6217–6224
Synthesis of carbo- and heterobiaryls by intermolecular radical
addition of aryl bromides onto aromatic solvents
*
´ ´
´
Araceli Nun˜ez, Aranzazu Sanchez, Carolina Burgos and Julio Alvarez-Builla
´
´
´
´
Departamento de Quımica Organica. Universidad de Alcala, 28871 Alcala de Henares, Madrid, Spain
Received 25 February 2004; revised 15 April 2004; accepted 7 May 2004
Available online 9 June 2004
Abstract—Tris(trimethylsilyl)silane (TTMSS) and azabisisobutyronitrile (AIBN) promoted the intermolecular arylation of aryl and
heteroaryl bromides onto aromatic solvents under thermal conditions via a radical pathway.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Biaryls (Ar1–Ar2) and related systems, such as hetero-
biaryls and arylheterocyclic compounds have found
numerous applications in several fields: as advanced
materials, biologically active molecules, chelating agents
or metal ligands.1–3 Consequently, a wide variety of
synthetic methods have been developed for their
preparation, with palladium cross-coupling reactions cur-
rently being the most popular choice.1,4 Additional methods
reported for the preparation of biaryls include some
examples involving arylation of arenes through radical
mechanisms. Intramolecular radical additions, of aryl
functionalized aryl iodides to benzene has recently been
radicals to benzene5 or heterocyclic rings,6 under reductive
Scheme 1.
process. The intermolecular radical addition of ortho-
applied by Crich and Sannigrahi in an elegant approach to
functionalised tetrahydrobenzofuranes.13
conditions, followed by rearomatisation, have been
reported. In this context, intramolecular arylations, by ipso
substitution of suitable sulfonyl,7 phosphinate,8 silyl9 or
In this paper, the results on the intermolecular addition of
benzylic ether10 derivatives, also under reductive con-
aryl (and heteroaryl) radicals onto arenes and heteroarenes
ditions, have been widely reported for the preparation of
are described. During the study, scope and limitations of the
both biaryls and arylheterocyclic derivatives. On the other
process were evaluated, by varying the radical acceptor
(usually the solvent) and the aryl radical donor.
hand, the intermolecular version of the radical arylation has
been scarcely explored. At the start of the present project,
only radical approaches based on photochemical arylation
of arenes, among other oxidative conditions, have been
described.11 Our group recently reported a simple method
2. Results and discussion
for the preparation of aryl compounds,12 based on thermal
2.1. Variations on the radical acceptor
intermolecular radical addition of aryl or heteroaryl radicals
onto benzene (Scheme 1). The process takes place under
reductive conditions, using the corresponding aryl bromides
as starting material and AIBN/TTMSS (azobis-isobutyro-
nitrile/tris(trimethylsilyl)silane) as initiator for the radical
In a preceding communication12 we reported phenylation of
2-bromopyridine 1a (Scheme 2, Z¼H; Table 1, entry 1).
The best results were obtained by slow addition (8 h) of a
solution of TTMSS (2 equiv.), AIBN (2 equiv.) and
2-bromopyridine (1 equiv.) in 5 mL of benzene, into an
additional 10 mL of benzene (Method A), to supply
2-phenylpyridine 2a in 41% yield. Similar results
were obtained from 3-bromopyridine 1b, which gave
Keywords: Aryl bromides; Arylation; Biaryls; Radicals and radical
reaction; Tris(trimethylsilyl)silane (TTMSS).
*
Corresponding author. Tel.: þ34-91-885-4606; fax: þ34-91-885-4686;
e-mail address: julio.alvarez@uah.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.038

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6218
3-phenylpyridine 2b in 74% yield (Table 1, entry 2).
Attempts to extend the scope of the process were carried out
using toluene (Scheme 2, Z¼Me; Table 1, entry 3) and
chlorobenzene (Scheme 2, Z¼Cl; Table 1, entry 4) as
aromatic solvents. In these cases, the best results were
obtained using chlorobenzene, an electron-poor substrate,
which produced a mixture of the 2-phenylpyridines (13:0:1
of the o/m/p isomers) with an overall yield of 84%. The
use of toluene led to a mixture of the corresponding
2-tolylpyridines (2:1:1 of the o/m/p isomers) in 61% overall
yield. As the best results were obtained using chloro-
benzene, other electron-deficient solvents were also tested,
such as benzaldehyde (Scheme 2, Z¼CHO; Table 1, entry
5) or nitrobenzene (Scheme 2, Z¼NO2; Table 1, entry 6):
but no arylated products were detected.
Pyridine, another electron-deficient substrate was also
tested. Thus, when the process was carried out using
2-bromopyridine 1a as a source of the 2-pyridyl radical, and
pyridine as the solvent, 2,30-bipyridine 3, was isolated, in a
Scheme 2.
Table 1. Variations of the (radical acceptor) solvent
Entry
Starting material
Solvent
Biaryl comp.
Ratio
—
Yield (%)a
Method
A
1
1a
Ph-H
41
2a
2b
2
3
4
1b
1a
1a
Ph-H
—
74
A
o/m/p
2:1:1
Ph-Me
Ph-Cl
61
84
A
A
2c–e
o/m/p
13:0:1
2f,g
—
5
6
1a
1a
Ph-CHO
Ph-NO2
—
—
—
—
A
A
—
7
1a
Pyr
—
—
30
A
3
3
8
9
1b
1a
Pyr
30
61
A
B
a:b
3:1
C10H8
4a,b
a:b
5:1
10
1b
C10H8
50
B
4c,d
a
Yields refer to isolated pure product. All the compounds were identified by spectroscopic and literature data. Method A: TTMSS (2 equiv.), AIBN (2 equiv.),
the corresponding pyridyl bromide 1 (1 equiv.) in the solvent (5 mL) added into an additional 10 mL of the corresponding solvent during 8 h, 80 8C, 24 h.
Method B:TTMSS(2 equiv.), AIBN (2 equiv.), the corresponding pyridyl bromide 1 inMeCN(5 mL) added over naphthalene (55 equiv.)during4 h, 80 8C, 24 h.

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6219
30% yield (Scheme 2; Table 1, entry 7). Surprisingly, the
same process using 3-b0romopyridine 1b as the starting
material, also yielded 2,3 -bipyridine 3, again in 30% yield,
and only traces of the alternative isomeric compound
(Scheme 2; Table 1, entry 8). In general, one would expect
that the regioselectivity of the process mainly depends on
the electrophilicity or nucleophilicity of both, radical and
acceptor, as well as on polar effects and orbital control. As
far as the character of attacking radicals is concerned, it is
now recognized that heteroaryl species with a carbon radical
adjacent to the heteroatom behave as electrophiles, with the
electrophilicity interpreted in terms of the inductive effect of
the ring heteroatom.11a,b In all examples discussed, the
2-pyridyl radical would act as an electrophile, thus attacking
either substituted benzenes or pyridine when they are both
acceptor and solvent. Almost all substituents stabilize
radicals, and so, substituted benzenes, including toluene
and chlorobenzene, usually react faster than benzene itself.
Furthermore, most substituted benzenes show some
preference for ortho/para attack, because attack at these
sites gives the more stable intermediates.14 Moreover, in the
case of chlorobenzene, the mesomeric p-donor character of
the chloro-substituent must be taken into consideration. In a
Scheme 3.
Table 2. Variations on the radical
Entry
Starting material
Biaryl compound
Ratio a:b:g
Yield (%)a
Method
A
1
5a
—
51
6a
6b
6c
2
5b
—
50
A
3
4
5c
5a
—
—
52
—
A
A
2e,7
2e,7
5
6
5a
5b
4:1:0
4:1:1
10
30
C
A
8a–c
8a–c
7
8
5b
5c
10:1:4
2:1:0
72
15
C
A
9a,b
9a–c
9
5c
2:1:0.1
20
C
a
Yields refer to isolated pure product. All the compounds were identified by spectroscopic and literature data. Method A: TTMSS (2 equiv.), AIBN (2 equiv.),
the corresponding aryl bromide 5 (1 equiv.) in the solvent (5 mL) added into an additional 10 mL of solvent during 8 h, 80 8C, 24 h. Method C: TTMSS
(2 equiv.), AIBN (2 equiv.), the corresponding pyridyl bromide 5 (1 equiv.) in pyridine (5 mL) added over additional 10 mL of pyridine and 2.5 mL of acetic
acid during 8 h, 80 8C, 24 h.

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6220
similar way, when the solvent is pyridine, the 2-pyridyl
radical would behave as an electrophile, thus attacking at
the 3-position, a situation in agreement with other photo-
chemical arylations described previously.11a In contrast, the
3-pyridyl radical, which is comparatively nucleophilic,
would attack preferentially at the 2-position of the pyridine
acceptor.
the mixture kept at 80 8C for a further 16 h, did not generate
any detectable biaryl (Table 2, entry 4). When the same
conditions were applied to 1-bromo-4-methoxy-benzene 5b
as the starting material, biaryls 8a–c were isolated in 30%
yield (4:1:1 of the a:b:g isomers) (Table 2, entry 6). The
same process, when applied from 4-bromo benzoic acid
methyl ester 5c, yielded 15% of biaryls 9a,b (2:1:0 of the
a:b:g isomers) (Table 2, entry 8). The experimental results
seem to suggest that all radical species used in this particular
type of reaction behave as relatively nucleophilic, with the
ring substituents, however, exerting some effect on the
reactivity of such radicals. The lack of reactivity for
compound 5a and the higher percentage of a-substitution
on pyridine in the other cases could, tentatively, be
explained by considering the following two classes of
factors:
Several attempts were undertaken to make the radical more
p-deficient (e.g., using 2-bromopyridine-N-oxide instead of
2-bromopyridine) or to increase the electrophilicity of the
solvent (e.g., using thiophene instead of pyridine). How-
ever, these approaches did not generate any satisfactory
results.
Other aromatic solvents were also tested. Reaction of the
2-pyridyl radical, obtained from 2-bromopyridine 1a on
naphthalene, using a modified experimental method
(Method B) (see Table 1 and Section 4) produced a 3:1
mixture of a/b naphthyl derivatives 4a,b in 61% yield
(Scheme 3; Table 1, entry 9). Similarly, 3-bromopyridine
1b, produced a 5:1 mixture of a/b 3-(naphthyl)pyridines
4c,d (Scheme 3; Table 1, entry 10). The regioselectivity of
the radical attack is clearly as one would expect, considering
orbital control, because of the symmetry of the system and
in agreement with the regioselectivity reported for other
radical arylations.14,15
(a) A relatively nucleophilic radical has a higher energy
SOMO and will react faster with molecules having a low-
energy LUMO.14,18,19
(b) For unprotonated pyridines, the reactivity and selectivity
on the homolytic phenylation appears to be mainly governed
by the stability of the intermediate radical adduct 1020
(Scheme 5), with regioselectivity being a.b for both the
more and the less nucleophilic radical (i.e., radicals derived
from 5b and 5c, respectively). Since there is no radical
p-stabilizing effect by aryl substituents, a relatively weak
inductive effect could be exerted by the relatively
p-excessive or p-deficient aryl substrate (intermediate
10a,b, where Y¼OMe or CO2Me, respectively),19 whereas
the absence of such effect in 5a should prevent the progress
of the reaction.
2.2. Variations on the aryl radical
It is an axiom in radical chemistry that the p-system in an
aryl radical should have little or no effect on its reactivity,
since the unpaired electron would be placed on the
s-skeleton.16,17 On this assumption, additional experiments
were carried out using 4-methylphenyl, 4-methoxyphenyl,
and 4-methoxycarbonylphenylbromides 5a–c as sources of
aryl radicals. In a previous communication12 we reported
these arylations using benzene as solvent, which yielded
compounds 6a–c (50–52%) essentially yielding the same
results for both, heterocyclic and carbocyclic radicals. The
experimental results are summarized in Table 2 (Entries
1–3) and in Section 4. The same process, but using pyridine
as solvent, is outlined in Scheme 4 and Table 2. The slow
addition (8 h) of a solution of TTMSS (2 equiv.), AIBN
(2 equiv.) and 1-bromo-4-methyl benzene 5a (1 equiv.) in
pyridine to an additional 10 mL of pyridine at 80 8C, with
Scheme 5.
Presumably, the radical arylation on protonated hetero-
aromatic bases will be more important, where the
dominant SOMO/LUMO interaction may well be stronger.
So in the case of unsubstituted pyridinium cation, reaction at
the a- and at the g-positions is predicted according to
theory.19,20 Bearing these factors in mind, and in accordance
with the work of Minisci20–22 and Togo,23,24 the reaction
was performed in an acidic medium. Thus, in protonated
pyridines, in which polarity is strongly increased, the polar
effect would play a significant role in determining both
Scheme 4.

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6221
reactivity and regioselectivity (Table 2).20 Protonated
heteroarenes are p-deficient substrates, which react with
nucleophilic radicals with high regioselectivity, and the rate
of radical addition correlated with nucleophilicity of the
attacking radical (derived from 5a and 5b, entries 5 and 7,
respectively), whereas the reaction with the less nucleo-
philic radical (derived from 5c, entry 9) is scarcely affected
with regard to reactivity and regioselectivity.
was observed (TLC analysis). The solution was concen-
trated, providing a crude mixture, which was separated by
flash chromatography (silicagel, hexanes/ethyl acetate
(80:20)), yielding the pure compounds.
4.4. Method C
A solution of TTMSS (498 mg, 2 mmol), AIBN (328 mg,
2 mmol), and the corresponding bromide 5a–c (1 mmol) in
5 mL of pyridine, was dropwise added with a syringe pump
over 8 h, to 10 mL of pyridine and 5 mL of acetic acid,
stirred at 80 8C (bath temperature). Stirring was maintained
at the same temperature for 24 h, then the solution was made
basic with potassium carbonate and extracted with ethyl
acetate. The combined organic phases were dried over
Na2SO4 and evaporated to dryness. The residue was purified
using flash chromatography to yield the corresponding
compounds 7–9.
3. Conclusion
As a conclusion, a simple method of synthesis of biaryl
compounds has been developed, based on the inter-
molecular radical addition of aryl or heteroaryl radicals
onto an aromatic solvent. The method is very efficient when
the aromatic solvent is benzene, but in general, occurs in
low yields on other arenes. Experimental results seem to
suggest that most aryl radicals, are nucleophilic to some
extent, with aryl substituents modulating the reactivity
through their electronic effect on the p-aryl system.
4.5. Preparation of arylpyridines 2a–g and bipyridine 3
4.5.1. 2-Phenylpyridine 2a.25 The general procedure
(Method A) using 1a (158 mg) as bromide and benzene as
solvent gave, after flash chromatography (silicagel,
hexanes/ethyl acetate (90/10)), a colorless liquid (63.5 mg,
41%). This product was identical to an authentic sample
obtained from Aldrich. 1H NMR (300 MHz, CDCl3) d 8.69
(td, 1H, J¼4.7, 1.4 Hz), 8.01 (dd, 2H, J¼8.4, 1.6 Hz), 7.69
(m, 2H), 7.45 (m, 3H), 7.19 (dd, 1H, J¼8.8, 4.7 Hz); 13C
NMR (75 MHz, CDCl3) d 157.1, 149.4, 139.2, 136.5, 128.8,
128.5, 126.7, 121.8, 120.3.
4. Experimental
4.1. General
All experiments were carried out under dry argon
atmosphere. Toluene and benzene were distilled from
sodium under dry argon. Chlorobenzene was distilled
from calcium chloride, under dry argon. Pyridine was
distilled from potassium hydroxide pellets under dry argon.
Acetonitrile was distilled from phosphorus pentoxide
under dry argon. Naphthalene was crystallized from
ethanol. All chemicals were purchased from Aldrich
4.5.2. 3-Phenylpyridine 2b.25,26 The general procedure
(Method A) using 1b as bromide (158 mg) and benzene as
solvent gave, after flash chromatography (silicagel,
hexanes/ethyl acetate (80:20)), a colorless liquid (115 mg,
74%). The product was identical to an authentic sample
obtained from Aldrich. 1H NMR (300 MHz, CDCl3) d 8.83
(dd, 1H, J¼2.6, 0.9 Hz), 8.57 (dd, 1H, J¼4.9, 1.6 Hz), 7.85
(ddd, 1H, J¼7.7, 2.6, 1.6 Hz), 7.56 (dd, 2H, J¼8.2, 1.4 Hz),
7.45 (m, 3H), 7.34 (ddd, 1H, J¼7.7, 4.9, 0.9 Hz); 13C NMR
(75 MHz, CDCl3) d 148.3, 148.2, 137.7, 136.4, 134.2,
128.9, 127.9, 127.0, 123.3.
1
Chemical company and were used without purification. H
and 13C were recorded on a Varian UNITY 300 MHz or a
VARIAN UNITY PLUS 500 MHz spectrometers. Mass
spectra were recorded on a VG AutoSec (Micromass
Instrument).
4.2. General procedure. Method A
A solution of TTMSS (498 mg, 2 mmol), AIBN (328 mg,
2 mmol), and the corresponding bromide 1a,b or 5a–c
(1 mmol) in 5 mL of the suitable solvent, was dropwise
added with a syringe pump along 8 h, to 10 mL of the same
solvent, stirred at 80 8C (bath temperature). Stirring was
maintained at the same temperature for 24 h, and full
consumption of starting material was observed (TLC
analysis). The pale yellow solution was concentrated in
vacuo, providing a crude mixture that was purified using
flash chromatography to yield the corresponding biaryl
compound.
4.5.3. 2-(20-Methylphenyl)pyridine 2c,27,28 2-(30-methyl-
phenyl)pyridine 2d27,28 and 2-(40-methylphenyl)pyridine
2e.11a,27,29 The general procedure (Method A) using 1a as
bromide (158 mg) and toluene as solvent, gave a mixture of
products (o/m/p, 2:1:1). After separation by flash chroma-
tography
(silicagel,
dichloromethane/ethyl
acetate
(100:2.5)), pure compounds 2c, 2d and 2e were obtained.
Yield 61% (50.5 mg of 2c (Rf¼0.35), 27 mg of 2d
(Rf¼0.41) and 25.5 mg of 2e (Rf¼0.40)). 2c Colorless oil;
1H NMR (500 MHz, CDCl3) d 8.68 (ddd, 1H, J¼4.8, 1.8,
1.0 Hz), 7.72 (dt, 1H, J¼7.7, 1.8 Hz), 7.37 (td, 1H, J¼7.7,
1.0 Hz), 7.36 (m, 1H), 7.27 (m, 3H), 7.22 (ddd, 1H, J¼7.7,
4.8, 1.0 Hz), 2.34 (s, 3H). 2d Colorless oil; 1H NMR
(500 MHz, CDCl3) d 8.68 (ddd, 1H, J¼4.8, 1.5, 1.0 Hz),
7.82 (bs, 1H), 7.73 (dt, 1H, J¼8.0, 1.5 Hz), 7.70 (m, 2H),
7.34 (t, 1H, J¼7.6 Hz), 7.21 (m, 1H), 7.20 (ddd, 1H, J¼8.0,
4.8, 1.9 Hz) 2.42 (s, 3H). 2e Colorless oil; 1H NMR
(300 MHz, CDCl3) d 8.67 (d, 1H, J¼4.4 Hz), 7.86 (d, 2H,
J¼8.1 Hz), 7.70 (m, 2H), 7.26 (d, 2H, J¼8.1 Hz), 7.20 (m,
4.3. Method B
A solution of TTMSS (498 mg, 2 mmol), AIBN (328 mg,
2 mmol) and the corresponding bromide 1a,b (1 mmol,
158 mg) in 5 mL of MeCN, was dropwise added with a
syringe pump over 4 h, to 7 g (55 mmol) of naphthalene,
stirred at 80 8C (bath temperature). Stirring was maintained
at the same temperature for 24 h, and full consumption of 1

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6222
1H), 2.44 (s, 3H). 13C NMR (75 MHz, CDCl3) d 157.2,
149.3, 138.6, 136.4, 136.3, 129.2, 126.5, 121.5, 120.0, 21.0.
chromatography 50% (a/b 5:1) of 3-Naphthalenyl-pyri-
dines 4c,d, (85.5 mg of 4c (Rf¼0.35) and 17 mg of 4d
(Rf¼0.23). 4c: colorless oil; 1H NMR (300 MHz, CDCl3) d
8.76 (d, 1H, J¼2.2 Hz), 8.67 (dd, 1H, J¼4.9, 1.6 Hz), 7.92
(m, 2H), 7.82 (m, 2H), 7.54 (m, 5H); 13C NMR (75 MHz,
CDCl3) d 150.5, 148.4, 137.4, 136.2, 133.8, 131.5, 128.5,
128.4, 127.4, 126.5, 126.1, 125.3, 125.2, 123.1; HPLC-MS
4.5.4. 2-(20-Chlorophenyl)pyridine 2f27,28 and 2-(40-
chlorophenyl)pyridine 2g.27 The general procedure
(Method A) using 1a as bromide (158 mg) and chloro-
benzene as solvent, gave a mixture of products (o/m/p,
13:0:1). After separation by flash chromatography (silica-
gel, hexanes/ethyl acetate (90:10)), pure compounds 2f and
2g were obtained. Yield 84% (148 mg of 2f (Rf¼0.35) and
11.5 mg of 2g (Rf¼0.45)). 2f Colorless oil; 1H NMR
(500 MHz, CDCl3) d 8.73 (ddd, 1H, J¼5.0, 1.7, 1.1 Hz),
7.75 (dt, 1H, J¼8.7, 1.7 Hz), 7.63 (td, 1H, J¼7.7, 1.1 Hz),
7.57 (m, 1H), 7.46 (m, 1H), 7.33 (m, 2H), 7.27 (ddd, 1H,
J¼7.7, 5.0, 1.1 Hz); 13C NMR (75 MHz, CDCl3) d 156.9,
149.5, 139.2, 135.8, 132.1, 131.5, 130.0, 129.4, 127.0,
124.8, 122.3. 2g Colorless oil; 1H NMR (300 MHz, CDCl3)
d 8.67 (d, 1H, J¼4.5 Hz), 7.93 (d, 2H, J¼8.6 Hz), 7.75 (dt,
1H, J¼7.2, 1.6 Hz), 7.69 (bd, 1H, J¼7.2 Hz), 7.44 (d, 2H,
J¼8.6 Hz), 7.24 (ddd, 1H, J¼7.2, 4.5, 1.6 Hz).
1
(CI) [Mþþ1]¼206.1. 4d: white solid, mp 101–103 8C; H
NMR (300 MHz, CDCl3) d 8.96 (d, 1H, J¼1.6 Hz), 8.60
(dd, 1H, J¼4.8, 1.6 Hz), 8.06 (s, 1H), 8.03 (td, 1H, J¼8.1,
1.6 Hz), 7.90 (m, 3H), 7.71 (dd, 1H, J¼8.5, 2.0 Hz), 7.53
(m, 2H), 7.40 (dd, 1H, J¼8.1, 4.8 Hz); 13C NMR (75 MHz,
CDCl3) d 148.5, 148.4, 135.0, 134.5, 133.5, 132.8, 128.8.
128.1, 127.6, 126.5, 126.3, 126.1, 124.9, 123.5; MS (CI,
70 eV) m/z (relative intensity) 206 (Mþþ1, 100), 159 (5).
4.7. Preparation of biphenyl compounds 6a–c and
arylpyridines 7–9
4.7.1. 4-Methylbiphenyl 6a.33,34 The general procedure
(Method A) using 5a as bromide (171 mg) and benzene as
solvent gave, after flash chromatography (silicagel,
hexanes/ethyl acetate (95:5)), a white solid, mp 46–47 8C
4.5.5. 2,30-Bipyridinyl 3.25,30 The general procedure
(Method A) using 1a (158 mg) as bromide and pyridine as
solvent gave, after flash chromatography (silicagel,
hexanes/ethyl acetate (30:70), Rf¼0.21) 47 mg, 30% yield
of bipyridine 3 as a colorless oil. Identical results were
obtained from 1b (158 mg) and only traces were detected of
1
(85.5 mg, 51%). H NMR (500 MHz, CD3OD) d 7.59 (dd,
2H, J¼8.3, 1.2 Hz), 7.50 (d, 2H, J¼8.1 Hz), 7.42 (t, 2H,
J¼8.3 Hz), 7.31 (td, 1H, J¼8.3, 1.2 Hz) 7.25 (d, 2H,
J¼8.1 Hz), 2.39 (s, 3H); 13C NMR (125 MHz, CD3OD) d
142.4, 139.6, 138.1, 130.4, 129.7, 127.9, 127.8, 127.7, 21.1.
1
other isomeric bipyridines. H NMR (300 MHz, CDCl3) d
9.17 (dd, 1H, J¼2.2, 0.7 Hz), 8.71 (d, 1H, J¼4.6 Hz), 8.64
(dd, 1H, J¼4.7, 1.7 Hz), 8.31 (ddd, 1H, J¼8.2, 2.2, 1.7 Hz),
7.77 (m, 2H), 7.40 (ddd, 1H, J¼8.2, 4.7, 0.7 Hz), 7.26 (ddd,
1H, J¼7.8, 4.6, 1.6 Hz); 13C NMR (75 MHz, CDCl3) d
154.8, 150.1, 149.9, 148.2, 137.1, 134.4, 123.7, 122.9,
120.7; MS (EI, 70 eV) m/z (relative intensity) 156 (Mþ,
100), 155 (Mþ21, 72), 130 (22), 78 (14).
4.7.2. 4-Methoxybiphenyl 6b.33,35 The general procedure
(Method A) using 5b as bromide (187 mg) and benzene as
solvent gave, after flash chromatography (silicagel,
hexanes/ethyl acetate (95:5)), a white solid, mp 86–87 8C
(92 mg, 50%); 1H NMR (300 MHz, CDCl3) d 7.56 (m, 4H),
7.43 (t, 2H, J¼7.5 Hz), 7.32 (tt, 1H, J¼7.5, 1.2 Hz) 6.99 (d,
2H, J¼8.8 Hz), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) d
159.1, 140.8, 133.7, 128.7, 128.1, 126.7, 126.6, 114.1, 55.3.
4.6. Preparation of naphthylpyridines 4a–d
4.6.1. 2-Naphthalen-1-yl-pyridine 4a31 and 2-naphtha-
len-2-yl-pyridine 4b.31 The general procedure (Method B)
using 1a (158 mg) as starting bromide gave, after flash
chromatography, 61% yield (a/b 3:1) of 2-naphthalenyl-
pyridines 4a,b, (94 mg of 4a (Rf¼0.56) and 30 mg of 4b
4.7.3. Biphenyl 4-carboxylic acid methyl ester 6c.34,36
The general procedure (Method A) using 5c as bromide
(215 mg) and benzene as solvent gave, after flash chroma-
tography (silicagel, hexanes/ethyl acetate (95:5)), a white
solid, mp 116–117 8C (110 mg, 52%). 1H NMR (300 MHz,
CDCl3) d 8.04 (d, 2H, J¼8.4 Hz), 7.59 (d, 2H, J¼8.4 Hz),
7.56 (dd, 2H, J¼7.4, 1.3 Hz); 7.44 (dd, 2H, J¼7.4, 7.2 Hz),
7.33 (tt, 1H, J¼7.2, 1.3 Hz) 3.89 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 166.9, 145.5, 139.9, 130.0, 128.8,
128.6, 128.1, 127.2, 126.9, 52.0.
1
(Rf¼0.58). 4a: yellow oil; H NMR (300 MHz, CDCl3) d
8.79 (dd, 1H, J¼4.8, 1.7 Hz), 8.08 (dd, 1H, J¼7.1, 2.9 Hz),
7.91 (d, 2H, J¼8.1), 7.82 (dt, 1H, J¼7.7, 1.7 Hz), 7.56 (m,
5H), 7.33 (ddd, 1H, J¼7.7, 4.8, 1.1 Hz); 13C NMR
(75 MHz, CDCl3) d 159.5, 149.7, 138.7, 136.5, 134.2,
131.4, 129.0, 128.5, 127.6, 126.6, 126.0, 125.8, 125.4,
125.2, 122.1. MS (EI, 70 eV) m/z (relative intensity) 205
(Mþ, 39), 204 (100), 176 (9), 126 (2). 4b: yellow solid; mp
77–78 8C; 1H NMR (300 MHz, CDCl3) d 8.75 (d, 1H,
J¼4.2 Hz), 8.49 (s, 1H), 8.14 (dd, 1H, J¼8.6, 1.5 Hz), 7.90
(m, 4H), 7.80 (td, 1H, J¼7.5, 1.8 Hz), 7.50 (m, 2H), 7.26
(dd, 1H, J¼7.5, 4.2 Hz); 13C NMR (75 MHz, CDCl3) d
157.3, 149.7, 136.7, 133.5, 133.4, 128.6, 128.3, 127.6,
126.4, 126.2, 124.5, 122.1, 120.7; MS (EI, 70 eV) m/z
(relative intensity) 205 (Mþ, 100), 204 (66), 176 (16), 126
(8).
4.7.4. 2-(40-Methylphenyl)pyridine 2e11a,27,29 and 3-(40-
methylphenyl)pyridine 7.11a The general procedure
(Method A) using 5a (171 mg) as starting bromide and
pyridine as solvent did not generate any biaryl compound.
The same process, using Method C gave, after separation by
flash chromatography (silicagel, hexanes/ethyl acetate
(80:20)), 10% yield of 40-methylphenyl)pyridines (a/b/g
4:1:0). 2e (13.5 mg, Rf¼0.80) colorless oil; 1H NMR
(300 MHz, CDCl3) d 8.67 (d, 1H, J¼4.4 Hz), 7.86 (d, 2H,
J¼8.1 Hz), 7.70 (m, 2H), 7.26 (d, 2H, J¼8.1 Hz), 7.20 (m,
1H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) d 157.2,
149.3, 138.6, 136.4, 136.3, 129.2, 126.5, 121.5, 120.0, 21.0;
MS (EI, 70 eV) m/z (relative intensity) 169 (Mþ, 100), 168
(59, Mþþ1), 154 (9), 51 (20). 7 (4 mg, Rf¼0.53) colorless
4.6.2. 3-Naphthalen-1-yl-pyridine 4c32 and 3-naphtha-
len-2-yl-pyridine 4d.31 The general procedure (Method B)
using 1b (158 mg) as starting bromide gave, after flash

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A. Nun˜ez et al. / Tetrahedron 60 (2004) 6217–6224
6223
oil; 1H NMR (300 MHz, CDCl3) d 8.82 (d, 1H, J¼2.3 Hz),
8.55 (dd, 1H, J¼4.6, 1.5 Hz), 7.85 (ddd, 1H, J¼7.81, 2.3,
1.5 Hz), 7.48 (d, 2H, J¼8.2 Hz), 7.35 (m, 1H), 7.30 (d, 2H,
J¼8.2 Hz), 2.42 (s, 3H); MS (EI, 70 eV) m/z (relative
intensity) 169 (Mþ, 83), 110 (100), 80 (30).
134.4, 130.3, 129.7, 127.0, 123.6, 52.1; MS (EI, 70 eV) m/z
(relative intensity) 213 (Mþ, 68), 182 (100), 154 (27), 127
(21).
9c (1 mg from Method C) (Rf¼0.15) white solid, mp 103–
105 8C; 1H NMR (300 MHz, CDCl3) d 8.70 (d, 2H,
J¼4.2 Hz), 8.15 (d, 2H, J¼8.4 Hz, 7.70 (d, 2H,
J¼8.4 Hz), 7.54 (d, 2H, J¼4.2 Hz), 3.94 (s, 3H); MS (EI,
70 eV) m/z (relative intensity) 213 (Mþ, 95), 182 (100), 154
(56), 127 (66), 80 (48).
4.7.5. 2-(40-Methoxyphenyl)pyridine 8a,11a,27 3-(40-
methoxyphenyl)pyridine 8b11a and 4-(40-methoxy-
phenyl)pyridine 8c.37 The general procedure (Method A)
using 5b (187 mg) as starting bromide and pyridine as
solvent gave, after separation by flash chromatography
(silicagel, hexanes/ethyl acetate (70:30)), 30% yield of
methoxyphenylpyridines 8a–c (a/b/g 4:1:1). The same
process, using Method C gave 72% yield of methoxy-
phenylpyridines 8a–c (a/b/g 10:1:4). 8a (37 mg from
Method A or 92.5 mg from Method B) (Rf¼0.80) colorless
Acknowledgements
Financial support by the Comision Interministerial de
1
´
Ciencia y Tecnologıa (CICYT, project BQU2001-1508)
and a grant to one of us by the Universidad de Alcala (A.N)
plates, mp 53–54 8C; H NMR (300 MHz, CDCl3) d 8.65
´
(dd, 1H, J¼4.7, 1.8 Hz), 7.95 (d, 2H, J¼7.9 Hz), 7.72 (ddd,
1H, J¼8.0, 6.9, 1.8 Hz), 7.66 (dd, 1H, J¼8.0, 1.5 Hz), 7.16
(ddd, 1H, J¼6.9, 4.7, 1.5 Hz), 6.98 (d, 2H, J¼7.9 Hz), 3.90
(s, 3H); 13C NMR (75 MHz, CDCl3) d 160.3, 156.9, 149.3,
136.7, 131.7, 128.1, 121.3, 119.9, 114.0, 55.3; MS (EI,
70 eV) m/z (relative intensity) 185 (Mþ, 100), 170 (36), 142
(45), 141 (31), 84 (14). 8b (9 mg from Method A or 9 mg
from Method C) (Rf¼0.35) colorless plates, mp 63–64 8C;
1H NMR (300 MHz, CDCl3) d 8.80 (d, 1H, J¼1.8 Hz), 8.53
(dd, 1H, J¼4.7, 1.4 Hz), 7.83 (ddd, 1H, J¼8.1, 1.8, 1.4 Hz),
7.51 (d, 2H, J¼8.8 Hz), 7.33 (ddd, 1H, J¼8.1, 4.7, 0.7 Hz),
7.01 (d, 2H, J¼8.8 Hz), 3.80 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 159.8, 148.0, 147.9, 136.2, 133.8, 130.2, 128.2,
123.4, 114.5, 55.3; MS (EI, 70 eV) m/z (relative intensity)
185 (Mþ, 100), 170 (54), 142 (52), 115 (30). 8c (9 mg from
Method A or 30 mg from Method C) (Rf¼0.22), white solid,
mp 95–96 8C; 1H NMR (300 MHz, CDCl3) d 8.60 (dd, 2H,
J¼4.6, 1.6 Hz), 7.60 (d, 2H, J¼9 Hz), 7.51 (dd, 2H, J¼4.6,
1.6 Hz), 7.01 (d, 2H, J¼9 Hz), 3.85 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 160.8, 150.3, 148.1, 130.5, 128.3,
121.3, 114.8, 55.6; MS (EI, 70 eV) m/z (relative intensity)
185 (Mþ, 100), 170 (34), 142 (42),115 (32), 86 (51), 84 (75).
are gratefully acknowledged.
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