Suzuki-miyaura reactions of 2,7-dichloro-1,8-naphthyridine

Article abstract of DOI:10.1055/s-0032-1318003

2,7-Diaryl- and 2,7-dialkenyl-1,8-naphthyridines were prepared in high yields by Suzuki-Miyaura reactions of 2,7-dichloro-1,8-naphthyridines. While most of the products proved to be not or only weakly fluorescent, we observed a strong fluorescence in case of 2,7-bis(4-methoxyphenyl)-1,8-naphthyridine containing two electron-donating aryl groups. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318003

LETTER
▌359
lSetuterzuki–Miyaura Reactions of 2,7-Dichloro-1,8-naphthyridine
Suzuki–Miyaura Reactions of 2,7-Dichloro-1,8-naphthyridine
Peter Ehlers,a,b Andranik Petrosyan,a,b,c Tariel V. Ghochikyan,c Ashot S. Saghyan,c,d Antje Neubauer,e
Stefan Lochbrunner,e Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany
c
Faculty of Chemistry, Yerevan State University, Alex Manoogian 1, 0025 Yerevan, Armenia
d
Scientific and Production Center ‘Armbiotechnology’ of NAS RA, Gyurjyan str. 14, 0056 Yerevan, Armenia
e
Institut für Physik, Universität Rostock, Universitätsplatz 3, 18051 Rostock, Germany
Received: 06.12.2012; Accepted: 17.12.2012
substituted naphthyridines. Recently, we have reported
regioselective Suzuki–Miyaura reactions of 5,7-dichloro-
1,6-naphthyridine.13 2,7-Dichloro-1,8-naphthyridine rep-
resents an interesting starting material for the synthesis of
Abstract: 2,7-Diaryl- and 2,7-dialkenyl-1,8-naphthyridines were
prepared in high yields by Suzuki–Miyaura reactions of 2,7-dichlo-
ro-1,8-naphthyridines. While most of the products proved to be not
or only weakly fluorescent, we observed a strong fluorescence in
case of 2,7-bis(4-methoxyphenyl)-1,8-naphthyridine containing substituted 1,8-naphthyridines. In this context, palladium-
catalyzed Sonogashira,14 Stille,15 carboxylation,16 amina-
two electron-donating aryl groups.
tion,17 and amidation reactions have been reported.18
Key words: catalysis, heterocycles, palladium, cross-coupling
reactions, nitrogen
Herein, we report what are, to the best of our knowledge,
the first Suzuki–Miyaura reactions19 of 2,7-dichloro-1,8-
naphthyridine. These reactions provide a convenient
approach to 2,7-diaryl-1,8-naphthyridines.
Substituted naphthyridines are of considerable pharma-
cological relevance, because of their ability to act as mul-
tiple hydrogen bond acceptors in the interaction with
human receptors. Ferrarini and coworkers showed that
different 2-phenyl-1,8-naphthyridines have high affinity
towards adenosine receptor A1 up to the subnanomolar
range with good selectivity between the adenosine recep-
tors A1/A2a and A1/A3.1 Galatsis et al. studied various ary-
lated naphthyridines as non-competitive metabotropic
glutamate receptor 5 (mGluR5) antagonists which are
promising agents against pain and disorders related to the
central nervous system, including anxiety and Parkinson’s
disease.2 1,8-Naphthyridines also exhibit antibacterial,3
antitumor,4 neurotoxic,5 neuroprotective,6 anticonvulsant
and cardiac7 activities. In addition, they represent interest-
ing building blocks for noncovalent assemblies in supra-
molecular chemistry.8 In addition, 1,8-naphthyridines
represent sensitive probes in analytical chemistry, be-
cause of their ligation to metal ions or their noncovalent
interaction with organic molecules (by hydrogen bonds).
These interactions have an effect on absorption and fluo-
rescence properties of the naphthyridine. In fact, naphthy-
ridines have been applied as receptor molecules for the
analysis of biologically relevant species, such as mono-
saccharides,9 mercury ions,10 guanine11 and guanosine tri-
phosphate.12
2,7-Dichloro-1,8-naphthyridine (3) was prepared, accord-
ing to the procedure reported by Newkome et al., by reac-
tion of 2,6-diaminopyridine (1) with diacid 2 (Scheme
1).20
H2N
HO
N
NH2
i–iii
1
Cl
N
N
Cl
O
OH
ref. 20
OH
3
2
O
Scheme 1 Synthesis of 2,7-dichloro-1,8-naphthyridine (3; ref. 20).
Reagents and conditions: (i) H2SO4, 3 h, 110 °C; (ii) NaNO2, H2SO4,
5 min, 20 °C; (iii) PCl5, POCl3, reflux.
To identify the best conditions for Suzuki–Miyaura reac-
tions of 3, we tested different catalyst systems (Scheme
2). For our initial trials, phenylboronic acid, THF and ce-
sium carbonate were used as reagent, solvent and base, re-
spectively (Table 1, entries 1–5). The employment of
Pd(PPh3)4 as the catalyst gave product 4a, albeit, in only
27% yield (entry 1). The use of Pd2(dba)3 (2.5 mol%) in
the presence of S-Phos (10 mol%), a biaryl ligand devel-
oped by Buchwald and co-workers, resulted in a dramatic
In recent years, palladium-catalyzed cross-coupling reac-
tions of halogenated naphthyridines have been studied.
These reactions provide a convenient approach to various
PhB(OH)2
conditions
see Table 1
Ph
N
N
Ph
Cl
N
N
Cl
3
4a
SYNLETT 2013, 24, 0359–0362
Advanced online publication: 10.01.2013
DOI: 10.1055/s-0032-1318003; Art ID: ST-2012-D1044-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Scheme 2 Optimization of the synthesis of 4a

360
P. Ehlers et al.
Table 1 Optimization of the Synthesis of 4a
Entry Catalyst Solvent Base
LETTER
two absorption maxima at λ = 277 nm (ε = 3.6 M–1cm–1)
and at λ = 373 nm (ε = 2.9 M–1cm–1). The fluorescence
maximum appears at λ = 402 nm with a small shoulder at
lower energies (Figure 1). A good quantum yield of φ =
0.5 was determined in dichloromethane using quinine sul-
fate as standard. The strong fluorescence can be explained
by charge transfer in case of the push-pull substituted
molecule 4f containing an electron-withdrawing hetero-
cyclic core structure and two electron-donating 4-me-
thoxyphenyl groups.
Temp Yield
(°C) (%)a
1
2
3
4
5
6
7
8
Pd(PPh3)4
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
60 27
60 51
60 46
60 62
60 65
Pd2(dba)3/HP(t-Bu)3BF4 THF
Pd2(dba)3/P(Cy)3
Pd2(dba)3/X-Phos
Pd2(dba)3/S-Phos
Pd2(dba)3/S-Phos
Pd2(dba)3/S-Phos
Pd2(dba)3/S-Phos
THF
THF
THF
Table 2 Synthesis of 4a–m
dioxane Cs2CO3 100 85
toluene Cs2CO3 100 75
dioxane K3PO4 100 90
4
a
Product
Yield (%)a
90
a Yields of isolated products.
N
N
increase of the yield to 65% yield (entry 5). The replace-
ment of THF by toluene and 1,4-dioxane, solvents with
higher boiling point, allowed for the synthesis of 4a in
75% and 85% yields, respectively (entries 6 and 7). Final-
ly, we observed that the use of potassium phosphate in-
stead of cesium carbonate resulted in a further increase of
the yield to 90% (entry 8).21,22
b
c
92
89
N
N
S
N
N
S
The preparative scope was next studied. The reaction of 3
with various arylboronic acids, following our optimized
protocol (Table 1, entry 8), afforded 2,7-diaryl-1,8-napht-
hyridines 4a–m in good to very good yields (except for
4e) (Scheme 3, Table 2). The moderate yield of 4e can be
explained by the steric hindrance of 2,6-dimethoxy-
phenylboronic acid. Several functional groups were toler-
ated, including the vinyl, fluoro, and acetyl group.
Heterocyclic boronic acids, i.e. 2-thienylboronic acid, and
alkenylboronic acids, i.e. trans-2-phenylvinylboronic
acid, were successfully employed. Good yields were
obtained for reactions of both electron-rich and electron-
poor arylboronic acids. The slightly decreased yield of
vinyl-substituted derivative 4l (64%) might be explained
by a competing Heck reaction of the double bond. How-
ever, the corresponding products could not be isolated or
detected in the reaction mixture.
OMe
OMe
N
N
d
84
OMe
OMe
OMe
OMe
e
f
N
N
39
99
OMe
MeO
N
N
N
MeO
OMe
N
g
82
O
O
ArB(OH)2
i
Ar
N
N
Ar
Cl
N
N
Cl
4a–m
3
h
i
N
N
72
84
Scheme 3 Synthesis of 4a–m. Reagents and conditions: (i)
Pd2(dba)3 (2.5 mol%), S-Phos (10 mol%), 3 (0.4 mmol), ArB(OH)2
(1.2 mmol), K3PO4 (1.2 mmol), 1,4-dioxane (3 mL), 100 °C, 20 h.
F
F
Most of the products proved to be not or only weakly flu-
orescent. However, we observed a strong fluorescence in
the case of naphthyridines derived from electron-rich
arylboronic acids. The fluorescence properties of 2,7-
bis(4-methoxyphenyl)-1,8-naphthyridine (4f) were stud-
ied in detail (Figure 1). The UV–Vis spectrum of 4f shows
N
N
F3C
CF3
Synlett 2013, 24, 359–362
© Georg Thieme Verlag Stuttgart · New York

LETTER
Suzuki–Miyaura Reactions of 2,7-Dichloro-1,8-naphthyridine
361
Table 2 Synthesis of 4a–m (continued)
References and Notes
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4
j
Product
Yield (%)a
N
N
N
92
N
k
93
CF3
CF3
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Figure 1 UV–Vis and fluorescence spectra of 4f; solid line: UV–Vis
spectrum; dashed line: fluorescence spectrum
In conclusion, we have developed a new and convenient
method for the synthesis of novel 2,7-diaryl- and 2,7-di-
alkenyl-1,8-naphthyridines by Suzuki–Miyaura reactions.
Naphthyridine 4f shows blue fluorescence (emission at λ
= 402 nm with a good quantum yield of φ = 0.5). Our fu-
ture studies will be directed to the synthesis and character-
ization of other donor-substituted 2,7-diaryl- and 2,7-
dialkenyl-1,8-naphthyridines and to the synthesis of non-
symmetrical 2,7-diaryl-1,8-naphthyridines.
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m
iotSrat
ungIifoop
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 359–362

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P. Ehlers et al.
LETTER
(18) Ligthart, G. B. W. L.; Ohkawa, H.; Sijbesma, R. P.; Meijer,
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extracted twice with CH2Cl2. The combined organic layers
were dried with Na2SO4, filtered and the solvent was
evaporated. The residue was purified by column
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A.; Yamamoto, Y. Chem. Lett. 2011, 40, 894. (d) Kotha, S.;
Lahiri, K.; Kashinath, D. Tetrahedron 2002, 48, 9633.
(20) Newkome, G. R.; Garbis, S. J.; Majestic, V. K.; Fronczek, F.
R.; Chiari, G. J. Org. Chem. 1981, 46, 833.
(21) General Experimental Procedure: To an argon-flushed
glass pressure tube were added Pd2(dba)3 (0.01 mmol, 2.5
mol%), S-Phos (0.04 mmol, 10 mol%), 3 (80 mg, 0.4 mmol),
the arylboronic acid (1.2 mmol, 3.0 equiv), K3PO4 (1.2
mmol, 3.0 equiv), followed by anhyd 1,4-dioxane (3 mL).
The tube was closed by a teflon screw cap and the reaction
mixture was stirred at 100 °C for 20 h. Subsequently the
mixture was cooled to r.t. and diluted with H2O and CH2Cl2.
The layers were separated and the aqueous layer was
chromatography (silica gel, hexane–CH2Cl2).
(22) Synthesis of 2,7-Diphenyl-1,8-naphthyridine (4a):
Following the general procedure, 4a was isolated as a
colorless solid (101 mg, 90%); mp 195–197 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.37–7.47 (m, 6 H, CHAr), 7.86 (d,
3J = 8.7 Hz, 2 H, CHHetar), 8.15 (d, 3J = 8.5 Hz, 2 H, CHHetar),
8.21 (dd, 3J = 8.0 Hz, 4J = 1.6 Hz, 4 H, CHAr). 13C NMR (75
MHz, CDCl3): δ = 119.6 (CHAr/Hetar), 120.6 (CAr/Hetar), 128.1,
128.7 (CHAr), 130.0, 137.4 (CHAr/Hetar), 138.7, 156.1, 160.9
(CAr/Hetar). IR (ATR): 3045 (w), 1583 (m), 1537 (m), 1463
(m), 1305 (m), 1141 (m), 1117 (m), 922 (m), 849 (s), 781 (s),
611 (m) cm–1. MS (EI, 70 eV): m/z (%) = 282 (100) [M+],
253 (2), 205 (4), 203 (4), 177 (4), 151 (4), 140 (8), 127 (4).
HRMS (EI, 70 eV): m/z calcd for C20H14N2: 282.11515;
found: 282.11479.
Synlett 2013, 24, 359–362
© Georg Thieme Verlag Stuttgart · New York

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