Tandem and transition metal-free synthesis of novel benzoimidazo-quinazoline as highly selective Hg2+ sensors

Article abstract of DOI:10.1007/s11164-017-3239-2

A one-pot procedure for the synthesis of novel planar aza-heterocycles possessing good fluorescence potencies was described. These benzo-imidazopyrimido[4,5-b]quinolone derivatives came from the reaction of 2-chloroquinoline-3-carboxaldehydes and 2-aminobenzimidazole using K₂CO₃ in DMF. The fluorescence study of these conjugated systems was also considered, which revealed that they have highly selective sensing of mercury. Consequently, to investigate another aspect of the reaction, a three-component reaction was developed by adding malononitrile to the aforementioned starting materials in the presence of l-proline under reflux condition in H₂O/EtOH to provide amino-quinolin-3-yl-dihydrobenzo-imidazo-pyrimidine-3-carbonitriles in good yields.

Full text of DOI:10.1007/s11164-017-3239-2

Res Chem Intermed
https://doi.org/10.1007/s11164-017-3239-2
Tandem and transition metal‑free synthesis of novel
2+
benzoimidazo‑quinazoline as highly selective Hg
sensors
1
1
1
1
Morteza Shiri · Majid M. Heravi · Zeinab Faghihi · Vahideh Zadsirjan ·
1
1
Masoumeh Mohammadnejad · Maryam Ranjbar
Received: 12 August 2017 / Accepted: 18 December 2017
©
Springer Science+Business Media B.V., part of Springer Nature 2017
Abstract A one-pot procedure for the synthesis of novel planar aza-hetero-
cycles possessing good ꢀuorescence potencies was described. These benzo-
imidazopyrimido[4,5-b]quinolone derivatives came from the reaction of 2-chloro-
quinoline-3-carboxaldehydes and 2-aminobenzimidazole using K CO in DMF. The
2
3
ꢀ
uorescence study of these conjugated systems was also considered, which revealed
that they have highly selective sensing of mercury. Consequently, to investigate
another aspect of the reaction, a three-component reaction was developed by adding
malononitrile to the aforementioned starting materials in the presence of l-proline
under reꢀux condition in H O/EtOH to provide amino-quinolin-3-yl-dihydrobenzo-
2
imidazo-pyrimidine-3-carbonitriles in good yields.
Keywords One-pot synthesis · Transition metal-free · Fluorescent ·
2
-Aminobenzimidazole · 2-Chloroquinoline-3-carboxaldehydes
Introduction
Quinolines are one of the most prevalent N-heteroaromatic molecules [1–4] incor-
porated into the buildings of various pharmaceuticals [5–11]. 2-Chloroquinoline-
3
-carbaldehydes are imperative quinolines employed for the formation of a number
of heterocyclic compounds [12–14]. Benzimidazoles [15] are also found exclusively
in many drugs [16–19]. For instance, 2-substituted-5-amino-benzimidazoles are
known for cytotoxic activities [20]. According to the reports, the fused heterocycles
[21, 22] are frequently of greater application than the monocyclic structures [23, 24]
*
Morteza Shiri
mshiri@alzahra.ac.ir
1
Department of Chemistry, Alzahra University, Vanak, Tehran 1993893973, Iran
1
3

M. Shiri et al.
involving functional materials [25], molecular recognition [26], medicinal chemis-
try [27], and coordination chemistry [28]. A few fused-ring structures including the
benzimidazole and quinazolinone structures have been explored to show a powerful
immunosuppressive property [29] or antiproliferative activity in human tumor cell
lines [30, 31].
Fluorescent probes for identifying heavy metal ions in biological and environ-
mental systems have obtained signiꢁcant attention [32]. One of the main and most
hazardous impurity metal ions is mercury that can exert long-standing contamina-
tive eꢂects and create severe health diꢃculties because of its capability to pass via
biological membranes [33]. Henceforth, there is a great need to plan, manufacture,
and employ ꢀuorescent sensors with extraordinary selectivity and sensitivity for
2
+
Hg .
Recently, benzo[4.5]imidazo[2,1-b]quinazolin-12-ones were synthesized from
-aminobenzimidazole and 2-haloaroyl chlorides [34]. Also, Ma et al. [34] syn-
2
thesized a range of benzo[4,5]imidazo[1,2-a]quinazoline and imidazo[1,2-a]quina-
zoline derivatives. To the best of our knowledge, there are only a few reports on
the synthesis of such planar-fused heterocycles as mentioned above. The planarity
of these fused systems allows them to easily interact with DNA for use in human
tumor research [31, 35]. The assemblage of quinoline to pyrimidine and imidazole
would lengthen the conjugated systems. A compound comprising more than four
N-containing fused heterocycles seems plausible to acquire new thought-provoking
potencies. Accordingly, in continuation of our research in developing heterocyclic
compounds including 2-chloroquinoline-3-carbaldehydes [36–43], we employed
a method to accumulate these various aromatic heterocycles via a one-pot tandem
procedure. The two-component products, benzo-imidazopyrimido [4,5-b]quinolo-
nes, and the subsequent three-component derivatives, amino-quinolin-3-yl-dihy-
drobenzo-imidazo-pyrimidine-3-carbonitriles, were developed in easy mild condi-
tions which are discussed here.
Experimental
General
1
Melting points were taken by using a 9200-Branread Electrothermal apparatus. H-
1
3
NMR and C-NMR spectra were recorded on Bruker 300 and 400 spectrometers.
1
H-NMR spectra were referenced to tetramethylsilane (0.00 ppm) using DMSO-d
6
1
3
or CDCl as solvents. C-NMR spectra were referenced to solvent carbons. IR spec-
3
tra were recorded using a FT-IR Tensor 27. A Leco CHNS, model 932, was used for
elemental analysis.
Synthesis of 3a–f: general procedure
A mixture of 1H-benzo[d]imidazole-2-amine 1 (1.0 mmol), 2-chloro-quinoline-
3
-carbaldehydes 2 (1.1 mmol) and K CO (1 mmol) in DMF (5 mL) was stirred at
2
3
1
3

Tandem and transition metal‑free synthesis of novel…
1
20 °C under reꢀux condition (or under MW conditions, 120 °C, 5 × 1 min) TLC
was employed to monitor the end of the reaction. It was then poured onto water
(
20 mL) to precipitate a yellowish product. The pure product was collected after ꢁl-
tering and simply washing with water.
Synthesis of 4a–g: general procedure
A mixture of 1H-benzo[d]imidazole-2-amine 1 (1 mmol), 2-chloroquinoline-3-car-
baldehydes 2 (1 mmol) and malononitrile (1.1 mmol) in the presence of l-proline
(
0.15 mmol) in EtOH/H O (1:1, 5 mL) was stirred under reꢀux condition for an
2
appropriate reaction time. The progress of the reaction was monitored by TLC.
Then, the mixture was cooled to room temperature, ꢁltered oꢂ, and the obtained
solid residue was washed with H O. The crude products were puriꢁed by recrystal-
2
lization from EtOH and H O.
2
Experimental and physical data
Benzo[4′,5′]imidazo[2′,1′:2,3]pyrimido[4,5‑b]quinolone (3a)
Yellow powder (95%), m.p. > 300 °C, Anal. calcd. for C H N : C, 75.54; H, 3.73;
1
7
10
4
N, 20.73, Found: C, 75.62; H, 3.57; N, 20.51, FT-IR (KBr): ν
= 3021, 1608,
max
−1 1
1
551, 1515, 1466, 1438, 1253, 1170, 730 cm ; H-NMR (300 MHz, DMSO-d ):
6
δ = 7.64 (2H, m, CH-19, 20), 7.20 (1H, t, J = 14.8 Hz, J = 7.8 Hz, CH-1), 8.02 (1H,
t, J = 15 Hz, J = 7.8 Hz, CH-2), 8.12 (2H, m, CH-18, 21), 8.33 (1H, d, J = 8.4 Hz,
CH-6), 8.93 (1H, s, CH-10), 9.22 (1H, d, J = 8.4 Hz, CH-3), 9.35 (1H, s, CH-14)
1
3
ppm; C-NMR (100 MHz, CDCl ): δ = 116.4, 119.9, 124.2, 124.9, 126.6, 128.0,
3
1
30.0, 133.9, 141.1 ppm.
1
0‑Methylbenzo[4′,5′]imidazo[2′,1′:2,3]‑pyrimido[4,5‑b]quinolone (3b)
Yellow powder (90%), m.p. > 300 °C; Anal. calcd. for C H N : C, 76.04; H,
1
8
12 4−
4
.25; N, 19.71, Found: C, 76.12; H, 4.17; N, 19.60, FT-IR (KBr): ν = 3012, 1603,
max
−1 1
1
550, 1509, 1444, 1222, 822, 758, 733 cm ; H-NMR (400 MHz, CDCl ): δ = 2.66
3
(
3H, s, CH ), 7.63 (2H, m, CH-19, 20), 7.86 (1H, d, J = 8.4 Hz, CH-21), 7.87 (1H,
3
s, CH-6), 8.12 (1H, d, J = 7.2 Hz, CH-2), 8.24 (1H, d, J = 8.4 Hz, CH-18), 8.80
1
3
(
1H, s, CH-10), 9.24 (1H, d, J = 7.2 Hz, CH-21), 9.30 (1H, s, CH-6) ppm; C-
NMR (100 MHz, CDCl ): δ = 21.6, 116.6, 120.6, 124.6, 125.2, 125.6, 127.8, 128.4,
3
1
36.2, 136.8, 138.5, 145.6, 148.1, 158.3 ppm.
1
2‑Methylbenzo[4′,5′]imidazo[2′,1′:2,3]‑pyrimido[4,5‑b]quinoline (3c)
Yellow powder (85%), m.p. > 300 °C; Anal. calcd. for C H N : C, 76.04; H, 4.25;
1
8
12
4
N, 19.71, Found: C, 76.12; H, 4.12; N, 19.52; FT-IR (KBr): ν
= 3012, 1603,
max
−1
1
1
550, 1509, 1444, 1222, 822, 758, 733 cm ; H-NMR (400 MHz, DMSO-d ):
6
δ = 2.58 (3H, s, CH ), 7.60 (2H, m, CH-19, 20), 7.94 (2H, m, CH-1, 2), 8.05 (1H, m,
3
1
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M. Shiri et al.
CH-6), 8.22 (1H, d, J = 6.0 Hz, CH-21), 9.15 (1H, d, J = 6.0 Hz, CH-18), 9.24 (1H,
1
3
s, CH-10), 9.48 (1H, s, CH-14) ppm; C-NMR (100 MHz, DMSO-d ): δ = 20.1,
6
1
16.3, 119.8, 124.1, 124.8, 136.2, 140.1, 144.0, 145.1, 160.1 ppm.
1
0‑Methoxybenzo[4′,5′]imidazo[2′,1′:2,3]‑pyrimido[4,5‑b]quinolone (3d)
Yellow powder, m.p. > 300 °C; Anal. calcd. for C H N O: C, 71.99; H, 4.03;
1
8
12
4
N, 18.66; Found: C, 71.74; H, 4.12; N, 18.54; FT-IR (KBr): ν
= 3048, 1605,
max
3
−1 1
1
557, 1516, 1257, 1167, 1027 cm ; H-NMR (300 MHz, CDCl ): δ = 3.99 (3H,
s, OCH ), 7.27 (1H, m, CH-6), 7.50 (1H, m, CH-2), 7.59 (2H, m, CH-19, 20), 7.89
3
(
1H, d, J = 9 Hz, CH-3), 8.01 (2H, m, CH-18, 19), 8.65 (1H, s, CH-10), 9.16 (1H,
1
3
s, CH-14) ppm; C-NMR (100 MHz, CDCl ): δ = 53.5, 106.6, 111.2, 111.9, 117.2,
3
1
1
20.2, 121.9, 124.9, 128.1, 129.8, 130.5, 132.4, 134.1, 135.1, 140.0, 143.4, 147.0,
49.3, 154.3 ppm.
1
1‑Methoxybenzo[4′,5′]imidazo[2′,1′:2,3]‑pyrimido[4,5‑b]quinolone (3e)
Yellow powder (83%), m.p. > 300 °C; Anal. calcd. for C H N O (MW = 300.31),
1
8
12
4
C, 71.99; H, 4.03; N, 18.66; Found: C, 71.73; H, 4.19; N, 18.52; FT-IR (KBr):
−
1 1
ν
= 3015, 1601, 1555, 1513, 1236, 1161, 754 cm ; H-NMR (00 MHz, DMSO-
max
6
d ): δ = 4.07 (3H, s, OCH ), 7.40 (H, m, CH-1) 7.55 (2H, m, CH-19, 20), 7.75
3
(
1H, s, CH-3), 7.95 (1H, CH-6), 8.25 (1H, d, J = 6.0 Hz, CH-21), 9.15 (1H, d,
1
3
J = 6.0 Hz, CH-18), 9.25 (1H, s, CH-10), 9.40 (1H, s, CH-14) ppm; C-NMR
100 MHz, DMSO-d ): δ = 56.1, 106.5, 106.7, 111.3, 116.5, 116.8, 119.7, 119.9,
(
6
1
23.8, 124.0, 124.9, 125.2. 131.3, 131.4, 140.2, 140.3, 142.7, 159.6 ppm.
Benzo[h]benzo[4′,5′]imidazo[2′,1′:2,3]‑pyrimido[4,5‑b]quinoline (3f)
Yellow powder (85%), m.p. > 300 °C; Anal. calcd. for C H N : C, 78.73; H, 3.78;
2
1
12
4
N, 17.49; Found: C, 78.80; H, 3.70; N, 17.57; FT-IR (KBr): ν
= 3026, 1598,
max
−1 1
1
553, 1508, 1454, 1390, 769, 739 cm ; H-NMR (400 MHz, DMSO-d ): δ = 7.62
6
(
3H, m, CH-19, 20, 23), 7.80 (4H, m, CH-21, 22, 24), 8.16 (1H, d, J = 6.8 Hz,
1
3
CH-3), 8.78 (1H, s, CH-10), 9.25 (2H, m, CH-6, 25), 9.39 (1H, s, CH-14) ppm; C-
NMR (100 MHz, DMSO-d ): δ = 117.2, 119.4, 125.4, 125.9, 126.3, 126.4, 128.4,
6
1
28.6, 129.1, 129.3, 130.1, 131.3, 135.6, 140.1, 144.1 ppm.
4
‑Amino‑2‑(2‑chloroquinolin‑3‑yl)‑1,2‑dihydrobenzo[4,5]imidazo [1,2‑a]
pyrimidine‑3‑carbonitrile (4a)
Yellow powder, m.p.: 260–263 °C; Anal. Calcd. for C H ClN : C, 64.43; H, 3.51;
2
0
13
6
N, 22.54; Found: C, 64.28; H, 3.37; N, 22.39; FT-IR (KBr): ν
= 3478, 3385,
max
−
1
3
122, 3061, 3005, 2867, 2187, 1869, 1668, 1618, 1594, 1563, 1471, 1445 cm ;
1
H-NMR (400 MHz, DMSO-d ): 5.83 (1H, s, CH-11), 7.02 (2H, s, NH ), 7.17
6
2
1
3
(
4H, m, CH-21-24), 7.87 (4H, m, CH-1-3, 6), 8.57 (2H, s, NH, CH-10) ppm; C-
NMR (100 MHz, DMSO-d ): δ = 52.0, 60.6, 113.1, 119.1, 120.6, 123.9, 127.4,
6
1
3

Tandem and transition metal‑free synthesis of novel…
1
1
28.0, 128.2, 128.8, 129.8, 131.8, 133.1, 138.8, 144.0, 147.0, 149.3, 150.2, 150.3,
52.2 ppm.
4
‑Amino‑2‑(2‑chloro‑6‑methoxyquinolin‑3‑yl)‑1,2 dihydrobenzo[4,5]imidazo[1,2‑a]
pyrimidine‑3‑carbonitrile (4b)
Yellow powder, m.p.: 263–266 °C; Anal. calcd. for C H ClN O: C, 62.61; H, 3.75;
2
1
15
6
N, 20.86; Found: C, 62.52; H, 3.85; N, 20.95; FT-IR (KBr): ν
= 3477, 3377,
max
−
1 1
3
121, 3003, 2874, 2177, 1666, 1620, 1591, 1473, 1447 cm ; H-NMR (400 MHz,
DMSO-d ): δ = 3.89 (3H, s, OCH ), 5.79 (1H, s, CH-11), 7.00 (1H, s, NH), 7.17
6
3
(
4H, m, CH-21-24), 7.69 (5H, m, NH , CH-2, 3, 6), 8.41 (1H, s, CH-10) ppm;
2
1
3
C-NMR (100 MHz, DMSO-d ): δ = 51.9, 56.2, 60.6, 106.5, 113.0, 116.7, 120.6,
6
1
23.9, 124.2, 128.8, 129.4, 129.8, 133.4, 137.4, 143.0, 146.4, 150.2, 158.5 ppm.
4
‑Amino‑2‑(2‑chloro‑6‑methylquinolin‑3‑yl)‑1,2‑dihydrobenzo[4,5]imidazo[1,2‑a]
pyrimidine‑3‑carbonitrile (4c)
Yellow powder, m.p.: 256–259 °C; Anal. calcd. for C H ClN : C, 65.20; H, 3.91;
2
1
15
6
N, 21.72; Found: C, 65.11; H, 3.79; N, 21.58; FT-IR (KBr): ν
= 3472, 3374,
max
−
1
1
3
124, 2886, 2183, 1666, 1624, 1593, 1474, 1446 cm ; H-NMR (400 MHz,
DMSO-d ): δ = 5.79 (1H, s, CH-11), 7.00 (1H, s, NH), 7.17 (4H, m, CH-21-24),
6
1
3
7
.80 (5H, m, NH , CH-2, 3, 6), 8.40 (1H, s, CH-10) ppm; C-NMR (100 MHz,
2
DMSO-d ): 21.5, 51.9, 60.6, 113.0, 116.7, 119.0, 120.6, 123.9, 127.4, 127.4, 127.7,
6
1
29.8, 133.1, 133.9, 137.9, 137.9, 145.6, 148.3, 150.2, 150.2, 152.1 ppm.
4
‑Amino‑2‑(2‑chloro‑8‑methylquinolin‑3‑yl)‑1,2‑dihydrobenzo[4,5]imidazo[1,2‑a]
pyrimidine‑3‑carbonitrile (4d)
Yellow powder, m.p.: 262–265 °C; Anal. calcd. for C H ClN : C, 65.20; H, 3.91;
2
1
15
6
N, 21.72; Found: C, 65.28; H, 3.79; N, 21.57; FT-IR (KBr): ν
= 3408, 3263,
max
−
1
1
3
141, 2187, 1677, 1631, 1599, 1470, 1441, 1401 cm ; H-NMR (400 MHz,
DMSO-d ): δ = 2.70 (3H, s, CH -26), 5.84 (1H, s, CH-11), 7.15 (4H, m, CH-21-24),
6
3
1
3
7
.75 (5H, m, NH , CH-1, 2, 6), 8.52 (1H, s, CH-10), 8.57 (1H, s, NH) ppm; C-
2
NMR (100 MHz, DMSO-d ): 17.9, 51.9, 60.7, 112.9, 116.7, 119.0, 120.6, 123.9,
6
1
1
26.6, 127.5, 127.9, 129.8, 131.7, 132.8, 135.9, 139.1, 143.9, 146.1, 148.3, 150.2,
52.2 ppm.
4
‑Amino‑2‑(2,6‑dichloroquinolin‑3‑yl)‑2,10‑dihydrobenzo[4,5]imidazo[1,2‑a]
pyrimidine‑3‑carbonitrile (4e)
Yellow powder, m.p.: 220–225 °C; Anal. calcd. for C H C N C, 58.98; H, 2.97;
2
0
12 l2
6
N, 20.64; Found: C, 58.87; H, 2.76; N, 20.51; FT-IR (KBr): ν = 3391, 3321, 3319,
max
−1 1
2
857, 2177, 1672, 1645, 1595, 1473, 1449 cm ; H-NMR (400 MHz, DMSO-d ):
6
δ = 5.83 (1H, s, CH-11), 7.03 (1H, s, NH), 7.16 (4H, m, CH-21-24), 7.89 (5H, m,
1
3
NH , CH-1, 2, 6), 8.59 (1H, s, NH) ppm; C-NMR (100 MHz, DMSO-d ): 51.9,
2
6
1
3

M. Shiri et al.
6
1
0.3, 113.1, 116.7, 119.0, 120.6, 123.9, 127.5, 128.3, 129.8, 130.1, 132.2, 132.5,
34.3, 138.1, 143.9, 145.5, 149.8, 150.4, 152.1 ppm.
4
‑Amino‑2‑(2‑chloropyridin‑3‑yl)‑2,10‑dihydrobenzo[4,5]imidazo[1,2‑a]
pyrimidine‑3‑carbonitrile (4f)
Yellow powder, m.p.: 234–238 °C; Anal. calcd. for C H ClN C, 59.54; H, 3.44;
1
6
11
6
N, 26.04; Found C, 59.43; H, 3.48; N, 26.11; FT-IR (KBr): ν = 3483, 3384, 3124,
max
−1 1
2
920, 2182, 1666, 1624, 1561, 1475, 1449 cm ; H-NMR (400 MHz, DMSO-d ):
6
δ = 5.67 (1H, s, CH-9), 7.00 (1H, s, NH), 7.16 (4H, m, CH-17, 20), 7.89 (4H, m,
1
3
NH , CH-1, 2, 6), 8.42 (1H, s, NH) ppm; C-NMR (100 MHz, DMSO-d ): 51.4,
2
6
6
1
0.4, 113.0, 116.7, 118.9, 120.6, 123.9, 124.5, 129.8, 136.2, 138.5, 143.9, 149.0,
49.9, 150.3, 152.1 ppm.
4
‑Amino‑2‑(5‑chloro‑3‑methyl‑1‑phenyl‑1H‑pyrazol‑4‑yl)‑2,10‑dihydrobenzo‑[4,5]
imidazo‑[1,2‑a]pyrimidine‑3‑carbonitrile (4g)
Yellow powder, m.p.: 242–246 °C; Anal. calcd. for C H ClN C, 62.77; H, 4.01;
2
1
16
7
N, 24.40; Found C, 62.66; H, 4.11; N, 24.23; FT-IR (KBr): ν
= 3451, 3264,
max
−
1 1
3
041, 2922, 2852, 2229, 1677, 1674, 1502, 1473, 1441 cm ; H-NMR (400 MHz,
DMSO-d ): δ = 2.19 (3H, s, Me), 4.41 (1H, s, NH), 5.42 (1H, s, CH-13), 7.15 (4H,
6
1
3
m, CH-23-26), 7.89 (6H, m, NH , CH-7-11), 8.38 (1H, s, NH) ppm; C-NMR
2
(
100 MHz, DMSO-d ): 12.3, 43.3, 57.5, 109.5, 110.6, 117.3, 119.0, 119.4, 124.7,
6
1
26.3, 128.5, 129.2, 130.5, 137.1, 139.6, 147.0, 150.4, 157.8, 167.3 ppm.
Results and discussion
Initially, 2-chloroquinoline-3-carbaldehydes were synthesized according to the
published procedure [44]. The reaction condition was optimized with 2-chloro-
3
-quinolinecarboxaldehyde 1a and 1H-benzo[d]imidazole-2-amine 2 leading to 3a
(
Scheme 1).
As shown in Table 1, Cs CO was as equally eꢃcient as K CO , and a strong
2
3
2
3
inorganic base like NaOH and KOH did not favor the reaction (Table 1, entries 1–4).
K CO at 120 °C aꢂorded the best yields (Table 1, entry 5). Moreover, among sol-
2
3
vents such as EtOH, MeCN and DMF, the latter provided the best yields (Table 1).
The reaction was also repeated under MW irradiation, which aꢂorded the desired
products in the shortest time.
A variety of 2-chloro-3-quinolinecarboxaldehydes containing electron-donating
and electron-deꢁcient substituents were then examined under both thermal and
microwave conditions (Fig. 1). The best yield resulted from the reaction of 2-amin-
obenzimidazole with aldehydes containing electron-donating groups. The aldehydes
containing electron-withdrawing groups such as Cl and Br were also examined. In
the case of bromide, no product was almost formed even at lengthier time. Alde-
hydes containing chloride aꢂorded the main products in very low yield, as did a
mixture of side products.
1
3

Tandem and transition metal‑free synthesis of novel…
Scheme 1 Reaction of 2-aminobenzimidazole and 2-chloro-3-quinolinecarboxaldehyde
Table 1 Optimization of
Yield (%)a
Entry
Solvent
Catalyst
Temp (°C)
Time
reaction conditions
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
DMF
EtOH
EtOH
MeCN
DMF
Cs CO3
100
100
100
100
100
120
100
100
100
MW
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
5 min
71
70
20
30
40
90
60
23
30
91
2
K CO
2
3
NaOH
KOH
KtOBu
K CO
2
3
HOAc
l-proline
l-proline
K CO
1
0
2
3
Reaction conditions: 2-aminobenzimidazole (1 mmol), 2-chloro-
3
-quinolinecarboxaldehyde 2a (1.1 mmol) and catalyst (1 equiv) in
solvent (5 mL)
a
Isolated yield
To extend the reaction scope, 2-aminobenzimidazole was replaced by more
polar nitrogen containing the anlogue, 3-amino-1,2,4-triazole, and the reaction was
repeated under the same conditions. The reaction with 2-chloroquinoline-3-car-
baldehyde 2a in the presence of K CO in DMF under both reꢀux and MW condi-
2
3
tions did not provide any of the desired product.
Next, we examined a three-component reaction adding malononitrile as a third
fraction to investigate the cyclization pattern and the desired product. 2-Aminoben-
zimidazole 1, 2-chloroquinoline-3-carbaldehyde 2a and malononitrile were reacted
under the same condition of K CO in DMF/reꢀux. Interestingly, the characteriza-
2
3
tion of the product demonstrated that the malononitrile had not participated in the
1
3

M. Shiri et al.
N
N
Me
N
N
N
N
N
N
N
N
N
N
Me
3a, 95%
3b, 90 %
3c, 85%
MeO
N
N
N
N
N
MeO
N
N
N
N
N
N
N
3d, 85 %
3e, 83 %
3f, 85 %
Fig. 1 Various benzo-imidazopyrimido-[4,5-b]quinolones 3a–f
reaction and 3a had been isolated again (Scheme 2). Changing the condition to
EtOH/H O and l-proline as catalyst under the reꢀux condition provided a new prod-
2
1
uct, characterized to be an imidazo-pyrimidine derivative 4a (Scheme 2). H-NMR
spectrum of the puriꢁed product depicted the key signals including a down-ꢁelded
sharp singlet for benzylic hydrogen at 5.8 ppm, and three mobile hydrogens at 7.7
and 8.6 ppm for the NH and NH groups, respectively. It also displayed 9 aromatic
2
protons in predicted chemical shifts between 7.0 and 8.6 ppm.
To reach the best conditions for expanding the reaction, various solvents and
quantities of the catalyst was tried. The best yield of the desired product was
obtained in EtOH/H O as solvent and l-proline as catalyst. This optimal reaction
2
Scheme 2 Three-component reaction of 2-chloro-quinoline-3-carbaldehydes, 2-aminobenzimidazole
and malononitrile
1
3

Tandem and transition metal‑free synthesis of novel…
condition was then applied to the synthesis of diꢂerent derivatives to establish the
generality of the method (Fig. 2). As anticipated, the aldehydes containing electron-
donating groups provided the corresponding products in higher yields than with
electron-donating groups.
As a sample ligand, ꢀuorescence spectra of benzo-imidazopyrimido [4,5-b]qui-
noline derivative 3a were obtained at the excitation wavelength of 350 nm. The
maximum ꢀuorescence intensity was observed at 490 nm with a low concentration
−
5
−1
(
1 × 10 mol L ) related to the extended π-electronic structure (Fig. 3).
To study the applicability of this important property, the aꢃnity of this ligand to
diꢂerent metal ions was also investigated. The ꢀuorescence intensity of the ligand
2
+
2+
2+
3
a was recorded in the presence of diꢂerent metal ions, such as Zn , Cu , Ni ,
2+ 2+ 2+ 2+ 2+ + + 3+ 2+ 2+
Fe , Cd , Co , Mn , Mg , K , Na , Al , and Hg . The eꢂect of Hg was
dramatically diꢂerent from the other metal ions and increased the ꢀuorescence
2
+
intensity of the ligand. Zn showed a slight decrease in ꢀuorescence intensity but
3
+
2+
Al and Ni showed a small enhancement. Moreover, the other metal ions did not
display any change in this ꢁeld. Therefore, the metal ions that might coexist in the
2
+
diverse samples did not interfere in the ꢀuorescence response to Hg . In order to
study the eꢃciency of the sensing eꢂect of the ligand, titration with diꢂerent con-
2
+
centrations of Hg was performed. The ꢀuorescence intensity of the ligand was
2
+
gradually increased upon the concentration molar ratio addition of Hg from 0.05
to 2.0 equivalents (Fig. 3). The eꢃcient ꢀuorescence response of the ligand toward
2
+
Hg demonstrated that the synthetic polycyclic ligand 3, benzo-imidazopyrimido
[
4,5-b]quinoline, can be used as a novel sensor for the detection of this heavy toxic
metal ion in real samples.
Fig. 2 Diꢂerent amino-quinolin-3-yl-dihydrobenzo-imidazo-pyrimidine-3-carbonitriles 4
1
3

M. Shiri et al.
−5
Fig. 3 Fluorescence spectra of polycyclic ligand 3a (1 × 10 M) in DMSO with increasing amounts of
2
+
Hg (0, 0.05, 0.08, 0.1, 0.3, 0.5, 0.8, 1.0, 2.0 equiv.) (λ = 350 nm). Inset the ꢀuorescence intensity at
ex
2
+
4
90 nm of ligand 3a as a function of Hg concentration
Conclusion
A series of N-containing planar aza-heterocycles were developed using K CO in
2
3
DMF via a one-pot transition metal-free cascade process. Since long conjugation
was formed through the cyclization, these new benzo-imidazo-pyrimido-quinoline
2
+
derivatives were demonstrated to be a potent sensor toward Hg compared with
a large number of diꢂerent metal ions examined. Furthermore, the addition of a
third reagent, malononitrile, to the previous starting materials, 2-chloro-quinoline-
3
-carbaldehyde and 2-aminobenzimidazole, did not achieve the expected product in
the same reaction conditions. However, by changing the condition to l-proline/H O/
2
EtOH/reꢀux, the novel amino-quinolin-3-yl-dihydrobenzo-imidazo-pyrimidine-
3
-carbonitrile derivatives were obtained in good yield.
Acknowledgements The authors appreciate ꢁnancial supports from Alzahra University and Iran
National Science Foundation (INSF).
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