Diverse synthesis of novel bisterpyridines via Suzuki-type cross-coupling

Article abstract of DOI:10.1021/ol062788h

A new protocol is presented for the synthesis of novel bisterpyridine derivatives using palladium-catalyzed Miyaura- and Suzuki-type cross-couplings as the key reactions. This protocol is quick, efficient, mild, and broadly applicable for the construction of versatile bisterpyridines by symmetric and unsymmetric introduction of various substituants in the pyridine rings as well as by tuning the spacers for bridging the two terpyridine moieties.

Full text of DOI:10.1021/ol062788h

ORGANIC
LETTERS
2007
Vol. 9, No. 4
559-562
Diverse Synthesis of Novel
Bisterpyridines via Suzuki-Type
Cross-Coupling
Fu She Han,† Masayoshi Higuchi,*,† and Dirk G. Kurth*,†,‡
Functional Modules Group, Organic Nanomaterials Center, National Institute for
Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan and
Max-Planck-Institute of Colloids and Interfaces, Research Campus Golm, D-14424,
Potsdam, Germany
higuchi.masayoshi@nims.go.jp; kurth@mpikg.mpg.de
Received November 16, 2006
ABSTRACT
A new protocol is presented for the synthesis of novel bisterpyridine derivatives using palladium-catalyzed Miyaura- and Suzuki-type cross-
couplings as the key reactions. This protocol is quick, efficient, mild, and broadly applicable for the construction of versatile bisterpyridines
by symmetric and unsymmetric introduction of various substituents in the pyridine rings as well as by tuning the spacers for bridging the two
terpyridine moieties.
Metallo-supramolecular polymers have recently attracted
growing interest within the domain of material and supra-
molecular chemistry,1 molecular biology,2 and nano science.3
In this context, particular attention has been paid to the
ditopic bisterpyridine derivatives because this type of
compound is chemically and thermally stable and forms, as
a tridentate ligands, stable complexes with a large variety
of transition-metal ions, associated with a rich variety of
interesting properties.3a,4 However, versatile preparation of
bisterpyridine-based coordination polymers has been seri-
ously restricted due to the limited availability of suitable
ligands, and studies have focused mainly on ligands such as
1,4-bis(2,2′:6′,2′′-terpyridine-4-yl)benzene. To date, two
strategies are commonly employed to synthesize bister-
pyridine derivatives.4a,5 One is the base-mediated aldol
condensation of a dialdehyde with an acetylpyridine, for the
(4) For a recent comprehensive review, see: (a) Andres, P. R.; Schubert,
U. S. AdV. Mater. 2004, 16, 1043-1068 and references therein. For recent
research articles, see: (b) Carlson, C. N.; Kuehl, C. J.; Da-Re, R. E.;
Veauthier, J. M.; Schelter, E. J.; Milligan, A. E.; Scott, B. L.; Bauer, E. D.;
Thompson, J. D.; Morris, D. E.; John, K. D. J. Am. Chem. Soc. 2006, 128,
7230-7241. (c) Laine´, P. P.; Bedioui, F.; Loiseau, F.; Chiorboli, C.;
Campagna, S. J. Am. Chem. Soc. 2006, 128, 7510-7521. (d) Se´ne´chal-
David, K.; Leonard, J. P.; Plush, S. E.; Gunnlaugsson, T. Org. Lett. 2006,
8, 2727-2730. (e) Coronado, E.; Gala´n-Mascaro´s, J. R.; Marti-Gastaldo,
C.; Palomares, E.; Durrant, J. R.; Vilar, R.; Gra¨tzel, M.; Nazeeruddin, M.
K. J. Am. Chem. Soc. 2005, 127, 12351-12356. (f) Cui, Y.; He, C. Angew.
Chem., Int. Ed. 2004, 43, 4210-4212. (g) Baitalik, S.; Wang, X.; Schmehl,
R. H. J. Am. Chem. Soc. 2004, 126, 16304-16305. (h) Cui, Y.; He, C. J.
Am. Chem. Soc. 2003, 125, 16202-16203.
† National Institute for Materials Science.
‡ Max-Planck-Institute of Colloids and Interfaces.
(1) Constable, E. C. In ComprehensiVe Supramolecular Chemistry; Lehn,
J. M., Ed.; Pergamon, 1996; Vol. 9, pp 213-252.
(2) (a) Song, B.; Wang, G.; Tan, M.; Yuan, J. J. Am. Chem. Soc. 2006,
128, 13442-13450. (b) Hovinen, J.; Hakala, H. Org. Lett. 2001, 3, 2473-
2476.
(3) (a) Kolb, U.; Bu¨scher, K.; Helm, C. A.; Lindner, A.; Thu¨nemann,
A. F.; Menzel, M.; Higuchi, M.; Kurth, D. G. Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 10202 - 10206. (b) Oh, M.; Mirkin, C. A. Nature 2005, 438,
651-654. (c) Kurth, D. G.; Higuchi, M. Soft Matter 2006, 2, 915-927.
10.1021/ol062788h CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/25/2007

preparation of diazachalcone, followed by a bis-1,4-addition
of the resulting azachalcone with a pyridinium nucleophile.5
Another is the 4′-position substitution reactions of comm-
ericially available 4′-Cl (or OH) monoterpyridines.4a How-
ever, because of the frequent application of strong bases and/
or employment of the bis-1,4-addition reaction in these
conventional methods, their general application intrinsically
suffers from many drawbacks such as the preparation of
unsymmetric ligands, the introduction of functional groups
at the ring periphery, and the availability of different spacers
for bridging the two terpyridine moieties. These drawbacks,
thereby, prevent flexible design and synthesis of bister-
pyridines with structural and functional diversity.
Therefore, development of a general and efficient protocol
for the synthesis of bisterpyridines is highly desirable. Herein,
we describe a Suzuki coupling protocol, which permits the
versatile synthesis of bisterpyridines. Although Suzuki
coupling has been used in a broad range of sp2 C-C bond
formations,6 only very few examples are reported for the
construction of structurally unique bisterpyridines.7
an intramolecular dehydration, to afford the monoterpyridines
4 and 5, respectively, in good yield. For further functional-
ization, the terpyridine 4 was oxidized with m-CPBA to give
N,N′′-dioxidized compound 6 in excellent yield. The resulting
dioxide 6 was then subjected to a Reissert-Henze-type
reaction9 to produce the 6,6′′-dicarbonitrile 7. Alternatively,
nucleophilic substitution of 6,6′′-dibromo-terpyridine 5 with
NaOMe gave the corresponding 6,6′′-dimethoxyl derivative
8 in quantitative yield. The functional groups in pyridine
rings, such as the bromide in 5, the carbonitrile in 7, and
the methoxyl group in 8, can be readily transformed into a
number of other functional groups. The efficient synthesis
makes these monoterpyridines attractive precursors for the
construction of diverse bisterpyridine derivatives.
With these useful monoterpyridines in hand, our attention
shifted first to the construction of symmetric bisterpyridines
by using Suzuki-type cross-coupling. The first challenge here
is to successfully synthesize the terpyridine boronic esters
(acids), a class of compounds rarely reported.7 We initially
tried the classical reaction of a lithium reagent 9, generated
in situ from terpyridine 4 and BuLi or tBuLi, with a trialkyl
borate 10 (Scheme 2).10 However, extensive efforts under
Synthesis of monoterpyridine derivatives 4, 5, 7, and 8 is
outlined in Scheme 1. On the basis of a modified one-pot
Scheme 2. Preparation of Terpyridine Boronic Esters
Scheme 1. Synthesis of Monoterpyridines
various conditions proved to be fruitless, and only a small
amount of boronic esters contaminated by some unknown
impurities were obtained (ca. 30%). The major product was
found to be the debrominated 1211 (>50%).
Kro¨hnke procedure,8 4-bromobenzaldehyde 1 and 2 equiv
of 2-acetylpyridines (2 or 3) reacted sequentially in a
Claisen-Schmidt aldol condensation,8 a 1,4-addition, and
(7) After the submission of this manuscript, an example for the synthesis
of fluorenyl-bridged unsubstituted bis- and tristerpyridines was reported
using Suzuki cross-coupling. See: Yuan, S.; Chen, H.; Zhang, Y.; Pei, J.
Org. Lett. 2006, 8, 5701-5704.
(8) Eryazici, I.; Moorefield, C. N.; Durmus, S.; Newkome, G. R. J.
Org. Chem. 2006, 71, 1009-1014.
(5) (a) Vaduvescu, S.; Potvin, P. G. Eur. J. Inorg. Chem. 2004, 1763-
1769. (b) Constable, E. C.; Thompson, A. M. W. C. J. Chem. Soc., Dalton
Trans. 1992, 3467-2475. (c) Kro¨hnke, F. Synthesis 1976, 1-24.
(6) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483 and
references therein.
(9) Pauvert, M.; Collet, S. C.; Bertrand, M.; Guingant, A. Y.; Evain,
M. Tetrahedron Lett. 2005, 46, 2983-2987.
(10) Jacob, J.; Sax, S.; Piok, T.; List, E. J. W.; Grimsdale, A. C.; Mu¨llen,
K. J. Am. Chem. Soc. 2004, 126, 6987-6995.
560
Org. Lett., Vol. 9, No. 4, 2007

Our efforts then focused on a Miyaura-type cross-coupling
strategy for the preparation of terpyridine boronic esters.12
We were pleased to find that treatment of 4 with 1.1 equiv
of bis(pinacolato)diboron 13 led to a smooth conversion of
substrate 4 under all three different conditions tried (Table
1, entries 1-3). Careful spectroscopic analyses revealed that
satisfactory yield. Thus, the final optimized conditions were
5 mol % of PdCl2(PPh3)2, K2CO3, DMSO, and 80 °C. Under
these conditions, 14a was obtained in 86% yield when the
reaction was scaled up to 300 mg.14 The structure of 14a is
determined by standard spectroscopic techniques, including
1H and 13C NMR and mass spectrometry, as well as X-ray
crystallographic analysis (Figure 1).15
Table 1. Optimization of the Suzuki Dimerization Coupling
Reaction of Terpyridine 4 with Bis(pinacolato)diboron 13a
entry
catalyst
base
°C/h
80/6
solvent yieldc (%)
Figure 1. X-ray crystal structure of 14a. Displacement ellipsoids
represent 50% probability.
1
2
3
4
5
6
7
8
9
PdCl2(dppf)b
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
KOAc
KOAc
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMF
97d
95d
95d
89
b
80/6
80/16
80/18
80/18
100/16 DMSO
60/16
80/20
Next, the methodology was extended to the synthesis of a
range of symmetric bisterpyridines having various functional
groups in the pyridine rings. As shown in Scheme 3, the
88
88
DMSO
dioxane
DMSO
DMSO
51
-
73
40
e
NaHCO3 80/20
KF 80/20
10
Scheme 3. Synthesis of Substituted Bisterpyridines
a Conditions for entries 1-3: 50 mg (0.128 mmol) of 4, 1.1 equiv of
bis(pinacolato)diboron 13, 5 mol % of catalyst unless otherwise noted, 3.0
equiv of base, 80 °C. Conditions for entries 4-10: 50 mg (0.128 mmol)
b
of 4, 0.52 equiv of 13, 5 mol % of catalyst, 3.0 equiv of base, 80 °C. 30
mol % of catalyst. cIsolated yield by column chromatography on basic Al2O3,
unless otherwise noted. dCombined total yield of the mixture of 11 (major)
e
and 14a (minor). Only a trace amount of product was detected by TLC.
the product was a hard to separate mixture of 11 (major)
and the dimerized product 14a (minor).
The detection of 14a is attractive because it implies that
high-yielding dimerization would be possible via a one-pot
tandem Miyaura boronic ester formation and Suzuki coupling
if the reaction conditions such as the amount of boron
reagent, bases, solvents, and temperature were properly
controlled, thereby providing a much faster procedure for
synthesizing bisterpyridines of the symmetric type than a
stepwise one. Accordingly, the reaction conditions were
further optimized using PdCl2(PPh3)2 as catalyst instead of
PdCl2(dppf) in standard Miyaura conditions.13 It was im-
mediately clear that the outcome of the reaction was
markedly affected by base, solvent, and temperature (Table
1, entries 4-10). In general, use of stronger bases such as
K2CO3 and of polar solvents such as DMSO and DMF (Table
1, entries 4 and 5) gave the dimerized product 14a in a
dimerization occurred efficiently for both electron-deficient
(7) and electron-rich (8) substrates to give 14b and 14c,
respectively. The relatively low yield for 14b is due to the
extremely poor solubility in many solvents such as DMSO,
DMF, THF, CHCl3, CH2Cl2, and other protic solvents,
resulting in a partial precipitation of the product from the
reaction system.16 When 5 was subjected to cross-coupling
under the same conditions, a complex mixture was obtained,
probably resulting from the competitive boronic ester forma-
tion of the bromides in benzene and pyridine rings as well
as from the following competitive Suzuki coupling reac-
tions.17
(14) Reaction at a larger scale was not tried.
(15) Crystal data for 14a at 110 K: C42H28N6 (MW: 616.71), 0.20 ×
0.05 × 0.04 mm3, colorless needle crystal, monoclinic, space group C2/c,
a ) 28.0200(12) Å, b ) 10.6337(3) Å, c ) 10.9221(4) Å, V ) 3201.6(2)
Å3, â ) 100.330(3)°, Z ) 4; final R1 ) 0.0445 for all 15 519 reflections
of I >2σ(I), wR2 ) 0.1404 for all 15 519 reflections.
(16) Due also to the poor solubility, characterization of 14b by NMR
spectroscopy was difficult, but mass spectrometry revealed a characteristic
peak corresponding to 14b (see Supporting Information).
(11) Mutai, T.; Cheon, J.; Arita, S.; Araki, K. J. Chem. Soc., Perkin
Trans. 2 2001, 1045-1050.
(12) (a) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron
Lett. 1997, 38, 3447-3450. (b) Ishiyama, T.; Murata, M.; Miyaura, N. J.
Org. Chem. 1995, 60, 7508-7510.
(13) Because use of PdCl2(dppf) afforded a product with the contamina-
tion of unremovable red color.
Org. Lett., Vol. 9, No. 4, 2007
561

On the basis of the experiences for the synthesis of
symmetric bisterpyridines 14a-c, bisterpyridines of the
unsymmetric type 15a-b were also synthesized efficiently
via a one-pot procedure involving boronic ester formation
followed by in situ Suzuki cross-coupling (Scheme 4). Thus,
Scheme 5. Synthesis of Bisterpyridines by Tuning Spacers
Scheme 4. Synthesis of Unsymmetric Bisterpyridines
18a in good yields. Further exploration showed that the
electron-deficient (7) and electron-rich (8) substrates are also
compatible with this synthetic strategy, providing the cor-
responding coupling products 18b and 18c, respectively, in
high yields.
monoterpyridine 4 was treated with 1.1 equiv of bis-
(pinacolato)diboron 13 under modified Miyaura conditions13
until the starting material had disappeared as monitored by
TLC. Then, the reaction vessel was recharged in situ with
1.0 equiv of electron-deficient 7 (or electron-rich 8), 5 mol
% of PdCl2(PPh3)2, and 3.0 equiv of K2CO3. The mixture
was heated further under stirring until 7 (or 8) had disap-
peared. Purification of the reaction mixtures afforded the
desired unsymmetric bisterpyridine 15a and 15b, respec-
tively, in good isolated yield. It should be noted that such
types of unsymmetric ligands are anticipated to be interesting
for the fabrication of metallo-supramolecular polymers
containing different metal ions in a well-defined way,
providing new materials with novel functions. However, it
is extremely difficult to synthesize this type of ligands
according to the established procedures.4a,5
Having established a robust Suzuki-type protocol ac-
complishing the synthesis of bisterpyridines of symmetrically
and unsymmetrically substituted types, we became interested
in extending this protocol to the construction of other new
bisterpyridines by tuning the spacers for bridging the two
terpyridine moieties. For this purpose, we adopted a Suzuki
bis-coupling strategy as outlined in Scheme 5. Here, 1,3-
diboronate 17 was prepared from 1,3-dibromobenzene 16
via Miyaura cross-coupling. Then, Suzuki bis-coupling of
17 with 2 equiv of 4 gave the corresponding bisterpyridine
In conclusion, we have developed a new protocol to access
bisterpyridine derivatives using palladium-catalyzed Miyaura-
and Suzuki-type cross-couplings as the key reactions. This
protocol is shown to be quick, efficient, mild, and broadly
applicable for the synthesis of a large variety of sym-
metrically and unsymmetrically functionalized, as well as
spacer tunable bisterpyridines. Besides, the methoxyl and
carbonitrile functionalities either in the monoterpyridines or
in the bisterpyridines are ready for further versatile deriva-
tization. As a result, flexible design and synthesis of
bisterpyridine derivatives with structural and functional
diversity are possible employing the newly developed
methodology. On the other hand, the availability of a diverse
class of valuable bisterpyridines allows the versatile fabrica-
tion of novel metallo-supramolecular polymers. This work
along with the synthesis of structurally more complex
bisterpyridines is currently underway.
Acknowledgment. We thank the Ministry of Education,
Culture, Sports, Sciences, and Technology, Japan, for
financial support.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
for all new compounds (except for 14b) and 12. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) It was also reported that protonolysis of a C-B bond might occur
when the boron atom is attached to a carbon adjacent to heteroatoms (see
ref 9a), making the reaction more complicated.
OL062788H
562
Org. Lett., Vol. 9, No. 4, 2007