Synthesis of 10-phenyl-[1,2,4]triazolo[1,5-b] [2,7]naphthyridin-5(3H)-one derivatives

Article abstract of DOI:10.3184/174751914X13976543689677

Several new 10-phenyl-[1,2,4]triazolo[1,5-b][2,7]naphthyridin-5(3H)-one derivatives were synthesised by condensation of 2,3-diamino-4-phenyl-2,7- naphthyridin-1(2H)-one with aldehydes and also with acid anhydrides. Their structures were confirmed by

Full text of DOI:10.3184/174751914X13976543689677

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 MAY, 317–321
RESEARCH PAPER 317
Synthesis of 10‑phenyl‑[1,2,4]triazolo[1,5‑b] [2,7]naphthyridin‑5(3H)‑one
derivatives
Feng Xu, Zhen‑Zhen Yang, Li‑Min Xi, Jun‑Rong Jiang, Zhong‑Lu Ke and Han‑Gui Wu*
Biopharmaceutical Research and Development Centre, Taizhou Vocational & Technical College, Taizhou 318000, P.R. China
Several new 10‑phenyl‑[1,2,4]triazolo[1,5‑b][2,7]naphthyridin‑5(3H)‑one derivatives were synthesised by condensation of
2,3‑diamino‑4‑phenyl‑2,7‑naphthyridin‑1(2H)‑onewithaldehydesandalsowithacidanhydrides.Theirstructureswereconfirmed
by 1H NMR, 13C NMR, IR, mass spectra and elemental analysis. The key starting material 4‑[α‑cyano(phenyl)methyl]nicotinic
acid was easily cyclised to give 3‑amino‑4‑phenyl‑1H‑pyrano[3,4‑c]pyridin‑1‑one under alkaline conditions, the structure of
which was confirmed by X‑ray crystallography following conversion to the corresponding N,N‑dimethylformamidine derivative.
Keywords: triazole, naphthyridinone, crystal structure, synthesis of 10‑phenyl‑[1,2,4]triazolo[1,5‑b][2,7]naphthyridin‑5(3H)‑one
derivatives
Compounds containing the 2,7‑naphthyridin‑1(2H)‑one
skeleton have anti‑microbial,1 anticancer,2 renin‑inhibitory3
and vasorelaxant4 activities. Recently, some 2,7‑naphthyridin‑
1(2H)‑one derivatives were isolated from natural products. For
example, Gross et al.5 isolated a new marine algal alkaloid,
named lophocladine A, from a red alga, Lophocladia sp.,
which exhibited δ‑opioid receptor antagonist activity. Mukhtar
et al.4 isolated a new alkaloid, named neonaucline, from the
leaves of Ochreinauclea maingayii (Hook. f.) Ridsd, which
showed excellent vasorelaxant activity. Angustinine, a new
benzopyridoquinolizine alkaloid from Alangium lamarckii,
exhibited various physiological activities (Fig. 1).6
Although some syntheses of tricyclic structures containing
a 2,7‑naphthyridin‑1(2H)‑one unit have been reported,7–10 there
havebeenfewreportsonsyntheticroutesto[1,2,4]triazolo[1,5‑b]
[2,7]naphthyridin‑5(3H)‑one derivatives. There is only one
literature reported synthesis of [1,2,4]triazolo[1,5‑b][2,7]
naphthyridin‑5(3H)‑one derivatives from benzimidazo[1,2‑b]
[2,7]naphthyrid‑12‑ones in the presence of hydrazine hydrate
and potassium carbonate in N,N‑dimethylformamide.11
The drawback of this method is the difficulty of accessing
benzimidazo [1,2‑b][2,7]naphthyrid‑12‑ones. We describe here
a convenient synthetic route to 10‑phenyl‑[1,2,4] triazolo[1,5‑b]
[2,7] naphthyridin‑5(3H)‑one derivatives, which are the
derivatives of lophocladine A.
dimethyl sulfate in acetone at room temperature provided the
ester 2.12 Compound 2 was then treated with 80% hydrazine
hydrate at 80 °C for 30 min to yield 3. Different aromatic
aldehydes (4a–k) were cyclised with 3 in DMF at 130 °C to
form 6a–k; alternatively different acid anhydrides (5d, 5f, 5j,
5l–n) were reacted with 3 at 130 °C to yield 6d, 6f, 6j, 6l–n,
respectively.
The yields of 6g–k were high, and the reaction rate for 6g–k
(8–15 h) was much quicker than for 6a–e (20–40 h). One reason
could be the lack of conjugation between the naphthyridine
ring and the aromatic ring, which has an electron‑withdrawing
group. On the other hand, the yields of 6a–e were relatively
low because of an effective conjugation they have with the
aromatic ring, which has an electron‑donating group in the
intermediates which cyclise to compounds 6a–e. Because of
their higher reactivity, the reaction rate for aliphatic anhydrides
(5l–n) (5–10 h) was quicker than for the aryl anhydrides (5d, 5f
or 5j) (10–20 h).
In the IR spectra of 6, the most characteristic absorptions
were at 3130–3218 cm–1 (NH) and at 1617–1696 cm–1 (C=O).
1
In the H NMR spectra of compounds 6a–n, characteristic
signals due to the NH protons appeared at 12.64–13.20 ppm,
and signals due to the ring protons at the 6‑, 8‑ and 9‑positions
of the naphthyridine ring appeared at 9.02–9.20 ppm, 7.59–
7.84 ppm and 7.12–7.32 ppm, respectively. In the 13C NMR
spectra, the signals observed in the region of 156.2–156.6 ppm,
144.5–149.8 ppm and 108.9–110.0 ppm accounted for the
carbons at 6‑, 8‑ and 9‑positions of the naphthyridine ring,
respectively, and the signals observed in the region of 156.2–
156.7 ppm accounted for the C=O function at the 5‑position of
the naphthyridine ring.
Results and discussion
The reactions employed for the synthesis of 10‑phenyl‑[1,2,4]
triazolo[1,5‑b][2,7]naphthyridin‑5(3H)‑one derivatives 6 are
summarised in Scheme 1. Compound 1 was prepared from
the reaction of benzyl cyanide and 4‑chloronicotinic acid in
N‑methyl‑2‑pyrrolidinone (NMP) containing an excess of
potassium tert‑butoxide at 130 °C for 30 min. Subsequent
methylation of 1 with a stoichiometric amount of K2CO3 and
It was noted that 1 was unstable at room temperature and
slowly cyclised to compound 7 under alkaline conditions
(Scheme 2). However, according to the literature,12 the
H
O
H
O
MeO
N
O
NH
N
N
N
NH
N
O
O
O
lophocladines A
neonaucline
Angustinine
Fig. 1 Some 2,7‑naphthyridinones from natural products.
* Correspondent. E‑mail: taizhihaiyangkeji@ 126.com

318 JOURNAL OF CHEMICAL RESEARCH 2014
Ph
Ph
CN
COOH
CN
COOMe
l
C
COOH
ii
i
N
N
N
1
2
Ph
N
Ar
N
N
N
H
iv
Ph
O
NH2
NH2
6a-k
iii
N
N
Ph
v
N
O
R
3
N
N
N
H
O
6d, 6f, 6j, 6l-n
a:
f:
b:
c:
d:
e:
4-HO-3-MeOC6H3; 4-MeC6H4; 4-MeO-3-HOC6H3; 4-MeOC6H4; 2-HOC6H4;
g: h: i: j: k: l: m:
C6H5; 2,4-Cl2C6H3; 4-FC6H4; 2-ClC6H4; 4-ClC6H4; 4-NO2C6H4; Pr;
n:
Et; Me
Scheme 1 Synthesis of the compounds 6a–n. Reagents and conditions: (i) PhCH2CN, KOtBu, NMP, 130 °C; (ii) Me2SO4, K2CO3,
acetone, rt; (iii) 80% NH2NH2·H2O, 80 °C; (iv) ArCHO (4), DMF, 130 °C (v) (RCO)2O (5), DMF, 130 °C.
Ph
Ph
Ph
CN
COOH
CHN(CH3)2
N
NH2
(MeO)2CHN(CH3)2
CH2Cl2, rt
alkali
N
O
N
O
N
1
O
7
O
8
Ph
OH
NH
N
O
9
Scheme 2 Synthesis of compound 8.
AC500 (500 MHz) spectrometer. Compounds were dissolved in
DMSO‑d6, and chemical shifts were referenced to TMS. Mass spectra
were obtained on a Agilent 1260 Ion Trap LC‑MS 500 analysis system.
Elemental analyses were performed on a Thermo‑Finnigan Flash EA
1112 instrument. TLC was carried out on silica gel UV‑254 plates.
2,3-Diamino-4-phenyl-2,7-naphthyridin-1(2H)-one (3): Hydrazine
hydrate (50 mL, 80%, 824 mmol) was added to compound 2 (5.0 g,
20 mmol) at room temperature, the mixture was kept under magnetic
stirring for 10 min, then was warmed to 80 °C for 30 min. After
cooling to room temperature, the pale yellow solid that precipitated
was collected by filtration, washed with cold water, and dried under
reduced pressure at 60 °C. The product had a good purity and was used
in the next step without any purification after the usual workup. (4.0 g,
80%, m.p. 271–274 °C); νmax/cm–1 3436, 3264, 3023, 1670, 1588, 1511,
1320, 1184. 1H NMR (DMSO‑d6, 500 MHz) δ 9.07 (s, 1H, H‑8), 8.18(d,
1H, J=5.9 Hz, H‑6), 7.53–7.56 (m,2H, ArH),7.45–7.46 (m, 1H, ArH),
7.29–7.30 (m, 2H, ArH), 6.60(d,1H, J=5.9 Hz, H‑5), 6.24 (s, 2H, NH2),
5.68 (s, 2H, NH2); 13C NMR (DMSO‑d6, 125 MHz) δ 160.8, 150.6, 149.7,
149.3, 142.2, 134.5, 132.0 (2C), 130.0 (2C), 128.1, 114.6, 113.0, 92.0; ESI‑
MS, m/z (%): 253.2 [(M+H)+, 100]; Anal. calcd for C14H12N4O: C, 66.65;
H, 4.79; N, 22.21; O, 6.34; found: C, 66.67; H, 4.79; N, 22.20; O, 6.33%.
possible cyclisation by‑product was 3‑hydroxy‑4‑phenyl‑2,7‑
naphthyridin‑1(2H)‑one 9. The characterisation data from H
1
NMR, MS and elemental analysis for the by‑product could not
differentiate the isomers (compounds 7 and 9) which have the
same elemental composition and similar structures. Therefore,
we resorted to single‑crystal X‑ray diffraction to solve this
problem. It was found that 7 could be easily reacted with
N,N‑dimethylformamide dimethyl acetal in CH2Cl2 at room
temperature to yield 8 in good yield (Scheme 2). The structure
of 8 was confirmed by X‑ray crystallographic analysis. From
Fig. 2, it is obvious that the structure of 8 was N,N‑dimethyl‑N′‑
(1‑oxo‑4‑phenyl‑1H‑pyrano[3,4‑c]pyridin‑3‑yl)formamidine, a
derivative of compound 7. Therefore, we can conclude that the
structure of the by‑product was 7, not compound 9 as reported
in the literature.
Experimental
Melting points were carried out on a XRC‑1 apparatus and are
uncorrected (Beijing Technical Instrument Co.). IR spectra were
recorded for KBr discs of solid materials, on a Nicolex FI‑IR‑170
instrument. The 1H NMR and 13C NMR spectra were run on a Bruker

JOURNAL OF CHEMICAL RESEARCH 2014 319
2-(4-Methoxyphenyl)-10-phenyl-[1,2,4]triazolo[1,5-b][2,7]
naphthyridin-5(3H)-one (6d): Dark yellow solid; yield 62%,
m.p.>300 °C;νmax/cm–1 3137, 3061, 2965, 2832, 1676, 1606, 1543,
1
1326, 1247, 1163, 1026, 778; H NMR (DMSO‑d6, 500 MHz) δ 12.88
(br.s, 1H, NH), 9.07 (s, 1H, H‑6), 8.07(d, 2H, J=8.9 Hz, ArH), 7.63 (d,
1H, J=7.2 Hz, H‑8), 7.50–7.57 (m, 4H, ArH), 7.40 (t, 1H, J=7.1 Hz,
ArH), 7.17 (d, 1H, J=7.2 Hz, H‑9), 7.04 (d, 2H, J=8.9 Hz, ArH); 13C
NMR (DMSO‑d6, 125 MHz) δ 163.3, 161.2, 156.6, 156.3, 145.5, 135.3,
134.7, 131.4 (2C), 131.3, 129.0 (2C), 128.9 (2C), 128.8, 127.3 (2C), 127.2,
115.7, 109.1, 100.8, 55.7; ESI‑MS, m/z (%): 391.1 [(M+Na)+, 5], 371.2
[( M + H )+, 100], 369.1[(M+H)+, 2]; Anal. calcd for C22H16N4O2: C, 71.73;
H, 4.38; N, 15.21; O, 8.69; found: C, 71.75; H, 4.38; N, 15.20; O, 8.67%
2-(2-Hydroxyphenyl)-10 -phenyl-[1,2,4]triazolo[1,5-b]
[2,7]naphthyridin-5(3H)-one (6e): Yellow solid; yield 53%,
m.p.>300 °C;νmax/cm–1 3213, 3151, 3055, 2967, 2850, 1654, 1549,
1
1458, 1328, 1245, 1127, 1102, 772; H NMR (DMSO‑d6, 500 MHz) δ
13.20 (br.s, 1H, NH), 11.7 (s, 1H, OH), 9.20 (s, 1H, H‑6), 8.11 (d, 1H,
J=7.8 Hz, ArH), 7.76 (d, 1H, J=7.3 Hz, H‑8), 7.54–7.59 (m, 4H, ArH),
7.44(t, 1H, J=6.9 Hz, ArH), 7.37(t, 1H, J=7.8 Hz, ArH), 7.32(d, 1H,
J=7.3 Hz, H‑9), 6.98 (t, 1H, J=7.8 Hz, ArH), 6.95 (d, 1H, J=8.2 Hz,
ArH); 13C NMR (DMSO‑d6, 125 MHz) δ 162.8, 158.0, 156.2, 154.6,
145.2, 136.0, 134.6, 132.5, 131.3, 131.0 (2C), 129.1 (2C), 128.9,
127.8, 127.6, 119.6, 117.6, 116.1, 114.0, 109.7; ESI‑MS, m/z (%): 355.4
[( M + H )+,49]; Anal. calcd for C21H14N4O2: C, 71.18; H, 3.98; N, 15.81; O,
9.03; found: C, 71.19; H, 3.98; N, 15.80; O, 9.02%
Fig. 2 Molecular structure of compound 8 at the 50% probability level.
Synthesis of compounds (6a–k); general procedure
A
mixture of 2,3‑diamino‑4‑phenyl‑2,7‑naphthyridin‑1(2H)‑one
3 (1.0 g, 4.0 mmol) in DMF (30 mL) with the appropriate aromatic
aldehyde (4.1 mmol) was heated to 130 °C for 20–30 h during which
time the progress of the reaction was monitored by TLC (ethyl
acetate:ethanol 9:1). The reaction mixture was then cooled to
room temperature and concentrated under reduced pressure. Ethyl
acetate (10 mL) was then added to the residue and a yellow solid was
precipitated, collected by filtration and recrystallised from anhydrous
ethanol to give a pure product.
2-(4-Hydroxy-3-methoxyphenyl)-10-phenyl-[1,2,4]triazolo[1,5-b]
[2,7]naphthyridin-5(3H)-one (6a): Orange solid; yield 55%,
m.p.>300 °C. νmax/cm–1 3241, 3099, 2974, 2929, 1656, 1616, 1539, 1421,
1328, 1254, 1128, 778;1H NMR (DMSO‑d6, 500 MHz) δ 12.87 (br.s, 1H,
NH), 9.44 (s, 1H, OH), 9.06 (s, 1 H, H‑6), 7.51–7.64 (m, 7H, 6ArH+1,
H‑8), 7.40 (t, 1H, J=6.9 Hz, ArH), 7.15 (d, 1H, J=7.3 Hz, H‑9), 6.87(d,
1H, J=8.2 Hz, ArH), 3.86 (s, 3H, OCH3); 13C NMR (DMSO‑d6,
125 MHz) δ 163.4, 156.6, 156.4, 149.6, 147.1, 144.5, 135.2, 134.5, 131.3
(2C), 131.1, 128.9 (2C), 128.8, 127.0, 124.1, 115.7, 114.0, 112.3, 109.1,
101.3, 56.2; ESI‑MS, m/z (%): 407.1 [(M+Na)+, 13], 387.1 [(M+H)+,
60]; Anal. calcd for C22H16N4O3: C, 68.74; H, 4.20; N, 14.58; O, 12.49;
found: C, 68.77; H, 4.19; N, 14.55; O, 12.47%
2-(4-Methylphenyl)-10-phenyl-[1,2,4]triazolo[1,5-b][2,7]
naphthyridin-5(3H)-one (6b): Dark yellow solid; yield 60%,
m.p.>300 °C;νmax/cm–1 3050, 2974, 2929, 1667, 1616, 1534, 1442, 1329,
1256, 1133, 778; 1H NMR (DMSO‑d6, 500 MHz) δ 12.89 (br.s, 1H, NH),
9.07 (s, 1H, H‑6), 8.03 (d, 2H, J=8.1 Hz, ArH), 7.62 (d, 1H, J=7.3 Hz,
H‑8), 7.50–7.57 (m, 4H, ArH), 7.41 (t, 1H, J=6.9 Hz, ArH), 7.30 (d, 2H,
J=8.1 Hz, ArH), 7.16 (d, 1H, J=7.3 Hz, H‑9), 2.37 (s, 3H, CH3); 13C
NMR (DMSO‑d6, 125 MHz) δ 163.5, 156.6, 156.5, 144.5, 140.1, 135.1,
134.6, 131.3 (2C), 131.1, 129.7 (2C), 128.9 (2C), 128.6, 127.5 (2C), 127.4,
115.8, 109.0, 101.3, 21.5; ESI‑MS, m/z (%): 375.1 [(M+Na+), 57], 353.1
[( M + H+), 100]; Anal. calcd for C22H16N4O: C, 74.98; H, 4.58; N, 15.90;
O, 4.54; found: C, 75.01; H, 4.57; N, 15.89; O, 4.53%
2-(3-Hydroxy-4-methoxyphenyl)-10-phenyl-[1,2,4]triazolo[1,5-b]
[2,7]naphthyridin-5(3H)-one (6c): Dark yellow solid; yield 59%,
m.p.>300 °C;νmax/cm–1 3172, 3051, 2967, 2841, 1675, 1528, 1441, 1340,
1253, 1123, 1018, 776;1H NMR (DMSO‑d6, 500 MHz) δ 12.84 (br.s, 1H,
NH),9.26 (s, 1H, OH), 9.05 (s, 1H, H‑6), 7.48–7.61 (m, 7H, 6ArH+1
H‑8), 7.41(t, 1H, J=6.9 Hz,ArH), 7.15 (d, 1H, J=7.4 Hz, H‑9), 7.01
(d, 1H, J=8.3 Hz, ArH), 3.81 (s, 3H, OCH3); ESI‑MS, m/z (%): 407.1
[( M + Na)+, 3], 387.1 [(M+H)+, 50]; 13C NMR (DMSO‑d6, 125 MHz) δ
163.5, 156.6, 156.4, 149.8, 147.0, 144.5, 135.2, 134.5, 131.4(2C), 131.3,
128.9 (2C), 128.8, 127.3, 124.1, 115.7, 114.6, 112.5, 109.0, 101.1, 56.1;
Anal. calcd for C22H16N4O3: C, 68.74; H, 4.20; N, 14.58; O, 12.49; found:
C, 68.76; H, 4.19; N, 14.58; O, 12.48%
2,10-Diphenyl-[1,2,4]triazolo[1,5-b][2,7]naphthyridin-5(3H)-one
(6f): Orange solid; yield 81%, m.p.>300 °C;νmax/cm–1 3218, 3063,
1
2971, 2921, 1654, 1612, 1541, 1328, 1252, 1123, 1048, 772; H NMR
(DMSO‑d6, 500 MHz) δ 12.91 (br.s, 1H, NH), 9.09 (s, 1H, H‑6),
8.14–8.16 (m, 2H, ArH), 7.63(d, 1H, J=7.4 Hz, H‑8), 7.49–7.57 (m, 7H,
ArH), 7.42 (t, 1H, J=7.1 Hz, ArH), 7.19 (d, 1H, J=7.4 Hz, H‑9); 13
C
NMR (DMSO‑d6, 125 MHz) δ 163.5, 156.7, 156.6, 144.5, 135.1, 134.7,
131.4, 131.3 (2C), 131.1, 130.5, 129.2 (2C), 129.0 (2C), 127.5 (2C),
127.4, 115.8, 109.0, 101.3; ESI‑MS, m/z (%): 361.1 [(M+Na)+,98], 339.1
[( M + H )+,100]; Anal. calcd for C21H14N4O: C, 74.54; H, 4.17; N, 16.56;
O, 4.73; found: C, 74.55; H, 4.17; N, 16.55; O, 4.72%
2-(2,4-Dichlorophenyl)-10-phenyl-[1,2,4]triazolo[1,5-b]
[2,7]naphthyridin-5(3H)-one (6g): Yellow solid; yield 82%,
m.p.>300 °C;νmax/cm–1 3164, 3063, 2971, 2925, 1650, 1541, 1315, 1240,
1043, 776;1H NMR (CDCl3, 500 MHz) δ 12.97 (br.s, 1H, NH), 9.11
(s, 1H, H‑6), 7.94 (d, 1H, J=8.4 Hz, ArH), 7.78 (s, 1H, ArH), 7.66 (d,
1H, J=7.6 Hz, H‑8), 7.49–7.57 (m, 5H, ArH), 7.39 (t, 1H, J=7.3 Hz,
ArH), 7.23 (d, 1H, J=7.6 Hz, H‑9); 13C NMR (DMSO‑d6, 125 MHz)
δ 162.2, 156.7, 156.5, 144.5, 136.0, 135.3, 135.1, 134.6, 134.2, 132.7,
131.2 (2C), 131.1, 128.9 (2C), 128.5, 127.9, 127.5, 115.9, 109.1, 100.8;
ESI‑MS, m/z (%):408.0 [(M+2)+, 4]; 407.0 [(M+H)+, 6];Anal. calcd for
C21H12Cl2N4O: C, 61.93; H, 2.97; N, 13.76; O, 3.93; found: C, 61.95; H,
2.97; N, 13.74; O, 3.92%
2-(4-Fluorophenyl)-10-phenyl-[1,2,4]triazolo[1,5-b][2,7]
naphthyridin-5(3H)-one (6h): Red brown solid; yield 78%,
m.p.>300 °C;νmax/cm–1 3143, 3051, 2921, 2850, 1617, 1612, 1533, 1482,
1366, 1236, 1181, 774;1H NMR (DMSO‑d6, 500 MHz) δ 12.64 (br.s, 1H,
NH), 9.08 (s, 1H, H‑6), 8.18(dd, 2H, J=8.9 Hz, J=5.9 Hz, ArH), 7.65
(d, 1H, J=7.4 Hz, H‑8), 7.51–7.60 (m, 4H, ArH), 7.41 (t, 1H, J=7.0 Hz,
ArH), 7.32 (t, 2H, J=8.9 Hz, ArH), 7.18 (d, 1H, J=7.4 Hz, H‑9); 13C
NMR (DMSO‑d6, 125 MHz) δ 164.4(JC–F =292.1 Hz), 162.7, 156.6,
156.5, 144.7, 135.3, 134.8, 131.3 (2C), 131.1, 129.7 (2C) (JC–F =34.3 Hz),
128.9(2C) (JC–F =13.4 Hz), 128.8, 127.9 (JC–F =7.2 Hz), 127.4 (2C), 115.8,
109.1, 101.1; ESI‑MS, m/z (%): 379.1 [(M+Na)+,5], 359.1 [(M+H)+,16].
Anal. calcd for C21H13FN4O: C, 70.78; H, 3.68; N, 15.72; O, 4.49; found:
C, 70.76; H, 3.68; N, 15.74; O, 4.48%
2-(2- Chlorophenyl)-10 -phenyl-[1,2,4]t r ia zolo[1,5-b]
[2,7]naphthyridin-5(3H)-one (6i): Brown solid; yield 78%,
m.p.>300 °C;νmax/cm–1 3147, 3059, 2976, 2921, 1688, 1617, 1540,
1
1316, 1247, 1182, 1052, 804; H NMR (DMSO‑d6, 500 MHz) δ 12.94
(br.s, 1H, NH), 9.10 (s, 1H, H‑6), 7.88 (d, 1H, J=7.6 Hz, ArH), 7.65(d,
1H, J=7.4 Hz, H‑8), 7.60(d, 1H, J=7.9 Hz, ArH), 7.55–7.57 (m, 2H,
ArH), 7.49–7.52 (m, 3H, ArH), 7.46 (t, 1H, J=7.5 Hz, ArH), 7.39 (t, 1H,

320 JOURNAL OF CHEMICAL RESEARCH 2014
J=7.4 Hz, ArH), 7.23 (d, 1H, J=7.4 Hz, H‑9); 13C NMR (DMSO‑d6,
125 MHz) δ 162.2, 156.6, 156.4, 144.5, 136.0, 135.4, 135.3, 134.6, 132.7,
131.2 (2C), 131.1, 128.9 (2C), 128.6, 127.8, 127.6, 123.9, 115.8, 109.0,
101.3; ESI‑MS, m/z (%): 376.4 [(M+3)+,10], 375.3 [(M+2)+,43], 373.4
[( M + H )+,100]; Anal. calcd for C21H13ClN4O: C, 67.66; H, 3.51; N, 15.03;
O, 4.29; found: C, 67.68; H, 3.51; N, 15.01; O, 4.29%
2-Methyl-10-phenyl-[1,2,4]triazolo[1,5-b][2,7]naphthyridin-5(3H)-
one (6n): Orange solid; yield 51%, m.p. 245–248 °C (dec.) νmax/cm–1
3164, 2976, 2846, 1659, 1575, 1374, 1244, 1111, 1056, 701; H NMR
1
(DMSO‑d6, 500 MHz) δ 12.80 (br.s, 1H, NH), 9.05 (s, 1H, H‑6), 7.65
(d, 1H, J=7.1 Hz, H‑8), 7.46–7.51 (m, 4H, ArH), 7.37 (m, 1H, ArH),
7.14 (d, 1H, J=7.1 Hz, H‑9), 2.35 (s, 3H, CH3); 13C NMR (DMSO‑d6,
125 MHz) δ 167.3, 156.4, 144.8, 135.4, 134.5, 131.4, 131.3 (2C), 129.1,
128.9 (2C), 127.3, 115.5, 108.9, 100.5, 26.5; ESI‑MS, m/z (%):299.1
[( M + Na)+, 100], 277.2 [(M+H)+, 100]. Anal. calcd for C16H12N4O: C,
69.55; H, 4.38; N, 20.28; O, 5.79; found: C, 69.58; H, 4.37; N, 20.26; O,
5.78%.
2-(4 - Chlorophenyl)-10 -phenyl-[1,2,4]t r ia zolo[1,5-b]
[2,7]naphthyridin-5(3H)-one (6j): Brown solid; yield 85%,
m.p.>300 °C;νmax/cm–1 3147, 3055, 2967, 2925, 2846, 1653, 1542, 1328,
1
1248, 1128, 1093, 779; H NMR (DMSO‑d6, 500 MHz) δ 12.09 (br.s,
1H, NH), 9.19 (s, 1H, H‑6), 8.15 (d, 2H, J=8.5 Hz, ArH), 7.84 (d, 1H,
J=6.7 Hz, H‑8), 7.48–7.59 (m, 6H, ArH), 7.34 (t, 1H, J=7.4 Hz, ArH),
7.23 (d, 1H, J=6.7 Hz, H‑9); 13C NMR (DMSO‑d6, 125 MHz) δ 162.5,
156.6, 156.4, 148.1, 136.6, 135.4, 135.1, 131.3 (2C), 131.2, 129.2 (2C),
128.9 (2C), 128.6, 127.3 (2C), 127.1, 116.0, 110.0, 100.5; ESI‑MS, m/z
(%):376.3 [(M+3)+, 100], 375.3 [(M+2)+, 89], 373.4 [(M+H)+, 63];
Anal. calcd for C21H13ClN4O: C, 67.66; H, 3.51; N, 15.03; O, 4.29; found:
C, 67.63; H, 3.50; N, 15.05; O, 4.30%
3-Amino-4-phenyl-1H-pyrano[3,4-c]pyridin-1-one (7) A mixture
of 4‑[α‑cyano(phenyl)methyl]nicotinic acid 2 (1.0 g, 4.2 mmol) in
acetone (50 mL) and potassium carbonate (620 mg, 4.5 mmol) was
warmed to 50 °C for 2 h. The reaction mixture was then poured into
water (100 mL), a yellow solid was precipitated, collected by filtration,
washed with cold water, and recrystallised from anhydrous ethanol to
give a pure product (850 mg, 85%, m.p. 202–204 °C (dec.) νmax/cm–1
1
3302, 3160, 1734, 1643, 1587, 1441, 1301, 1182, 1045, 788; H NMR
2-(4-Nitrophenyl)-10-phenyl-[1,2,4]triazolo[1,5-b][2,7]
(DMSO‑d6, 500 MHz) δ 8.92 (s, 1H, H‑8), 8.28 (d, 1H, J=5.7 Hz, H‑6),
7.30–7.54 (m, 5H, ArH), 7.02 (s, 2H, NH2), 6.55 (d, 1H, J=5.7 Hz, H‑5);
13C NMR (DMSO‑d6, 125 MHz) δ 160.5, 158.3, 152.9, 151.8, 142.5,
132.8, 131.8 (2C), 129.9 (2C), 128.2, 114.5, 110.0, 88.7; ESI‑MS, m/z
(%): 239.3 [(M+H)+, 100]. Anal. calcd for C14H10N2O2: C, 70.58; H,
4.23; N, 11.76; O, 13.43; found: C, 70.61; H, 4.22; N, 11.74; O, 13.42%.
N,N-Dimethyl-N′-(1-oxo-4-phenyl-1H-pyrano[3,4-c]pyridin-3-yl)
formamidine (8) A mixture of 3‑amino‑4‑phenyl‑1H‑pyrano[3,4‑c]
pyridin‑1‑one 7 (2.0 g, 8.4 mmol) in CH2Cl2 (50 mL) with N,N‑
dimethylformamide dimethylacetal (1.79 mg, 13.4 mmol) was stirred at
naphthyridin-5(3H)-one
(6k):
Brown
solid;
yield
79%,
m.p.>300 °C;νmax/cm–1 3172, 3084, 2975, 2846, 1696, 1629, 1541, 1332,
1
1249, 1132, 1048, 776; H NMR (DMSO‑d6, 500 MHz) δ 13.02 (br.s,
1H, NH), 9.14 (s, 1H, H‑6), 8.39 (d, 2H, J=9.0 Hz, ArH), 8.35 (d, 2H,
J=9.0 Hz, ArH),7.68(d, 1H, J=7.3 Hz, H‑8), 7.53–7.58 (m, 4H, ArH),
7.42 (t, 1H, J=7.0 Hz, ArH), 7.21 (d, 1H, J=7.3 Hz, H‑9); 13C NMR
(DMSO‑d6, 125 MHz) δ 161.5, 156.7, 156.6, 149.1, 137.6, 135.4, 135.1,
131.4 (2C), 131.3, 129.0 (2C), 128.8, 128.6 (2C), 127.4 (2C), 127.3, 115.9,
109.1, 100.7; ESI‑MS, m/z (%): 385.4 [(M+2)+,10], 384.4 [(M+H)+,100];
Anal. calcd for C21H13N5O3: C, 65.79; H, 3.42; N, 18.27; O, 12.52; found:
C, 65.81; H, 3.42; N, 18.25; O, 12.51%
Synthesis of compounds (6d, 6f, 6j, 6l–n); general procedure
Table 1 Crystal data and experimental crystallographic details
A mixture of 2,3‑diamino‑4‑phenyl‑2,7‑naphthyridin‑1(2H)‑one 3
(0.5 g, 2.0 mmol) with the appropriate acid anhydride (20 mL) was
heated to 130 °C for 5–20 h during which time the progress of the
reaction was monitored by TLC (ethyl acetate:ethanol 9:1). After
cooling to room temperature, cold water (100 mL) and ethyl acetate
(20 mL) was added to the mixture. Concentrated hydrochloric acid
was then added dropwise to pH=1. After this the EtOAc phase was
discarded, and a saturated aqueous solution of K2CO3 was added to the
aqueous phase to pH=7, resulting in formation of an orange solid. The
solid was filtered off, washed thoroughly with water, and recrystallised
from anhydrous ethanol to give a pure product.
10-Phenyl-2-propyl-[1,2,4]triazolo[1,5-b][2,7]naphthyridin-5(3H)-
one (6l): Orange solid; yield 85%, m.p. 294–297 °C (dec.) νmax/cm–1
3155, 3055, 2963, 2867, 1684, 1617, 1541, 1395, 1332, 1249, 1178, 776;
1H NMR (DMSO‑d6, 500 MHz) δ 12.80 (br.s, 1H, NH), 9.02 (s, 1H,
H‑6), 7.59 (d, 1H, J=6.9 Hz, H‑8), 7.47–7.51 (m, 4H, ArH), 7.38 (m,
1H, ArH), 7.13(d, 1H, J=6.9 Hz, H‑9), 2.68(t, 2H, J=7.4 Hz, CH2),
1.72 (sext, 2H, J=7.4 Hz, CH2), 0.94 (t, 3H, J=7.4 Hz, CH3); 13C NMR
(DMSO‑d6, 125 MHz) δ 166.8, 156.5, 144.6, 135.1, 134.3, 131.5, 131.3
(2C), 129.0, 128.9 (2C), 127.3, 115.6, 108.9, 100.7, 30.8, 21.4, 14.3; ESI‑
MS, m/z (%): 327.1 [(M+Na)+,86], 305.1 [(M+H)+, 100];Anal. calcd for
C18H16N4O: C, 71.04; H, 5.30; N, 18.41; O, 5.26; found: C, 71.02; H, 5.29;
N, 18.43; O, 5.27%.
2-Ethyl-10-phenyl-[1,2,4]triazolo[1,5-b][2,7]naphthyridin-5(3H)-
one (6m): Orange solid; yield 77%, m.p. 279–282 °C (dec.) νmax/cm–1
3130, 3050, 2967, 2867, 1683, 1604, 1541, 1332, 1240, 1182, 1052, 818.
1H NMR (DMSO‑d6, 500 MHz) δ 12.79 (br.s, 1H, NH), 9.03 (s, 1H,
H‑6), 7.61 (d, 1H, J=7.0 Hz, H‑8), 7.46–7.51 (m, 4H, ArH), 7.38 (m, 1H,
ArH), 7.12 (d, 1H, J=7.0 Hz, H‑9), 2.73 (q, 2H, J=7.6 Hz, CH2), 1.26
(t, 3H, J=7.6 Hz, CH3); 13C NMR (DMSO‑d6, 125 MHz) δ 167.8, 156.5,
145.3, 135.4, 134.6, 131.3 (2C), 131.1, 129.0 (2C), 128.5, 127.2, 115.5,
109.0, 100.7, 27.4, 12.8; ESI‑MS, m/z (%): 313.1 [(M+Na)+,89], 291.1
[( M + H )+,100]; Anal. calcd for C17H14N4O: C, 70.33; H, 4.86; N, 19.30;
O, 5.51; found: C, 70.32; H, 4.86; N, 19.29; O, 5.52%.
Compound
Empirical formula
Formula weight
Temperature/K
Wavelength
Crystal system
Space group
a/Å
b/Å
c/Å
α/°
β/°
γ/°
Volume/Å3
Z
8
C17H15N3O2
293.32
153 (2)
λ=0.71073Å
triclinic
P
1
6.881(2)
9.768(2)
11.809(2)
93.539(14)
104.125 (10)
106.151(8)
732.1(3)
2
Density/calculated/Mg m–3
Absorption coefficient/mm−1
F000
Crystal size/mm
θ range for data collection/°
1.331
0.09
308
0.47×0.42×0.34
2.63–29.14
–8≤h≤9, –13≤k≤13,
–16≤l≤16
hkl range
Reflections collected
Unique/Rint
A
9185
3086 (0.0246)
0.0536
B
0.1160
Refinement method
Data/restraints/parameters
Goodness‑of‑fit on F2
Final R indices [I>2σ/I]
R indices (all data)
Largest diff. peak and hole/e Å−3
CCDC deposit no.
Full–matrix least–squares on F2
3852/0/201
0.999
R1 =0.0430,wR2 = 0.1054
R1 =0.0572, wR2 = 0.1136
0.260/–0.179
935919

JOURNAL OF CHEMICAL RESEARCH 2014 321
Table 2 Selected bond lengths (Å) and bond angles (°) of compound 8
O1–C6
O2–C6
N1–C1
N2–C5
N3–C16
C1–C2
C3–C7
C4–C5
C6–C7
C6–O1–C5
N2–C5–C4
C4–C5–O1
O2–C6–C7
1.3780 (13)
1.2069 (14)
1.3509 (16)
1.3557 (14)
1.4517 (16)
1.3722 (16)
1.4030 (16)
1.3680 (15)
1.4587 (15)
123.42 (9)
O1–C5
N1–C8
N2–C15
N3–C15
N3–C17
C2–C3
C3–C4
C4–C9
C7–C8
C15–N2–C5
N2–C5–O1
O2–C6–O1
O1–C6–C7
1.3873 (13)
1.3305 (15)
1.3071 (14)
1.3319 (15)
1.4551 (15)
1.4109 (15)
1.4344 (15)
1.4892 (15)
1.4000 (16)
120.78 (10)
116.40 (9)
122.21 (11)
121.37 (10)
126.67 (11)
117.06 (10)
116.27 (10)
Table 3 Bond lengths (Å) and angles (°) of hydrogen bonds and C–H‑‑‑π
interactions for compound 8.
d(D–H)
0.95(2)
0.98(2)
D–H⋅⋅⋅A
d(H⋅⋅⋅A)
2.43(3)
2.50(3)
2.81(2)
2.73(2)
d(D⋅⋅⋅A)
3.260(2)
3.389(2)
3.564(2)
3.589(2)
∠DHA
146
151
135
151
C(15)–H(15)⋅⋅⋅O(2)ii
C(17)–H(17A)⋅⋅⋅O(2)ii
Fig. 3 The crystal packing of 8 viewed down the a axis showing the
C–H···O intermolecular hydrogen bonds as dashed lines. Reagents and
conditions: (i) PhCH2CN, KOtBu, NMP, 130 °C; (ii) Me2SO4, K2CO3, acetone,
room temperature; (iii) 80% NH2NH2·H2O, 80 °C; (iv) ArCHO (4), DMF,
130 °C; (v) (RCO)2O (5), DMF, 130 °C.
C(17)–H(17C)‑‑‑Cg(1)iii 0.98(2)
C(1)–H(1)‑‑‑‑Cg(2)iv
0.95(2)
Symmetry codes: (ii) 2–x, 1–y, 1–z; (iii) 1–x, 1–y, 1–z; (iv) –x, 1–y, –z. Cg1
and Cg2 are centroids of pyridine ring and phenyl ring of compound 8,
respectively.
room temperature for 2 h. The reaction mixture was then concentrated
under reduced pressure. The crude residue was purified by column
chromatography (1:1 EtOAc:CH2Cl2) to afford 8 as a yellow solid
(2.34 g, 95%, m.p. 233–235 °C).νmax/cm–1 3064, 2924, 1723, 1631, 1577,
1491, 1398, 1117, 1022, 706; 1H NMR (DMSO‑d6, 500 MHz) δ 9.09 (s,
1H, H‑8), 8.48 (d, 1 H, J=5.7 Hz, H‑6), 8.32 (s, 1H, N=CH), 7.31–7.44
(m, 5H, ArH), 6.91 (d,1 H, J=5.7 Hz, H‑5), 3.12 (s, 3H, CH3), 2.80 (s,
3H, CH3); 13C NMR (DMSO‑d6, 125 MHz) δ 161.1, 156.0, 154.8, 153.4,
151.8, 146.9, 134.2, 131.7 (2C), 128.5 (2C), 127.4, 116.6, 113.1, 101.2,
34.7 (2C); ESI‑MS, m/z (%): 294.1 [(M+H)+,100]. Anal. calcd for
C17H15N3O2: C, 69.61; H, 5.15; N, 14.33; O, 10.91; found: C, 69.62; H,
5.15; N, 14.34; O, 10.89%
which forms six membered rings involving two molecules (Fig. 3,
Table 3). In addition, intermolecular π‑‑‑π[Cg1‑‑‑Cg1i = 3.692(2) Å;
symmetry code: (i)1–x,1–y,–z; Cg1 is centroid of the pyridine ring of
compound 8] and C–H‑‑‑π (Table 3) interactions further stabilise the
crystal structure.
The authors are indebted to the Program of Marine Biological
Resources Exploitation and Utilisation of Science and
Technology Innovation Team of Taizhou (Document of CPC
Taizhou Municipal Committee Office of Zhejiang Province
NO.(2012) 58), Biopharmaceutical R & D Centre, Taizhou
Vocational & Technical College.
X-ray crystallography
Received 19 January 2013; accepted 26 March 2014
Paper 1402409 doi: 10.3184/174751914X13976543689677
Published online: 6 May 2014
A yellow crystal of compound 8 was obtained by slow evaporation
from dichloromethane at room temperature. Diffraction data were
collected at 153 K by the ψ–ω scans technique, on a Rigaku AFC10
diffractometer with a Saturn724+ CCD detector using graphite‑
monochromated MoKα radiation from a rotating anode graphite source
(λ=0.71073 Å) using the CrystalClear program.13 The structures were
solved with SHELXS97 and refined with the full‑matrix least‑squares
procedure on F2 by SHELXL9714. Scattering factors incorporated
in SHELXL97 were used. The function ∑w(|Fo|2 –|Fc|2)2 was
minimised, with w–1 = [σ2(Fo)2 + (AP)2 + BP], where P= [Max(Fo2,0)+2
Fc/3].The final values of A and B are listed in Table 1 together with
relevant crystal data and refinement details. All non‑hydrogen atoms
were located in a difference Fourier map and refined anisotropically.
All hydrogen atoms located at geometrically calculated positions
and treated by a mixture of independent and constrained refinement.
Other details of the structures have been deposited with the Cambridge
Crystallographic Data Centre as deposition number CCDC 935919.
The packing view of 8 is shown in Fig. 3. The final values of A and B
are listed in Table 1 together with relevant crystal data and refinement
details. The selected bond lengths (Å) and bond angles (°) of compound
8 are shown in Table 2. The pyridine ring and pyranone ring are
almost coplanar within 0.02 Å. The atoms N2, N3, C15, C16 and C17
are almost coplanar within 0.01 Å. The pyranopyridine ring makes
dihedral angles of 6.31(2)° and 66.26(2)° with the N2/N3/C15/C16/
C17 chain and the phenyl ring, respectively. In the crystal structure,
intermolecular hydrogen bonds involving two directionally specific
C–H‑‑‑O interactions stabilise the packing along the [011] direction,
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