Naphthyridines. Part 3: First example of the polyfunctionally substituted 1,2,4-triazolo[1,5-g][1,6]naphthyridines ring system

Article abstract of DOI:10.1016/j.tet.2009.09.082

Treatment of 1,2,4-triazoles (1) with diethylmalonate in bromobenzene gave 1,2,4-triazolo-[1,5-a]pyridines 2. Chlorination of 2 using POCl₃/DMF (Vilsmeier reagent) led to the isolation of 7-chloro-6-formyl-1,2,4-triazolo[1,5-a]pyridine derivati

Full text of DOI:10.1016/j.tet.2009.09.082

Tetrahedron 65 (2009) 9843–9849
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Naphthyridines. Part 3: First example of the polyfunctionally substituted
1,2,4-triazolo[1,5-g][1,6]naphthyridines ring system
,
a
a
b
Ramadan Ahmed Mekheimer a , Yusria Rizk Ibrahim , Eltaib Ali Ahmed , Wolfgang Frey
*
a Department of Chemistry, Faculty of Science, El-Minia University, El-Minia 61519, Egypt
b Institute fu¨r Organische Chemie, Pfaffenwaldring 55, Universita¨t Stuttgart, D-70569 Stuttgart, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 May 2009
Received in revised form 30 August 2009
Accepted 17 September 2009
Available online 22 September 2009
Treatment of 1,2,4-triazoles (1) with diethylmalonate in bromobenzene gave 1,2,4-triazolo-
[1,5-a]pyridines 2. Chlorination of 2 using POCl3/DMF (Vilsmeier reagent) led to the isolation of
7-chloro-6-formyl-1,2,4-triazolo[1,5-a]pyridine derivative 4, which reacted with the stabilized ylid 5 to
afford 6-ethoxycarbonylvinyl-1,2,4-triazolo[1,5-a]-pyridines 6. Azidation of 6 yielded the correspond-
ing azido compound 7, (Scheme 2). Reduction of 7 with Na2S2O4 gave the corresponding 7-amino
compound 8, which cyclized in boiling DMF to give the novel 1,2,4-triazolo[1,5-g][1,6]naphthyridines
9. On the other hand, reacting 7 with one equivalent of PPh3 (aza-Wittig reaction) in CH2Cl2 gave
7-imino-phosphorane derivative 10, and subsequent cyclization in boiling DMF afforded the new
1,2,4-triazolo[1,5-g][1,6]naphthyridine derivative 11 (Scheme 3). However, treatment of 10 with phenyl
isothiocyanate in 1,2-dichlorobenzene at reflux temperature gave the new 1,2,4-triazolo[1,5-g]
[1,6]naphthyridine derivative 14 (Scheme 4). Refluxing 6 with excess of a primary amines 15a,b in
absolute. EtOH yielded the corresponding 7-alkyl-amino-1,2,4-triazolo[1,5-a]pyridines 16a,b. These
obtained amines 16a,b underwent intramolecular heterocyclization in boiling DMF to give the novel 9-
alkyl-1,2,4-triazolo[1,5-g][1,6]-naphthyridines 17a,b, in excellent yields (Scheme 5).
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
A series of novel 1,6-naphthyridine derivatives were prepared as
potential inhibitors of human topoisomerase I,26 anticonvulsive
1,2,4-Triazoles and their derivatives are important constitu-
ents of pharmacologically active compounds, as these systems
have demonstrated a broad spectrum of biological activities such
as antifungal,1–3 antiinflammatory,4–6 antibacterial,7–10 anticon-
vulsant,11,12 and anticancer13–16 activities. Several compounds
containing 1,2,4-triazole rings are well known as drugs. For ex-
ample, vorozole, letrozole, and anastrozole are non-steroidal
drugs used for the treatment of cancer,17 while loreclezole is used
as anticonvulsant18 and fluconazole is used as an antimicrobial
drugs.19 Furthermore, fused 1,2,4-triazoles have acquired con-
siderable importance because of their CNS depressant, anti-
allergy, antiinflammatory, and antimicrobial properties.20–23
1,6-Naphthyridine derivatives constitute an important class of
compounds possessing diverse types of biological properties.
Recently, 1,4-dihydro-4-oxo-1,6-naphthyridine derivatives have
been described as antibacterial agents.24 5-Substituted-8-
hydroxy-1,6-naphthyridine-7-carboxamides are useful as HIV
integrase inhibitors for the treatment of HIV infection (AIDS).25
agents,27 potential antimalarials,28 p38 mitogen-activated pro-
tein kinase inhibitors,29 and spleen tyrosine kinase inhibitors.30
Considerable attention has recently been focused on procedures
for the modification of 1,6-naphthyridine derivatives with the
aim of searching for new biological active compounds. With the
importance of these compounds in mind, we targeted the syn-
thesis of a system that combines these two biolabile components
together, viz. 1,2,4-triazole and 1,6-naphthyridine moieties, to
give a compact structure like the title compounds with the
expected significant biological activity.
Recently, we have been involved in the synthesis and chemistry
of novel naphthyridine derivatives with a prospect to incorporate
diverse bioactive heterocyclic nucleus intact for evaluating their
biological significance and also as a reagent for effective functional
group interconversion.31,32 To the best of our knowledge, there are
no reports on the synthesis of the title compounds.
As a continuation of our search for more potent naphthyridine
derivatives, we now report the first members of
a novel
heterosystem, 1,2,4-triazolo[1,5-g][1,6]naphthyridine derivatives
encompassing bioactive molecules, i.e., 1,2,4-triazole and 1,6-
naphthyridine. The 7-azidotriazolopyridines 7 appear to serve as
a good building block for these heterocycles.
* Corresponding author. Tel.: þ02 0109309076.
E-mail address: rmekh@yahoo.com (R.A. Mekheimer).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.082

9844
R.A. Mekheimer et al. / Tetrahedron 65 (2009) 9843–9849
Cl
CHO
O
N
N
EtS
EtS
N
O
CO2Et
CO2Et
N
N
Ph
CN
O
N
N
DMF
3
EtS
EtS
N
POCl3
70%
Ph Br/
66%
N
OH
CN
Ph
Ph
CN
CHO
Cl
1
N
2
N
N
Ph
CN
4
Scheme 1.
2. Results and discussion
The synthesis of this key intermediate 7 from the easily accessible
3-ethylthio-5-cyanomethyl-4-phenyl-1,2,4-triazole (1)33 is summa-
rized in Scheme 1. Beginning with the triazole 1, treatment with
diethylmalonate in bromobenzene at reflux temperature afforded
2-ethylthio-1,5-dihydro-7-hydroxy-5-oxo-1-phenyl-1,2,4-triazolo[1,
5-a]pyridine-8-carbo-nitrile (2). Reacting 2 with the Vilsmeir–Haack
reagent at 65–70 ꢀC for 6 h led directly to 7-chloro-6-formyl-1,2,4-
triazolo[1,5-a]pyridine derivative 4. The structure of 4 was identified
over the possible isomer 3 by the IR spectrum, which exhibited an
absorptionbandat1660 cmꢁ1 duetothe–C]Oforanamidecarbonyl
group. Treatment of 4 with an equimolar amount of [(ethoxy-
carbonyl)methylene]triphenyl-phosphorane (5) in CHCl3 at room
temperature gave 7-chloro-6-ethoxy-carbonylvinyl-2-ethylthio-1,5-
dihydro-5-oxo-1-phenyl-1,2,4-triazolo[1,5-a]pyridine-8-carbonitrile
(6) (Scheme 2). The 1H NMR spectrum included a characteristic AB
system (7.29 and 7.86 ppm, with a coupling constant J¼16 Hz) that
indicated a trans-configuration for the vinylic protons in this com-
pound. The structure of 6 was unambiguously confirmed by X-ray
crystallography.34 Compound 6 (figures, bottom-with X-ray num-
bering) was crystallized with two independent molecules (Molecules
A and B) in (Figs.1 and 2) the asymmetric unit of the space group P-1.
The molecules differ slightly in the orientation of their substituents,
which are attached to the flat bicyclic system. The angles between the
best plane through the atoms of the acrylicethylester side chain and
thebestplane throughtheatoms of thebicycliccoreare19.0(3)ꢀ (Mol.
A) and 35.9(3)ꢀ (Mol. B), respectively. The phenyl moiety shows
a nearly perpendicular orientation to the bicyclic system with angles
of 77.1(2)ꢀ (Mol. A) and 69.5(2)ꢀ (Mol. B), respectively. In contrast to
the expected results the positions of the oxygen O1A,B and the
chlorine Cl1A,B are reversed, clearly indicated by the distances of
C1A,B-O1A,B of 1.201(8) A and C3A,B-Cl1A,B of 1.728(7) A. The double
bond C6A,B-N1A,B of the triazole moiety is identified by the distance
of 1.299(9) A and the double bond C10A,B–C11A,B of the acrylic-
ethylester side chain is verified by the distance of 1.31(1) A.
Figure 1. Molecule A of the asymmetric unit of the X-ray structure.
the reaction product on the basis of its elemental analysis and
spectral data (MS, IR, 1H and 13C NMR) (see Experimental).
As the preparation of the novel tricyclic systems, namely 1,2,4-
triazolo[1,5-g]-[1,6]naphthyridines, is the main target of this
synthetic program, the 7-azido-1,2,4-triazolo-[1,5-a]pyridine de-
rivatives 7 was selected as a model compound for studying all
the reactions leading to the construction of novel tricyclic sys-
tems that incorporate a triazole nucleus in addition to naph-
thyridine moiety. As a model experiment, we first reacted 7 with
Na2S2O4. Thus, reduction of the azide moiety in 7 with Na2S2O4
furnished the corresponding 7-amino-triazolopyridines 8 in 96%
yield.
Azidation of 6 with sodium azide in DMF at room temperature
gave the corresponding 7-azidotriazolopyridine derivatives
7
(Scheme 2). The structure of 7 was established and confirmed for
H
CO2Et
O
O
PPh3
3
5
4
C
α
CO2Et
6
N
N
CHCl3 / rt
61%
NaN3
C
N
N
2
β
CH-CO2Et
5
H
4
EtS
EtS
7
DMF / rt
94%
N
N
1
8a
Cl
N3
8
Ph
Ph
CN
CN
7
6
Scheme 2.

R.A. Mekheimer et al. / Tetrahedron 65 (2009) 9843–9849
9845
Figure 2. Molecule B of the asymmetric unit of the X-ray structure.
Attention was next turned to the cyclization of amino com-
pound 8 to 1,2,4-triazolo-[1,5-g][1,6]naphthyridines 9. Thus, when
compound 8 was heated in DMF at reflux temperature, an intra-
molecular cyclization took place that led directly to the previously
unknown ring system 2-ethylthio-1,5,8,9-tetrahydro-5,8-dioxo-1-
phenyl-1,2,4-triazolo-[1,5-g][1,6]naphthyridine-10-carbonitrile (9)
(Scheme 3), in fair yield (62%).
(phenylamino)-1,2,4-triazolo-[1,5-g][1,6]naphthyridine-7-carboxy-
late (14) in 86% yield (Scheme 4). The formation of tricyclic
system 14 can be explained by an initial aza Wittig-type reaction
between the iminophosphorane group directly linked to the
heterocyclic ring and 1.25 equiv of the phenyl isothiocyanate to
give carbodiimide 12, as a highly reactive intermediate, which
undergoes intramolecular cyclization by nucleophilic attack of
The iminophosphoranes of heterocyclic compounds have
proved to be very versatile synthons for the construction of
heterocondensed systems through an aza-Wittig reaction in very
mild reaction conditions.35 Encouraged by this result, and given
our interest in developing synthetic approaches with a view to
synthesize new derivatives of the interesting tricyclic system
1,2,4-triazolo[1,5-g][1,6]naphthyridines, we next examined the
synthesis of iminophosphorane 10. Staudinger reaction of azide
7 with triphenylphosphine in CH2Cl2 at room temperature pro-
vided at the desired key intermediate iminophosphorane 10.
When iminophosphorane 10 was heated to reflux in dry DMF
for 40 h, an intramolecular aza-Wittig cyclization, involving an
ester functionality occurred to afford triphenylphosphine oxide
and the interesting heterocycle 1,2,4-triazolo[1,5-g][1,6]naph-
thyridine 11 (Scheme 3). The structure of 11 was established and
confirmed for the reaction product on the basis of its elemental
analysis and spectral data (see Experimental). On the other
hand, treatment of iminophosphorane 10 with phenyl iso-
thiocyanate in refluxing 1,2-dichlorobenzene for 4 h gave the
novel ethyl 10-cyano-2-ethylthio-1,5-dihydro-5-oxo-1-phenyl-8-
the b-carbon atom of the vinyl moiety on the central carbon of
H
CO2Et
CH CH
O
O
CO2Et
NPh
N
N
N
N
EtS
EtS
N
N
N
N
C
NPh
Ph
Ph
CN
13
CN
12
PhNCS
180 °C
O
O
CO2Et
CO2Et
NHPh
N
N
N
N
EtS
EtS
N
N
N
N=PPh3
Ph
Ph
CN
10
CN
14
(86%)
Scheme 4.
O
O
CO2Et
N
N
N
DMF/
N
O
Na2S2O4
EtS
EtS
-EtOH
62%
MeOH/H2O
96%
N
N
N
O
NH2
H
Ph
Ph
CN
8
CN
9
7
O
CO2Et
N
N
N
PPh3
N
DMF/
N
EtS
EtS
-O=PPh3
98%
CH2Cl2 / rt
88%
N
N=PPh3
N
OEt
Ph
Ph
CN
10
CN
11
Scheme 3.

9846
R.A. Mekheimer et al. / Tetrahedron 65 (2009) 9843–9849
O
O
O
RNH2
15a,b
CO2Et
CO2Et
N
N
N
N
N
N
DMF/
Δ
EtS
EtS
EtS
86-95%
abs. EtOH
Δ / 6h
86-93%
N
N
N
N
R
O
NHR
Cl
Ph
Ph
Ph
CN
16a,b
CN
6
CN
17a,b
15, 16, 17
R
a
b
isobutyl
butyl
Scheme 5.
the carbodiimide moiety to yield a further intermediate 13,
which then undergoes a proton shift to afford the final product
14 (see Scheme 4).
spectrometers with DMSO as solvent and TMS as an internal
standard. Chemical shifts are expressed in values (ppm).
d
We next considered the possibility that this design strategy
could be extended to the preparation of new derivatives of the
interesting triazolonaphthyridines of type 17, that are alkylated at
the heterocyclic nitrogen (i.e., at position 9). We attempted re-
action of the chloro compound 6 with alkylamines. Heating to
reflux compound 6 with an excess of alkylamines 15a,b in
absolute EtOH for 6 h gave in each case the corresponding
7-alkylamino-1,2,4-triazolo[1,5-a]-pyridines 16a,b. Only the (E)-
isomer was obtained for compounds 7, 8, 10, and 16a,b and in all
cases, the 1H NMR spectra included a characteristic AB system
that indicated the trans-configuration of vinylic protons in these
compounds (see Experimental). When compounds 16a,b were
heated in DMF at reflux temperature, an intramolecular hetero-
cyclization across the electrophilic ester functionality was oc-
curred to give the hitherto unknown fused tricyclic systems
17a,b, namely 9-alkyl-2-ethylthio-1,5,8,9-tetrahydro-5,8-dioxo-1-
phenyl-1,2,4-triazolo[1,5-g][1,6]naphthyridine-10-carbonitriles, as
new model system for 1,2,4-triazolonaphthyridines (Scheme 5).
Interestingly, a characteristic feature of the 1H NMR spectra of
compounds 17a,b was the downfield shift by approx. 0.90 ppm of
the N-CH2 signals caused by the anisotropic effect of the ring
nitrogen. From these results, we concluded that intramolecular
cyclocondensation between the amino and ester groups in 16a,b
occurred with the formation of the first example of a linear,
anellated 1,2,4-triazolo-[1,5-g][1,6]naphthyridines.
4.2. Synthesis of 2-ethylthio-1,5-dihydro-7-hydroxy-5-oxo-1-
phenyl-1,2,4-triazolo[1,5-a]-pyridine-8-carbonitrile (2)
A mixture of compound 1 (0.50 g, 2.046 mmol) and diethyl-
malonate (0.656 g, 4.095 mmol) in bromobenzene (5 mL) was
heated to reflux for 20 h, during, which a colorless solid product
separated out. After cooling to room temperature, the resulting
solid product was filtered off, washed with MeOH, dried, and
recrystallized from DMF to give compound 2 as colorless solid;
0.420 g (66%); mp 330–331 ꢀC, dec; IR (KBr) 3450, 3100, 2900,
2200, 1660 cmꢁ1; 1H NMR (300 MHz, DMSO-d6)
d 11.68 (1H, s, OH);
7.58–7.69 (5H, m, Ar-H), 5.50 (1H, s, H-6), 3.22 (2H, q, J¼7.2 Hz,
CH2), 1.36 (3H, t, J¼7.2 Hz, CH3); 13C NMR (75 MHz, DMSO-d6)
d
171.9 (C-7); 159.7 (C]O), 158.6 (C-8a), 151.8 (C-2), 137.5 136.7,
135.9, 135.7, 134.8, 134.0 (Ar-C), 117.0 (CN), 93.7 (C-6), 67.7 (C-8),
31.3 (CH2), 19.4 (CH3); MS m/z (%): 313 (Mþþ1, 17), 312 (Mþ, 100),
283 (5), 268 (6), 242 (25), 216 (5), 194 (4), 185 (7), 161 (9), 142 (7),
118 (14), 105 (19), 91 (6), 77 (50), 69 (16), 51 (16), 44 (7). Anal. Calcd
for C15H12N4O2S: C, 57.68; H, 3.87; N,17.94; S,10.27. Found: C, 57.78;
H, 3.69; N, 18.07; S, 10.19.
4.3. Synthesis of 7-chloro-2-ethylthio-6-formyl-1,5-
dihydro-5-oxo-1-phenyl-1,2,4-triazolo[1,5-a]
pyridine-8-carbonitrile (4)
Phosphoryl chloride (0.69 g, 4.50 mmol) was added dropwise to
cooled dimethyl-formamide (0.117 g, 1.603 mmol) at 0 ꢀC, and the
temperature of the reaction mixture was maintained at 0–5 ꢀC.
Compound 2 (0.20 g, 0.641 mmol) was added and the reaction
mixture was stirred at 65–70 ꢀC for 6 h. After cooling, the reaction
mixture was poured into cold H2O (20 mL). The obtained pre-
cipitate was filtered, washed with H2O, dried and recrystallized
from MeOH to give compound 4 as yellowish solid; 0.160 g (70ꢁ%1);
3. Conclusions
In summary, the results obtained in this third-generation ver-
sion of our annulation strategy have demonstrated for the first time
a new, simple and general methodology for the construction of
a wide variety of biologically important novel 1,2,4-triazolo[1,5-
g][1,6]-naphthyridines, obtainable only with difficulty otherwise.
Currently, further studies in our laboratory aimed at the synthesis
of new fused 1,2,4-triazolonaphthyridines are under investigation
and will be published in due course.
mp 250–251 ꢀC; IR (KBr) 3100, 2900, 2870, 2200, 1720, 1660 cm
;
1H NMR (300 MHz, DMSO-d6)
d 10.20 (1H, s, CHO), 7.70 (5H, m, Ar-
H), 3.33 (2H, q, J¼7 Hz, CH2), 1.42 (3H, t, J¼7 Hz, CH3); 13C NMR
(75 MHz, DMSO-d6) d 185.8 (CHO); 156.5 (CO),153.6 (C-7), 148.3 (C-
4. Experimental
4.1. General
8a), 147.2 (C-2), 132.2 129.9, 129.6, 128.6 (Ar-C), 110.8 (CN), 110.1 (C-
6), 75.1 (C-8), 26.5 (CH2), 14.1 (CH3); MS m/z (%): 360 (Mþ, 6), 358
(Mþ, 15), 330 (84), 295 (26), 271 (20), 243 (19), 119 (20), 77 (100), 51
(41), 27 (34). Anal. Calcd for C16H11ClN4O2S: C, 53.56; H, 3.09; Cl,
9.88; N, 15.61; S, 8.94. Found: C, 53.47; H, 2.88; Cl, 10.14; N, 15.49; S,
8.73.
Melting points were taken on a Gallenkamp apparatus and are
uncorrected. IR spectra were obtained with a Shimadzu 470 spec-
trophotometer as dispersions in KBr. Microanalyses were per-
formed by the microanalytical Data Unit at Cairo University, and
analytical values obtained were within ꢂ0.4% of the calculated
values. Mass spectra were registered on a Shimadzu GC–MS-QP
2010 instrument at 70 eV. 1H and 13C NMR spectra were recorded
on a Bruker-DPX-300 (300 MHz for 1H and 75 MHz for 13C) and Fa.
Bruker ARX500 (500.1 MHz for 1H NMR and 125.8 MHz for 13C)
4.4. Synthesis of 7-chloro-6-ethoxycarbonylvinyl-2-ethylthio-
1,5-dihydro-5-oxo-1-phenyl-1,2,4-triazolo[1,5-a]pyridine-8-
carbonitrile (6)
A mixture of 4 (0.50 g, 1.39 mmol) and 5 (0.485 g, 1.39 mmol) in
CHCl3 (10 mL) was stirred for 2 h at room temperature (25 ꢀC). The

R.A. Mekheimer et al. / Tetrahedron 65 (2009) 9843–9849
9847
mixture was evaporated to dryness in vacuo. MeOH (3 mL) was
4.7. 2-Ethylthio-1,5,8,9-tetrahydro-5,8-dioxo-1-phenyl-1,2,4-
added to the remaining oily residue with scratching. The pre-
cipitated solid product was collected by filtration, washed with cold
MeOH, dried and recrystallized from MeOH to give compound 6 as
yellowish solid; 0.366 g (61%); mp 184–185 ꢀC; IR (KBr) 3100, 2970,
triazolo[1,5-g][1,6]naphthyridine-10-carbonitrile (9)
A solution of compound 8 (0.20 g, 0.488 mmol) in DMF (7 mL)
was heated under reflux for 110 h. Afterconcentration and cooling to
room temperature, a small amount of EtOH (2 mL) was added. Then,
the resulting solid product was collected by filtration, dried, and
recrystallized from EtOH to give compound 9 as buff solid; 0.110 g
(62%); mp 302–303 ꢀC; IR (KBr) 3450, 3050, 2950, 2900, 2200,1680,
2930, 2220, 1710, 1680 cmꢁ1 1H NMR (500 MHz, DMSO-d6)
; d 7.86
(1H, d, J¼16 Hz, ]CH), 7.70 (5H, m, Ar-H), 7.29 (1H, d, J¼16 Hz,
CH]), 4.20 (2H, q, J¼7 Hz, CH2), 3.32 (2H, q, J¼7 Hz, CH2), 1.41 (3H,
t, J¼7 Hz, CH3), 1.25 (3H, t, J¼7 Hz, CH3); 13C NMR (125.8 MHz,
DMSO-d6)
d
166.9 (CO, ester), 156.0 (CO, amide), 151.9 (C-8a), 146.2
1660 cmꢁ1; 1H NMR (500 MHz, DMSO-d6)
d 11.34 (1H, br s, NH), 8.14
(C-2), 145.5 (C-7), 136.1 (Ca), 132.1, 129.9, 129.7, 128.6 (Ar-C), 119.7
(C-6), 111.5 (CN), 109.1 (Cb), 73.4 (C-8), 60.0 (CH2), 26.3 (CH2), 14.1
(2CH3); MS m/z (%): 430 (Mþ, 9), 428 (Mþ, 13), 393 (12), 355 (100),
327 (41), 295 (22), 267 (16), 240 (11), 231 (12), 205 (21), 88 (17), 77
(81), 51 (62), 50 (29). Anal. Calcd for C20H17ClN4O3S: C, 56.01; H,
4.00; Cl, 8.27; N, 13.06; S, 7.48. Found: C, 56.19; H, 3.87; Cl, 8.38; N,
12.88; S, 7.67.
(1H, d, J¼9 Hz, H-6), 7.68 (5H, m, Ar-H), 6.37 (1H, d, J¼9 Hz, H-7), 3.28
(2H, q, J¼7 Hz, CH2), 1.41 (3H, t, J¼7.6 Hz, CH3); 13C NMR (75 MHz,
DMSO-d6)
d 162.0 (CO), 156.6 (CO), 152.2 (C-10a), 148.5 (C-2), 147.3
(C-9a),136.7 (C-6), 131.6,130.5, 129.7, 128.9 (Ar-C), 122.7 (C-7), 115.2
(CN),113.6 (C-5a), 61.3 (C-10), 26.3 (CH2),14.2 (CH3); MS m/z (%): 364
(Mþþ1, 46), 363 (Mþ,100), 361 (16), 335 (22),109 (6), 92 (4), 77 (28),
64 (10), 52 (8), 51 (22). Anal. Calcd for C18H13N5O2S: C, 59.49; H, 3.61;
N, 19.27; S, 8.82. Found: C, 59.32; H, 3.52; N, 19.43; S, 9.05.
4.5. Synthesis of 7-azido-6-ethoxycarbonylvinyl-2-ethylthio-
1,5-dihydro-5-oxo-1-phenyl-1,2,4-triazolo[1,5-a]pyridine-8-
carbonitrile (7)
4.8. Synthesis of 6-ethoxycarbonylvinyl-2-ethylthio-1,5-
dihydro-5-oxo-1-phenyl-7-[(triphenylphosphoranylidene)-
amino]-1,2,4-triazolo[1,5-a]pyridine-8-carbonitrile (10)
Sodium azide (0.060 g, 0.932 mmol) was added to a solution of 6
(0.20 g, 0.466 mmol) in DMF (5 mL) and the mixture was stirred for
3 h at room temperature (25 ꢀC). Then, the reaction mixture was
poured into H2O (10 mL) and the precipitated solid product was
collected by filtration, washed well with H2O, dried, and recrys-
tallized from CHCl3 to give compound 7 as yellowish solid; 0.190 g
(94%); mp 164–166 ꢀC, dec; IR (KBr) 3100, 2950, 2220, 2130, 1710,
A mixture of the azide 7 (0.130 g, 0.30 mmol) and triphenyl-
phosphine (0.078 g, 0.30 mmol) in CH2Cl2 (5 mL) was stirred for 2 h
at room temperature. After concentration, the resulting solid
product was filtered off, washed with a small amount of EtOH,
dried, and recrystallized from CHCl3 to give 10 as yellow solid;
0.176 g (88%); mp 254–255 ꢀC; IR (KBr) 3050, 2990, 2940, 2220,
1690, 1670 cmꢁ1 1H NMR (300 MHz, DMSO-d6)
; d 7.85 (1H, d,
1680 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6)
d
7.82 (1H, d, J¼16 Hz,
J¼16 Hz, ]CH), 7.49–7.67 (20H, m, Ar-H), 6.75 (1H, d, J¼16 Hz,
CH]), 3.95 (2H, q, J¼7 Hz, CH2), 3.22 (2H, q, J¼7 Hz, CH2), 1.37 (3H,
t, J¼7 Hz, CH3), 1.07 (3H, t, J¼7 Hz, CH3); 13C NMR (75 MHz, DMSO-
]CH), 7.69 (5H, m, Ar-H), 7.15 (1H, d, J¼16 Hz, CH]), 4.17 (2H, q,
J¼7 Hz, CH2), 3.30 (2H, q, J¼7.2 Hz, CH2), 1.41 (3H, t, J¼7.2 Hz, CH3),
1.25 (3H, t, J¼7.2 Hz, CH3); 13C NMR (75 MHz, DMSO-d6)
d 167.2 (CO,
d6)
d 167.7 (CO, ester); 161.7 (CO, amide), 153.6 (C-8a), 152.4 (C-7),
ester), 155.7 (CO, amide), 152.6 (C-8a), 147.9 (C-2), 145.8 (C-7), 134.8
(Ca), 132.0, 129.8, 129.6, 128.7 (Ar-C), 117.9 (C-6), 110.2 (CN), 103.4
(Cb), 67.0 (C-8), 60.0 (CH2), 26.3 (CH2), 14.1 (2CH3); MS m/z (%): 407
(Mþ-N2, 92), 406 (10), 378 (5), 362 (26), 361 (100), 333 (18), 305
(13), 280 (3), 276 (14), 249 (2), 77 (31), 51 (16). Anal. Calcd for
C20H17N7O3S: C, 55.16; H, 3.93; N, 22.52; S, 7.36. Found: C, 55.33; H,
4.12; N, 22.67; S, 7.19.
146.0 (C-2), 140.0 (Ca), 132.3, 132.2, 132.1, 131.2, 130.6, 130.1, 129.4,
128.8, 128.7, 128.6 (Ar-C), 114.6 (Cb), 112.3 (CN), 103.7 (3Jcp¼7.1 Hz,
C-6), 70.8 (3Jcp¼10.6 Hz, C-8), 58.7 (CH2), 26.1 (CH2), 14.2 (2CH3);
MS m/z (%): 670 (Mþþ1, 4), 669 (Mþ, 7), 596 (20), 569 (5), 391 (23),
376 (16), 363 (25), 336 (11), 334 (19), 277 (36), 262 (100), 261 (28),
201 (16), 183 (33), 171 (5), 152 (10), 109 (9), 108 (16), 107 (13), 103
(9), 77 (22), 61 (7), 51 (6). Anal. Calcd for C38H32N5O3PS: C, 68.15; H,
4.82; N, 10.46; S, 4.79. Found: C, 68.24; H, 4.64; N, 10.59; S, 4.95.
4.6. Synthesis of 7-amino-6-ethoxycarbonylvinyl-2-ethylthio-
1,5-dihydro-5-oxo-1-phenyl-1,2,4-triazolo[1,5-a]pyridine-8-
carbonitrile (8)
4.9. Synthesis of 8-ethoxy-2-ethylthio-1,5-dihydro-5-oxo-1-
phenyl-1,2,4-triazolo[1,5-g]-[1,6]naphthyridine-10-
carbonitrile (11)
Sodium dithionite (0.40 g, 2.30 mmol) was added portion wise
to a stirred suspension of 7 (0.20 g, 0.459 mmol) in a 2:1 MeOH/
H2O (30 mL) mixture. Stirring was maintained at room temperature
for 2 h, during this period of time a yellow solid product was
formed. Then, the reaction mixture was poured into H2O (15 mL).
The resulting solid product was collected by filtration, washed well
with H2O, dried, and recrystallized from CHCl3 to give compound 8
as yellowish solid; 0.180 g (96%); mp 261–262 ꢀC; IR (KBr) 3350,
3200, 3050, 2980, 2900, 2200, 1690, 1660 cmꢁ1; 1H NMR (500 MHz,
A solution of compound 10 (0.20 g, 0.299 mmol) in dry DMF
(7 mL) was heated to reflux for 40 h. After concentration and
cooling to room temperature, MeOH (3 mL) was added. The pre-
cipitated solid product was collected by filtration, dried, and
recrystallized from EtOH to give compound 11 as yellow solid;
0.115 g (98%), mp 230–232 ꢀC; IR (KBr) 3070, 2975, 2910, 2210,
1667 cmꢁ1; 1H NMR (500 MHz, DMSO-d6)
d
8.43 (1H, d, J¼9 Hz, H-
6), 7.67–7.78 (5H, m, Ar-H), 6.80 (1H, d, J¼9 Hz, H-7), 4.43 (2H, q,
DMSO-d6)
d
7.78 (1H, d, J¼15 Hz, ]CH), 7.65 (5H, m, 5Ar-H), 7.12
J¼7 Hz, CH2), 3.29 (2H, q, J¼7 Hz, CH2), 1.42 (3H, t, J¼7 Hz, CH3),1.35
(1H, d, J¼15 Hz, CH]), 6.97 (2H, s, NH2), 4.14 (2H, q, J¼7 Hz, CH2),
3.24 (2H, q, J¼7 Hz, CH2), 1.34 (3H, t, J¼7 Hz, CH3), 1.25 (3H, t,
(3H, t, J¼7 Hz, CH3); 13C NMR (75 MHz, DMSO-d6)
d 162.2 (C-8),
156.5 (CO), 151.5 (C-10a), 150.9 (C-9a), 148.3 (C-2), 137.4 (C-6), 131.6,
130.3, 129.6, 128.8 (Ar-C), 115.6 (CN), 107.2 (C-7), 104.6 (C-5a), 61.0
(C-10), 59.8 (CH2), 26.2 (CH2), 14.5 (CH3), 14.1 (CH3); MS m/z (%):
392 (Mþþ1, 36), 391 (Mþ, 100), 390 (25), 378 (18), 377 (29), 376
(99), 375 (16), 365 (18), 364 (15), 363 (76), 362 (18), 350 (7), 348
(25), 347 (23), 346 (9), 334 (24), 316 (10), 290 (7), 278 (9), 260 (7),
246 (7), 206 (10), 109 (16), 77 (84), 64 (15), 51 (32). Anal. Calcd for
C20H17N5O2S: C, 61.37; H, 4.38; N, 17.89; S, 8.19. Found: C, 61.19; H,
4.49; N, 18.01; S, 8.26.
J¼7 Hz, CH3); 13C NMR (125.8 MHz, DMSO-d6)
d 168.0 (CO, ester);
156.0 (CO, amide), 153.8 (C-7), 153.1 (C-8a), 146.0 (C-2), 136.7 (Ca),
131.6, 130.4, 129.6, 128.8 (Ar-C), 113.4 (Cb), 112.6 (CN), 93.0 (C-6),
60.2 (C-8), 59.1 (CH2), 26.1 (CH2), 14.3 (CH3), 14.2 (CH3); MS m/z (%):
410 (Mþþ1, 14), 409 (Mþ, 29), 364 (12), 338 (14), 337 (70), 336
(100), 309 (11), 308 (15), 307 (19), 276 (7), 77 (27), 51 (12). Anal.
Calcd for C20H19N5O3S: C, 58.67; H, 4.68; N, 17.10; S, 7.83. Found: C,
58.86; H, 4.51; N, 17.19; S, 8.04.

9848
R.A. Mekheimer et al. / Tetrahedron 65 (2009) 9843–9849
4.10. Synthesis of ethyl 10-cyano-2-ethylthio-1,5-dihydro-5-
oxo-1-phenyl-8-(phenyl-amino)-1,2,4-triazolo[1,5-
g][1,6]naphthyridine-7-carboxylate (14)
DMSO-d6) d 168.0 (CO, ester), 156.9 (CO, amide), 153.5 (C-7), 152.8
(C-8a), 146.8 (C-2), 137.2 (Ca), 131.3, 130.8, 129.4, 128.8 (Ar-C), 114.0
(Cb), 113.6 (CN), 95.7 (C-6), 60.9 (C-8), 59.3 (CH2), 43.8 (CH2), 30.7
(CH2), 26.3 (CH2), 18.4 (CH2), 14.3 (CH3), 14.2 (CH3), 13.4 (CH3); MS
m/z (%): 466 (Mþþ1, 13), 465 (Mþ, 14), 424 (17), 423 (40), 422 (67),
421 (10), 420 (18), 419 (18), 403 (18), 393 (51), 392 (67), 391 (8), 380
(18), 379 (30), 378 (100), 377 (18), 376 (17), 375 (13), 364 (41), 363
(71), 362 (10), 350 (21), 349 (26), 348 (87), 337 (13), 336 (22), 335
(24), 334 (17), 320 (25), 308 (11), 288 (16), 77 (47), 55 (15), 51 (17).
Anal. Calcd for C24H27N5O3S: C, 61.92; H, 5.85; N, 15.04; S, 6.89.
Found: C, 62.07; H, 5.66; N, 15.25; S, 7.09.
A mixture of compound 10 (0.20 g, 0.299 mmol) and phenyl
isothiocyanate (0.05 g, 0.370 mmol) in 1,2-dichlorobenzene (5 mL)
was heated to reflux for 4 h. After concentration and cooling to
room temperature, the resulting solid product was collected by
filtration, washed with MeOH, dried, and recrystallized from MeOH
to give compound 14 as greenish solid; 0.130 g (86%); mp 301–
302 ꢀC; IR (KBr) 3260, 3050, 2990, 2200, 1690, 1670 cmꢁ1; 1H NMR
(500 MHz, DMSO-d6) d 10.65 (1H, s, NH), 8.82 (1H, s, H-6), 7.94 (2H,
d, J¼8 Hz, Ar-H), 7.74 (5H, m, Ar-H), 7.25 (2H, t, J¼8 Hz, Ar-H), 7.05
(1H, t, J¼8 Hz, Ar-H), 4.31 (2H, q, J¼7 Hz, CH2), 3.28 (2H, q, J¼7 Hz,
CH2), 1.41 (3H, t, J¼7 Hz, CH3), 1.37 (3H, t, J¼7 Hz, CH3); 13C NMR
4.12. General procedure for the synthesis of 9-alkyl-2-
ethylthio-1,5,8,9-tetrahydro-5,8-dioxo-1-phenyl-1,2,4-
triazolo[1,5-g][1,6]naphthyridine-10-carbonitriles 17a,b
(75 MHz, DMSO-d6) d 165.8 (CO, ester), 155.4 (CO, amide), 155.1 (C-
9a), 154.9 (C-8), 152.8 (C-10a), 148.2 (C-2), 140.5 (C-6), 131.5, 130.3,
129.6,128.7,128.4,123.0,120.6 (Ar-C),112.5 (CN),105.6 (C-5a),105.3
(C-7), 69.1 (C-10), 61.4 (CH2), 26.2 (CH2), 14.0 (CH3), 13.8 (CH3); MS
m/z (%): 511 (Mþþ1, 28), 510 (Mþ, 100), 509 (18), 466 (14), 465 (14),
464 (50), 438 (16), 437 (52), 436 (22), 350 (10), 92 (3), 77 (66), 61
(7), 51 (21); Anal. Calcd for C27H22N6O3S: C, 63.52; H, 4.34; N, 6.46;
S, 6.28. Found: C, 63.69; H, 4.18; N, 16.35; S, 6.19.
A solution of compounds 16a,b (0.20 g, 0.430 mmol) in DMF
(10 mL) was heated to reflux for 40 h. After concentration and
cooling to room temperature, H2O (10 mL) was added and the
resulting solid product was collected by filtration, washed with H2O
and dried to give compound 17a. In the case of 17b, the reaction
mixture was refluxed for 125 h and then it was worked up as de-
scribed for 17a.
4.11. General procedure for the synthesis of 7-alkylamino-6-
ethoxycarbonylvinyl-2-ethylthio-1,5-dihydro-5-oxo-1-phenyl-
1,2,4-triazolo[1,5-a]pyridine-8-carbonitrile 16a,b
4.12.1. 9-Isobutyl-2-ethylthio-1,5,8,9-tetrahydro-5,8-dioxo-1-phenyl-
1,2,4-triazolo[1,5-g]-[1,6]naphthyridine-10-carbonitrile
(17a). Yellowish solid; 0.155 g (86%); mp 126–127 ꢀC, dec (from
CHCl3); IR (KBr) 3050, 2950, 2850, 2200, 1660 cmꢁ1 1H NMR
;
A mixture of compound 6 (0.140 g, 0.33 mmol) and alkylamines
15a,b (0.096 g, 1.31 mmol) in absolute EtOH (10 mL) was heated to
reflux for 6 h, until TLC showed the disappearance of the starting
compounds. After concentration and cooling to room temperature,
the resulting solid product was collected by filtration, washed with
EtOH, dried, and recrystallized from CHCl3 to give compounds 16a,b.
(500 MHz, DMSO-d6)
d
8.07 (1H, d, J¼10 Hz, H-6), 7.61–7.68 (5H, m,
Ar-H), 6.30 (1H, d, J¼10 Hz, H-7), 4.13 (2H, br, CH2), 3.20 (2H, q,
J¼7 Hz, CH2), 1.89 (1H, m, aliph. CH), 1.37 (3H, t, J¼7 Hz, CH3), 0.87
(6H, d, J¼6 Hz, 2CH3); 13C NMR (75 MHz, DMSO-d6)
d 162.1 (CO),
156.3 (CO),152.1 (C-10a), 148.4 (C-2), 147.2 (C-9a),136.6 (C-6), 131.4,
130.9, 129.6, 128.8 (Ar-C), 115.0 (CN), 113.5 (C-5a), 101.8 (C-7), 60.9
(C-10), 54.7 (CH2), 28.9 (aliph. CH), 26.3 (CH2), 19.7 (2CH3), 14.1
(CH3); MS m/z (%): 420 (Mþþ1, 24), 419 (Mþ, 21), 367 (18), 364 (25),
363 (62), 347 (28), 336 (14), 335 (31), 334 (22), 324 (18), 318 (23),
311 (75), 310 (25), 283 (17), 282 (22), 266 (15), 262 (16), 235 (13),
181 (11), 179 (14), 142 (11), 120 (14), 118 (16), 109 (18), 105 (12), 96
(15), 91 (18), 77 (100), 64 (17), 63 (13), 61 (11), 57 (14), 55 (8), 53
(20), 52 (18), 51 (41), 50 (24). Anal. Calcd for C22H21N5O2S: C, 62.99;
H, 5.05; N, 16.69; S, 7.64. Found: C, 62.78; H, 5.19; N, 16.82; S, 7.47.
4.11.1. 7-(Isobutylamino)-6-ethoxycarbonylvinyl-2-ethylthio-1,5-di-
hydro-5-oxo-1-phenyl-1,2,4-triazolo[1,5-a]pyridine-8-carbonitrile
(16a). Yellowish solid; 0.142 g (93%); mp 122–124 ꢀC, dec; IR (KBr)
3350, 3050, 2950, 2900, 2850, 2200, 1680, 1660 cmꢁ1 1H NMR
;
(500 MHz, DMSO-d6)
d
7.84 (1H, d, J¼15 Hz, ]CH), 7.62 (5H, m, Ar-
H), 7.05 (1H, d, J¼15 Hz, CH]), 6.91 (1H, t, J¼5 Hz, NH), 4.14 (2H, q,
J¼7 Hz, CH2), 3.23 (4H, m, 2CH2), 1.89 (1H, m, aliph. CH), 1.38 (3H, t,
J¼7 Hz, CH3), 1.24 (3H, t, J¼7 Hz, CH3), 0.84 (6H, d, J¼6 Hz, 2CH3);
13C NMR (75 MHz, DMSO-d6)
d 168.1 (CO, ester), 156.9 (CO, amide),
4.12.2. 9-Butyl-2-ethylthio-1,5,8,9-tetrahydro-5,8-dioxo-1-phenyl-
1,2,4-triazolo[1,5-g][1,6]-naphthyridine-10-carbonitrile
(17b). Yellowish solid; 0.171 g (95%); mp 130–132 ꢀC (from MeOH);
153.6 (C-7), 152.9 (C-8a), 146.8 (C-2), 137.2 (Ca), 131.4, 130.7, 129.5,
128.8 (Ar-C), 114.0 (Cb), 113.7 (CN), 95.7 (C-6), 61.0 (C-8), 59.2 (CH2),
53.6 (CH2), 28.8 (aliph. CH), 26.3 (CH2), 19.6 (2CH3), 14.3 (CH3), 14.2
(CH3); MS m/z (%): 466 (Mþþ1, 12), 465 (Mþ, 19), 422 (73), 394 (26),
393 (24), 392 (51), 380 (13), 379 (18), 378 (60), 377 (16), 364 (37),
363 (38), 350 (54), 349 (40), 348 (100), 336 (52), 335 (19), 334 (18),
321 (31), 320 (34), 311 (32), 309 (15), 307 (22), 302 (15), 295 (13),
290 (13), 288 (15), 275 (15), 262 (18), 232 (18), 193 (13), 179 (15),
168 (14), 145 (6), 136 (16), 118 (19), 105 (16), 104 (16), 100 (6), 92
(11), 91 (18), 77 (82), 73 (4), 66 (15), 64 (16), 61 (15), 57 (23), 56 (14),
55 (23), 51 (42), 50 (17). Anal. Calcd for C24H27N5O3S: C, 61.92; H,
5.85; N, 15.04; S, 6.89. Found: C, 62.11; H, 5.78; N, 14.88; S, 6.76.
IR (KBr) 3050, 2960, 2850, 2200, 1660 cmꢁ1 1H NMR (500 MHz,
;
DMSO-d6)
d
8.13 (1H, d, J¼10 Hz, H-6), 7.66 (5H, m, Ar-H), 6.40 (1H,
d, J¼10 Hz, H-7), 4.29 (2H, t, J¼7.6 Hz, CH2), 3.30 (2H, q, J¼7 Hz,
CH2), 1.58 (2H, m, CH2), 1.40 (3H, t, J¼7 Hz, CH3), 1.24 (2H, m, CH2),
0.83 (3H, t, J¼7 Hz, CH3); 13C NMR (75 MHz, DMSO-d6)
d 162.1 (CO),
156.4 (CO),152.1 (C-10a), 148.4 (C-2), 147.2 (C-9a),136.6 (C-6), 131.5,
130.9, 129.6, 128.9 (Ar-C), 115.1 (CN), 113.5 (C-5a), 101.8 (C-7), 60.9
(C-10), 44.0 (CH2), 30.8 (CH2), 26.3 (CH2), 18.6 (CH2), 14.1 (CH3), 13.5
(CH3); MS m/z (%): 420 (Mþþ1, 16), 419 (Mþ, 33), 403 (15), 402 (45),
390 (14), 377 (18), 376 (12), 364 (42), 363 (100), 348 (12), 336 (10),
335 (14), 313 (9), 290 (8), 278 (11), 277 (10), 262 (7), 149 (10), 83 (4),
77 (37), 71 (7), 61 (6), 57 (10), 56 (8), 55 (15), 51 (17). Anal. Calcd for
C22H21N5O2S: C, 62.99; H, 5.05; N, 16.69; S, 7.64. Found: C, 63.13; H,
5.16; N, 16.50; S, 7.85.
4.11.2. 7-(Butylamino)-6-ethoxycarbonylvinyl-2-ethylthio-1,5-dihy-
dro-5-oxo-1-phenyl-1,2,4-triazolo[1,5-a]pyridine-8-carbonitrile
(16b). Yellowish solid; 0.130 g (86%); mp 226–228 ꢀC; IR (KBr)
3350, 3050, 2950, 2900, 2850, 2200, 1680, 1660 cmꢁ1 1H NMR
;
(500 MHz, DMSO-d6)
d
7.68 (1H, d, J¼16 Hz, ]CH); 7.62 (5H, m, Ar-
H), 7.04 (1H, d, J¼16 Hz, CH]), 6.88 (1H, t, J¼5 Hz, NH), 4.15 (2H, q,
J¼7 Hz, CH2), 3.42 (2H, q, J¼7 Hz, CH2), 3.23 (2H, q, J¼7 Hz, CH2),
1.54 (2H, m, CH2), 1.37 (3H, t, J¼7 Hz, CH3), 1.26 (3H, t, J¼7 Hz, CH3),
1.24 (2H, m, CH2), 0.84 (3H, t, J¼7 Hz, CH3); 13C NMR (75 MHz,
Acknowledgements
We are thankful to prof. Dr. Volker Ja¨ger and Dr. Peter Fischer,
Institute fu¨r Organische Chemie, Pfaffenwaldring 55, Universita¨t

R.A. Mekheimer et al. / Tetrahedron 65 (2009) 9843–9849
9849
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