An efficient synthesis of 1-(4H-1,2,4-triazol-3-yl)-hexahydroquinoline-3-carbonitrile and their spiro derivatives from β-enaminones

Article abstract of DOI:10.3987/COM-15-13353

A series of N-((1, 2, 4-triazol-3-yl)-enamine and N-((1, 2, 3-triazol-4-yl)-enamine were prepared and reacted with a,β-unsaturated nitriles to yield novel N-(4H-1,2, 4-triazol-3-yl)hexahydroquinoline-3-carbonitriles and their fused and spiro derivatives.

Full text of DOI:10.3987/COM-15-13353

HETEROCYCLES, Vol. 92, No. 4, 2016, pp. -. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 25th October, 2015, Accepted, 12th February, 2016, Published online, 2nd May, 2016
DOI: 10.3987/COM-15-13353
AN EFFICIENT SYNTHESIS OF 1-(4H-1,2,4-TRIAZOL-3-YL)-
HEXAHYDROQUINOLINE-3-CARBONITRILE AND THEIR SPIRO
DERIVATIVES FROM β-ENAMINONES
Said A. S. Ghozlan,a Doaa M. Abdelmoniem,a Mohamed F. Mady,b,c Amr M.
Abdelmoniem a and Ismail A. Abdelhamid a*
aDepartment of Chemistry, Faculty of Science, Cairo University, 12613 Giza, A.
R. Egypt
bDepartment of Green Chemistry, National Research Centre, Dokki, Giza, Egypt,
P.O. 12622
cDepartment of Mathematics and Natural Science, Faculty of Science and
Technology, University of Stavanger, N-4036 Stavanger, Norway
e-mail: ismail_shafy@yahoo.com, ismail_shafy@cu.edu.eg
Abstract
–
A
series
of
N-((1,2,4-triazol-3-yl)-enamine
and
N-((1,2,3-triazol-4-yl)-enamine were prepared and reacted with α,β-unsaturated
nitriles to yield novel N-(4H-1,2,4-triazol-3-yl)hexahydroquinoline-3-carbonitriles
and their fused and spiro derivatives. Dimroth type rearrangement of the prepared
quinoline derivatives 7a,b and 15a,b was observed in acetic anhydride leading to
the
formation
of
substituted
pyrimido[4,5-b]quinolines
11a,b,
spiro[indoline-3,5'-pyrimido[4,5-b]quinoline] 19 and spiro[indoline-3,5'-[1,3]-
oxazino[4,5-b]quinoline] 22.
INTRODUCTION
In the last decades, multicomponent cyclocondensations involving aldehydes, activated nitriles and
enamines, leading to quinoline and fused quinoline systems, have been widely investigated.1–7 In addition,
quinoline scaffold represents a class of medicinally significant compounds that possess a wide variety of
biological properties such as antimicrobial,8,9 anticancer,8–17 antiviral18 and anti-inflammatory agents.19
Moreover, the spirooxindole system is the core structure of the most distinguished heterocyclic ring
systems, which constitutes the core structural element of many pharmacological agents and natural
alkaloids, among them, spirotryprostatin B,20 gelsemine III,21 horsfiline IV22 and pteropodine II.20 As a
part of an ongoing research program on Michael addition reactions,23–28 as well as on the utility of

enamines29–32 in organic synthesis, we report the results of our investigations concerning the reactivity
patterns of the cyclic enamines towards substituted cinnamonitriles aiming at the synthesis of
N-(4H-1,2,4-triazol-3-yl)hexahydroquinoline-3-carbonitriles and their spiro derivatives.
RESULTS AND DISCUSSION
The N-(1,2,4-triazol-3-yl)enamine 3a was obtained through the reaction of dimedone 1 and
3-amino-4H-1,2,4-triazole 2a using a catalytic amount of trichloroacetic acid (TCAA) as a catalyst under
solvent-free conditions. When equimolar amounts of 3a and arylidenemalononitriles 4a-d were refluxed
in alcohol for 3 h, N-(4H-1,2,4-triazol-3-yl)hexahydroquinoline-3-carbonitrile compounds 7a-d were
obtained in high yields. The formation of compounds 7a-d apparently involves the formation of Michael
adducts 5, which undergo an intramolecular cyclization into 6. The formation of the final isolable
products 7a-d is completed via isomerization of 6 (Scheme 1).
The constitutions of compounds 7a-d were established spectroscopically. For example, the IR spectrum
of 7a indicated the presence of a CN group (ν 2185 cm-1), one CO group (ν 1658 cm-1) and characteristic
1
broad bands at ν 3429, 3325 and 3147 cm-1, which refer to the NH2 and NH groups. The H NMR
spectrum revealed a singlet signal at δ 4.42 ppm (1 H) assigned to quinoline-H4, as well as two broad
singlets at δ 5.81 (2 H) and 14.53 (1 H) ppm referring to NH2 and triazole-NH, respectively. The multiplet
13
at δ 7.16-7.33 (5 H) ppm was assigned to the aryl protons. The C NMR spectrum showed the carbonyl
carbon signal at δ 196.0 ppm, that for the quinoline-C4 at δ 36.4 ppm, as well as the other signals of the
carbon atoms of the aromatic system.
O
O
Ar
CN
CN
EtOH/piperidine
(0.2 mL)
O
NH2
NH
Ar
CN
CN
TCAA/120 °C
20 min
+
+
NH
NH
NH
N
reflux, 3 h
N
O
N
N
NH
N
N
5
3a
1
2a
4a, Ar = C6H5
b, Ar = 4-ClC6H4
c, Ar = 4-MeOC6H4
d, Ar = 3,4-(OCH2O)C6H3
O
Ar
N
O
Ar
CN
NH
CN
N
NH2
N
NH
N
NH
N
N
7a, Ar = C6H5 (92%)
6
b, Ar = 4-ClC6H4 (89%)
c, Ar = 4-MeOC6H4 (87%)
d, Ar = 3,4-(OCH2O)C6H3 (87%)
Scheme 1. Synthesis of N-(4H-1,2,4-triazol-3-yl)hexahydroquinoline-3-carbonitriles 7a-d

In attempts to produce tetrahydro-8H-[1,2,4]triazolo[4',3':5,6][1,3,5]triazino[1,2-a]quinoline-7-
carbonitrile derivatives 8 by the action of acetic anhydride on compounds 7, the desired products were
not produced, instead the N-(1,2,4-triazol-3-yl)tetrahydropyrimido[4,5-b]quinoline-4,6-dione derivatives
11 are obtained as sole products. Compounds 11 are assumed to be formed via initial acylation of 7 to
give 9 that then cyclized into 10 which underwent Dimroth rearrangement into 11. Similar mechanism
was followed under the same conditions.24 It worth mentioning that boiling compound 7b in acetic
anhydride not only undergoes Dimroth rearrangement but also affects a further acylation of the triazole-
NH leading to 11b (Scheme 2).
Scheme 2. Synthesis of pyrimido[4,5-b]quinoline-4,6-dione derivatives 11a,b
Encouraged by the results acquired from the enamine 3a, we attempted to expand the scope of this
reaction to prepare tetracyclic structures. Thus the enamine carrying carbonyl group on the triazole ring
3b was prepared similarly from dimedone 1 and 5-amino-1,2,3-triazole derivative 2b and reacted with
arylidenemalononitriles
4a,b.
The
reaction
results
in
the
formation
of
the
hexahydro[1,2,3]triazolo[4',5':5,6]pyrimido[1,2-a]quinoline-6-carbonitrile derivatives 13 as products of
cyclization with water elimination. The reaction proceeds via intermediacy of 12. The structure of
compounds 13 was established through inspection of their spectroscopic data. The mass spectrum of 13a
1
revealed a molecular ion peak as a base peak at m/z 522 corresponding to the loss of water. H NMR
revealed a singlet signal at δ 4.88 ppm corresponding to H-7. All other signals appeared at their expected
positions (scheme 3).

Scheme 3. Synthesis of [1,2,3]triazolo[4',5':5,6]pyrimido[1,2-a]quinoline-6-carbonitrile derivatives 13a,b
Motivated by these results and in the light of our interest in the synthesis of spiro-heterocyclic
compounds,26–28 we report herein the synthesis of the spiro-tetracyclic structures. Thus, we managed to
prepare
novel
spirocyclic
2-oxoindole
derivatives
of
2-amino-1-(4H-1,2,4-triazol-3-
yl)hexahydroquinoline-3-carbonitrile 15a-c via the reaction of the cyclic enamine 3a with 3-
cyanomethylidene-2-oxoindoles 14a-c in the presence of piperidine as a catalyst over 3 h (Scheme 4).
Compounds 15 were characterized spectroscopically.
Scheme 4. Synthesis of spirocyclic compounds 15a-c
Boiling compound 15a in acetic anhydride for a long period results in the formation of 19. In this respect,
the initially formed spiro [1,3]oxazino[4,5-b]quinoline]-4-imine 18 undergoes Dimroth rearrangement to
give 19. On the other hand, 15b containing an ester group in acetic ahydride gives compound 20 that
tautomerizes into compound 21. The cyclization of 21 via the loss of EtOH molecule leads to the
formation of the spiro[indoline-3,5'-[1,3]oxazino[4,5-b]quinoline]-2,4',6'-trione 22 (Scheme 5).

1
The structure of compounds 19 and 22 were confirmed based on spectral data. Thus the H NMR
spectrum of 19 indicated the absence of isatin-NH and appearance of acetyl group at δ 2.01 ppm. In
addition, it showed the pyrimidine-CH3 at δ 2.56 ppm. The two signals at δ 12.53 and 14.37 ppm are
1
assigned to pyrimidine-NH and triazole-NH, respectively. On the other hand, H NMR spectrum of 19
showed the absence of ester group. The two signals at δ 2.07 and 2.57 ppm are assigned to acetyl and
pyrimidine-CH3 groups, respectively. Moreover, the triazole NH appeared at δ 14.54 ppm. All other
signals appeared at their expected positions.
Scheme 5. Synthesis of fused spirocyclic compounds 19 and 22
CONCLUSIONS
The cyclic enamines incorporating triazole, behaving like C-nucleophiles, affect simple and facile
Michael addition reactions with various arylidenemalononitriles, and 3-cyanomethylene-2-oxindoles,
respectively, to give different N-(4H-1,2,4-triazol-3-yl)hexahydroquinoline-3-carbonitriles and their
spirooxindole derivatives.
EXPERIMENTAL
Melting points were measured with a Stuart melting point apparatus and are uncorrected. The IR spectra
1
13
were recorded using a FTIR Bruker–vector 22 spectrophotometer as KBr pellets. The H and C NMR
spectra were recorded in DMSO–d6 and CDCl3 as solvent on Varian Gemini NMR spectrometer at 400
MHz and 100 MHz, respectively, using TMS as internal standard. Chemical shifts are reported as δ
values in ppm. Mass spectra were recorded with a Shimadzu GCMS–QP–1000 EX mass spectrometer in
EI (70 eV) model. The elemental analyses were performed at the Micro analytical center, Cairo
University.

General procedure for synthesis of compounds 3a,b
Enamines 3a,b are prepared as similar to the method reported in literature.34
To a mixture of dimedone (1.00 g, 7.14 mmol) and 3-amino-1,2,4-triazole 2a (0.60 g, 7.14 mmol) or
5-amino-2H-1,2,3-triazole 2b (1.8 g, 7.14 mmol) was added trichloroacetic acid (0.23 g, 1.41 mmol). The
mixture was heated at 120 °C for 20 min. The crude product was separated and crystallized with EtOH to
give compounds 3a,b
3-((4H-1,2,4-Triazol-3-yl)amino)-5,5-dimethylcyclohex-2-en-1-one (3a)
Yellow crystals (1.24 g, 84%), Mp 296-298 °C, IR (KBr): ν 3428, 3280 (2NH), 1579 (CO) cm-1, 1H NMR
(400 MHz, DMSO-d6): δ 1.00 (s, 6H, 2CH3), 2.05 (s, 2H, CH2), 2.39 (s, 2H, CH2), 6.43 (s, 1H, dimedone
=CH), 8.37 (s, 1H, triazole CH), 9.53 (br s, 1H, enamine NH), 13.63 (br s, 1H, triazole NH) ppm, MS (EI,
70 eV): m/z (%) 206 ([M]+, 28), 191 (29), 150 (49), 122 (100), 95 (18), Anal. Calcd for C10H14N4O: C,
58.24; H, 6.84; N, 27.17. Found: C, 58.18; H, 6.76; N, 27.09.
3-((5-Benzoyl-2-phenyl-2H-1,2,3-triazol-4-yl)amino)-5,5-dimethylcyclohex-2-en-1-one (3b)
1
Yellow crystals (2.45 g, 89%), Mp > 300 °C, IR (KBr): ν 3435 (br, NH), 1745, 1623 (2CO) cm-1, H
NMR (400 MHz, CDCl3): δ 1.19 (s, 6H, 2CH3), 2.34 (s, 2H, CH2), 2.54 (s, 2H, CH2), 6.98 (s, 1H, CH),
13
7.44-8.49 (m, 10H, ArH), 9.06 (br s, 1H, NH) ppm, C NMR (100 MHz, CDCl3): δ 28.3 (2CH3), 33.0
(C), 43.8 (CH2), 50.48 (CH2), 106.9 (CH), 119.2 (CH), 128.6 (CH), 129.5 (CH), 130.4 (CH), 132.5 (C),
133.8 (C), 136.3 (C), 138.9 (C), 151.2 (C), 153.8 (C), 187.6 (C), 199.4 (C) ppm, MS (EI, 70 eV): m/z (%)
386 (10), 371 (36), 105 (100), 77 (69), Anal. Calcd for C23H22N4O2: C, 71.48; H, 5.74; N, 14.50. Found:
C, 71.39; H, 5.71; N, 14.42.
General procedure for synthesis of compounds 7a-d
A mixture of enamine 3a (0.21 g, 1 mmol) and cinnamonitriles 4a-d (1 mmol) in EtOH (15 mL) is heated
at reflux in the presence of piperidine (0.2 mL) for 3 h. The crude products were collected and
crystallized from EtOH-dioxane (2:1).
2-Amino-7,7-dimethyl-5-oxo-4-phenyl-1-(4H-1,2,4-triazol-3-yl)-1,4,5,6,7,8-hexahydroquinoline-3-
carbonitrile (7a)
Yellowish white crystals (0.33 g, 92%), Mp > 300 °C, IR (KBr): ν 3429, 3325, 3147 (NH2 and NH), 2185
(CN), 1658 (CO) cm-1, 1H NMR (400 MHz, DMSO-d6): δ 0.83 (s, 3H, CH3), 0.92 (s, 3H, CH3), 1.94-2.19
(m, 4H, 2CH2), 4.42 (s, 1H, CH), 5.81 (br s, 2H, NH2), 7.16-7.33 (m, 5H, ArH), 8.78 (s, 1H, triazole CH),
14.53 (br s, 1H, triazole NH) ppm, 13C NMR (100 MHz, DMSO-d6): δ 27.0 (CH3), 28.3 (CH3), 32.3 (C),
36.4 (CH), 40.2 (CH2), 49.6 (CH2), 61.4 (C), 114.0 (C), 121.0 (C), 126.5 (CH), 126.8 (CH), 128.4 (CH),
145.9 (C), 149.8 (C), 154.6 (C), 156.2 (CH), 161.2 (C), 195.0 (C) ppm, MS (EI, 70 eV): m/z (%) 360
([M]+, 39), 283 (100), Anal. Calcd for C20H20N6O: C, 66.65; H, 5.59; N, 23.32. Found: C, 66.56; H, 5.49;
N, 23.29.

2-Amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-1-(4H-1,2,4-triazol-3-yl)-1,4,5,6,7,8-hexahydroqui-
noline-3-carbonitrile (7b)
Yellow crystals (0.35 g, 89%), Mp > 300 °C, IR (KBr): ν 3440, 3322, 3115 (NH2 and NH), 2187 (CN),
1
1659 (CO) cm-1, H NMR (400 MHz, DMSO-d6): δ 0.81 (s, 3H, CH3), 0.91 (s, 3H, CH3), 1.91-2.25 (m,
4H, 2CH2), 4.43 (s, 1H, CH), 5.86 (br s, 2H, NH2), 7.25-7.38 (m, 4H, ArH), 8.77 (s, 1H, triazole CH),
14.49 (br s, 1H, triazole NH) ppm, 13C NMR (100 MHz, DMSO-d6): δ 27.7 (CH3), 28.1 (CH3), 32.5 (C),
36.0 (CH), 40.1 (CH2), 49.9 (CH2), 61.7 (C), 114.4 (C), 120.7 (C), 128.2 (CH), 128.6 (CH), 131.5 (C),
144.0 (C), 144.9 (C), 149.8 (C), 150.5 (CH), 161.6 (C), 195.0 (C) ppm, MS (EI, 70 eV): m/z (%) 396
([(M+2)+], 1.4), 394 ([M+], 4), 283 (100), Anal. Calcd for C20H19ClN6O: C, 60.84; H, 4.85; Cl, 8.98; N,
21.28. Found: C, 60.77; H, 4.79; Cl, 8.91; N, 21.23.
2-Amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-1-(4H-1,2,4-triazol-3-yl)-1,4,5,6,7,8-hexahydro-
quinoline-3-carbonitrile (7c)
Bright yellow crystals (0.34 g, 87%), Mp > 300 °C, IR (KBr): ν 3444, 3329, 3128 (NH2 and NH), 2187
(CN), 1659 (CO) cm-1, 1H NMR (400 MHz, DMSO-d6): δ 0.82 (s, 3H, CH3), 0.91 (s, 3H, CH3), 1.93-2.18
(m, 4H, 2CH2), 3.71 (s, 3H, OCH3), 4.38 (s, 1H, CH), 5.77 (br s, 2H, NH2), 6.84-7.28 (m, 4H, ArH), 8.78
13
(s, 1H, triazole CH), 14.51 (br s, 1H, triazole NH) ppm, C NMR (100 MHz, DMSO-d6): δ 26.9 (CH3),
28.2 (CH3), 32.2 (C), 35.5 (CH), 40.3 (CH2), 49.5 (CH2), 55.0 (CH2), 61.6 (C), 113.7 (CH), 114.2 (C),
121.0 (C), 127.8 (CH), 138.0 (C), 145.6 (C), 149.4 (C), 150.3 (C), 154.3 (CH), 157.8 (C), 195.0 (C) ppm,
MS (EI, 70 eV): m/z (%) 390 ([M+], 39), 283 (100), Anal. Calcd for C21H22N6O2: C, 64.60; H, 5.68; N,
21.52. Found: C, 64.55; H, 5.52; N, 21.44.
2-Amino-4-(benzo[d][1,3]dioxol-5-yl)-7,7-dimethyl-5-oxo-1-(4H-1,2,4-triazol-3-yl)-1,4,5,6,7,8-hexa-
hydroquinoline-3-carbonitrile (7d)
Yellow crystals (0.35 g, 87%), Mp > 300 °C, IR (KBr): ν 3450, 3330, 3129 (NH2 and NH), 2188 (CN),
1
1662 (CO) cm-1, H NMR (400 MHz, DMSO-d6): δ 0.83 (s, 3H, CH3), 0.92 (s, 3H, CH3), 1.93-2.24 (m,
4H, 2CH2), 4.35 (s, 1H, CH), 5.80 (br s, 2H, NH2), 5.95 (s, 2H, OCH2O), 6.71-6.84 (m, 3H, ArH), 8.78 (s,
1H, triazole CH), 14.53 (br s, 1H, triazole NH) ppm, 13C NMR (100 MHz, DMSO-d6): δ 27.0 (CH3), 28.1
(CH3), 32.2 (C), 36.0 (CH), 41.4 (CH2), 49.5 (CH2), 61.5 (C), 100.7 (CH2), 114.1 (C), 107.0 (CH), 107.9
(CH), 119.8 (C), 120.9 (CH), 139.9 (C), 145.8 (C), 147.3 (C), 149.5 (C), 150.3 (C), 154.3 (CH), 161.2 (C),
195.0 (C) ppm, MS (EI, 70 eV): m/z (%) 404 ([M]+, 46), 283 (100), Anal. Calcd for C21H20N6O3: C,
62.37; H, 4.98; N, 20.78. Found: C, 62.29; H, 4.93; N, 20.71.
General procedure for synthesis of compounds 11a,b
Compound 7a or 7b (10 mmol) was heated at reflux in acetic anhydride (5 mL) for 3 h. The excess
solvent was evaporated under vacuum and the residue was washed with 0.2 N aq. NaHCO3 (20 mL). The
crude product was crystallized from EtOH-dioxane (3:1).

2,8,8-Trimethyl-5-phenyl-10-(4H-1,2,4-triazol-3-yl)-5,8,9,10-tetrahydropyrimido[4,5-b]quinoline-4,
6(3H,7H)-dione (11a)
Yellowish white crystals (0.33 g, 82%), Mp > 300 °C, IR (KBr): ν 3368, 3133 (2NH), 1659, 1626 (2CO)
cm-1, 1H NMR (400 MHz, DMSO-d6): δ 0.78 (s, 3H, CH3), 0.93 (s, 3H, CH3), 1.75 (m, 2H, 2CH2), 2.04 (s,
3H, CH3), 2.24 (m, 2H, 2CH2), 5.04 (s, 1H, CH), 7.09-7.34 (m, 5H, ArH), 8.66 (s, 1H, triazole CH), 12.29
13
(br s, 1H, pyrimidine NH), 14.51 (br s, 1H, triazole NH) ppm, C NMR (100 MHz, DMSO-d6): δ 21.0
(CH3), 26.2 (CH3), 29.1 (CH3), 31.8 (C), 34.3 (CH), 40.3 (CH2), 49.5 (CH2), 101.6 (C), 112.2 (C), 126.1
(CH), 127.6 (CH), 127.8 (CH), 145.3 (C), 145.6 (C), 149.3 (C), 150.7 (C), 152.8 (C), 157.0 (CH), 161.4
(C), 194.8 (C) ppm, MS (EI, 70 eV): m/z (%) 402 ([M+], 30), 325 (100), Anal. Calcd for C22H22N6O2: C,
65.66; H, 5.51; N, 20.88. Found: C, 65.58; H, 5.44; N, 20.79.
10-(4-Acetyl-4H-1,2,4-triazol-3-yl)-5-(4-chlorophenyl)-2,8,8-trimethyl-5,8,9,10-tetrahydropyrimido-
[4,5-b]quinoline-4,6(3H,7H)-dione (11b)
Yellow crystals (0.37 g, 77%), Mp > 300 °C, IR (KBr): ν 3101 (2NH), 1761, 1663, 1602 (3CO) cm-1, 1H
NMR (400 MHz, DMSO-d6): δ 0.81 (s, 3H, CH3), 0.96 (s, 3H, CH3), 1.91 (m, 2H, 2CH2), 2.07 (s, 3H,
CH3), 2.27 (m, 2H, 2CH2), 2.72 (s, 3H, COCH3), 5.03 (s, 1H, CH), 7.18-7.42 (m, 4H, ArH), 9.49 (s, 1H,
triazole CH), 12.36 (br s, 1H, pyrimidine NH) ppm, 13C NMR (100 MHz, DMSO-d6): δ 21.4 (CH3), 22.3
(CH3), 27.2 (CH3), 29.5 (CH3), 32.5 (C), 33.7 (CH), 40.5 (CH2), 50.1 (CH2), 102.7 (C), 114.0 (C), 128.2
(CH), 129.7 (CH), 132.2 (C), 143.4 (C), 144.3 (C), 149.3 (C), 153.7 (C), 157.4 (CH), 163.4 (C), 167.6 (C),
195.5 (C) ppm, MS (EI, 70 eV): m/z (%) 463 ([(M-15)+], 0.5), 436 (10), 367 (74), 325 (100), Anal. Calcd
for C24H23ClN6O3: C, 60.19; H, 4.84; Cl, 7.40; N, 17.55. Found: C, 60.11; H, 4.69; Cl, 7.31; N, 17.48.
General method for synthesis of compounds 13a,b
A mixture of enamine 3b (0.21 g, 1 mmol) and cinnamonitriles 4a,b (1 mmol) in pyridine (5 mL) is
heated at reflux for 3 h. The excess pyridine was removed at reduced pressure and the resulting residue
was treated with aq. HCl (0.2 N, 10 mL). The crude products were collected and crystallized from
EtOH-dioxane (2:1).
10,10-Dimethyl-8-oxo-2,4,7-triphenyl-2,7,8,9,10,11-hexahydro-[1,2,3]triazolo[4',5':5,6]pyrimido[1,2-
a]quinoline-6-carbonitrile (13a)
1
Yellow crystals (0.41 g, 78%), Mp > 300 °C, IR (KBr): ν 2198 (CN), 1640 (CO) cm-1, H NMR (400
MHz, DMSO-d6): δ 1.01 (s, 3H, CH3), 1.15 (s, 3H, CH3), 2.23, 2.47, 2.84, 3.64 (4 m, 4H, 2CH2), 4.88 (s,
1H, CH), 7.33-8.61 (m, 15H, ArH) ppm, MS (EI, 70 eV): m/z (%) 522 ([M+], 24), 445 (100), 77 (63),
Anal. Calcd for C33H26N6O: C, 75.84; H, 5.01; N, 16.08. Found: C, 75.69; H, 4.93; N, 16.01.
7-(4-Chlorophenyl)-10,10-dimethyl-8-oxo-2,4-diphenyl-2,7,8,9,10,11-hexahydro-[1,2,3]triazolo[4',5':
5,6]pyrimido[1,2-a]quinoline-6-carbonitrile (13b)
Yellow crystals (0.42 g, 76%), Mp = 293-295 °C, IR (KBr): ν 2199 (CN), 1638 (CO) cm-1, 1H NMR (400

MHz, DMSO-d6): δ 1.06 (s, 3H, CH3), 1.14 (s, 3H, CH3), 2.23, 2.46, 2.84, 3.62 (4 m, 4H, 2CH2), 4.90 (s,
1H, CH), 7.36-8.61 (m, 14H, ArH) ppm, MS (EI, 70 eV): m/z (%) 558 ([(M+2)+], 13), 556 ([M+], 36), 445
(100), 77 (73), Anal. Calcd for C33H25ClN6O: C, 71.15; H, 4.52; Cl, 6.36; N, 15.09. Found: C, 71.09; H,
4.44; Cl, 6.19; N, 15.03.
General procedure for synthesis of compounds 15a-c
A mixture of enamine 3a (0.21 g, 1 mmol) and 3-cyanomethylene-2-oxindoles 14a-c (1 mmol) in EtOH
(15 mL) is heated at reflux in the presence of piperidine (0.2 mL) for 3 h. The crude products were
collected and crystallized from EtOH-dioxane (2:1).
2'-Amino-7',7'-dimethyl-2,5'-dioxo-1'-(4H-1,2,4-triazol-3-yl)-5',6',7',8'-tetrahydro-1'H-spiro[indoli-
ne-3,4'-quinoline]-3'-carbonitrile (15a)
Red crystals (0.34 g, 85%), Mp > 300 °C, IR (KBr): ν 3442, 3315, 3213, 3137 (NH2 and 2NH), 2198
1
(CN), 1708, 1634 (2CO) cm-1, H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 3H, CH3), 0.91 (s, 3H, CH3),
1.88-2.15 (m, 4H, 2CH2), 5.78 (br s, 2H, NH2), 6.76-7.14 (m, 4H, ArH), 8.79 (s, 1H, triazole CH), 10.25
13
(br s, 1H, oxindole NH), 13.85 (br s, 1H, triazole NH) ppm, C NMR (100 MHz, DMSO-d6): δ 26.7
(CH3), 27.9 (CH3), 32.0 (C), 41.4 (CH2), 49.3 (C), 50.1 (CH2), 61.0 (C), 102.2 (C), 109.0 (CH), 111.4 (C),
118.4 (CH), 120.8 (CH), 121.5 (C), 122.7 (CH), 136.2 (C), 141.6 (C), 145.9 (C), 150.4 (C), 151.3 (C),
153.5 (CH), 156.5 (C), 194.0 (C) ppm, MS (EI, 70 eV): m/z (%) 401 ([M+], 20), 384 (9), 375 (17), 358
(31), 347 (51), 325 (27), 317 (100), 300 (21), 290 (38), Anal. Calcd for C21H19N7O2: C, 62.83; H, 4.77; N,
24.42. Found: C, 62.77; H, 4.63; N, 24.31.
Ethyl 2'-amino-7',7'-dimethyl-2,5'-dioxo-1'-(4H-1,2,4-triazol-3-yl)-5',6',7',8'-tetrahydro-1'H-spiro-
[indoli-ne-3,4'-quinoline]-3'-carboxylate (15b)
Orange crystals (0.37 g, 83%), Mp > 300 °C, IR (KBr): ν 3451, 3322, 3173, 3122 (NH2 and 2NH), 1678,
1658, 1640 (3CO) cm-1, 1H NMR (400 MHz, DMSO-d6): δ 0.79 (s, 3H, CH3), 0.87 (s, 3H, CH3), 0.87 (t,
3H, J = 7.2 Hz, CO2CH2CH3), 1.79-2.12 (m, 4H, 2CH2), 3.67 (q, 2H, J = 7.2 Hz, CO2CH2CH3), 6.64-7.05
(m, 4H, ArH), 7.24 (br s, 2H, NH2), 8.83 (s, 1H, triazole CH), 9.97 (br s, 1H, oxindole NH), 14.58 (br s,
1H, triazole NH) ppm, 13C NMR (100 MHz, DMSO-d6): δ 13.0 (CH3), 26.5 (CH3), 27.9 (CH3), 31.5 (C),
40.4 (CH2), 48.6 (C), 50.2 (CH2), 58.6 (CH2), 79.2 (C), 107.8 (C), 113.7 (CH), 120.3 (CH), 122.1 (CH),
122.2 (C), 126.8 (CH), 137.3 (C), 143.7 (C), 145.9 (C), 149.7 (C), 151.9 (CH), 154.2 (C), 168.4 (C),
193.6 (C) ppm, MS (EI, 70 eV): m/z (%) 448 ([M+], 9), 402 (11), 375 (100), Anal. Calcd for C23H24N6O4:
C, 61.60; H, 5.39; N, 18.74. Found: C, 61.53; H, 5.34; N, 18.68.
2'-Amino-1,7',7'-trimethyl-2,5'-dioxo-1'-(4H-1,2,4-triazol-3-yl)-5',6',7',8'-tetrahydro-1'H-spiro[indo-
line-3,4'-quinoline]-3'-carbonitrile (15c)
Brick-red crystals (0.35 g, 84%), Mp > 300 °C, IR (KBr): ν 3444, 3335, 3141 (NH2 and NH), 2190 (CN),
1
1689, 1653 (2CO) cm-1, H NMR (400 MHz, DMSO-d6): δ 0.85 (s, 3H, CH3), 0.91 (s, 3H, CH3),

1.90-2.13 (m, 4H, 2CH2), 3.14 (s, 3H, NCH3), 5.84 (br s, 2H, NH2), 6.95-7.26 (m, 4H, ArH), 8.79 (s, 1H,
13
triazole CH), 14.33 (br s, 1H, triazole NH) ppm, C NMR (100 MHz, DMSO-d6): δ 18.2 (CH3), 26.3
(CH3), 27.4 (CH3), 28.0 (CH3), 32.2 (C), 40.6 (CH2), 48.2 (C), 49.7 (CH2), 56.9 (C), 107.6 (C), 118.1
(CH), 122.3 (CH), 122.8 (CH), 128.1 (CH), 134.6 (C), 142.8 (C), 144.6 (C), 150.4 (C), 151.3 (C), 154.2
(CH), 165.5 (C), 194.3 (C) ppm, MS (EI, 70 eV): m/z (%) 415 ([M+], 13), 372 (8), 361 (15), 331 (78), 304
(47), 234 (32), 146 (64), 83 (100), Anal. Calcd for C22H21N7O2: C, 63.60; H, 5.10; N, 23.60. Found: C,
63.55; H, 5.06; N, 23.49.
General procedure for synthesis of compounds 19 and 22
Compound 15a or 15b (10 mmol) was heated at reflux in acetic anhydride (5 mL) for 3 h. The excess
solvent was evaporated under vacuum and the residue was washed with 0.2 N aq. NaHCO3 (20 mL). The
crude product was crystallized from EtOH-dioxane (3:1).
1-Acetyl-2',8',8'-trimethyl-10'-(4H-1,2,4-triazol-3-yl)-8',9'-dihydro-3'H-spiro[indoline-3,5'-pyrimido-
[4,5-b]quinoline]-2,4',6'(7'H,10'H)-trione (19)
Red crystals (0.37 g, 76%), Mp > 300 °C, IR (KBr): ν 3432 (br, 2NH), 1762, 1658, 1601 (3CO) cm-1, 1H
NMR (400 MHz, DMSO-d6): δ 0.82 (s, 3H, CH3), 0.93 (s, 3H, CH3), 1.85-1.91 (m, 2H, CH2), 2.01 (s, 3H,
COCH3), 2.15-2.34 (m, 2H, CH2), 2.56 (s, 3H, pyrimidine CH3), 7.08-8.07 (m, 4H, ArH), 8.75 (s, 1H,
13
triazole CH), 12.53 (br s, 1H, pyrimidine NH), 14.37 (br s, 1H, triazole NH) ppm, C NMR (100 MHz,
DMSO-d6): δ 21.2 (CH3), 26.4 (CH3), 26.8 (CH3), 29.1 (CH3), 32.1 (C), 40.2 (CH2), 49.6 (C), 49.9 (CH2),
101.5 (C), 115.4 (C), 123.1 (CH), 121.6 (CH), 128.3 (CH), 128.4 (C), 133.1 (CH), 140.4 (C), 143.9 (C),
145.0 (C), 153.6 (C), 153.7 (C), 157.9 (CH), 161.8 (C), 171.2 (C), 179.3 (C), 194.8 (C) ppm, MS (EI, 70
eV): m/z (%) 485 ([M+], 22), 442 (100), 359 (23), Anal. Calcd for C25H23N7O4: C, 61.85; H, 4.78; N,
20.20. Found: C, 61.79; H, 4.65; N, 20.09.
1-Acetyl-2',8',8'-trimethyl-10'-(4H-1,2,4-triazol-3-yl)-8',9'-dihydrospiro[indoline-3,5'-[1,3]oxazino-
[4,5-b]quinoline]-2,4',6'(7'H,10'H)-trione (22)
1
Orange crystals (0.37 g, 72%), Mp > 300 °C, IR (KBr): ν 3198 (NH), 1736, 1649, 1615 (3CO) cm-1, H
NMR (400 MHz, DMSO-d6): δ 0.84 (s, 3H, CH3), 0.93 (s, 3H, CH3), 1.93-2.02 (m, 2H, CH2), 2.07 (s, 3H,
COCH3), 2.16-2.34 (m, 2H, CH2), 2.57 (s, 3H, oxazine CH3), 7.14-8.09 (m, 4H, ArH), 8.81 (s, 1H,
triazole CH), 14.54 (br s, 1H, triazole NH) ppm, MS (EI, 70 eV): m/z (%) 486 ([M+], 19), 443 (100), 401
(15), 360 (22), Anal. Calcd for C25H22N6O5: C, 61.72; H, 4.56; N, 17.28. Found: C, 61.64; H, 4.43; N,
17.16.
ACKNOWLEDGEMENTS
Ismail A. Abdelhamid is deeply indebted to the Alexander von Humboldt foundation, Germany, for
granting him a postdoctoral fellowship.

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