Consecutive nucleophilic substitution and aza Diels-Alder reaction - An efficient strategy to functionalized 2,2′-bipyridines

Article abstract of DOI:10.1016/j.tetlet.2005.12.006

An efficient strategy for the synthesis of functionalized 2,2′-bipyridines is reported. The strategy is based on readily available 3-pyridyl-1,2,4-triazine 4-oxides and uses a reaction sequence of nucleophilic substitution of hydrogen and aza Diels-Alder

Full text of DOI:10.1016/j.tetlet.2005.12.006

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 869–872
Consecutive nucleophilic substitution and
aza Diels–Alder reaction—an efficient strategy to
functionalized 2,20-bipyridines
a,b
Dmitry N. Kozhevnikov,a,b, Valery N. Kozhevnikov, Anton M. Prokhorov,a
Maria M. Ustinova,a Vladimir L. Rusinov,a Oleg N. Chupakhin,b
Grigory G. Aleksandrovb and Burkhard Ko¨nigc
*
aUral State Technical University, Mira 19, 620002 Ekaterinburg, Russia
bInstitute of Organic Synthesis, Ural Branch of Russian Academy of Sciences, Kovalevskoy 22, 620219 Ekaterinburg, Russia
cInstitut fu¨r Organische Chemie, Universita¨t Regensburg, D-93040 Regensburg, Germany
Received 18 October 2005; revised 29 November 2005; accepted 1 December 2005
Abstract—An efficient strategy for the synthesis of functionalized 2,20-bipyridines is reported. The strategy is based on readily avail-
able 3-pyridyl-1,2,4-triazine 4-oxides and uses a reaction sequence of nucleophilic substitution of hydrogen and aza Diels–Alder
reaction.
Ó 2005 Elsevier Ltd. All rights reserved.
Polypyridines (i.e., 2,20-bipyridines, 2,20:60,200-terpyri-
dines, phenanthrolines and their azaanalogues, etc.)
continue to attract appreciable attention with practical
applications ranging from catalysis1 and photocatalysis2
to analytical reagents3 and selective extracting agents in
the management of nuclear wastes.4 Thus it still needs to
develop directed synthetic routes to suitable polypyri-
dine units and effective methods for their functionaliza-
tion. In particular, introduction of an aryl substituent
increases luminescence. The highest emission quantum
yields (up to Uf = 0.80) were achieved for 5-aryl-2,20-
bipyridines.5 Acetylene moiety is a very desirable func-
tion in polypyridines. It serves as a conjugating linkage
between functional parts of molecular devices.6 It opens
a way to polymers with special properties.7 Introduction
of an ethynyl group improves significantly photo physi-
cal,8 magnetic9 properties, etc. The carborane cage
changes electronic properties of polypyridines and their
complexes.10 The nido-carborane moiety forms the 13-
vertex metallocarboranes.11 Pyridines containing thio-
phene residue in the a-position forms cyclometallated
Pt-, Pd-, Ir-complexes with significant phosphorescent
properties12 and catalytic activity.13 The presence of o-
hydroxy- or o-alkoxyphenyl in a-position of a pyridine
ligand gives additional O-chelating centres.14
Recently we reported a strategy for the synthesis of
substituted 2,20-bipyridines based on readily available
pyridyl-1,2,4-triazine 4-oxides 1.15 The strategy includes
two steps (Scheme 1). The first one is an aromatic nucleo-
philic substitution of hydrogen—the typical reaction
for 1,2,4-triazines that provides one-step introduction
of various functional substituents into the hetero-
cycles.16 The second step is a transformation of 1,2,4-tri-
azines to pyridines with retention of all substituents via
an aza Diels–Alder reaction.17 It is also noteworthy that
the intermediate substituted pyridyltriazines are interest-
ing compounds in their own right due to their applica-
tion in transition metal analysis3 or in the separation
N
N
Ar
N
Ar
Ar
NuH
RCOCl
Nu
Py
N
N
dienophile
-N2
Py
H
N+
O
Nu
N
Py
Aza Diels-Alder
reaction
Nucleophilic substitution
of hydrogen
*
Corresponding author. Tel.: +7 343 375 4501; fax: +7 343 374
0458; e-mail: dnk@htf.ustu.ru
Scheme 1. Synthetic strategy towards functionalized bipyridines.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.006

870
D. N. Kozhevnikov et al. / Tetrahedron Letters 47 (2006) 869–872
of lanthanides and actinides in the management of
nuclear waste.4
ethynylbipyridine 6a with CuCl2Æ2H2O in acetonitrile
resulted in complex [Cu(6a)Cl2]. The X-ray diffraction
study19 confirms that the ligand 6a behaves as bidentate
ligand and that co-ordination around the Cu(II) ion is
distorted tetragonal. A view of [Cu(6a)Cl2] is given in
Figure 1.
We describe here an application of the methodology for
the synthesis of different a-substituted 2,20-bipyridines.
The starting materials for all transformations were 3-
(2-pyridyl)-1,2,4-triazine 4-oxides (1a–c), obtained in
three steps from available acetophenones and pyridine-
2-carboxaldehyde.15
The same approach was used for the synthesis of carbo-
rane-substituted bpy. Lithiation of 2-phenyl-1,2-di-
carba-closo-dodecaborane gave the corresponding
1-lithium-1,2-dicarba-closo-dodecaborane and this was
reacted with 1,2,4-triazine 4-oxide 1a in THF. Treat-
Thus, triazine 1b underwent nucleophilic substitution of
hydrogen with the lithium salt of (trimethylsilyl)acetyl-
ene yielding 5-(trimethylsilyl)ethynyl-6-tolyl-3-(2-pyr-
idyl)-1,2,4-triazine (2b) in 39% yield (Scheme 2).
Treatment on the reaction mixture with acetyl chloride
was necessary to provide aromatization of the inter-
mediate r-adducts (Scheme 1). The following aza
Diels–Alder reaction of 2b with 2,5-norbornadiene as
dienophile afforded the desired 6-(trimethylsilyl)ethyn-
yl-5-tolyl-2,20-bipyridine (3b) in good yield (67%).
Hydrolysis of 3b in K2CO3/MeOH led to the formation
of 6-ethynyl-5-tolyl-2,20-bipyridine (4) in 80% yield
(Scheme 2).18 The reaction of phenylacetylene with
1,2,4-triazine 4-oxide 1a proceeded by the same manner.
Following refluxing of 6-phenyl-5-phenylethynyl-3-(2-
pyridyl)-1,2,4-triazine (5a) with 2,5-norbornadiene gave
5-phenyl-6-phenylethynyl-2,20-bipyridine (6a) in 52%
overall yield (Scheme 2).
˚
Figure 1. ORTEP view of [Cu(6a)Cl2]. Selected bonds length (A):
It is noteworthy that 6-substituents on bpy often inter-
fere with complexation. In spite of this, reaction of
Cu(1)–Cl(1) 2.229, Cu(1)–N(1) 2.011, Cu(1)–N(2) 1.992, C(17)–C(18)
1.196.
Ar
Tol
iii
Ar
N
N
ii
N
80%
3b
N
N
R
N
H
N
R
N
4
3b (R = SiMe3)
6a (R = Ph)
2b (R = SiMe3)
5a (R = Ph)
Ph
Ph
Ph
Ph
N
N
ii
N
i
90%
N
N
N
8
7
iv
Cl
56%
Cl
Ar
N
vi
85%
N
v
Ar
O
N
N
28%
N+
O
S
Me
S
N
N
N
N
N
9
1a,b,c
10
Ph
N
Ph
vii
54%
N
viii
82%
N
Ar = Ph (a),
Tol (b)
N
N
N
HO
OH
4-Cl-C6H4 (c)
11
HO
OH
12
Scheme 2. Reagents and conditions: (i) Me3SiCCH or PhCCH, BuLi, then 1a or 1b, ꢀ78 °C, 20 min, then MeCOCl; (ii) 2,5-norbornadiene, toluene,
reflux, 5 h; (iii) K2CO3/MeOH, rt, 1 h; (iv) Ph–C2B10H11, BuLi, 15 min, then 1a, ꢀ50 °C, 20 min and then (MeCO)2O; (v) 2-bromothiophene, Mg rt,
3 h, then Me2NCOCl, 15 min; (vi) 2,5-norbornadiene, o-xylene, reflux, 8 h; (vii) resorcinol, TFA, rt, 14 h; (viii) 2,5-norbornadiene, o-xylene, reflux,
32 h.

D. N. Kozhevnikov et al. / Tetrahedron Letters 47 (2006) 869–872
871
ment of the resulting mixture with N,N-dimethylcarba-
S
S
moyl chloride resulted in the formation of 1,2,4-triazi-
nyl-1,2-dicarba-closo-dodecaborane (7) in 48–55% yield
(Scheme 2). The electron withdrawing closo-carborane
moiety facilitates the inverse electron demand aza
Diels–Alder reaction of 1,2,4-triazines. Thus, refluxing
of the triazine 7 with 2,5-norbornadiene in toluene
yielded corresponding 1-(2,20-bipyridine-3-yl)carborane
8 (Scheme 2). The structure of the latter was defined
N
N
N
N
N
N
N
N
Cl
Cu
N
Cl
Cu
S
N
N
N
S
N
N
N
Cu
Cu
Cu N
N
Cu
Cu
N
Cu N
S
N
N
S
N
N
Cl
N
Cl
N
N
N
N
N
N
N
N
1
by H, 13C and 11B NMR spectroscopy.
S
S
Figure 3. Formation of chains of [Cu2(10)2Cl3]+ along the axis c
(hydrogens, chlorophenyls and non-bridging chlorines are omitted).
6-Thienyl-2,20-bipyridine 9 was obtained through the
suggested approach. Thus, the reaction of triazine 1c
with 2-bromothiophene in THF solution in the pres-
ence of magnesium (in situ formation of a Grignard
reagent) and treatment of the resulting mixture with
N,N-carbamoyl chloride gave 6-(4-chlorophenyl)-3-(2-
pyridyl)-5-(2-thienyl)-1,2,4-triazine (10) in 35% yield.
The following aza Diels–Alder reaction of 10 with 2,5-
norbornadiene proceeded in refluxing o-xylene resulting
in the desired thienyl-substituted 2,20-bipyridine 9 in
good yield (78%) (Scheme 2).
of the first ligand and the aryl substituent of the second
ligand are almost co-planar (distances between the
˚
planes are 3.5 and 3.6 A) that causes p–p-interaction be-
tween both ligands and their orthogonal orientation.
Thus, the thienyl in 10 defines regioselectivity of the
co-ordination (N-1 and N-2 instead of N-4), and geo-
metry of the final complex as well.
In the crystal cell, the cations [Cu2(10)2Cl3]+ form dim-
mers due to an interaction of one of the non-bridging Cl
atoms with one of the Cu(II) atom of the second cation
(distance Cu(1)–Cl(3A) is 2.961 A). These dimmers form
chains along the c axis due to p-stacking between thien-
Theoretically, the thiophene residue in 9 and 10 can play
a vital role in the formation of cyclometallated com-
plexes,12 or can act as a bulk substituent interfering with
complexation. Our preliminary studies show that tri-
azine 10 co-ordinates a metal cation by N-1 and N-2,
but not N-4 due to steric hindrances by the thienyl.
Thus, reaction of 10 with CuCl2Æ2H2O in acetonitrile
gave complex [Cu2(10)2Cl3]2[Cu2Cl6]. In accordance
with X-ray crystallographic study,20 two Cu(II) atoms
in the complex cation [Cu2(10)2Cl3] (Fig. 2) have dis-
torted square pyramidal co-ordination: chelating nitro-
gen atoms of the pyridyl and the 1,2,4-triazine (N-2
atom) moieties of the first ligand 10, and two chlorine
atoms (one is bridging between Cu(II) atoms) are in
the base, and N-1 nitrogen of the 1,24-triazine moiety
of the second ligand 10 is in the vertex. The heterocyclic
part of every ligand is planar, the chlorophenyl is dis-
torted due to the bulk thienyl (torsion angles are 67.2°
and 88.1°). At the same time, the heterocyclic fragment
˚
yl-1,2,4-triazine moieties (distance between the heterocy-
˚
clic planes is 3.6 A) (Fig. 3).
The complex anions [Cu2Cl6]2ꢀ lie in corners of the crys-
tal cell. In these binuclear anions [Cu2Cl6]2ꢀ, two Cu(II)
atoms are bridged through two chlorine atoms; twisted
tetragonal co-ordination of each Cu(II) is completed
with two additional chlorine atoms. Distance between
Cu(II) atoms in [Cu2Cl6]2ꢀ is 3.389 A (Fig. 2).
˚
6-(2,4-Dihydroxyphenyl)-2,20-bipyridine (11) was ob-
tained through modified route. Triazine 1a reacted with
the neutral nucleophile—resorcinol in trifluoroacetic
acid to give the product of nucleophilic substitution of
hydrogen—hydroxyphenyltriazine 12 in 65% yield. The
next step—the aza Diels–Alder reaction proceeded after
32 h refluxing of 12 in o-xylene to afford hydroxy-
phenylbipyridine 11 (Scheme 2). Significantly low rate
of the reaction is due to electron donating properties
of the resorcinol moiety that deactivates the 1,2,4-tri-
azine as diene in the inverse electron demand Diels–
Alder reaction.
In conclusion, functionalized bi- and terpyridines are
available from 1,2,4-triazine 4-oxides. The sequence of
introduction of additional substituents by nucleophilic
substitution of hydrogen and transformation of the
1,2,4-triazines to pyridines by aza Diels–Alder reaction
gives access to various substituted 2,20-bipyridines. Each
step of the synthesis allows diversification, if desired.
The method is limited by 5-(hetero)aryl bipys, however
it could be considered as a strong feature because of lack
of other convenient methods for the synthesis of such
compounds and good luminescent properties expected
for them. The second limitation is nucleophiles with
Figure 2. ORTEP view of [Cu2(10)2Cl3]2[Cu2Cl6]. Selected bonds
˚
length (A): Cu(1)–Cl(1) 2.279, Cu(1)–N(1) 2.014, Cu(1)–N(4) 2.028,
Cu(2)–N(3) 2.438.

872
D. N. Kozhevnikov et al. / Tetrahedron Letters 47 (2006) 869–872
16. Kozhevnikov, D. N.; Rusinov, V. L.; Chupakhin, O. N.
Adv. Heterocycl. Chem. Katritzky, A. R., Ed. 2002, 82,
261–305, and references cited therein.
strong electron donating properties are expected to pre-
vent the transformation of 1,2,4-triazines to pyridines.
17. (a) Pabst, G. R.; Pfuller, O. C.; Sauer, J. Tetrahedron 1999,
¨
55, 8045–8064; (b) Branowska, D.; Rykowski, A.;
Wysocki, W. Tetrahedron Lett. 2005, 46, 6223–6226; (c)
Kozhevnikov, V. N.; Kozhevnikov, D. N.; Shabunina, O.
V.; Rusinov, V. L.; Chupakhin, O. N. Tetrahedron Lett.
2005, 46, 1791–1793.
Acknowledgement
The authors thank the Russian Foundation for Basic
Researches (grant no. 05-03-32134) for financial
support.
18. Ethynyl-2,20-bipyridine (4). BuLi (2 mL of 2.5 M solution
in hexane, 5 mmol) was added under argon to a solution
of (trimethylsilyl)acetylene (0.705 mL, 5 mmol) in dry
THF (30 mL). The resulting solution was added dropwise
to a suspension of 1,2,4-triazine 4-oxide 1b (1.32 g,
5 mmol) in THF (30 mL) at ꢀ78 °C. The mixture was
stirred for 20 min, and acetyl chloride (0.356 mL, 5 mmol)
was added. The solvent was removed under reduced
pressure and the residue was treated with toluene (20 mL).
The toluene solution was separated from solids, and the
solvent was removed. The residue was treated with
acetonitrile (1 mL), yellow crystals were filtered off and
recrystallized from acetonitrile to give 2b (670 mg, 39%).
The ethynyltriazine 2b (344 mg, 1 mmol) and 2,5-norbor-
nadiene (0.54 mL, 5 mmol) were dissolved in toluene
(20 mL) and heated at reflux for 5 h. The solvent was
removed under reduced pressure, and the residue was
treated with acetonitrile. Resulting solids were filtered off
to yield 3 (230 mg, 67%). To remove the trimethylsilyl
group bipyridine 3b (171 mg, 0.5 mmol) was dissolved in
MeOH (20 mL), K2CO3 (350 mg, 2.5 mmol) was added,
and the mixture was stirred at rt for 1 h. The solvent was
removed under reduced pressure and the residue extracted
with hot hexane. Evaporation of hexane gave the desired
ethynylbipyridine 4 (108 mg, 80%).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.12.006.
References and notes
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19. Complex [Cu(6a)Cl2]. Solution of the ligand 6a (50 mg,
0.15 mmol) in acetonitrile (30 mL) was added to a solution
of CuCl2Æ2H2O (26 mg, 0.15 mmol) in acetonitrile
(30 mL). The resulting dark brown solution was kept for
3 days at rt. Dark-green crystals that appeared were
filtered off. Crystal data for [Cu(6a)Cl2]: C24H16N2Cl2Cu,
FW = 466.83, triclinic, a = 9.114(2), b = 10.008(2), c =
˚
12.397(3) A, a = 112.34(3)°, b = 102.08(3)°, c = 92.20(3),
3
˚
ꢀ
V = 1014.0(4) A , T = 293(2) K, space group P1, Z = 2,
4688 reflections measured, 4631 unique (Rint = 0.0156),
which were used in all calculations. R1 = 0.0336,
wR2 = 0.0768.
20. Complex [Cu2(10)2Cl3]2[Cu2Cl6]. Solution of the ligand 10
(53 mg, 0.15 mmol) in acetonitrile (30 mL) was added to a
solution of CuCl2Æ2H2O (26 mg, 0.15 mmol) in acetonitrile
(30 mL). The resulting dark brown solution was kept for
3 days at rt. Dark-green crystals that appeared were
filtered off. Crystal data for [Cu2(10)2Cl3]2[Cu2Cl6]: C36H22-
Cl8Cu3N8S2, FW = 1104.96, triclinic, a = 10.7873(16),
˚
b = 12.9549(19), c = 15.241(2) A, a = 69.217(4)°, b =
3
˚
85.042(4)°, c = 86.426(4), V = 1982.7(5) A , T = 120(2)
K, space group P1, Z = 2, 6693 reflections measured,
ꢀ
5233 unique (Rint = 0.0557), which were used in all
13. Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A.
J. Am. Chem. Soc. 2000, 122, 5043–5051.
calculations. R1 = 0.0.0810, wR2 = 0.1698.
Crystallographic data for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
290967 and 290968. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (0) 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
14. (a) Malkov, A. V.; Bell, M.; Castelluzzo, F.; Kocˇovsky, P.
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J. C.; Ward, M. D. Polyhedron 1996, 15, 2019–2022.
15. Kozhevnikov, V. N.; Kozhevnikov, D. N.; Nikitina, T. V.;
Rusinov, V. L.; Chupakhin, O. N.; Zabel, M.; Ko¨nig, B. J.
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