Palladium-catalyzed Suzuki coupling towards 2-amino-1,8-naphthyridines

Article abstract of DOI:10.3987/COM-14-13140

Several 2-amino-6-aryl-1,8-naphthyridines were reported. The cyclocondensation of 2,6-diaminopyridine, 2-bromomalonaldehyde in phosphoric acid resulted in the formation of 2-amino-6-bromo-1,8-naphthyridine, which was converted into 2-amino-6-aryl-1,8-naph

Full text of DOI:10.3987/COM-14-13140

HETEROCYCLES, Vol. 91, No. 5, 2015
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HETEROCYCLES, Vol. 91, No. 5, 2015, pp. 1001 - 1006. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 1st December, 2014, Accepted, 24th March, 2015, Published online, 6th April, 2015
DOI: 10.3987/COM-14-13140
PALLADIUM-CATALYZED SUZUKI COUPLING TOWARDS
2-AMINO-1,8-NAPHTHYRIDINES
Hangming Ge and Qiancai Liu*
School of Chemistry and Molecular Engineering, East China Normal University,
Shanghai 200241, China *Corresponding author. Tel. & Fax: +86 21 5434 0097;
E-mail: qcliu@chem.ecnu.edu.cn
Abstract
–
Several 2-amino-6-aryl-1,8-naphthyridines were reported. The
cyclocondensation of 2,6-diaminopyridine, 2-bromomalonaldehyde in phosphoric acid
resulted in the formation of 2-amino-6-bromo-1,8-naphthyridine, which was converted
into 2-amino-6-aryl-1,8-naphthyridines by palladium-catalyzed Suzuki reaction with
arylboronic acid. It is shown that the Suzuki coupling with palladium catalyst (Pd-132)
could be completed efficiently with lower catalyst loading and good to excellent yields.
The title compounds were characterized by NMR spectra and mass spectra.
Organic molecules with naphthrydine skeleton have attracted numerous attention. They could be used as
anti hepatitis C (HCV) agents.1 Water soluble (η6-arene)ruthenium(II) complexes based on pyrazolyl-
naphthryridine ligands could be used as catalysts for the hydrogenation of aromatic ketones.2 The
naphthyridine-based compounds could also be utilized as probes and sensors, for example, Jachak3a
reported that benzo[b][1,8]naphthyridienes could be as fluorescent agents with human serum albumin
(HAS) and Bovine serum albumin (BSA). Some others reported ferrocene naphthyridine derivatives such
as di-substituted ferrocene derived FecDN behave as a selective visual chemosensor for mercury ions
with good selectivity and sensitivity.3b Naphthalimide-naphthyridines have also been synthesized for the
detection of hydroxyl radicals, which could be used to distinguish hydroxyl radicals from other reactive
oxygen species with high selectivity and short response time.3c A rhodamine B based chemosensor
containing 2-amino-7-methyl-1,8-naphthyridine moiety was reported for colorimetric and fluorescent
response on corresponding nucleoside polyphosphates through multi-hydrogen bond interaction.3d
Lanthanide complex Gd-ANAMD with 2-amino-7-methyl-1,8-naphthyridine moiety as ligand was
achieved for selective magnetic resonance imaging towards GMP over other ribonucleotide

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polyphosphates.3e 1,8-Naphthyridine-modified rhodamine B has also been used as sensor to detect
Cu2+ selectively with a dramatic color change.3f Some 1,8-naphthyridines display red-fluorescence
emissions and two-photon absorption properties.3g
However no any information about 6-aryl-2-aminonaphthyridines has been reported up to now which
might be due to the synthetic difficult of the key precursor 2-amino-6-bromonaphthyridine.4 We have
ever reported some aza-heterocycles by different synthetic approaches.5,6 With 2-amino-6-bromo-
naphthyridine as a suitable precursor, the Suzuki cross coupling reaction with different arylboronic acid
could be employed to construct 2-amino-6-arylnaphthyridines for further evaluation of their properties.
Considering the potential application of 2-amino-6-arylnaphthyridines, it is worthy to explore the method
with palladium catalyst system.
The initial effort on the Suzuki coupling of 2-amino-6-bromo-naphthyridine and 4-methylphenylboronic
acid has been performed with Pd(PPh3)4 (10% mole loading)ˈhowever only an inseparable mixture was
obtained (crude yield ca. 13.7%). We envisage that a novel phosphine based catalyst, [(A-taPhos)2PdCl2]
(CAS No. 887919-35-9, Pd-132), which is highly effective for various cross couplings such as Suzuki(or
Suzuki-Miyaura), Negeshi-like, Sonogashira-like reactions with mild reaction conditions and different
halide or pseudohalide substrates as early reported, might be a suitable catalyst for this coupling. 7-9
Cl
N
P
Pd P
Cl
N
(A-taPhos)2PdCl2
Scheme 1. Catalyst [(A-taPhos)2PdCl2]
Since naphthyridine-based molecules could be potentially useful in medicinal chemistry and opt-electric
areas, we are interested in 6-aryl-2-aminonaphthyridines. The precursor 2-amino-6-bromonaphthyridine is
synthesized from the reaction of 2,6-diaminopyridine, 2-bromomalonaldehydre in phosphoric acid with
heating as previously reported.4 It is proved that the separation of this intermediate is quite difficult due to
its low solubility. The Suzuki coupling of 2-amino-6-bromonaphthyridine with different arylboronic acids
is performed in the presence of [(A-taPhos)2PdCl2] and it is pleased to find that all of these reactions
proceed with good to excellent yields (50 % to 98 %) with a relatively low catalyst loading (ca. 0.8% ),

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1003
while it is no need to protect amino group during the process (Scheme 2).
Ar
Br
Br
85% H3PO4
(A-taPhos)2PdCl2
+
ArB(OH)2,DME,H2O,
K2CO3, TBAB, heat
heat, 30.3%
N
N
NH2
N
N
NH2
H2N
N
NH2 OHC
CHO
Ar = 4-MePh(1), 97.6%
4-EtPh(2),80.6%
4-nBuPh(3), 51.7%
4-MeOPh(4),50.4%
2-furyl (5),81.4%
Scheme 2. Synthetic approach toward target molecules
In conclusion, we developed an easy and simple synthetic method towards 2-amino-6-naphthyridines by
palladium-catalyzed Suzuki cross coupling of amino-substituted aryl bromide with different arylboronic
acid with low catalyst loading and without protection of amino group. This method might be applied to
the construction of other aza-heterocycles from suitable precursors with amino-substituent.
EXPERIMENTAL
All chemical are commercially available as analytic grade and used without further purification. Solvents
are purified according to standard methods prior to use. 1H NMR and 13C NMR spectra were measured on
a Bruker Avance III 500MHz spectrometer (1H NMR 500 MHz, 13C NMR125 MHz). Mass spectra were
measured on Bruker Daltonics maXis Impact spectrometer. Melting point was measured on an X-4
micrographic melting point measuring instrument. Mass spectra were measured on micOTOF II (ESI).
Synthetic procedures
2-Amino-6-bromonaphthyridine is prepared according to literature.4
A mixture of 2,6-diaminopyridine (6.0 g, 55 mmol) and 2-bromo-1,3-malonaldehyde (8.0 g, 53 mmol) in
85% orthophosphorous acid (160 mL) was heated at reflux for 6 h, then it was stirred at room temperature
till the reaction is completed by thin layer chromatography (TLC) monitoring. The reaction mixture was
neutralized with aq. NH4OH to afford a dark-brown solid, which was filtered and dried before dissolved
in MeOH with assistance of ultrasonic instrument. The target molecule was then separated by column
chromatography to afford a pale-yellow solid (3.85 g, 30.3%) Rf = 0.39 (CH2Cl2:MeOH = 10:1)㸪mp
160-162 oC. (Lit.4 mp 210-212 °C). 1H NMR (500 MHz, DMSO-d6) δ: 7.82 (d, J = 2.6 Hz, 1H), 7.46 (d, J
= 2.6 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.14 (s, 2H), 5.99 (d, J = 8.8 Hz, 1H).
Pd(PPh3)4-catalyzed the Suzuki cross coupling towards compound 1
A pressure flask was charged with 2-amino-6-bromonaphthyridineꢀ (0.56 mmol) and 4-methyl-

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HETEROCYCLES, Vol. 91, No. 5, 2015
phenylboronic acid (1.12 mmol), K2CO3 (1 g, 7.24 mmol), Bu4NBr (0.3 g, 0.93 mmol), H2O (1.5 mL,
83.3 mmol), and DME (30 mL). Nitrogen was bubbled into the mixture for 10 min before Pd(PPh3)4 (65
ꢀ
mg, 5.6*10-2 mmol) was introduced and the flask was screwed up. The mixture was heated at 120 °C for
16 h. After cooling, the volatiles were removed under vaccum before the residues were subjected to
column chromatography to afford compound 1 (18 mg, crude yield ca. 13.7%) with impurity which could
not be removed (see supporting information).
General procedure for the Suzuki cross coupling reaction by Pd-132
A pressure flask was charged with 2-amino-6-bromonaphthyridine (0.56 mmol) and arylboronic acid
(1.12 mmol), K2CO3 (1 g, 7.24 mmol), Bu4NBr (0.3 g, 0.93 mmol), H2O (1.5 mL, 83.3 mmol), and DME
(30 mL). Nitrogen was bubbled into the mixture for 5 min before [(A-taPhos)2PdCl2 (5 mg, 7.06*10-3
o
mmol) was introduced and the flask was screwed up. The mixture was heated at 120 C for 16 h. After
cooling, the volatiles were removed under vaccum before the residues were subjected to column
chromatography to afford the target molecules.
Compound 1, pale-yellow solid (128 mg, 97.6%), mp 161.1-161.9 oC . Rf = 0.4 (DCM㸸MeOH=10:1). 1H
NMR (500 MHz, DMSO-d6) δ: 8.12 (d, J = 2.5 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H),
6.79 (d, J = 8.1 Hz, 2H), 6.43 (d, J = 8.0 Hz, 2H), 6.25 (s, 2H), 6.01 (d, J = 8.8 Hz, 1H), 1.47 (s, 3H). 13C
NMR (126 MHz, DMSO-d6) δ: 149.96 (s), 138.42 (s), 134.15 (s), 133.60 (s), 129.77 (s), 129.29 (s),
126.42 (s), 114.11 (s), 13.52 (s). HR-MS (ESI) Required for C15H13N3: 235.11, found 236.1186 (M+H+).
1
Compound 2 brown solid (112 mg, 80.6%). mp 162-163 oC. Rf =0.35 (DCM㸸MeOH=10:1). H NMR
(500 MHz, DMSO-d6) δ: 8.08 (s, 1H), 7.40 (s, 1H), 7.10 (d, J = 10.3 Hz, 1H), 6.77 (d, J = 6.4 Hz, 2H),
6.41 (d, J = 6.7 Hz, 2H), 6.05 (s, 2H), 5.99 (d, J = 8.7 Hz, 1H), 1.72 (s, 2H), 0.29 (s, 3H). 13C NMR (126
MHz, DMSO-d6) δ: 180.70 (s), 176.01 (s), 170.17 (s), 163.06 (s), 157.82 (s), 154.67 (s), 153.13 (s),
148.82 (s), 148.51 (s), 146.40 (s), 136.46 (s), 133.84 (s), 43.10 (s), 33.48 (s). Required for C16H15N3
249.13, found 250.1354 (M+H+).
1
Compound 3. pale-yellow solid (80 mg, 51.7%), mp 269-269.8 oC. Rf =0.34 (DCM㸸MeOH=10:1). H
NMR (500 MHz, DMSO-d6) δ: 8.14 (d, J = 2.5 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H),
6.81 (d, J = 8.1 Hz, 2H), 6.53 (s, 2H), 6.45 (d, J = 8.1 Hz, 2H), 6.06 (d, J = 8.9 Hz, 1H), 1.75 (t, J = 7.6
13
Hz, 2H), 0.70 (s, 2H), 0.44 (dd, J = 14.9, 7.4 Hz, 2H), 0.02 (t, J = 7.4 Hz, 3H). C NMR (126 MHz,
DMSO-d6) δ: 160.70 (s), 156.01 (s), 150.17 (s), 143.06 (s), 137.82 (s), 134.67 (s), 133.13 (s), 128.82 (s),
128.51 (s), 126.40 (s), 116.46 (s), 113.84 (s), 27.82 (s), 23.10 (s), 19.20 (s), 13.48 (s). HR-MS (ESI)
Required for C18H19N3: 277.16, found 277.9551.
Compound 4 brown solid (78 mg, 50.4%). mp 248-249 oC. Rf =0.38 (DCM㸸MeOH=10:1). 1H NMR (500
MHz, DMSO-d6) δ: 8.05 (s, 1H), 7.31 (s, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 8.2 Hz, 2H), 6.11 (d,

HETEROCYCLES, Vol. 91, No. 5, 2015
1005
13
J = 8.3 Hz, 2H), 6.01 (s, 2H), 5.94 (d, J = 8.7 Hz, 1H), 2.86 (s, 3H). C NMR (126 MHz, DMSO-d6) δ:
160.66 (s), 158.93 (s), 155.91 (s), 150.17 (s), 137.79 (s), 132.69 (s), 129.70 (s), 128.69 (s), 127.68 (s),
116.49 (s), 114.60 (s), 113.81 (s), 55.22 (s). Required for C15H13N3O 251.11, found: 252.1145 (M+H+).
Compound 5 yellow solid (96 mg, 81.6%). mp 158-159 oC. Rf =0.33 (DCM㸸MeOH=10:1). 1H NMR (500
MHz, DMSO-d6) δ: 8.18 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.91 (s,
13
1H), 6.14 (d, J = 3.2 Hz, 1H), 6.06 (s, 2H), 5.98 (d, J = 8.8 Hz, 1H), 5.75 (s, 1H). C NMR (126 MHz,
DMSO-d6) δ: 160.74 (s), 148.00 (s), 143.03 (s), 137.74 (s), 129.82 (s), 120.04 (s), 116.28 (s), 114.05 (s),
112.16 (s), 105.64 (s), 39.52 (s). Required for C12H9N3O: 211.07, found: 212.0828 (M+H+).
ACKNOWLEDGEMENTS
We thank the large instrumental open foundation of East China Normal University and “ECNU Da Xia
fund for undergraduate student research training” (2012DX-186) and the State innovative program for
undergraduates research training (1310269020) for financial support.
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