Photo- and electrochemical properties of novel 7-substituted naphthyridine derivatives

Article abstract of DOI:10.3987/COM-08-S(D)53

Here we report a new class of 1,8-naphthyridine derivatives, 2-amino-7-(3,4-dimethoxyphenyl)-1,8-naphthyridine, 2-amino-7-(3,4-dihydroxy phenyl)-1,8-naphthyridine, 2-amino-(5,6-dimethoxy-1 H-indenyl [2,3-b])-1,8-naphthyridine, and 2-amino-(5,6-dihydroxy-1

Full text of DOI:10.3987/COM-08-S(D)53

HETEROCYCLES, Vol. 79, 2009
411
HETEROCYCLES, Vol. 79, 2009, pp. 411 - 415. © The Japan Institute of Heterocyclic Chemistry
Received, 30th September, 2008, Accepted, 19th November, 2008, Published online, 26th November, 2008.
DOI: 10.3987/COM-08-S(D)53
PHOTO- AND ELECTROCHEMICAL PROPERTIES OF NOVEL
7-SUBSTITUTED NAPHTHYRIDINE DERIVATIVES
Junya Chiba*, Yasuhiro Doi, and Masahiko Inouye*
Graduate School of Pharmaceutical Sciences, University of Toyama, Sugitani
2630, Toyama 930-0194, Japan; E-mail: chiba@pha.u-toyama.ac.jp;
inouye@pha.u-toyama.ac.jp
Abstract – Here we report a new class of 1,8-naphthyridine derivatives,
2-amino-7-(3,4-dimethoxyphenyl)-1,8-naphthyridine, 2-amino-7-(3,4-dihydroxy
phenyl)-1,8-naphthyridine,
naphthyridine, and
2-amino-(5,6-dimethoxy-1H-indenyl[2,3-b])-1,8-
2-amino-(5,6-dihydroxy-1H-indenyl[2,3-b])-1,8-
naphthyridine. All of these compounds were synthesized via naphthyridine-ring
forming reaction with 2,6-diaminopyridine-3-carboxaldehyde as a key step. The
two dimethoxy derivatives showed predominant fluorescent emission around 400
nm in MeCN. Cyclic voltammetry of the two dihydroxy derivatives in
phosphate buffer showed oxidation potentials of 0.21~0.25 V vs. Ag/AgCl.
Naphthyridines have been widely developed and are in clinical trials for low-toxic medicine such as
analgesic,1 anitibiotics,2 and antitumor agent,3 etc. These heterocyclic compounds have a basic skeleton
of 2-amino-1,8-naphthyridine which serves a hydrogen-bonding array of a donor–acceptor–acceptor
(DAA, D: donor; A: acceptor) fashion. Therefore, 1,8-naphthyridine derivatives which selectively bind
to nucleobases could recently be utilized as an important probe for detecting single nucleotide
polymorphisms (SNPs) concerning with various gene disease or trinucleotide repeats as seen in
Huntington disease.4,5 With this in mind, development of new naphthyridine derivatives having
photochemical and/or electrochemical activities is highly desired for providing useful detection probes as
well as candidates of novel drugs. Herein, we would like to communicate synthesis and photo- and
electrochemical properties of new 7-substituted 1,8-naphthyridine derivatives, 2-amino-7-
(3,4-dimethoxyphenyl)-1,8-naphthyridine (1), 2-amino-7-(3,4-dihydroxyphenyl)-1,8-naphthyridine (2),
2-amino-(5,6-dimethoxy-1H-indenyl[2,3-b])-1,8-naphthyridine (3), and 2-amino-(5,6-dihydroxy-
1H-indenyl[2,3-b])-1,8- naphthyridine (4).

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HETEROCYCLES, Vol. 79, 2009
Scheme 1a Synthetic routes for novel 7-substituted naphthyridine derivatives.
CHO
NH2
R1
R1
H2N
N
N
H2N
N
N
R2
H2N
N
R2
1: R1 = OMe
2: R1 = OH
5
3: R2 = OMe
4: R2 = OH
a
c
b
c
aKey: (a) MeONa, 3,4-dimethoxyacetophenone, toluene; (b) MeONa,
3,4-dimethoxy-1-indanone, toluene; (c) pyridine hydrochloride.
The new 1,8-naphthyridines were synthesized via naphthyridine-ring forming reaction with
2,6-diaminopyridine-3-carboxaldehyde (5) which was prepared according to literature procedure (Scheme
1).6 Treatment of 5 with MeONa and 3,4-dimethoxyacetophenone in toluene at reflux for 1 h led to
2-amino-7-(3,4-dimethoxyphenyl)-1,8-naphthyridine (1) in 88% yield.7 Following deprotection of
methyl group with pyridine hydrochloride at 200 ºC for
1
h
gave water-soluble
By using of
2-amino-7-(3,4-dihydroxyphenyl)-1,8-naphthyridine (2) in 78% yield.8
3,4-dimethoxy-1-indanone instead of 3,4-dimethoxyacetophenone, 2-amino-(5,6-dimethoxy-1H-
indenyl[2,3-b])-1,8-naphthyridine (3) and 2-amino-(5,6-dihydroxy-1H-indenyl[2,3-b])-1,8-
naphthyridine (4) were prepared in a manner similar to the synthetic procedures described for 1 and 2.9
Figures 1A and 1C display absorption spectra (solid line) of the dimethoxy derivatives 1 and 3 which
showed absorption maxima at 370 nm and 382 nm with the absorption coefficients of 2.43 x 104 and 4.45
x 104 mol-1dm3cm-1, respectively, so that these naphthyridines exist as a pale yellow solid. The
fluorescence spectra of those exhibited predominant emission around 400 nm in MeCN (dotted line). In
the cases of the two dihydroxy derivatives 2 and 4 in phosphate buffer (pH 7.0), an absorption maxima
were observed at 361 nm and 388 nm with the absorption coefficients of 1.58 x 104 and 1.25 x 104
mol-1dm3cm-1, respectively (Figures 1B and 1D), while these fluorescence emissions were negligible.
120
80
40
0
0.3
0.2
0.1
0
0.2
B
A
0.1
0
300
400
500
600
300
400
500
600
Wavelength (nm)
Wavelength (nm)

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C
D
200
100
0
0.4
0.2
0
0.1
0
300
400
500
600
300
400
500
600
Wavelength (nm)
Wavelength (nm)
Figure 1. Absorption (solid line) and fluorescence (dotted line) spectra of 10 µM 7-substituted
1,8-naphthyridines at 25 °C. (A) 1 in MeCN (λex = 370 nm), (B) 2 in 65 mM phosphate (pH 7.0), (C) 3
in MeCN (λex = 382 nm), and (D) 4 in 65 mM phosphate (pH 7.0).
6
3
A
B
4
2
2
1
0
0
-2
-1
-4
-2
-0.2
-0.2
0
0
0.4
0.6
0.4
0.6
0.2
0.2
Potential (V vs. Ag/AgCl)
Potential (V vs. Ag/AgCl)
Figure 2. Cyclic voltammograms at 25 °C of (A) 2 (0.5 mM) and (B) 4 (0.5 mM) in 65 mM phosphate
(pH 7.0) with a scanning rate of 0.1 V/s, a gold working electrode, a saturated Ag/AgCl reference
electrode, and a platinum wire auxiliary electrode.
Electrochemical measurements were carried out for all of the new 1,8-naphthyridines. Used was a
normal three-electrode configuration consisting of a commercially available gold working electrode, a
saturated Ag/AgCl reference electrode, and a platinum wire auxiliary electrode. Cyclic voltammetry
(CV) was performed at 25.0±0.1 °C scanning range from –0.2 to +0.6 V with a scanning rate of 0.1 V/s in
appropriate media that had been thoroughly degassed with N2. Dimethoxy derivatives 1 and 3 showed
no electrochemical response within the scanning range (1 mM in MeCN, 100 mM tetrabutylammmonium
perchlorate). Figure 2 shows that naphthyridines 2 and 4 have an oxidation potential at 0.21 and 0.25 V
and a reduction potential at 0.13 and 0.14 V in 65 mM phosphate, respectively, that fall within a favorable
potential range for electrochemical detection of biological targets in aqueous media.

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In conclusion, we synthesized novel 7-substituted 1,8-naphtyridines that possess photochemical or
electrochemical activities adequate for detecting biomolecules. Development of a simple and efficient
detection-system for significant biological targets is now underway by using these naphthyridine
derivatives.
REFERENCES AND NOTES
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7. To a MeOH (10 mL) solution of Na (168 mg, 7.29 mmol) was added 3,4-dimethoxyacetophenone
(1.31 g, 7.29 mmol), and the mixture was stirred for 5 min at rt. To the solution was added 5 (1.00
g, 7.29 mmol) and toluene (10 mL), and then the resulting mixture was refluxed for 1 h. After
removal of the solvents, the residue was solidified with water (10 mL), and the precipitate was
filtered and washed with water. The obtained solid was dissolved in 2N HCl, and the aqueous
solution was then neutralized with K2CO3. After filtration, the resulting solid was chromatographed

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(SiO2; eluent, MeOH : CH2Cl2 = 5 : 95) to give crude 1 (1.80 g, 88%). Recrystallization from
MeOH gave pure 1 as a pale yellow solid. Mp 241~243 ºC; IR (KBr) 3461, 3282, 3116, 1638,
1595, 1503, 1146, 804 cm-1; 1H NMR (DMSO-d6) δ 8.07 (d, J = 8.5 Hz, 1 H), 7.92 (d, J = 8.5 Hz, 1
H), 7.87 (d, J = 2.0 Hz, 1 H), 7.77 (d, J = 8.5 Hz, 2 H), 7.07 (d, J = 8.5 Hz, 1 H), 6.81 (brs, 2 H),
13
6.77 (d, J = 8.5 Hz, 1 H), 3.88 (s, 3 H), 3.84 (s, 3 H); C NMR (DMSO-d6) δ 161.1, 157.2, 156.7,
150.2, 149.0, 137.3, 137.1, 131.8, 119.8, 115.5, 113.7, 112.6, 111.6, 110.1, 55.6, 55.4; HRMS (ESI)
calcd for MH+, C16H16N3O2: 282.1243; found 282.1229.
8. A mixture of 1 (300 mg, 1.07 mmol) and pyridine hydrochloride (3.0 g, 26.0 mmol) was heated to
200 ºC for 1 h. After cooled to rt, the residue was solidified with water (100 mL), and the resulting
precipitate was filtered, washed with EtOH and Et2O, and air-dried to give 2 (240 mg, 78%) as a
yellow powder. Mp 251~252 ºC (decomp.); IR (KBr) 3328, 3170, 1668, 1613, 1291, 1154 cm-1; 1H
NMR (DMSO-d6) δ 9.72 (brs, 1 H), 9.33 (brs, 1 H), 8.35 (dd, J = 9.0, 2.5 Hz, 2 H), 8.18 (brs, 2 H),
7.97 (d, J = 8.5 Hz, 1 H), 7.68 (d, J = 2.0 Hz, 1 H), 7.57 (dd, J = 8.0, 2.3 Hz, 1 H), 7.07 (d, J = 9.5
Hz, 1 H), 6.91 (d, J = 8.5 Hz, 1 H); 13C NMR (DMSO-d6) δ 159.4, 156.6, 148.9, 146.7, 145.9, 142.5,
138.5, 128.1, 119.8, 117.3, 116.1, 114.8, 114.2, 113.4; HRMS (ESI) calcd for MH+, C14H12N3O2:
254.0930; found 254.0921.
9. For 3: To a MeOH (20 mL) solution of Na (352 mg, 15.3 mmol) was added
3,4-dimethoxy-1-indanone (2.94 g, 15.3 mmol), and the mixture was stirred for 5 min at rt. To the
solution was added 5 (2.10 g, 15.3 mmol) and toluene (50 mL), and then the resulting mixture was
refluxed for 1 h. After removal of the solvents, the residue was solidified with water (50 mL), and
the precipitate was filtered and washed with water. The crude solid was dissolved in a small
amount of DMF, and then to the solution was added an appropriate amount of Et2O. The resulting
solid was filtered to give pure 3 (2.16 g, 48%) as a pale yellow solid. Mp >248 ºC (decomp.); IR
1
(KBr) 3317, 3139, 1600, 1498, 1365, 1292 cm-1; H NMR (DMSO-d6) δ 8.05 (s, 1 H), 7.91 (d, J =
8.5 Hz, 1 H), 7.53 (s, 1 H), 7.28 (s, 1 H), 6.74 (d, J = 8.5 Hz, 1 H), 6.57 (brs, 2 H), 3.90 (s, 3 H), 3.87
(s, 5 H); 13C NMR (DMSO-d6) δ 162.6, 160.3, 156.8, 151.1, 149.1, 138.8, 137.7, 132.7, 131.1, 130.4,
114.7, 111.3, 108.7, 103.6, 55.8, 55.6, 33.1; HRMS (ESI) calcd for MH+, C17H16N3O2: 294.1243;
found 294.1248. For 4: This compound was obtained from 3 (300 mg, 1.02 mmol) in a manner
similar to that described for 2. 4 (256 mg, 83%) was obtained as a dark yellow powder. Mp >259
ºC (decomp.); IR (KBr) 3461, 3171, 1666, 1477, 1300 cm-1; 1H NMR (DMSO-d6) δ 9.97 (brs, 1 H),
9.71 (brs, 1 H), 9.18 (brs, 1 H), 8.33–8.14 (m, 3 H), 7.53 (s, 1 H), 7.11 (s, 1 H), 7.05 (d, J = 9.0 Hz, 1
13
H), 3.86 (s, 2 H); C NMR (DMSO-d6) δ 163.4, 156.4, 150.4, 147.3, 146.2, 142.5, 139.6, 134.3,
132.5, 129.0, 113.4, 112.3, 112.0, 108.0, 33.0; HRMS (ESI) calcd for MH+, C15H12N3O2: 266.0930;
found 266.0922.