Simple and efficient synthesis of 2,7-difunctionalized-1,8-naphthyridines

Article abstract of DOI:10.3390/10080929

The syntheses in good yields of some new difunctionalized 1,8-naphthyridines 4, 6, 8 and 9 and a novel triethylene glycol ether-linked dinaphthyridine, 10a, along with the mononaphthyridine-linked ether alcohol 10b are described. An improved and milder method for the synthesis of 2,7-diamino-1,8-naphthyridine (14) is also reported.

Full text of DOI:10.3390/10080929

Molecules 2005, 10, 929-936
molecules
ISSN 1420-3049
http://www.mdpi.org
Simple and Efficient Synthesis of 2,7-Difunctionalized-1,8-
Naphthyridines
Shyamaprosad Goswami *, Reshmi Mukherjee, Rakhi Mukherjee, Subrata Jana, Annada C.
Maity, and Avijit Kumar Adak
Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah-711 103,
West Bengal, India. Fax: (+91)-33-26682916.
* Author to whom correspondence should be addressed. E-mail: spgoswamical@yahoo.com
Received: 25 August 2004; in revised form: 23 November 2004 / Accepted: 6 January 2005 /
Published: 31 August 2005
Abstract: The syntheses in good yields of some new difunctionalized 1,8-naphthyridines
4, 6, 8 and 9 and a novel triethylene glycol ether-linked dinaphthyridine, 10a, along with
the mononaphthyridine-linked ether alcohol 10b are described. An improved and milder
method for the synthesis of 2,7-diamino-1,8-naphthyridine (14) is also reported.
Keywords: Naphthyridines, 2,7-difunctionalized-1,8-naphthyridines, 2,7-diamino-1,8-
naphthyridine.
Introduction
Naphthyridine or naphthyridone systems are of great importance due to their broad spectrum of
biological activities. Substituted 1,8-naphthyridine compounds are used as antihypertensives,
antiarrhythmics, herbicide safeners and also as immunostimulants [1-3]. We are interested in
2,7-difunctionalized-1,8-naphthyridines because of their aforesaid potential medicinal activity as well
as for their use as important binding units in the molecular design of synthetic receptors [4]. This
communication describes the first synthesis of four 2,7-difunctionalized-1,8-naphthyridines; viz. 2-
amino-7-hydroxymethyl-1,8-naphthyridine (5), 2-amino-1,8-naphthyridine-7-carboxaldehyde (6), 2,7-
dimethyl-4-methoxy-1,8-naphthyridine (8) and 4-methoxy-1,8-naphthyridine-2,7-dicarboxaldehyde (9)
and a novel triethylene glycol ether-linked dinaphthyridine compound, 1,2-bis-[2-(2,7-dimethyl-1,8-
naphthyridin-4-yloxy)ethoxy]ethane (10a) along with the mononaphthyridine-linked ether alcohol

Molecules 200X, Y
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(10b). A new synthesis of 2,7-diamino-1,8-naphthyridine 14 by a more efficient reaction under milder
conditions is also reported here.
Results and Discussion
Naphthyridines 2-6 were synthesized starting from 2-amino-7-methylnaphthyridine (1), which is
obtained by the condensation of commercially available 2,6-diaminopyridine and 3-oxo-butyraldehyde
dimethyl acetal following a reported procedure [5]. The 7-methyl group of 2-acetylamino-7-methyl-
1,8-naphthyridine (2) is oxidized with selenium dioxide in dioxane to the corresponding aldehyde 3,
followed by deprotection of the N-acetyl group by hydrolysis with 1N hydrochloric acid, which
afforded the desired 2-amino-1,8-naphthyridine-7-carboxaldehyde (6) in 85% yield (Scheme 1).
Scheme 1.
ii
i
AcHN
N
N
CHO
AcHN
N
N
H2N
N
N
3
1
2
iii
iv
v
H2N
N
N
AcHN
N
N
H2N
N
N
CHO
5
6
4
OH
OH
Reagents, conditions and yields: (i) acetic anhydride, 80ºC, 12h., 87%. (ii) SeO2,
dioxane, 50-55ºC, 4h., 75%. (iii) 1N HCl, reflux, 0.5h., 85%. (iv) NaBH4, dry
THF, 3-4h, 85%. (v) 1N NaOH, r.t.,12h., 80%.
The conversion of aldehyde 3 into 2-amino-7-hydroxymethyl-1,8-naphthyridine (5) was achieved
by sodium borohydride reduction of the former to give 2-acetylamino-7-hydroxymethyl-1,8-
naphthyridine (4), followed by mild alkaline hydrolysis (1N NaOH).
Compound 8 is made in excellent yield (95%) starting from 4-chloro-2,7-dimethyl-1,8-
naphthyridine (7) [6] by stirring at room temperature with methanolic potassium hydroxide.
Compound 8 is then oxidized with SeO2 in dioxane at room temperature to produce 4-methoxy-1,8-
naphthyridine-2,7-dicarboxaldehyde (9) in 90% yield. The synthesis of the novel di- and mono-
naphthyridines 10a-b with triglycol spacers is achieved by substitution of the chlorine atom by both
two as well as only one of the hydroxyl functions of triethylene glycol, respectively (Scheme 2).

Molecules 200X, Y
931
Scheme 2.
O
O
O
N
O
Cl
N
N
N
N
10a
i
+
N
O
O
O
OH
7
N
N
ii
10b
OMe
N
OMe
iii
OHC
N
CHO
N
N
8
9
Reagents, conditions and yields: (i) Triethylene glycol, KOH, THF, 60ºC, 80%.
(ii) MeOH, KOH, 4h., 90%. (iii) SeO2, dioxane, r.t., 90%.
The synthesis of 2,7-diamino-1,8-naphthyridine 14 is described in Scheme 3. The advanced starting
compound 11 was prepared according to the literature method [7, 8]. Compound 11 was then
converted into the chloroamino intermediate 12 by direct reaction with POCl3 without conventional
protection of the amino group. The substitution of chloro by azide was smoothly achieved by the
treatment of 12 with sodium azide in DMF at 60 ºC to produce 13 in 90% yield, while the reaction of
12 with benzylamine lead to 15 in 50% yield. The target compound 14 was then synthesized, albeit in
poor yield (25%), by refluxing compound 12 with NaNH2 in xylene. However, excellent yields (98%)
of 14 can be achieved via the reduction of the azide derivative 13 with Zn/AcOH.
Scheme 3.
i
ii
H2N
N
N
H
O
H2N
N
N
NHCH2Ph
H2N
N
N
Cl
15
12
11
v or vi
iii
iv
H2N
N
N
N
H2N
N
N
N
N
NH2
H2N
N
N
N3
14
13
Reagents, conditions and yields. (i) POCl3, reflux, 4h., 60%. (ii) PhCH2NH2,
120ºC, 6h., 50%. (iii) NaN3, DMF, 60ºC, 4h., 90%. (iv) Zn, AcOH, reflux, 3h.,
98%. (v) NaNH2, xylene, reflux, 25%. (vi) ammonolysis.

Molecules 200X, Y
932
Compound 14 is also obtained by direct ammonolysis of compound 12 at high temperature in a
sealed tube. But care must be taken during this procedure as it was found to be dangerous and the yield
is also poor compared to that of azide reduction with Zn/AcOH .
Conclusions
We have synthesized a series of functionalized naphthyridines and novel triethylene glycol-linked
mono- and di-naphthyridines in good yields by simple and efficient procedures. All the naphthyridines
and the intermediates were well characterized by spectroscopic means. A new, efficient and practical
method under mild conditions for the synthesis of 2,7-diamino-1,8-naphthyridine (14) has also been
developed, which also improves the yield for the synthesis of this compound.
Acknowledgements
Financial assistance from the Department of Science and Technology (DST), and the Council of
Scientific and Industrial Research (CSIR), Govt. of India is gratefully acknowledged. S.J., and A.K.A.
thank CSIR and A.C.M. thanks UGC for research fellowships.
Experimental
General
Melting points (m.p) were recorded on a Toshniwal hot-coil stage melting point apparatus and are
uncorrected. NMR spectra were recorded in CDCl3 (unless otherwise mentioned) with TMS as the
internal standard on Bruker AM 200 MHz and 300 MHz NMR instruments. Chemical shifts are given
in δ (ppm) scale and J values in Hz respectively. IR spectra were measured in KBr disks with a Perkin
Elmer (Model 883) spectrometer. Mass spectra (JEOL JMS600), and elemental analyses were obtained
from the IICB, and the IACS (Kolkata) respectively. All solvents were dried prior to use by common
methods. Silica gel (60-120 mesh) has been used for all chromatographic purifications. Starting
materials were either commercially available (purchased from Fluka and Aldrich) or synthesized
according to the cited literature procedures.
2-Acetylamino-7-methyl-1,8-naphthyridine (2): Distilled acetic anhydride (0.5 mL) was added to
2-methyl-7-amino-1,8-naphthyridine (1, 0.158 g, 1.0 mmol) and the reaction mixture was stirred
overnight at 80 ºC. The excess acetic anhydride was removed under vacuum. To this, diethyl ether was
added, and the solid separated was collected by filtration. The solid was washed thoroughly with
NaHCO3 solution, dried and crystallized from chloroform-methanol to afford the title compound 2
1
(0.174g, 87%) as a yellow solid; m.p. 280 ºC [lit. [5] 279-281 ºC]; H-NMR (200 MHz) δ: 8.70 (bs,
1H), 8.44 (d, 1H, J = 8.8 Hz), 8.12 (d, 1H, J = 8.8 Hz), 8.00 (d, 1H, J = 8.2 Hz), 7.30 (d, 1H, J = 7.5
Hz), 2.74 (s, 3H), 2.27 (s, 3H); IR (cm-1): 1503, 1606, 1697, 3005, 3176; Anal. Calcd for C11H11N3O:
required C, 65.65; H, 5.50; N, 20.88. Found: C, 65.58; H, 5.42; N, 20.95.

Molecules 200X, Y
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2-Acetylamino-1,8-naphthyridine-7-carboxaldehyde (3): To a stirred solution of selenium dioxide
(0.11 g, 1.0 mmol) in dioxane (10 mL) containing 2-3 drops of water, compound 2 (0.201 g, 1.0 mmol)
was added and heated for 4 h at 50-55 ºC. The hot solution was filtered through a pad (2-3 cm) of
Celite and the solvent was removed through the short path distillation. The residue was extracted with
chloroform and washed well with water. The organic layer after evaporation and column
chromatography purification gave the desired compound 3 (0.161g, 75%); m.p 215 ºC; 1H-NMR (200
MHz) δ: 10.23 (s, 1H), 8.70 (d, 1H, J = 8.9 Hz), 8.52 (bs, 1H), 8.37 (d, 1H, J = 3.1 Hz), 8.34 (d, 1H, J
= 4.0 Hz), 8.13 (d, 1H, J = 8.1 Hz), 2.32 (s, 3H); 13C-NMR (50 MHz) δ: 193.41, 169.59, 154.51,
139.36, 138.22, 123.11, 117.52, 117.07, 25.00; IR (cm-1): 1607, 1703, 3060, 3186; Anal. Calcd for
C11H9N3O2: required C, 61.39; H, 4.21; N, 19.52. Found: C, 61.31; H, 4.25; N, 19.45.
2-Acetylamino-7-hydroxymethyl-1,8-naphthyridine (4): To a solution of 3 (0.215 g, 1.0 mmol) in dry
THF (10 mL), sodium borohydride (0.016 g, 0.433 mmol) was added and stirred under nitrogen for
half an hour. THF was then removed and the excess borohydride was decomposed by dropwise
addition of 2.5 N HCl. The mixture was extracted with choloroform. The organic layer was washed
with water, dried (Na2SO4) and evaporated under reduced pressure to give the title compound 4 (0.184
g, 85%) which was sufficiently pure for the next step. M.p. 240 ºC (decomp.); 1H-NMR (200 MHz) δ:
8.69 (bs, 1H), 8.52 (d, 1H, J = 8.8 Hz), 8.19 (d, 1H, J = 8.8 Hz), 8.11 (d, 1H, J = 8.2 Hz), 7.30 (d, 1H,
J = 8.2 Hz), 4.96 (s, 2H), 3.41 (bs, 1H, OH), 2.46 (s, 3H); IR (cm-1): 1296, 1389, 1696, 3203, 3391,
3733; Anal. Calcd for C11H11N3O2: required C, 60.82; H, 5.10; N, 19.34. Found: C, 60.72; H, 5.14; N,
19.40.
2-Amino-7-hydroxymethyl-1,8-naphthyridine (5): Compound 4 (0.217 g, 1.0 mmol) was taken up in
1N NaOH (3 mL) and stirred overnight. The reaction mixture was then neutralized with acetic acid,
and extracted with 5% methanol in chloroform solution. The organic layer was dried (Na2SO4) and
then evaporated under reduced pressure to give the desired product 5 (0.140g, 80%); m.p. 240 ºC;
1H-NMR (10% DMSO-d6 in CDCl3, 200 MHz) δ: 7.73 (d, 1H, J = 8.0 Hz), 7.63 (d, 1H, J = 8.0 Hz),
6.99 (d, 1H, J = 8.0 Hz), 6.64 (d, 1H, J = 8.0 Hz), 5.80 (bs, 2H), 4.63 (s, 2H), 2.67 (bs, 1H, OH); MS
(FAB): m/z (%): 176 (MH+, 100), 159 (20), 146 (40), 75 (95), 57 (75); Anal. Calcd for C9H9N3O:
required C, 61.70; H, 5.18; N, 23.99. Found: C, 61.71; H, 5.20; N, 24.02.
2-Amino-1,8-naphthyridine-7-carboxaldehyde (6): A mixture of compound 3 (0.215 g, 1.0 mmol) and
1N HCl (1.0 mL) in dioxane (10 mL) was refluxed for 30 min. Then the solution was cooled to room
temperature, and neutralized carefully with NaOH solution. The precipitate formed was filtered, which
afforded the desired compound 6 (0.147 g, 85%); 1H-NMR (200 MHz) δ: 10.19 (s, 1H), 8.1 (d, 1H, J =
8.0 Hz), 7.94 (d, 1H, J = 8.0 Hz), 7.84 (d, 1H, J = 8.0 Hz), 6.88 (d, 1H, J = 8.0 Hz), 5.18 (bs, 2H); IR
(cm-1): 1305, 1387, 1701, 3332; MS (FAB): m/z (%): 173 (M+, 65), 159 (30), 145 (45), 117 (25), 97
(35), 81 (45), 69 (95), 57 (100); Anal. Calcd for C9H7N3O: required C, 62.42; H, 4.07; N, 24.26.
Found: C, 62.40; H, 4.10; N, 24.28.
2,7-Dimethyl-4-methoxy-1,8-naphthyridine (8): To a methanolic solution of 2,7-dimethyl-4-chloro-1,8-
naphthyridine (7, 0.193 g, 1.0 mmol), solid KOH (0.056 g, 1.0 mmol) was added and stirred for 4 h at

Molecules 200X, Y
934
80 ºC. The solvent was stripped off. The residue was added to water and extracted with
dichloromethane. The solvent was evaporated to dryness to get the desired compound 8 (0.169 g,
90%); mp. 130 ºC; 1H-NMR (200 MHz) δ: 8.31 (d, 1H, J = 8.3 Hz), 7.21 (d, 1H, J = 8.3 Hz), 6.60 (s,
1H), 4.01 (s, 3H), 2.73 (s, 3H), 2.70 (s, 3H); IR (cm-1): 1092, 1133, 1181, 1606; Anal. Calcd for
C11H12N2O3: required C, 70.19; H, 6.43; N, 12.96. Found: C, 70.21; H, 6.45; N, 12.99.
4-Methoxy-1,8-naphthrydine-2,7-dicarboxaldehyde (9): To a stirred solution of 8 (0.188 g, 1.0 mmol)
in dioxane (10 mL), SeO2 (0.33 g, 3.0 mmol) was added and stirring was continued for 12 h. The
reaction mixture was filtered through a 4-5 cm pad of Celite-silica gel. Water (5 mL) was added to the
dioxane solution, followed by extraction with dichloromethane. The organic solvent was evaporated
1
under reduced pressure to give the desired compound 9 (0.194 g, 90%); m.p. 210 ºC; H-NMR (200
MHz) δ: 10.32 (s, 1H), 10.26 (s, 1H), 8.81 (d, 1H, J = 8.2 Hz), 8.18 (d, 1H, J = 8.3 Hz), 7.54 (s, 1H),
4.20 (s, 3H); IR (cm-1): 1091, 1170, 1606, 1705; MS (EI): m/z (%): 216 (M+, 100), 188 (95), 173 (20),
158 (40), 129 (25), 90 (95), 71 (50), 57 (75); Anal. Calcd. for C11H8N2O3: required C, 61.11; H, 3.73;
N, 12.96. Found: C, 61.10; H, 3.75; N, 13.00.
1,2-bis-[2-(2,7-dimethyl-1,8-naphthyridin-4-yloxy)ethoxy]ethane (10a) and 1,2-[2-(2,7-dimethyl-1,8-
naphthyridin-4-yloxy)ethoxy]ethane (10b): A solution of triethylene glycol (0.150 g, 1.0 mmol), and
KOH (0.112 g, 2.0 mmol) in dry THF (10 mL) was added the solution of compound 7 (0.386 g, 2.0
mmol) and the mixture was heated at 60 ºC for 24 h. Then the solvent was removed to dryness and
dichloromethane was added to the residue. The organic layer was washed with water, dried (Na2SO4)
and solvent was removed under reduced pressure to give a brown gum. Column chromatography of the
crude product eluting with 1% methanol in chloroform afforded first the di-naphthyridine polyether
10a (0.369 g, 80%) as an off-white solid. 1H-NMR (200 MHz) δ: 8.36 (d, 2H, J = 8.3 Hz), 7.22 (d, 2H,
J = 8.3 Hz), 6.61 (s, 2H), 4.32 (t, 4H, J = 4.6 Hz), 3.96 (t, 4H, J = 4.6 Hz), 3.58 (t, 4H, J = 4.3 Hz),
2.73 (s, 6H), 2.70 (s, 6H); MS (FAB): m/z (%): 462 (M+, 5), 427 (10), 405 (10), 325 (5), 225 (10), 203
(100), 187 (20), 175 (40), 159 (10); Anal. Calcd. for C26H30N4O4: required C, 67.48; H, 6.53; N, 12.01.
Found: C, 67.62; H, 6.45; N, 11.95. Further elution gave the mono-naphthyridine 10b (0.08 g, 15-
1
18%) as a light yellow semi-solid. H-NMR (300 MHz) δ: 8.41 (d, 1H, J = 8.4 Hz), 7.21 (d, 1H, J =
8.3 Hz), 6.69 (s, 1H), 4.38 (t, 2H, J = 4.4 Hz), 4.00 (t, 2H, J = 4.2 Hz), 3.80-3.76 (m, 4H), 3.74-3.70
(m, 2H), 3.62 (t, 2H, J = 4.4 Hz), 2.76 (s, 3H), 2.75 (s, 3H), 2.36 (s, 1H); MS (EI): m/z (%): 306 (M+,
5), 289 (10), 276 (10), 262 (10), 232 (20), 188 (25), 174 (100), 157 (20), 145 (65), 116 (25), 93 (20),
74 915); Anal. Calcd for C16H22N2O4: required C, 62.73; H, 7.23; N, 9.14. Found: C, 62.70; H, 7.26;
N, 9.20.
2-Amino-7-chloro-1,8-naphthyridine (12): A mixture of the compound 11 (4.0 g, 0.024 mol) in freshly
distilled POCl3 (25 mL) was refluxed for 4h. Excess POCl3 was distilled off and the reaction mixture
was poured onto ice-cold water. After neutralization with Na2CO3, a yellow solid appeared, which was
collected by filtration and recrystallized from methanol-ether to give 12 (2.67 g, 60%). M.p. 170 ºC;
1H-NMR (200 MHz) δ: 7.86 (d, 1H, J = 4.0 Hz), 7.82 (d, 1H, J = 4.0 Hz), 7.17 (d, 1H, J = 8.0 Hz),
6.75 (d, 1H, J = 8.0 Hz), 5.33 (bs, 2H); IR (cm-1): 1437, 1489, 1607, 1695, 3311; MS (FAB) (m/z):

Molecules 200X, Y
935
179.5 (M+, 100%); Anal. Calcd. for C8H6N3Cl: required C, 53.49; H, 3.36; N, 23.39. Found: C, 53.41;
H, 3.40; N, 23.50.
2-Amino-7-azido-1,8-naphthyridine (13): To a stirred solution of 12 (0.4 g, 2.22 mmol) in dry DMF (5
mL), sodium azide (0.289 g, 4.44 mmol) was added and the mixture stirred for 4h at 60 ºC. The
precipitated NaCl was filtered off. The filtrate was distilled under reduced pressure to remove DMF.
The solid was washed well with water and air-dried to give the title compound 13 (0.248 g, 95%); mp.
275 ºC; 1H-NMR (200 MHz) δ: 8.1 (d, 1H, J = 8.0 Hz), 7.76 (d, 1H, J = 8.0 Hz), 7.69 (d, 1H, J = 8.0
Hz), 6.9 (d, 1H, J = 8.0 Hz), 5.5 (bs, 2H); IR (cm-1): 1651, 3168, 3321.
2,7-Diamino-1,8-naphthyridine (14) from 13: To a stirred solution of the azo compound 13 (0.8 g, 4.3
mmol) in glacial acetic acid (12.72 mL), zinc dust (2.12 g) was added and refluxed for 3 h. A
precipitate was obtained which was filtered. Acetic acid was removed under reduced pressure to give
the desired pure product as a yellowish brown solid 14 (0.674 g, 98%); m.p. 222-223 ºC [lit.[6] 223
1
ºC]; H-NMR (DMSO-d6, 200 MHz) δ: 7.67 (d, 2H, J = 10.0 Hz), 6.53 (d, 2H, J = 8.0 Hz), 7.25 (bs,
4H); IR (cm-1): 1267, 1385, 1641, 2925, 3427; MS (FAB) (m/z): 160 (M+, 52%); Anal. Calcd for
C8H8N4: required C, 59.98; H, 5.03; N, 34.97. Found: C, 59.95; H, 5.10; N, 35.00.
2,7-Diamino-1,8-naphthyridine (14) from 12: To a stirred solution of sodium amide (1.086 g, 0.025
mol) in dry xylene (100 mL) compound 12 (1.0 g, 0.005 mol) was added and heated at 1300C under
nitrogen for 12 h. The precipitate obtained was filtered and poured onto ice to quench excess sodium
amide. Water was removed by distillation under reduced pressure and the solid was extracted with
methanol-chloroform (15:85) to afford the desired product 14 (0.21 g, 25%) identical in all respects
with the above.
2-Amino-7-benzylamino-1,8-naphthyridine (15): A suspension of 2-Amino-7-chloro-1,8-naphthyridine
(12, 0.175 g, 1.0 mmol), and distilled benzylamine (0.5 mL) was heated for 6h at 120 ºC. The sticky
precipitate was washed with water followed by acetone and it was then air-dried. The crude solid was
recrystallized from methanol which afforded pure compound 15 (0.118 g, 50%); m.p > 300 ºC;
1H-NMR (200 MHz) δ: 7.65-7.57 (m, 2H), 7.40-7.29 (m, 6H), 6.48 (d, 1H, J = 8.5 Hz), 6.38 (d, 1H, J
= 8.6 Hz), 5.60 (bs, 2H), 4.73 (d, 2H, J = 4.0 Hz); IR (cm-1): 1526, 1627, 1660, 3173, 3351; Anal.
Calcd for C15H14N4: required C, 71.97; H, 5.63; N, 22.38. Found: C, 71.90; H, 5.60; N, 22.42.
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Molecules 200X, Y
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Samples Availability: Available from the authors.
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