Palladium-catalyzed synthesis of nonsymmetrically functionalized bipyridines, poly(bipyridines) and terpyridines

Article abstract of DOI:10.1002/ejoc.200390214

Palladium-catalyzed coupling reactions were employed to prepare nonsymmetric, densely functionalized bipyridines and oligo(bipyridines), featuring sensitive functionalities like alcohol, ester and aldehyde groups. Stille coupling between halo (poly)pyridine and the proper (poly)pyridyltin derivative afforded in good yields nonsymmetric, derivatized oligo(bipyridines), amenable to further synthetic modifications. The methodology was used also to synthesize highly functionalized terpyridines. A series of Suzuki and Stille palladium-promoted coupling reactions allowed us to obtain in good yields terpyridines bearing two different and differently functionalizable groups, valuable building blocks for the construction of complex supramolecular frameworks. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390214

FULL PAPER
Palladium-Catalyzed Synthesis of Nonsymmetrically Functionalized
Bipyridines, Poly(bipyridines) and Terpyridines
Alessandra Puglisi,[a] Maurizio Benaglia,*[a] and Giulia Roncan[a]
Keywords: Bipyridines / Terpyridines / Palladium catalysts / Oligopyridines / Stille coupling
Palladium-catalyzed coupling reactions were employed to
prepare nonsymmetric, densely functionalized bipyridines
and oligo(bipyridines), featuring sensitive functionalities like
alcohol, ester and aldehyde groups. Stille coupling between
halo(poly)pyridine and the proper (poly)pyridyltin derivative
afforded in good yields nonsymmetric, derivatized oligo(bi-
tionalized terpyridines. A series of Suzuki and Stille palla-
dium-promoted coupling reactions allowed us to obtain in
good yields terpyridines bearing two different and differently
functionalizable groups, valuable building blocks for the
construction of complex supramolecular frameworks.
pyridines), amenable to further synthetic modifications. The ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
methodology was used also to synthesize highly func-
Germany, 2003)
Introduction
tionalized bipyridines, poly(bipyridines), and terpyridines.
Here we wish to report the results of this study.
Nitrogen heterocycles are commonly employed in the
construction of supramolecular frameworks endowed with
novel photo-, electrochemical or catalytic properties.[1] In Results
this field oligo(bipyridines) and terpyridines have found
widespread use as building blocks in the assembling of new
supramolecular structures[2] that have been employed in
polymer and dendrimer chemistry,[3] and as chiral ligands
in asymmetric catalysis.[4]
To validate the possibility of exploiting palladium chem-
istry as a tool for the construction of poly(bipyridine)
frameworks, we decided at first to improve the synthesis of
the nonsymmetric, poly(bipyridine) alcohols 1 and 2
(Scheme 1).[14]
In this context it became more and more important to
develop efficient, high-yield synthetic strategies toward
these ligands. Several methods for the preparation of sym-
metrically substituted 2,2Ј-bipyridines are available,[5] the
most used being the Kronhke procedure[6] and the nickel-
promoted coupling of halopyridines.[7] On the contrary, the
synthesis of nonsymmetric oligopyridines and terpyridines
is much less straightforward, and until a few years ago only
a few examples were known.[8] The advent of palladium-
promoted Suzuki[9] and Stille[10] couplings has offered new
opportunities to build biaryl systems and recently examples
of Stille,[11] Suzuki,.[12]and Negishi[13] cross-coupling reac-
tions between halopyridines or pyridyl triflates and pyridyl-
based organometallic reagents have been reported. How-
ever, these procedures were generally limited to the prep-
aration of methyl- or alkyl-substituted bipyridines. To take
full advantage of these modern methodologies, we investi-
gated the use of tin derivatives and boronic acids for the
synthesis of nonsymmetrically substituted, highly func-
Scheme 1. Synthesis of poly(bipyridines) 1 and 2
[a]
These molecules have been prepared by reaction of 6,6Ј-
dimethyl-2,2Ј-bipyridine[7] with N-bromosuccinimide to
give both the di- (37% yield) and the monobromo (35%
yield) derivative. The monobromo derivative was hy-
Centro di Eccellenza CISI and Dipartimento di Chimica
Organica e Industriale, Universita’ degli Studi di Milano
Via Golgi 19, 20133 Milano, Italy
Fax: (internat.) ϩ 39-02/50314159
E-mail: maurizio.benaglia@unimi.it
1552
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0408Ϫ1552 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 1552Ϫ1558

Nonsymmetrically Functionalized Bipyridines, Poly(bipyridines) and Terpyridines
FULL PAPER
drolyzed to 6-(hydroxymethyl)-6Ј-methyl-2,2Ј-bipyridine corresponding trimethylstannyl derivative 10 in 87% yield
and its sodium salt reacted with 6,6Ј-bis(bromomethyl)- by the Pd(PPh3)4-catalyzed reaction with Me6Sn2 in DMF
2,2Ј-bipyridine to give, after K2CO3-promoted hydrolysis, for 12 h.[16]
the bis(bipyridine) alcohol 1 in 19.6% overall yield
Compound 10 was used as the starting material for the
(Scheme 1). An iterative procedure allowed to prepare the synthesis of an array of different structures. Coupling of 10
tris(bipyridine) alcohol 2 in 7.5% overall yield starting from with pyridine 4 afforded, after desilylation with Bu4NF, the
the commercially available 2-bromopicoline.[15]
bis(bipyridine) 1 in 57% yield over the two steps.[17] The
A more efficient synthesis has now been performed overall yield for 1 was 30.6% which favorably compares
(Scheme 2). Thus, the commercially available 2,6-dibromo- with the 19.6% yield reported for the previous synthesis of
pyridine was transformed by lithiation with n-butyllithium, this compound (Scheme 2). Similarly, the Pd0-promoted re-
treatment with N,N-dimethylformamide (DMF), and in situ action of 10 with bipyridine 7 followed by desilylation af-
reduction with NaBH4, into 2-bromo-6-(hydroxymeth- forded the tris(bipyridine) alcohol 2 in 47% yield (two
yl)pyridine (3), isolated in 98%yield by a single purification steps). In this case the overall yield of 2 starting form the
through a short plug of silica gel. Alcohol 3 was either pro- commercially available 2,6-dibromopyridine was 26%, much
tected as tert-butyldimethylsilyl ether 4 (96% yield), or con- higher than that of the previously reported preparation for
verted into its mesylate 5 (95% yield). Reaction of the latter this compound (7.5% yield).[14] Noteworthy, the tin deriva-
with the sodium alkoxide of 3 gave 6 in 93% yield after tive 10 was cross-coupled to 6 to afford in 50% yield the
flash chromatographic purification (Scheme 2). Lithiation bis(bipyridine) adduct 11, that presents a bromopyridine
of the former followed by treatment with Me3SnCl afforded functionality amenable to iteration of the coupling pro-
the corresponding trimethylstannyl derivative that was cou- cedure to yield functionalized tetrakis(bipyridines). More-
pled with 6 in THF (tetrahydrofuran) in the presence of over, this strategy allows to circumvent the solubility prob-
10% of Pd(PPh3)4; the expected product 7 was isolated after lems associated to the handling of these poly(bipyiridine)
chromatographic purification in 65% yield. Similarly, the moieties, that are poorly soluble in most organic and even
cross coupling reaction of 6 with 6-methyl-2-(trimethylstan- chlorinated solvents, thus making really troublesome the
nyl)pyridine, obtained in 95% yield by lithiation of 2- purification, isolation, and further manipulation of these
bromopicoline (8) and treatment with Me3SnCl, afforded compounds. On the contrary, in the present strategy the po-
adduct 9 in 66% yield. This was further converted into the ly(bipyridine) chain is built only in the very last step of the
Scheme 2. Synthesis of nonsymmetric, functionalized poly(bipyridines)
Eur. J. Org. Chem. 2003, 1552Ϫ1558
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A. Puglisi, M. Benaglia, G. Roncan
FULL PAPER
Scheme 3. Synthesis of nonsymmetric, functionalized terpyridines
synthesis, assembling two species readily soluble in many ine 19, bearing two different and differently functionalizable
organic solvents.
groups, an ester and an aldehyde.
To widen the scope of this chemistry, the synthesis of
bipyridines and terpyridines bearing different and more
versatile functional groups was then attempted. We were
pleased to find that the use of Stille coupling allowed the
preparation of nonsymmetrically substituted terpyridines
containing alcohol, ester or aldehyde groups which are very
difficult to prepare by other methods[18] (Scheme 3) and
open access to a variety of derivatives.
Thus, the Suzuki reaction between 4-formyl-substituted
phenylboronic acid and 2,6-dibromopyridine (12) (both
commercially available) promoted by Pd(OAc)2 and Ph3P
in toluene afforded the monocoupling product 13 in 55%
yield after chromatographic purification. This intermediate
was reduced to alcohol 14 (85% yield) by treatment with
NaBH4 and then protected either as acetate (15a), silyl
(15b) or allyl (15c) ether, in 91, 88, and 80% yield, respec-
tively.
Conclusions
We have demonstrated that Stille cross coupling represents
an efficient method to prepare asymmetrically func-
tionalized bipyridines, poly(bipyridines), and terpyridines,
that are valuable building blocks for the construction of
complex supramolecular frameworks. The mild reaction
conditions allow to synthesize densely functionalized mol-
ecules featuring sensitive functionalities like alcohol, alde-
hyde, and ester groups, amenable to further synthetic modi-
fications. The methodology represents a useful tool for the
synthesis of functionalized supramolecular structures and
is currently exploited in our group for building enantiomer-
ically pure double helicates, innovative β-turn mimics, and
topologically relevant molecules.
Aldehyde 13 was also successfully transformed in the cor-
responding trimethylstannyl derivative by Pd0-catalyzed re-
action with Me6Sn2 and coupled a second time to 12 to
Experimental Section
[16]
General: 1H NMR spectra were recorded at 300 MHz in CDCl3
unless otherwise stated, and were referenced to TMS (δ ϭ
0.00 ppm). 13C NMR spectra were recorded at 75 MHz and were
referenced to CDCl3 (δ ϭ 77.0 ppm). IR spectra were recorded on
thin films or as solutions in CH2Cl2. Compounds 1,[20] 2,[14b] 3,[21]
give the bipyridine 16 in 63% yield, which was finally first
converted into the tin derivative and then coupled to the
O-protected (hydroxymethyl)pyridines 15aϪc to afford the
corresponding, asymmetrically substituted terpyridines 17a,
17b, 17c in 71, 65, and 57% yield, respectively (Scheme 3).
It is worth mentioning that it was also possible to couple
the tin derivative of 16 with 2-bromo-6-(4-methoxycar-
4
[21] are known compounds; compound 8 is commercially available.
Synthesis of Compound 5: To a stirred solution of alcohol 3
bonylphenyl)pyridine (18)[19] to give in 48% yield terpyrid- (900 mg., 4.8 mmol) in dry THF under argon, at 0 °C, triethyl-
1554
Eur. J. Org. Chem. 2003, 1552Ϫ1558

Nonsymmetrically Functionalized Bipyridines, Poly(bipyridines) and Terpyridines
FULL PAPER
amine (0.87 mL, 6.23 mmol) and methanesulfonyl chloride O 6.39, Si 5.61; found C 57.54, H 6.06, Br 15.98, N 8.43, O 6.40,
(0.445 mL, 5.75 mmol) were added dropwise. The reaction mixture Si 5.63.
was stirred at room temperature for 12 h; then it was quenched
with an NH4Cl sat. sol., the organic phase was separated, the aque-
Synthesis of Compound 9
ous phase extracted twice with diethyl ether and the combined or-
ganic phases were dried with magnesium sulfate and concentrated
under vacuum to give a very viscous oil. The crude product was
Synthesis of 6-Methyl-2-(trimethylstannyl)pyridine: To a dry Et2O
solution of 2-bromo-6-methylpyridine (1.6 mmol, 0.275 g) at Ϫ78
°C under argon, a 1.6  solution of n-butyllithium in hexanes
(1.6 mmol, 1 mL) was added dropwise within 30 min; the reaction
mixture was stirred at Ϫ78 °C for 1 h, then a 1  solution of
Me3SnCl in dry THF was added dropwise (1.7 mmol, 1.7 mL), and
the reaction mixture was allowed to warm up to room temperature
and was stirred overnight. The solvent was evaporated and the
crude reaction mixture was rinsed with diethyl ether; the solid
(LiCl) was filtered and the solvent removed under vacuum to give
a pale yellow oil that was used in the next step without further
purification (401 mg, yield Ͼ 98%). 1H NMR: δ ϭ 0.30 (s, 9 H,
CH3Sn), 2.55 (s, 3 H, Me), 6.80Ϫ7.45 (m, 3 H) ppm.
used without further purification (1.21 g, yield 95%). 1H NMR:
3
δ ϭ 3.12 (s, 3 H, Me), 5.28 (s, 2 H, CH2OMs), 7.43 (d, JH,H
ϭ
3
3
12 Hz, 1 H), 7.48 (d, JH,H ϭ 12. Hz, 1 H), 7.62 (t, JH,H ϭ 12 Hz,
1 H) ppm. 13C NMR: δ ϭ 38.05, 72.5, 118.9, 120.9, 137.4, 158.2,
160.5 ppm. C7H8BrNO3S (266): calcd. C 31.59, H 3.03, Br 30.03,
N 5.26, O 18.04, S 12.05; found C 31.61, H 3.07, Br 30.08, N 5.29,
O 18.01, S 12.03.
Synthesis of Compound 6: A stirred 0.1  solution of alcohol 3
(530 mg, 2.82 mmol) in dry tetrahydrofuran under argon was added
to a suspension of NaH (50% dispersion in mineral oil, 162 mg,
3.38 mmol) in dry tetrahydrofuran. The reaction mixture was
Synthesis of Compound 9 (Cross Coupling Procedure): To a degassed
dry THF solution of 6-methyl-2-(trimethylstannyl)pyridine
(160 mg, 0.5 mmol) and ether 6 (271 mg, 0.7 mmol), Pd(PPh3)4
(40 mg, 0.035 mmol) was added and the reaction mixture was
heated to reflux for 15 h. The solvent was removed under vacuum
and the product 9 was purified by flash chromatography on silica
gel [dichloromethane/ethyl acetate (90:10) as eluent] to give a white
solid (122 mg, 66% yield). M.p. 164Ϫ166 °C 1H NMR: δ ϭ 2.60
(s, 3 H, Me), 4.80 (s, 2 H, OCH2Py), 4.90 (s, 2 H, OCH2BiPy), 7.19
stirred at room temperature for
1 h. Mesylate 5 (750 mg,
2.82 mmol) was then added and the reaction mixture was refluxed
overnight. The reaction mixture was then cooled, and residual so-
dium hydride quenched by addition of a small amount of meth-
anol. The solvent was removed under vacuum. The crude product
was purified by flash chromatography [dichloromethane/ethyl acet-
ate (95:5) as eluent] to give the product (0.98 g, 93% yield). M.p.
1
3
153Ϫ155 °C. H NMR: δ ϭ 4.75 (s, 4 H, CH2O), 7.41 (t, JH,H
ϭ
3
3
3
3
(d, JH,H ϭ 7 Hz, 1 H), 7.39 (d, JH,H ϭ 8 Hz, 1 H), 7.55 (d,
9 Hz, 1 H), 7.49 (d, JH,H ϭ 12 Hz, 1 H), 7.59 (d, JH,H ϭ 12 Hz,
1 H) ppm. 13C NMR: δ ϭ 74.5, 118.6, 120.3, 137.1, 158.0, 160.1
ppm. C12H10Br2N2O (358): calcd. C 38.29, H 2.63, Br 46.32, N
8.12, O 4.64; found C 38.28, H 2.59, Br 46.38, N 8.15, O 4.60.
3JH,H ϭ 8 Hz, 1 H), 7.50Ϫ7.60 (m, 2 H), 7.60 (t, JH,H ϭ 8 Hz, 1
3
3
3
H), 7.80 (t, JH,H ϭ 7 Hz, 2 H), 8.18 (d, JH,H ϭ 7 Hz, 1 H), 8.30
(d, 3JH,H ϭ 8 Hz, 1 H) ppm. 13C NMR: δ ϭ 24.3, 74.4, 74.7, 119.6,
120.8, 121.4, 121.6, 122.3, 122.7, 136.8, 137.3, 138.2, 152.3, 153.5,
154.1, 154.5, 157.2, 158.8 ppm. C18H16BrN3O (370): calcd. C 58.39,
H 4.36, Br 21.58, N 11.35, O 4.32; found C 58.34, H 4.36, Br 21.56,
N 11.33, O 4.30.
Synthesis of Compound 7
Synthesis of 2-[(tert-Butyldimethylsilyl)oxymethyl]-6-(trimethylstan-
nyl)pyridine: To a dry Et2O solution of silyl derivative 4 (1.32 mmol,
0.4 g) at Ϫ78 °C under argon, a 1.5  solution n-butyllithium in
hexanes (1.36 mmol, 0.9 mL) was added dropwise within 30 min;
the reaction mixture was stirred at Ϫ78 °C for 1 h, then a 1 
solution of Me3SnCl in dry THF was added dropwise (1.4 mmol,
1.4 mL) and the reaction mixture was allowed to warm up to room
temperature and was stirred overnight. The solvent was evaporated
and the crude reaction mixture was rinsed with diethyl ether; the
solid (LiCl) was filtered and the solvent removed under vacuum to
give a pale yellow oil that was used in the next step without further
purification (501 mg, yield Ͼ 98%). 1H NMR: δ ϭ 0.15 (s, 6 H,
CH3Si), 0.30 (s, 9 H, CH3Sn), 0.95 (s, 9 H, SitBu), 4.85 (s, 2 H,
Synthesis of Trimethylstannyl Derivative 10: To a degassed, dry
DMF solution of compound 9 (185 mg, 0.5 mmol), hexamethyldis-
tannane (327 mg, 1 mmol) was added dropwise. Pd(PPh3)4 (58 mg,
0.05 mmol) was added and the reaction mixture was heated at 120
°C for 15 h. The solvent was evaporated under vacuum and the
crude reaction mixture purified by chromatography through a very
short column on neutral alumina [dichloromethane/hexanes (70:30)
as eluent] to give the product as a very viscous oil (197 mg, 87%
yield). 1H NMR: δ ϭ 0.30 (s, 9 H, CH3Sn), 2.62 (s, 3 H, Me), 4.80
(s, 2 H, OCH2Py), 4.82 (s, 2 H, OCH2BiPy), 7.10 (d, 3JH,H ϭ 8 Hz,
3
3
1 H), 7.30 (d, JH,H ϭ 7 Hz, 1 H), 7.35 (d, JH,H ϭ 7 Hz, 1 H),
3
3
3
CH2O), 7.25Ϫ7.45 (m, 2 H), 7.50 (t, JH,H ϭ 9 Hz, 1 H) ppm.
7.50 (d, JH,H ϭ 8 Hz, 1 H), 7.51 (t, JH,H ϭ 8 Hz, 1 H), 7.60 (t,
3JH,H ϭ 8 Hz, 1 H), 7.82 (t, JH,H ϭ 8 Hz, 2 H), 8.15 (d, JH,H
ϭ
3
3
Synthesis of Compound 7 (Cross Coupling Procedure): To a degassed
dry THF solution of 2-[(tert-butyldimethylsilyl)oxymethyl]-6-(tri-
3
8 Hz, 1 H), 8.30 (d, JH,H ϭ 8 Hz, 1 H) ppm.
methylstannyl)pyridine (250 mg, 0.65 mmol) and ether 6 (370 mg, Synthesis of Compound 11: To a degassed dry DMF solution of
1 mmol), Pd(PPh3)4 (53 mg, 0.045 mmol) was added and the reac-
tion mixture was heated to reflux for 15 h. The solvent was re-
moved under vacuum and the product 7 was purified by flash chro-
trimethylstannyl derivative 10 (197 mg, 0.435 mmol) and ether 6
(236 mg, 0.6 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol) was added and
the reaction mixture was heated at 120 °C for 15 h. The solvent
matography on silica gel [dichloromethane/ethyl acetate (90:10) as was removed under vacuum and the product 11 was purified by
eluent] to give a white solid (218 mg, 0.42 mmol, 65% yield). M.p.
flash chromatography on silica gel [dichloromethane/ethyl acetate
135Ϫ138 °C 1H NMR: δ ϭ 0.11 (s, 6 H, CH3Si), 0.95 (s, 9 H, (30:70) as eluent] to give a white solid (122 mg, 50% yield). M.p.
1
SitBu), 4.75 (s, 2 H, OCH2Py), 4.81 (s, 2 H, OCH2BiPy), 4.90 (s, 2
184Ϫ186 °C (dec). H NMR: δ ϭ 2.60 (s, 3 H, Me), 4.80 (s, 2 H,
OCH2Py), 4.83 (s, 2 H, OCH2BiPyMe), 4.90 (s, 4 H, OCH2BiPy),
3
H, CH2OTBS), 7.39 (d, JH,H ϭ 10 Hz, 1 H), 7.50Ϫ7.60 (m, 4 H),
3
3
7.80 (t, JH,H ϭ 10 Hz, 2 H), 8.18 (d, JH,H ϭ 10 Hz, 1 H), 8.22 7.18 (d, 3JH,H ϭ 9 Hz, 1 H), 7.38 (d, 3JH,H ϭ 7 Hz, 1 H), 7.40Ϫ7.55
(d, JH,H ϭ 10 Hz, 1 H) ppm. 13C NMR: δ ϭ Ϫ0.1, 25.3, 73.3, (m, 5 H), 7.60 (t, JH,H ϭ 8 Hz, 2 H), 7.80 (m, 3 H), 8.20 (d,
74.3, 78.5, 119.6, 120.2, 120.4, 120.6, 126.3, 126.7, 136.5, 137.3,
3JH,H ϭ 7 Hz, 1 H), 8.30 (m, 2 H) ppm. 13C NMR: δ ϭ 23.7,
138.6, 153.3, 154.5, 154.7, 155.5, 157.8, 158.7 ppm. 73.8, 74.1, 74.3, 74.7, 118.6, 119.1, 119.3, 119.7, 120.3, 120.8, 121.2,
3
3
C24H30BrN3O2Si (500): calcd. C 57.59, H 6.04, Br 15.96, N 8.40,
121.6, 122.6, 122.9, 136.8, 137.3, 137.5, 137.8, 138.2, 152.3, 152.8,
Eur. J. Org. Chem. 2003, 1552Ϫ1558
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A. Puglisi, M. Benaglia, G. Roncan
FULL PAPER
153.5, 154.1, 154.5, 154.9, 157.2, 158.3, 158.9, 159.6 ppm.
C30H26BrN5O2 (568): calcd. C 63.38, H 4.61, Br 14.06, N 12.32, O
5.63; found C 63.41, H 4.58, Br 14.11, N 12.31, O 5.59.
Synthesis of O-Acetyl Derivative 15a: Alcohol 14 (1.1 g., 4.1 mmol)
was dissolved in 4 mL of pyridine and the solution was cooled to
0 °C. Acetic anhydride (7 mL) was added and the reaction mixture
was stirred at room temperature for 20 h. Water and dichlorometh-
ane were added, the two phases separated, the aqueous phase was
extracted twice with CH2Cl2 and the combined organic phases were
dried with magnesium sulfate and concentrated under vacuum. The
product was purified by flash chromatography on silica gel [di-
chloromethane/ethyl acetate (90:10) as eluent] to give a white solid
Synthesis of Compound 1: To a degassed dry DMF solution of tri-
methylstannyl derivative 10 (150 mg, 0.33 mmol) and silyl deriva-
tive 4 (100 mg, 0.33 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol) was ad-
ded and the reaction mixture was heated at 120 °C for 15 h. The
solvent was removed under vacuum, the crude reaction mixture
was dissolved in THF, Bu4NF (140 mg, 0.5 mmol) was added and
the solution was stirred at room temperature for 30 min; then the
solvent was evaporated under reduced pressure and the product 1
was purified by flash chromatography on silica gel [chloroform/
methanol (95:5) as eluent] to give a white solid (75 mg, 57% yield).
The product shows spectral characteristics identical to those re-
ported in the literature.[20] M.p. 172Ϫ174 °C (ref.[20] 178 °C).
1
(1.1 g, 91% yield). M.p. 68Ϫ69 °C. IR: ν˜ ϭ 1738 cmϪ1. H NMR:
3
δ ϭ 2.15 (s, 3 H, Ac), 5.18 (s, 2 H, CH2OAc), 7.40 (d, JH,H
ϭ
7.5 Hz, 1 H), 7.45 (d, 3JH,H ϭ 9.5 Hz, 2 H), 7.55 (t, 3JH,H ϭ 7.5 Hz,
3
3
1 H), 7.65 (d, JH,H ϭ 7.5 Hz, 1 H), 8.00 (d, JH,H ϭ 9.5 Hz, 2 H)
ppm. 13C NMR: δ ϭ 21.2, 65.9, 119.1, 126.6, 127.3, 128.7, 137.5,
139.1, 142.2, 142.5, 158.1, 170.9 ppm. C14H12BrNO2 (306): calcd.
C 54.92, H 3.95, Br 26.10, N 4.58, O 10.45; found C 54.89, H 3.98,
Br 26.08, N 4.55, O 10.50.
Synthesis of Compound 2: To a degassed dry DMF solution of tri-
methylstannyl derivative 10 (150 mg, 0.33 mmol) and compound 7
(171 mg, 0.3 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol) was added and
the reaction mixture was heated at 120 °C for 15 h. The solvent
was removed under vacuum, the crude reaction mixture was dis-
solved in THF, Bu4NF (140 mg, 0.5 mmol) was added and the solu-
tion was stirred at room temperature for 30 min; then the solvent
was evaporated under reduced pressure and the product 2 was puri-
fied by flash chromatography on neutral alumina (Brockman type
II) [dichloromethane/methanol (80:20) as eluent] to give a white
solid (84 mg, 47% yield). The product shows spectral characteristics
identical to those reported in the literature.[14b] M.p. 182Ϫ184 °C
(ref.[14b] 186 °C).
Synthesis of O-Silyl Derivative 15b: Alcohol 14 (1.37 g, 5.2 mmol)
was dissolved in 25 mL of DMF and the solution was cooled to 0
°C. tert-Butyldimethylsilyl chloride (0.78 g, 5.2 mmol) and triethyl-
amine (0.79 mL, 5.7 mmol) were added and the reaction mixture
was stirred at room temperature for 20 h. Water and diethyl ether
were added, the two phases separated, the aqueous phase was ex-
tracted twice with diethyl ether and the combined organic phases
were dried with magnesium sulfate and concentrated under vac-
uum. The product was purified by flash chromatography on silica
gel (dichloromethane as eluent) to give a white solid (1.59 g, 88%
1
yield). M.p. 62Ϫ65 °C. H NMR: δ ϭ 0.15 (s, 6 H, SiMe2), 0.95
(s, 9 H, tBuSi), 4.78 (s, 2 H, CH2OSi), 7.40 (d, 3JH,H ϭ 7 Hz, 1 H),
7.45 (d, 3JH,H ϭ 8.5 Hz, 2 H), 7.55 (t, 3JH,H ϭ 7 Hz, 1 H), 7.62 (d,
3JH,H ϭ 7 Hz, 1 H), 7.95 (d, 3JH,H ϭ 8.5 Hz, 2 H) ppm. 13C NMR:
δ ϭ 0.1, 25.8, 64.6, 118.6, 126.2, 126.4, 126.4, 136.5, 138.6, 142.0,
142.7, 158.5 ppm. C18H24BrNOSi (378): calcd. C 57.14, H 6.39, Br
21.12, N 3.70, O 4.23, Si 7.42; found C 57.10, H 6.37, Br 21.15, N
3.69, O 4.23, Si 7.46.
Synthesis of Aldehyde 13: To a degassed solution of 2,6-dibromopy-
ridine (12) (1.5 g, 6.3 mmol) in 100 mL of dry toluene, Pd(OAc)2
(210 mg, 0.95 mmol) and triphenylphosphane (500 mg, 1.9 mmol)
were added. After 10 min of stirring at room temperature, a 2 
Na2CO3 solution (19 mL, 38 mmol) and the commercially available
4-(formylphenyl)boronic acid (950 mg, 6.3 mmol) were added. The
reaction mixture was stirred at 90 °C for 20 h. The solvent was
evaporated and the crude reaction mixture purified by flash chro-
matography on silica gel (dichloromethane as eluent) to give prod-
uct 13 as a white solid (908 mg, 55% yield). M.p. 111Ϫ115 °C. IR:
ν˜ ϭ 1703.8 cmϪ1. 1H NMR: δ ϭ 7.49 (d, 3JH,H ϭ 8 Hz, 1 H), 7.69
(t, 3JH,H ϭ 8 Hz, 1 H), 7.80 (d, 3JH,H ϭ 8 Hz, 1 H), 8.00 (d, 3JH,H ϭ
Synthesis of O-Allyl Derivative 15c: A stirred 0.1  solution of al-
cohol 14 (258 mg, 0.98 mmol) in dry tetrahydrofuran under argon
was added to a suspension of NaH (50% dispersion in mineral
oil, 52 mg, 1.08 mmol) in dry tetrahydrofuran (3 mL). The reaction
mixture was stirred at 0 °C for 30 min. Allyl bromide (296 mg,
2.42 mmol) was then added and the reaction mixture was stirred
at room temperature overnight. The residual sodium hydride was
quenched by addition of a small amount of methanol and the sol-
vent was removed under vacuum. The product was purified by flash
chromatography on silica gel [dichloromethane/ethyl acetate (98:2)
as eluent] to give a white solid (241 mg, 81% yield). M.p. 51Ϫ53
3
10 Hz, 2 H), 8.30 (d, JH,H ϭ 10 Hz, 2 H), 10.05 (s, CHO, 1 H)
ppm. 13C NMR: δ ϭ 119.9, 127.5, 128.2, 130.3, 137.5, 139.3, 142.0,
142.8, 157.1, 191.9 ppm. C12H8BrNO (262): calcd. C 55.02, H 3.08,
Br 30.49, N 5.34, O 6.13; found C 55.02, H 3.04, Br 30.51, N 5.30,
O 6.13.
Synthesis of Alcohol 14: A solution of aldehyde 13 (300 mg,
1.14 mmol) in 12 mL of ethanol was cooled to 0 °C; NaBH4
(17.3 mg, 0.45 mmol) was added and the reaction mixture was
stirred for 10 min. A few drops of water were added, the ethanol
was evaporated, dichloromethane was added and the organic phase
was separated; the aqueous phase was extracted twice with CH2Cl2
and the combined organic phases were dried with magnesium sul-
fate and concentrated under vacuum. The product was purified by
flash chromatography on silica gel [dichloromethane/ethyl acetate
(60:40) as eluent] to give a white solid (295 mg, 98% yield). M.p.
128Ϫ131 °C. 1H NMR: δ ϭ 4.80 (s, 2 H, CH2OH), 7.40 (d, 3JH,H ϭ
1
3
°C. H NMR: δ ϭ 4.15 (d, JH,H ϭ 5 Hz, 2 H, OCH2CHϭCH2),
3
4.60 (s, 2 H, OCH2Ar), 5.33 (d, JH,H ϭ 8.5 Hz, 1 H, OCH2CHϭ
3
CH2), 5.39 (d, JH,H ϭ 15 Hz, 1 H, OCH2CHϭCH2), 6.03 (ddt,
3JH,H ϭ 8.5, 3JH,H ϭ 15, 3JH,H ϭ 5 Hz, 1 H, OCH2CHϭCH2), 7.33
3
3
(d, JH,H ϭ 9 Hz, 1 H), 7.46 (d, JH,H ϭ 8.5 Hz, 2 H), 7.65 (t,
3JH,H ϭ 9 Hz, 1 H), 7.70 (d, JH,H ϭ 9 Hz, 1 H), 8.00 (d, JH,H
ϭ
3
3
8.5 Hz, 2 H) ppm. 13C NMR: δ ϭ 71.3, 71.8, 117.4, 119.0, 126.4,
127.1, 127.8, 134.0, 137.7, 139.1, 140.5, 142.0, 160.0 ppm.
C15H14BrNO (304): calcd. C 59.23, H 4.64, Br 26.27, N 4.60, O
5.26; found C 59.26, H 4.65, Br 26.25, N 4.56, O 5.28.
3
3
7 Hz, 1 H), 7.45 (d, JH,H ϭ 7 Hz, 1 H), 7.60 (t, JH,H ϭ 7 Hz, 1 Synthesis of Aldehyde 16: To a solution of aldehyde 13 (116 mg,
3
3
H), 7.60 (d, JH,H ϭ 8.5 Hz, 2 H), 8.00 (d, JH,H ϭ 8.5 Hz, 2 H)
ppm. 13C NMR: δ ϭ 64.5, 118.9, 126.3, 127.2, 127.3, 130.5, 139.1,
142.2, 142.7, 158.0 ppm. C12H8BrNO (264): calcd. C 55.02; H 3.08;
0.44 mmol) in 6 mL of dry, degassed dimethoxyethane (DME)
hexamethyldistannane (288 mg, 0.88 mmol) and Pd(PPh3)4 (50 mg,
0.044 mmol) were added and the reaction mixture was refluxed for
Br 30.49; N 5.34; O 6.13; found C 55.02; H 3.04; Br 30.51; N 5.30; 18 h. The solvent was evaporated, the crude mixture was rinsed
O 6.13.
1556
with diethyl ether, filtered and the solvent removed under vacuum
Eur. J. Org. Chem. 2003, 1552Ϫ1558

Nonsymmetrically Functionalized Bipyridines, Poly(bipyridines) and Terpyridines
FULL PAPER
3
3
3
to give the crude trimethylstannyl derivative that was used without
further purification. To a solution of the tin derivative in dry, de-
gassed DME (7 mL) 2,6-dibromopyridine (83 mg, 0.35 mmol) and
6.05 (ddt, JH,H ϭ 8.5, JH,H ϭ 17, JH,H ϭ 3.5 Hz, 1 H,
OCH2CHϭCH2), 7.53 (d, JH,H ϭ 8.2 Hz, 2 H), 7.80 (d, JH,H
7.5 Hz, 1 H), 7.91 (d, JH,H ϭ 8 Hz, 1 H), 7.94 (t, JH,H ϭ 8 Hz, 1
3
3
ϭ
3
3
3
Pd(PPh3)4 (40 mg, 0.035 mmol) were added. The reaction mixture H), 7.90Ϫ8.10 (m, 4 H), 8.22 (d, JH,H ϭ 8.2 Hz, 2 H), 8.38 (d,
was stirred at 90 °C for 20 h. The solvent was evaporated and the 3JH,H ϭ 8 Hz, 2 H), 8.60 (d, JH,H ϭ 8 Hz, 1 H), 8.71 (d, JH,H
ϭ
3
3
3
3
crude reaction mixture purified by flash chromatography on silica
gel [dichloromethane/ethyl acetate (90:10) as eluent] to give product
16 as white solid (75 mg, 63% yield). M.p. 169Ϫ173 °C. IR: ν˜ ϭ
7 Hz, 1 H), 8.73 (d, JH,H ϭ 8 Hz, 1 H), 8.74 (d, JH,H ϭ 7 Hz, 1
H), 10.10 (s, 1 H, CHO) ppm. 13C NMR: δ ϭ 71.3, 71.9, 117.3,
119.5, 120.5, 120.6, 121.1, 121.3, 121.6, 127.1, 127.6, 128.2, 130.3,
1
3
1688.4 cmϪ1. H NMR: δ ϭ 7.54 (d, JH,H ϭ 8 Hz, 1 H), 7.72 (t, 134.8, 136.6, 137.7, 137.9, 138.0, 139.5, 145.0, 155.0, 155.1, 155.2,
3
3
3JH,H ϭ 8 Hz, 1 H), 7.80 (t, JH,H ϭ 7 Hz, 1 H), 7.86 (d, JH,H
ϭ
156.0, 156.1, 156.2, 192.2 ppm. C32H25N3O3 (483): calcd. C 79.48,
H 5.21, N 8.69, O 6.62; found C 76.51, H 5.19, N 8.72, O 6.58.
3
3
7 Hz, 1 H), 7.93 (d, JH,H ϭ 10 Hz, 2 H), 8.27 (d, JH,H ϭ 10 Hz,
3
3
2 H), 8.40 (d, JH,H ϭ 8 Hz, 1 H), 8.60 (d, JH,H ϭ 7 Hz, 1 H),
10.15 (s, CHO, 1 H) ppm. 13C NMR: δ ϭ 119.9, 120.8, 121.5,
127.5, 128.2, 130.1, 136.5, 138.0, 139.2, 141.5, 144.7, 154.5, 155.0,
157.1, 193.1 ppm. C17H11BrN2O (339): calcd. C 60.19, H 3.27, Br
23.56, N 8.26, O 4.72; found C 60.20, H 3.25, Br 23.58, N 8.24,
O 4.73.
Synthesis of Ester 18: To a degassed solution of 2,6-dibromopyri-
dine (12) (1.43 g, 6.03 mmol) in 100 mL of acetonitrile, (4-carboxy-
phenyl)boronic acid (1 g, 6.03 mmol) and Pd(PPh3)4 (346 mg,
0.3 mmol) were added. After 10 min of stirring at room tempera-
ture, a 2  Na2CO3 solution (6 mL, 12 mmol) was added and the
reaction mixture was stirred at 100 °C for 20 h. The solvent was
evaporated; to the crude reaction mixture 1  NaOH was added
(until pH basic), the aqueous phase was extracted with CH2Cl2,
then acidified with HCl (until pH neutral) and finally extracted
three times with ethyl acetate/methanol (95:5). The organic phase
was dried with magnesium sulfate and the solvents were evaporated
under vacuum. The crude reaction product was dissolved in meth-
anol (15 mL) and refluxed for 20 h in the presence of a catalytic
amount of p-toluenesulfonic acid. Product 18 was purified by flash
chromatography on silica gel [hexanes/ethyl acetate (50:50) as elu-
ent] to give a white solid (876 mg, 51% yield). M.p. 151Ϫ153 °C.
Synthesis of Compounds 17 (Cross Coupling Procedure): To a solu-
tion of aldehyde 16 (240 mg, 0.74 mmol) in 7 mL of dry, degassed
DME hexamethyldistannane (460 mg, 2.2 mmol) and Pd(PPh3)4
(84 mg, 0.074 mmol) were added and the reaction mixture was re-
fluxed for 18 h. The solvent was evaporated, the crude mixture was
rinsed with diethyl ether, filtered and the solvent removed under
vacuum to give the crude trimethylstannyl derivative that was used
without further purification. To a solution of the tin derivative in
dry, degassed DME (8 mL) compound 15a (or 15b or 15c)
(0.65 mmol) and Pd(PPh3)4 (63 mg, 0.055 mmol) were added. The
reaction mixture was stirred at 90 °C for 20 h. The solvent was
evaporated and the crude reaction mixture purified by flash chro-
matography on silica gel.
IR: ν˜ ϭ 1721.4 cmϪ1. H NMR: δ ϭ 3.90 (s, 3 H, OMe), 7.41 (d,
1
3JH,H ϭ 8 Hz, 1 H), 7.60 (t, JH,H ϭ 8 Hz, 1 H), 7.70 (d, JH,H
ϭ
3
3
3
3
8 Hz, 1 H), 8.05 (d, JH,H ϭ 10 Hz, 2 H), 8.12 (d, JH,H ϭ 10 Hz,
2 H) ppm. 13C NMR: δ ϭ 55.4, 119.8, 127.3, 128.2, 130.6, 137.5,
139.3, 142.0, 142.9, 156.7, 170.5 ppm. C13H10BrNO2 (292): calcd.
C 53.45, H 3.45, Br 27.35, N 4.79, O 10.95; found C 53.46, H 3.41,
Br 27.38, N 4.82, O 10.93.
Product 17a: Dichloromethane/ethyl acetate (90:10) as eluent.
White solid (224 mg, 71% yield). M.p. 218Ϫ221 °C. IR: ν˜ ϭ 1735.1,
1693.3 cmϪ1 1H NMR: δ ϭ 2.18 (s, 3 H, Ac), 5.22 (s, 2 H,
.
3
3
CH2OAc), 7.53 (d, JH,H ϭ 8 Hz, 2 H), 7.78 (d, JH,H ϭ 6.5 Hz, 1
Synthesis of Terpyridine 19: To a solution of aldehyde 16 (240 mg,
0.74 mmol) in 7 mL of dry, degassed DME hexamethyldistannane
(314 mg, 1.5 mmol) and Pd(PPh3)4 (84 mg, 0.074 mmol) were ad-
ded and the reaction mixture was refluxed for 18 h. The solvent
was evaporated, the crude mixture was rinsed with diethyl ether,
filtered and the solvent removed under vacuum to give the crude
trimethylstannyl derivative that was used without further purifi-
cation. To a solution of the tin derivative in dry, degassed DME
(10 mL) compound 18 (244 mg, 0.65 mmol) and Pd(PPh3)4 (63 mg,
0.055 mmol) were added. The reaction mixture was stirred at 90 °C
for 20 h. The solvent was evaporated and the crude reaction mix-
ture purified by flash chromatography on silica gel [dichlorometh-
ane/ethyl acetate (98:2) as eluent] to give a white solid (147 mg, 48%
3
H), 7.90 (d, JH,H ϭ 7 Hz, 1 H), 7.90Ϫ8.10 (m, 6 H), 8.20 (d,
3JH,H ϭ 8 Hz, 2 H), 8.40 (d, JH,H ϭ 9 Hz, 2 H), 8.60 (d, JH,H
ϭ
3
3
3
3
7 Hz, 1 H),.8.70 (d, JH,H ϭ 7 Hz, 1 H), 8.72 (d, JH,H ϭ 7 Hz, 1
H), 10.12 (s, CHO, 1 H) ppm. 13C NMR: δ ϭ 21.2, 66.1, 119.7,
120.5, 120.6, 121.1, 121.4, 121.6, 127.3, 127.6, 128.7, 130.3, 136.6,
136.9, 137.0, 137.8, 138.1, 139.5, 145.1, 155.0, 155.2, 155.2, 156.0,
156.1, 156.2, 171.0, 192.1 ppm. C31H23N3O3 (485): calcd. C 76.69,
H 4.77, N 8.65, O 9.89; found C 76.72, H 4.76, N 8.62, O 9.90.
Product 17b: Dichloromethane/ethyl acetate (99:1) as eluent. White
solid (236 mg, 65% yield). M.p. 212Ϫ215 °C. IR: ν˜ ϭ 1696.8 cmϪ1
.
1H NMR: δ ϭ 0.06 (s, 6 H, SiMe2), 0.90 (s, 9 H, tBuSi), 4.90 (s, 2
3
3
H, CH2OSi), 7.53 (d, JH,H ϭ 8 Hz, 2 H), 7.78 (d, JH,H ϭ 6.5 Hz,
yield). M.p. 135Ϫ137 °C. IR: ν˜ ϭ 1705.1, 1691 cmϪ1
(CF3COOD): δ ϭ 4.26 (s, 3 H, OMe), 8.21 (d, 3JH,H ϭ 7 Hz, 2 H),
.
1H NMR
3
3
1 H), 7.90 (d, JH,H ϭ 7 Hz, 1 H), 7.92 (t, JH,H ϭ 7 Hz, 1 H),
3
3
7.90Ϫ8.10 (m, 4 H), 8.20 (d, JH,H ϭ 8 Hz, 2 H), 8.38 (d, JH,H
ϭ
3
3
3
3
8.23 (d, JH,H ϭ 6.5 Hz, 1 H), 8.33 (d, JH,H ϭ 6 Hz, 1 H), 8.36
7.9 Hz, 2 H), 8.60 (d, JH,H ϭ 7 Hz, 1 H), 8.68 (d, JH,H ϭ 7 Hz,
3
(d, JH,H ϭ 6 Hz, 2 H), 8.49Ϫ8.60 (m, 4 H), 8.65 (t, 3JH,H ϭ 8 Hz,
3
3
1 H), 8.72 (d, JH,H ϭ 7 Hz, 1 H), 8.74 (d, JH,H ϭ 7 Hz, 1 H),
10.11 (s, 1 H, CHO) ppm. 13C NMR: δ ϭ 0.1, 18.2, 64.8, 119.2,
120.2, 120.5, 120.9, 121.2, 121.5, 126.4, 126.8, 127.5, 130.2, 136.5,
137.6, 137.7, 137.8, 138.0, 142.5, 144.9, 154.3, 154.3, 154.9, 155.1,
156.3, 156.4, 171.0, 192.1 ppm. C35H35N3O2Si (558): calcd. C
75.37, H 6.32, N 7.53, O 5.74, Si 5.04; found C 75.32, H 6.29, N
7.56, O 5.75, Si 5.08.
1 H), 8.71 (d, 3JH,H ϭ 7 Hz, 2 H), 8.80 (t, 3JH,H ϭ 7 Hz, 2 H), 8.90
(d, 3JH,H ϭ 7 Hz, 1 H), 8.93 (d, 3JH,H ϭ 7 Hz, 1 H), 10.18 (s, CHO,
1 H) ppm. 13C NMR (CF3COOD): δ ϭ 55.4, 126.1, 126.5, 128.4,
128.6, 129.6, 129.8, 130.7, 131.4, 133.1, 133.5, 135.6, 136.7, 138.4,
140.3, 143.5, 149.1, 149.2, 149.8, 150.2, 150.5, 150.6, 155.6, 155.8,
170.0, 198.1 ppm. C30H21N3O3 (471): calcd. C 76.42, H 4.49, N
8.91, O 10.18; found C 76.43, H 4.51, N 8.89, O 10.17.
Product 17c: Dichloromethane/ethyl acetate (90:10) as eluent.
White solid (178 mg, 57% yield). M.p. 202Ϫ207 °C. IR: ν˜ ϭ 1694.8
Acknowledgments
3
cmϪ1
.
1H NMR: δ ϭ 4.12 (d, JH,H ϭ 3.5 Hz, 2 H, OCH2CHϭ
3
CH2), 4.70 (s, 2 H, OCH2Ar), 5.30 (d, JH,H ϭ 8.5 Hz, 1 H, This work was supported by MIUR (Progetto Nazionale Stereose-
3
OCH2CHϭCH2), 5.37 (d, JH,H ϭ 17 Hz, 1 H, OCH2CHϭCH2),
Eur. J. Org. Chem. 2003, 1552Ϫ1558
lezione in Sintesi Organica Ϫ Metodologie ed Applicazioni).
1557

A. Puglisi, M. Benaglia, G. Roncan
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[5a]
For a few papers representing different strategies see:
K. T.
2-(trimethylstannyl)pyridine with
3 in DME afforded 6-
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