Synthesis of polyhalogenated 4,4′-bipyridines via a simple dimerization procedure

Article abstract of DOI:10.1021/jo100152e

Polyhalogenated 4,4′-bipyridines were conveniently synthesized in a single step starting from dihalopyridines. A mechanism was proposed on the basis of experiments performed with 2-chloro-5-bromopyridine 1a. 2-Chloro-4-lithio-5- bromopyridine A1 was produced via ortholithiation of 1a by using either LDA or t-BuLi bases. When LDA was used, dimer 3a containing two chlorines and two bromine atoms was formed predominantly accompanied by several byproducts whose structure and mechanism of formation are discussed. In the case of t-BuLi, although the major product was 2-chloropyridine 7, a new pyridone product 8 was formed that is probably the result of the dihydropyridine intermediate hydrolysis. The dimerization procedure involving LDA was employed to prepare a large number of halogenated 4,4′-bipyridines in moderate to good yields. In some specific cases, halogenated 3,4′ and 2,4′-bipyridines were obtained in lower yields and their structures were unambiguously assigned by X-ray diffraction analysis.

Full text of DOI:10.1021/jo100152e

pubs.acs.org/joc
Synthesis of Polyhalogenated 4,40-Bipyridines via a Simple
Dimerization Procedure
Mohamed Abboud,†,‡ Victor Mamane,*,† Emmanuel Aubert,*,‡
Claude Lecomte,‡ and Yves Fort†
†
ꢀ
Equipe Synthese Organometallique et Reactivite (SOR), Laboratoire SRSMC, UMR CNRS-UHP 7565
Institut Jean Barriol, Nancy Universiteꢁ, BP 70239, Bd des Aiguillettes, 54506 Vandoeuvre-les-Nancy,
ꢁ
ꢁ
ꢁ
‡
2
ꢁ
France, and Cristallographie, Resonance Magnetique et Modelisations (CRM ), UMR CNRS-UHP 7036
Institut Jean Barriol, Nancy Universiteꢁ, BP 70239, Bd des Aiguillettes, 54506 Vandoeuvre-les-Nancy, France
ꢁ
ꢁ
victor.mamane@srsmc.uhp-nancy.fr; emmanuel.aubert@crm2.uhp-nancy.fr
Received January 28, 2010
Polyhalogenated 4,40-bipyridines were conveniently synthesized in a single step starting from dihalo-
pyridines. A mechanism was proposed on the basis of experiments performed with 2-chloro-5-bromopyri-
dine 1a. 2-Chloro-4-lithio-5-bromopyridine A1 was produced via ortholithiation of 1a by using either
LDA or t-BuLi bases. When LDA was used, dimer 3a containing two chlorines and two bromine
atoms was formed predominantly accompanied by several byproducts whose structure and mechan-
ism of formation are discussed. In the case of t-BuLi, although the major product was 2-chloropyr-
idine 7, a new pyridone product 8 was formed that is probably the result of the dihydropyridine
intermediate hydrolysis. The dimerization procedure involving LDA was employed to prepare a large
number of halogenated 4,40-bipyridines in moderate to good yields. In some specific cases,
halogenated 3,40 and 2,40-bipyridines were obtained in lower yields and their structures were
unambiguously assigned by X-ray diffraction analysis.
Introduction
an important intermediate in the synthesis of viologens.3
Thus much effort has been made in the preparation of func-
tionalized 4,40-bipyridine derivatives. Different methods were
described in the literature particularly involving metal-
catalyzed reactions and sodium metal-induced dimerization.
Cross-coupling reactions4 often have been used but required
long reaction sequences for the preparation of the two coup-
ling partners. For the rapid synthesis of symmetrical bipyri-
dines bearing reactive functions, homocoupling reactions
represent an excellent alternative.5 The use of sodium metal
in order to induce 4,40-dimerization of pyridine has been known
for a long time but only simple alkyl-substituted pyridines
tolerated the use of the highly reducing conditions.6 It was
The 4,40-bipyridine skeleton represents an excellent build-
ing block in supramolecular chemistry1 and biology2 and is
(1) (a) Roesky, H. W.; Andruh, M. Coord. Chem. Rev. 2003, 236, 91–119.
(b) Rang, A.; Engeser, M.; Maier, N. M.; Nieger, M.; Lindner, W.; Schalley,
C. A. Chem.;Eur. J. 2008, 14, 3855–3859.
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N.; Viklund, J. Bioorg. Med. Chem. Lett. 2006, 16, 1397–1401. (b) Stanetty,
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and Applications of the Salts of 4,40-Bipyridines; Wiley: Chichester, UK, 2001.
(4) (a) Sbircea, L.; Sharma, N. D.; Clegg, W.; Harrington, R. W.; Horton,
P. N.; Hursthouse, M. B.; Apperley, D. C.; Boyd, D. R.; James, S. L. Chem.
Commun. 2008, 5538–5540. (b) Benniston, A. C.; Harriman, A.; Li, P.;
Rostron, J. P.; Harrington, R. W.; Clegg, W. Chem.;Eur. J. 2007, 13,
7838–7851. (c) Achmatowicz, M.; Hegedus, L. S.; David, S. J. Org. Chem.
2003, 68, 7661–7666. (d) Jouaiti, A.; Hosseini, M. W.; Kyritsakas, N. Chem.
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2005, 7, 1943–1946.
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3224 J. Org. Chem. 2010, 75, 3224–3231
Published on Web 04/28/2010
DOI: 10.1021/jo100152e
r
2010 American Chemical Society

Abboud et al.
JOCArticle
FIGURE 1. Reactivity of metalated pyridines in the 4-position.
shown that radical anions of pyridine were formed in this
reaction with subsequent dimerization and aromatization to
yield 4,40-bipyridine. Interestingly, a similar dimerization of
pyridine giving 2,20-bipyridine was described in the presence
of lithium diisopropylamide (LDA).7 It was shown that the
reaction probably occurred via a radical-anion intermediate
initiated by one-electron transfer from LDA.8 The same results
were found when reacting pyridine with the superbasic sys-
tem nBuLi-LiDMAE (lithium dimethylaminoethanolate).9
Other unusual dimerizations of pyridine derivatives in the
presence of lithium bases have been reported in the last years
(Figure 1). Although the radical-anion mechanism was not
excluded in the dimerization of I,10 the addition of the 4-lithio
pyridine derivative to the starting material was proposed in
cases of II11a and III.11b Lithium-magnesium mixed bases
were also shown to induce the 4,40-dimerization of pyridine
derivatives but only when I2 was used as the electrophile.12
This result was explained by the formation of intermediate IV,
which after 1,2-migration of the 4-pyridyl group delivered
V. Reaction of intermediate V with I2 furnished the iodo-
derivative VI, which suffered LiI elimination (Figure 1).12a
This paper reports results concerning the synthesis of new
functionalized 4,40-bipyridines starting from the relatively
unstable 4-lithio-dihalopyridines. In light of the isolation
and characterization of several byproducts from this reac-
tion a mechanism involving exclusively anionic intermedi-
ates is proposed.
Results and Discussion
During the study on the synthesis of ferroceno- and benzo-
(iso)quinolines,13 some 2-chloropyridines bearing a bromine
and a methyl group14 in vicinal positions were necessary. For
this purpose the directed ortholithiation was the method of
choice.15 Thus, 2-chloro-5-bromopyridine 1a was reacted in
the presence of LDA in THF to form the 4-lithio derivative
followed by trapping with methyl iodide. Along with the
expected product 2, a small amount of a dimeric material 3a
was isolated and its structure obtained by X-ray diffraction
(7) Clarke, A. J.; McNamara, S.; Meth-Cohn, O. Tetrahedron Lett. 1974,
15, 2373–2376.
(8) Newkome, G. R.; Hager, D. C. J. Org. Chem. 1982, 47, 599–601.
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3071–3080. (b) Gros, P.; Fort, Y.; Caubere, P. J. Chem. Soc., Perkin Trans. 1
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(13) (a) Mamane, V.; Fort, Y. J. Org. Chem. 2005, 70, 8220–8223.
€
(b) Mamane, V.; Louerat, F.; Iehl, J.; Abboud, M.; Fort, Y. Tetrahedron
2008, 64, 10699–10705.
(14) For the preparation and reactivity of methyl-substituted hetero-
cycles, see: (a) Mamane, V.; Aubert, E.; Fort, Y. J. Org. Chem. 2007, 72,
€
7294–7300. (b) Louerat, F.; Fort, Y.; Mamane, V. Tetrahedron Lett. 2009, 50,
5716–5718.
1997, 3597–3600.
(10) Epsztajn, J.; Bienek, A.; Brzezinski, J. Z.; Jozwiak, A. Tetrahedron
Lett. 1983, 24, 4735–4738.
ꢁ
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(11) (a) Mongin, F.; Trecourt, F.; Queguiner, G. Tetrahedron Lett. 1999,
40, 5483–5486. (b) Cottet, F.; Schlosser, M. Eur. J. Org. Chem. 2004, 3793–
3798.
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(12) (a) Awad, H.; Mongin, F.; Trecourt, F.; Queguiner, G.; Marsais, F.
Tetrahedron Lett. 2004, 45, 7873–7877. (b) Hawad, H.; Bayh, O.; Hoarau, C.;
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(15) (a) Turck, A.; Ple, N.; Mongin, F.; Queguiner, G. Tetrahedron 2001,
57, 4489–4505. (b) Schlosser, M.; Mongin, F. Chem. Soc. Rev. 2007, 36,
1161–1172.
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Trecourt, F.; Queguiner, G.; Marsais, F. Tetrahedron 2008, 64, 3236–3245.
ꢁ
J. Org. Chem. Vol. 75, No. 10, 2010 3225

Abboud et al.
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SCHEME 1. Initial Observation of Dimer 3a
method observed to induce rearomatization involved use of
I2 as the electrophile and resulted in the formation of 3a in a
good yield of 69% (entry 4).21,22
The remaining question concerned the higher formation of
4 in entry 2 compared to that in entries 3 and 4. Equilibrium
between A1 and A3 cannot be considered due to the fact that
all the reactions were performed under the same conditions
(1.05 equiv of LDA, -40 °C, 1 h); they differ only in the rearo-
matization step. Considering these observations, another
pathway involving intermediate A3 is proposed to explain
the formation of 4. After hydrolysis, A3 can be regenerated
through a -OH-mediated deprotonation of dihydropyridine
A4. After a 1,3-lithium shift leading to A5, LiBr elimination
would produce carbene A6, which after 1,2-hydride shift
would give dimer 4 (through intermediate A7).23
It was shown recently in our laboratory that stoichio-
metric t-BuLi could produce cleanly and rapidly A1 from 1a
at -78 °C while the lithium-bromine exchange was not obser-
ved.24 Half equivalent of t-BuLi was then used at -78 °C
in order to obtain an equimolar amount of 1a and A1 in the
reaction mixture (entry 5). Since the coupling was not effec-
tive at -78 °C, the temperature was raised to -30 °C and
unexpectedly 2-chloropyridine 7 was formed as the major
compound accompanied by the desired dimer 3a as well as 4
in low yields. Furthermore, pyridone 8 was formed in low
yield and its structure assigned based on X-ray single crystal
diffraction. The formation of 8 was explained by the partial
hydrolysis of intermediate A3. A similar pyridone formation
was recently observed by Collum and co-workers during
their study on the 3-picoline dimerization process.25 It is
worth noting that compound 8 was never observed when
using LDA as the base. This is probably due to the pre-
sence of iPr2NH in the reaction mixture, but the way it
could avoid the formation of 8 is still unclear. The low yield
of 3a and the high formation of 7 in the reaction of 1a with
t-BuLi can be interpreted by the fact that above -78 °C
the lithium-bromine exchange is the preferred process over
the ortholithiation. The use of I2 did increase the yield of 3a
with complete disappearance of 8 but we noticed that the
amount of 7 was again very high (entry 6). The absence of
2-chloro-5-iodopyridine in the reaction mixture indicated that
indicated a 4,40 connectivity (see the Supporting Information
for details) (Scheme 1).
In view of the importance of this new highly functionalized
4,40-bipyridine building block, experiments were conducted
in order to increase the yield of 3a and to have some insight
about the mechanism of its formation (Table 1).
When the reaction depicted in Scheme 1 was repeated without
electrophile, several products were obtained after purifica-
tion including the desired dimer 3a in 11% yield (entry 1). All
other compounds were isolated and their structure was assig-
ned on the basis of mass spectra and NMR analyses. The
structure of 6 was supported by X-ray diffraction (see the
Supporting Information for details). It appeared that raising
the temperature to rt overnight caused the degradation of the
lithio intermediates A1 and A2 to arynes B1 and B2.16 Thus,
reaction of B1 with LDA and A1 afforded respectively
compounds 5b17 and 4 while reaction of B2 with A1 delivered
6 (Scheme 2).18
A clean reaction was observed by performing the metala-
tion at -40 °C with 1.05 equiv of LDA. Under these condi-
tions, compounds 5a, 5b, and 6 were not observed but the
formation of 4 was still effective keeping the yield of 3a very
low (13%) (entry 2). A plausible mechanism for the formation
of 3a could be the direct attack of 1a by A1 in the 4-position
to give the dihydropyridine intermediate A319 followed by
hydrolysis to A4 and air oxidation (Scheme 3).20 Use of
MnO2 in order to accelerate the rearomatization step resul-
ted in the formation of dimer 3a in 52% yield while the for-
mation of 4 was considerably decreased (entry 3). Another
(21) For the oxidation of the Hantzch-1,4-dihydropyridine using mole-
cular iodine, see: (a) Yadav, J. S.; Reddy, B. V. S.; Sabitha, G.; Reddy, G. S. K. K.
Synthesis 2000, 1532–1534. (b) Zeynizadeh, B.; Dilmaghani, K. A.; Roozijoy, A.
J. Chin. Chem. Soc. 2005, 52, 1001–1004. (c) Filipan-Litvic, M.; Litvic, M.;
Vinkovic, V. Tetrahedron 2008, 64, 5649–5656.
ꢀ
(16) (a) Jamart-Gregoire, B.; Leger, C.; Caubere, P. Tetrahedron Lett.
1990, 31, 7599–7602. (b) Connon, S. J.; Hegarty, A. F. J. Chem. Soc., Perkin 1
2000, 1245–1249. (c) For a review on the use of arynes in organic synthesis,
see: Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701–730.
(17) Compound 5a was not isolated in this reaction but it is probably
formed (see ref 16a). For an unambiguous characterization of 5a and 5b, the
reaction of 1a with 2.1 equiv of LDA at -40 °C was performed followed by
raising the temperature to rt. Under these conditions, 5a and 5b were both
formed and isolated respectively in 31% and 25% yields.
(18) For the generation of 2,3-pyridyne intermediates and their use in
cycloaddition reactions, see: Connon, S. J.; Hegarty, A. F. Eur. J. Org.
Chem. 2004, 3477–3483.
(19) The observed selective addition of A1 to 1a in the 4-position over the
2-position was, however, unexpected in comparison with the dimerization
product obtained by lithiation of 2-chloro-5-trifluoromethylpyridine III
(ref 11b, Figure 1). Calculations (see the Supporting Information for details)
have shown the same charge distribution in 1a and III with the higher
positive charge in the 2-position. Presumably, the bromine atom in the
5-position of 1a participated in the approach of A1 by coordination to the
lithium.
(20) One referee suggested the possible formation of the double anion A8
generated from the reaction of A3 with the remaining LDA. However, when
the reaction mixture was quenched with iodomethane instead of I2, only the
N-methylated compound A3-Me was observed (see the 1H NMR spectrum of
the crude mixture in the Supporting Information) indicating that A8 was
probably not formed in the dimerization reaction of 1a.
(22) For the full optimization study with I2 as the electrophile, see Figure S1
in the Supporting Information.
(23) The authors are grateful to a referee for this mechanistic suggestion.
(24) (a) Pierrat, P.; Gros, P. C.; Fort, Y. Synlett 2004, 2319–2322.
(b) Pierrat, P.; Gros, P. C.; Fort, Y. J. Comb. Chem. 2005, 7, 879–886.
(25) Ma, Y.; Keresztes, I.; Lobkovsky, E.; Collum, D. B. J. Org. Chem.
2008, 73, 9610–9618.
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TABLE 1. Lithiation of 1a: Optimization of 3a Formation
entry
1
base (n equiv)
conditions (T, time)
-78 to rt, 12 h
treatment
H2O
conversion (%)
88
products
GC (%)
isolated yield (%)
LDA (1.2)
3a
4
5b
6
35
46
2
11
17
0.5
2
5
2
3
4
5
LDA (1.05)
LDA (1.05)
LDA (1.05)
t-BuLi (0.5)
-40 °C, 1 h
-40 °C, 1 h
-40 °C, 1 h
H2O
86
86
90
78
3a
4
3a
4
3a
4
3a
33
53
70
16
75
15
8
13
21
52
9
69
9
MnO2 then H2O
I2 then H2O
H2O
-78 to -30 °C, 30 min
then -30 °C, 2 h
4
7
8
3a
4
47
19
44
15
38
6
t-BuLi (0.5)
-78 to -30 °C, 30 min
then -30 °C, 2 h
I2 then H2O
77
7
33
iodinated pyridine 1f could be dimerized in the presence of
LDA to give compound 3f in a moderate yield of 44% (entry 5).
However, compound 3f was found to be unstable and should be
stored at low temperature. The dimerization of 2,3-dihalopyri-
dines 1g-i was more problematic, particularly 1h and 1i
in which halogen dance26 was the major process during the
lithiation step (entries 6-8). The expected tetrachlorinated
compound 3g could be isolated in a moderate yield from 2,3-
dichloropyridine 1g (entry 6). Under the same conditions,
2-chloro-3-bromopyridine 1h gave a complex mixture with
several products resulting from halogen dance and iodine
trapping as indicated by GC-MS analysis. To suppress the
iodinated products, the direct hydrolysis after the metalation
step was performed and compound 3h was isolated from the
complex mixture. Its structure was supported by X-ray diffrac-
tion analysis. Since this compound was not observed in
the presence of I2, its formation was explained analogously
to 4 (Scheme 5). Starting from 2,3-dibromopyridine 1i and
under the optimized conditions, the dimeric material 3i with a
3,40 connectivity was isolated in low yield. Probably, the
lithiation occurred, followed by the 3,4-bromine displacement
to form a new lithiated species that finally adds to the starting
pyridine 1i (Scheme 5). Another way to prepare a polyhaloge-
nated 3,40-bipyridine was to use 2,6-dibromopyridine 1j as the
substrate (entry 9). Indeed, 1j can simultaneously suffer lithia-
tion in the 3-position and addition in the 4-position thus
producing the 3,40-connectivity. The isolation of compound
3j in 15% yield is encouraging and optimization is necessary to
achieve better yields. Finally, the dimerization of 3,5-dihalo-
pyridines 1k-m was considered (entries 10-12). As depicted in
Figure 1, compound 3k was obtained in an excellent yield by
dimerization of 1k in the presence of Bu3MgLi followed by
quenching with iodine.12a,27 Under our conditions, the yield of
3k was moderate (entry 10) but the analogous compound 3l
bearing four bromine atoms was obtained in a good yield of
72% (entry 11). The lithiation of pyridine 1m was performed in
SCHEME 2. Formation and Reactivity of Arynes A1 and A2
2-chloropyridine 7 was probably formed in situ through the
reaction of the lithiated species with 2-bromo-2-methylpro-
pane (Scheme 4).
Synthesis of Halogenated Bipyridines. Under the optimized
conditions for the formation of 3a, several new bipyridines with
4,40 (and 3,40) connectivity were prepared (Table 2). The
presence of the chlorine in the 2-position was found crucial
since no dimeric product 3b was formed with 3-bromopyridine
1b as the substrate (entry 1). 2,5-Dihalopyridines were first eva-
luated in the dimerization process (entries 2-4). The dimeric
product 3c was not observed during the lithiation of 2,5-
dichloropyridine 1c at -40 °C. However, upon raising the
temperature to 0 °C the reaction occurred accompanied by
some degradation products thus explaining the low yield for
compound 3c (entry 2). As shown by entries 3 and 4, the
reaction performed better with bromide substitution on the
pyridine. Indeed, the reaction of 2-bromo-5-chloropyridine 1d
and 2,5-dibromopyridine 1e performed smoothly at -40 °C to
furnish respectively compounds 3d in a moderate yield (entry 3)
and 3e in a good yield (entry 4). It should be noted that even the
ꢁ
(26) (a) Mallet, M.; Queguiner, G. Tetrahedron 1985, 41, 3433–3440.
(b) For a general review, see: Schnuerch, M.; Spina, M.; Khan, A. F.;
Mihovilovic, M. D.; Stanetty, P. Chem. Soc. Rev. 2007, 36, 1046–1057.
(27) During the preparation of this paper, Do and Daugulis have repor-
ted the oxidative dimerization of pyridine 1k to the tetrachlorinated 2,20-
bipyridine by using the basic system iPrMgCl*LiCl þ ZnCl2 (1:0.25) in the
presence of oxygen and a catalytic amount of CuCl2, see: Do, H.-Q.;
Daugulis, O. J. Am. Chem. Soc. 2009, 131, 17052–17053.
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SCHEME 3. Proposed Pathways for the LDA-Mediated Dimerization of 1a
X-ray Diffraction Analysis
SCHEME 4. Proposed Pathways for the t-BuLi-Mediated
Dimerization of 1a
Crystal structures were determined by single crystal X-ray
diffraction for bipyridines with 4,40 (3a, 3h), 3,40 (3i, 3j), and 2,40
(6) connectivity and also for the new pyridone 8 (see the Suppor-
ting Information for full details). As expected from the chemical
content of these compounds, these structures are characterized
by a variety of intermolecular interactions competing with each
other, namely π-π stacking, halogen (including halogen
3 3 3
3 3 3
halogen, halogen N,O) and hydrogen (C-H π, C-H
3 3 3 3 3 3
N, C-H O, C-H halogen, N-H N) bonds.
3 3 3
3 3 3
3 3 3
Among the most remarkable interactions in these struc-
tures are short Br N and Br O intermolecular contacts
in 3a and 8, respectively. The interatomic distances in these
3 3 3
3 3 3
˚
contacts (3.006(2) A for Br N and 2.998(1) A for Br O)
˚
3 3 3
3 3 3
˚
are respectively 0.39 and 0.37 A shorter than the sum of the
corresponding van der Waals radii and lie within the short-
distance shoulder observed in the distance density function
plots obtained from a recent Cambridge Structural Database
analysis performed on Br O,N contacts, revealing these
contacts as specific interactions.29 The intermolecular
3 3 3
C-Br N,O angles are close to linearity (162.4(1)° and
3 3 3
164.41(5)°, respectively; Figure 2), in coherence with the elec-
trostatic model of halogen bonding where a positive σ hole
opposite to the covalent carbon-halogen bond is surroun-
dedbyanegativecrown,30 as recently shown by high-resolution
X-ray diffraction on hexachlorobenzene crystal.31 A recent
a THF/DMPU 4/1 mixture for solubility reasons.28 However,
the tetraiodo pyridine compound 3m was isolated in low yield
(entry 12).
(29) Gavezzotti, A. Mol. Phys. 2008, 1–13.
(30) Reddy, C. M.; Kirchner, M. T.; Gundakaram, R. C.; Padmanabhan,
K. A.; Desiraju, G. R. Chem.;Eur. J. 2006, 12, 2222–2234.
(31) Bui, T. T. T.; Dahaoui, S.; Lecomte, C.; Desiraju, G. R.; Espinosa, E.
Angew. Chem., Int. Ed. 2009, 48, 3838–3841.
(28) DMPU = 1,3-Dimethyltetrahydropyrimidin-2(1H)-one or N,N0-di-
methylpropyleneurea. For its first use as cosolvent for highly reactive bases,
see: Mukhopadhyay, T.; Seebach, D. Helv. Chim. Acta 1982, 65, 385–391.
3228 J. Org. Chem. Vol. 75, No. 10, 2010

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TABLE 2. Scope of the Reactiona
aReaction conditions: (i) 1 (1 mmol), LDA (1.05 mmol), THF, -40 °C, 1 h. (ii) I2 (1.05 mmol), -78 °C to rt, 1 h. bThe metalation was conducted at 0 °C
for 30 min. cDirect hydrolysis was performed (no iodine added). dThe metalation was performed in THF/DMPU 4/1 at -40 °C.
ca. -7 kcal mol-1 32
and competitive cocrystallization ex-
periments showed that halogen bonding could overwhelm
hydrogen bonding in some specific systems.33
,
SCHEME 5. Proposed Mechanisms for the Formation of 1h
and 1i
3
Halogen-halogen interactions are also present in these
structures, mostly of type-II. In this geometric arrangement,
the positive electron density hole on a first halogen atom
should be directed toward the negative crown of a second
halogen atom.31 These interactions are isolated (for example
˚
in 3j with Br Br=3.5614(4) A) or form infinite chains in 8
3 3 3
where cooperativity may thus be present to stabilize the
structure, as demonstrated by theoretical calculations on
model clusters of diatomic interhalogen molecules.34
Conclusion
We have developed a simple procedure for the synthesis of
halogenated 4,40-bipyridines based on the lithiation of halo-
pyridines. The mechanism of the reaction has been studied
by isolation and characterization of several byproducts.
(32) Riley, K. E.; Murray, J. S.; Politzer, P.; Concha, M. C.; Hobza, P.
J. Chem. Theory Comput. 2009, 5, 155–163.
(33) Corradi, E.; Meille, S. V.; Messina, M. T.; Metrangolo, P.; Resnati,
G. Angew. Chem., Int. Ed. 2000, 39, 1782–1786.
(34) Alkorta, I.; Blanco, F.; Elguero, J. Struct. Chem. 2009, 20, 63–71.
theoretical study showed that substitution on aromatic
rings bearing bromine influences the strength of halogen
bonding with acetone, with interaction energies up to
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Abboud et al.
JOCArticle
FIGURE 2. Short (a) Br O interactions in 8 and (b) Br N in 3a are shown as broken lines (bromine atoms in brown, chlorine in green,
3 3 3 3 3 3
oxygen in red).
Different parameters have to be respected for success of the
reaction: (i) two halogens are necessary in order to increase
the electrophilicity of the pyridine ring, (ii) one of these two
halogens has to be in the 3-position in order to induce the
ortho-lithiation in the 4-position, (iii) working at low tem-
perature is necessary to avoid aryne formation, and (iv) the
oxidant has to be added at the end of the reaction in order to
accelerate the rearomatization step and then to avoid the loss
of one halogen. The methodology was then applied to the
formation of several 4,40-bipyridines bearing chlorine, bro-
mine, and even iodine. In some cases we could isolate
bipyridines having 3,40 and 2,40 connectivity. Most represen-
tative products were characterized by X-ray diffraction and
showed specific halogen interactions which will be examined
in a dedicated work, motivated by the importance these
interactions have, for example, in biological systems.35
Knowing the importance of the 4,40-bipyridine unit in co-
ordination chemistry and in crystal design, we are also currently
preparing new metal complexes in order to study by X-ray
diffraction analysis the different modes of coordination of
the halogenated bipyridines as well as other functionalized
bipyridines obtained by cross-coupling reactions.
2,5,20,50-Tetrachloro-[4,40]bipyridinyl (3c): mp 117-119 °C;
1H NMR (250 MHz, CDCl3) δ 7.27 (s, H), 8.53 (s, 2H); 13C
NMR (62.5 MHz, CDCl3) δ 125.0, 129.4, 144.7, 149.8, 150.0;
MS (EI) m/z 294 (Mþ, 100), 257 (45), 221 (20), 186 (20); HRMS
m/z calcd for C10H5N2Cl4 294.9172, found 294.9185 [MH]þ.
2,20-Dibromo-5,50-dichloro-[4,40]bipyridinyl (3d):mp 110-112 °C;
1H NMR (400 MHz, CDCl3) δ 7.41 (s, 2H), 8.52 (s, 2H); 13C NMR
(50 MHz, CDCl3) δ 128.6, 130.1, 140.0, 144.3, 150.2; MS (EI) m/z
382 (Mþ, 100), 303 (65), 222 (40), 187 (35); HRMS m/z calcd for
C10H5Br2Cl2N2 382.8169, found 382.8174 [MH]þ.
2,5,20,50-Tetrabromo-[4,40]bipyridinyl (3e): mp 188-189 °C;
1H NMR (200 MHz, CDCl3) δ 7.37 (s, 2H), 8.64 (s, 2H); 13C
NMR (50 MHz, CDCl3) δ 119.8, 128.7, 140.9, 147.9, 152.6; MS
(EI) m/z 472 (Mþ, 100), 391 (55), 312 (45), 231 (35), 152 (50);
HRMS m/z calcd for C10H5Br4N2 472.7140, found 472.7142
[MH]þ.
1
2,20-Dibromo-5,50-diiodo-[4,40]bipyridinyl (3f): 75 °C dec; H
NMR (250 MHz, DMSO) δ 7.76 (s, 2H), 8.90 (s, 2H); 13C NMR
(62.5 MHz, DMSO) δ 97.4, 128.1, 141.0, 154.7, 157.3; MS (EI)
m/z 566 (Mþ, 40), 439 (100), 312 (10), 233 (20), 152 (60); HRMS
m/z calcd for C10H5Br2I2N2 566.6883, found 566.6899 [MH]þ.
2,3,20,30-Tetrachloro-[4,40]bipyridinyl (3g): mp 200-201 °C;
1H NMR (200 MHz, CDCl3) δ 7.16 (d, J=4.8 Hz, 2H), 8.43 (d,
J = 5 Hz, 2H); 13C NMR (62.5 MHz, CDCl3) δ 123.4, 129.1,
146.1, 147.2, 150.8; MS (EI) m/z 294 (Mþ, 100), 259 (80), 222
(30), 186 (20); HRMS m/z calcd for C10H5Cl4N2 294.9172,
found 294.9204 [MH]þ.
Experimental Section
3-Bromo-2,20-dichloro-[4,40]bipyridinyl (3h): mp 153-155 °C;
1H NMR (250 MHz, CDCl3) δ 7.16 (d, J=4.6 Hz, 1H), 7.27 (d,
J=4.4 Hz, 1H), 7.37 (s,1H), 8.42 (d, J=4.6 Hz, 1H), 8.53 (d, J=
4.5 Hz, 1H); 13C NMR (62.5 MHz, CDCl3) δ 120.0, 122.1, 123.5,
123.9, 147.9, 149.1, 149.7, 150.1, 152.0, 152.8; MS (EI) m/z 304
(Mþ, 100), 269 (25), 188 (15), 223 (10), 152 (15); HRMS m/z
calcd for C10H6N2BrCl2 303.9062, found 304.9079 [MH]þ.
2,4,20,30-Tetrabromo-[3,40]bipyridinyl (3i): mp 106-108 °C;
1H NMR (200 MHz, CDCl3) δ 7.14 (d, J = 4.4 Hz, 1H), 7.65
(d, J=4.8 Hz, 1H), 8.28 (d, J=5.0 Hz, 1H), 8.47 (d, J=4.6 Hz,
1H); 13C NMR (62.5 MHz, CDCl3) δ 124.2, 124.9, 127.4, 134.2,
137.9, 142.0, 145.4, 148.6, 149.9, 150.5; MS (EI) m/z 472 (Mþ,
50), 393 (100), 312 (50), 231 (35), 152 (30); HRMS m/z calcd for
C10H4Br4N2Na 494.6960, found 494.6950 [MNa]þ.
Representative Procedure for the Dimerization of Halopyri-
dines with LDA: Preparation of 5,50-Dibromo-2,20-dichloro-
[4,40]bipyridinyl (3a) (Table 1, entry 4). Freshly distilled diiso-
propylamine (0.15 mL, 1.05 mmol) was added to dry THF (6 mL)
and the solution was cooled to -40 °C. A solution of n-butyl-
lithium (1.6 M in hexanes, 0.66 mL, 1.05 mmol) was added drop-
wise under argon atmosphere. After the solution was stirred for
5 min at -40 °C, 5-bromo-2-chloropyridine 1a (192 mg, 1 mmol)
solubilized in dry THF (4 mL) was added. The mixture was then
stirred at -40 °C for 1 h and cooled to -78 °C then I2 (254 mg,
1 mmol) in THF (4 mL) was added dropwise. After the solution
was warmed to rt, the reaction was quenched with aqueous
Na2S2O3 and the mixture was extracted with ethyl acetate, dried
over MgSO4, and concentrated. The crude product was purified
by chromatography on silica gel to give 3a (132 mg, white
powder, 69% yield). Mp 163-165 °C; 1H NMR (400 MHz,
CDCl3) δ 7.24 (s, 2H), 8.66 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 119.0, 125.0, 148.2, 150.7, 152.2; MS (EI) m/z 382
(Mþ, 70), 303 (100), 222 (55); HRMS m/z calcd for C10H5N2-
Br2Cl2 384.8145, found 384.8147 [MH]þ.
2,6,20,60-Tetrabromo-[3,40]bipyridinyl (3j): mp 208-209 °C;
1H NMR (200 MHz, CDCl3) δ 7.46 (d, J = 8 Hz, 1H), 7.52
(s, 2H), 7.61 (d, J = 8 Hz, 1H); 13C NMR (62.5 MHz, CDCl3) δ
125, 127.3, 127.7, 133.7, 139.9, 140.2, 141.1, 141.6, 149.9; MS
(EI) m/z 472 (Mþ, 100), 391 (20), 312 (40), 231 (25), 152 (25);
HRMS m/z calcd for C10H5Br4N2 472.7140, found 472.7133
(MH)þ.
3,5,30,50-Tetrachloro-[4,40]bipyridinyl (3k): mp 102-104 °C;
(35) Auffinger, P.; Hays, F. A.; Westhof, E.; Ho, P. S. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 16789–16794.
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 4H); 13C NMR (100 MHz,
3230 J. Org. Chem. Vol. 75, No. 10, 2010

Abboud et al.
JOCArticle
CDCl3) δ 131.3, 140.0, 147.9; MS (EI) m/z 294 (Mþ, 100), 257
(30), 222 (20); HRMS m/z calcd for C10H5Cl4N2 294.9172,
found 294.9200 [MH]þ.
chromatography on silica gel to give pyridone 8 (27 mg, white
powder, 15% yield). Mp 205-207 °C; 1H NMR (400 MHz,
DMSO) δ 2.47 (dd, J = 4.4 Hz, 1H), 3.22 (dd, J = 16.8, 8.9 Hz,
1H), 4.24 (dd, J=8.8, 4.2 Hz, 1H), 6.84 (d, J=5.2 Hz, 1H), 7.31
(s, 1H), 8.67 (s, 1H), 9.66 (d, J=4.6 Hz, 1H); 13C NMR (100 MHz,
DMSO) δ 36.4, 44.8, 96.6, 121.0, 123.4, 129.7, 150.1, 151.4,
152.4,166.1; MS (EI) m/z 287 (Mþ, 100), 366 (80), 178 (45); HRMS
m/z calcd for C10H8N2OBr2Cl 366.8691, found 366.8676 (MH)þ.
3,5,30,50-Tetrabromo-[4,40]bipyridinyl (3l): mp 148-150 °C;
1H NMR (400 MHz, CDCl3) δ 8.82 (s, 4H); 13C NMR (100 MHz,
CDCl3) δ 120.8, 146.7, 150.8; MS (EI) m/z 472 (Mþ, 100), 391
(25), 312 (40); HRMS m/z calcd for C10H5Br4N2 472.7140,
found 472.7180 [MH]þ.
1
3,5,30,50-Tetraiodo-[4,40]bipyridinyl (3m): mp 230 °C dec; H
NMR (400 MHz, CDCl3) δ 8.99 (s, 4H); 13C NMR (100 MHz,
CDCl3) δ 157.8, 156.9, 96.2; HRMS m/z calcd for C10H5I4N2
660.6637, found 660.6626 [MH]þ.
Acknowledgment. We gratefully acknowledge the CNRS
ꢁ
and Nancy Universite for financial support. The authors
thank Dr. P. C. Gros for helpful discussions and the Service
Reaction of 1a with t-BuLi: Formation of 5,50-Dibromo-20-
chloro-3,4-dihydro-1H-[4,40]bipyridinyl-2-one (8) (Table 1, entry 5).
To a solution of 5-bromo-2-chloropyridine 1a (192 mg, 1 mmol)
in THF (4 mL) cooled at -78 °C, under argon atmosphere, was
added dropwise t-BuLi (0.3 mL, 0.5 mmol). After addition, the
temperature was raised to -30 °C during 30 min, and the mix-
ture was stirred at -30 °C for 2 h. The reaction was quenched by
addition of water and the solution was warmed to rt. The reac-
tion mixture was extracted with ethyl acetate, dried over MgSO4,
and concentrated. The crude product was dried under vacuum
overnight to remove 2-chloropyridine 7 and then purified by
ꢁ
Commun de Diffraction X (Nancy Universite) for providing
access to crystallographic experimental facilities. The Insti-
tut Jean Barriol is thanked for providing access to computa-
tional facilities.
Supporting Information Available: Experimental procedures
of Table 1, spectroscopic data of compounds 4, 5a, 5b, and 6,
NMR spectra of all compounds, crystallographic data, and CIF
files of compounds 3a, 3h, 3i, 3j, 6, and 8. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 10, 2010 3231