Photochemical synthesis of indazolo[3,2-b]quinazolines and their redox-switching properties

Article abstract of DOI:10.1016/j.dyepig.2014.11.020

Several indazolo[3,2-b]quinazolines were synthesized in moderate to good yields by exposing 2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinazolines to UV light (306 nm) in acetonitrile. The scope, limitation, and possible mechanism of this light-mediated reaction as well as the redox-switching properties of the target compounds were explored. Reduction of the colored indazolo[3,2-b]quinazoline with sodium borohydride resulted in a distinct change to colorless and a sharp increase in fluorescence intensity. The reduced product can be swiftly reverted to the original form by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone oxidation. The reversible redox-switching between the indazolo[3,2-b]quinazoline and its reduced product utilizing chemical reduction and oxidation as two external stimuli with dual output properties; that is, color change and emission variation was reported.

Full text of DOI:10.1016/j.dyepig.2014.11.020

Dyes and Pigments 114 (2015) 259e266
Contents lists available at ScienceDirect
Dyes and Pigments
journal homepage: www.elsevier.com/locate/dyepig
Photochemical synthesis of indazolo[3,2-b]quinazolines and their
redox-switching properties
,
*
Shi-Chen Li a, Wei-Fang Jhang a, Teau-Jiuan Liou b, Ding-Yah Yang a
a Department of Chemistry, Tunghai University, No. 1727, Sec. 4, Taiwan Boulevard, Xitun District, Taichung 40704, Taiwan
b Department of Applied English, Chaoyang University of Technology, No. 168, Jifeng E. Rd., Wufeng District, Taichung 41349, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Several indazolo[3,2-b]quinazolines were synthesized in moderate to good yields by exposing 2-(2-
nitrophenyl)-1,2,3,4-tetrahydroquinazolines to UV light (306 nm) in acetonitrile. The scope, limitation,
and possible mechanism of this light-mediated reaction as well as the redox-switching properties of the
target compounds were explored. Reduction of the colored indazolo[3,2-b]quinazoline with sodium
borohydride resulted in a distinct change to colorless and a sharp increase in fluorescence intensity. The
reduced product can be swiftly reverted to the original form by 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone oxidation. The reversible redox-switching between the indazolo[3,2-b]quinazoline and
its reduced product utilizing chemical reduction and oxidation as two external stimuli with dual output
properties; that is, color change and emission variation was reported.
Received 4 October 2014
Received in revised form
21 November 2014
Accepted 25 November 2014
Available online 3 December 2014
Keywords:
Indazolo[3,2-b]quinazoline
Redox switch
Photochemistry
Nitrene
© 2014 Elsevier Ltd. All rights reserved.
Biradical
Fluorescence
1. Introduction
as shown in Fig. 2. The successful formation of an indazole func-
tionality via light-mediated cyclization of an N-(2-nitrobenzyl)an-
Indazoloquinazolines refer to a small family of indazole- and
quinazoline-fused heterocycles, including indazolo[2,3-a]quinazo-
lines [1], indazolo[2,3-c]quinazolines [2], and indazolo[3,2-b]quina-
zolines[3e6](Fig.1).Themolecularscaffoldsofindazoloquinazolines
are rarely present in the natural products, but indazoloquinazoline-
derived compounds have been reported to possess a wide range of
biological activities. Some indazolo[2,3-a]quinazoline derivatives [7],
for instance, were found to exhibit anti-bacterial activity against
Gram-negative bacteria and anti-fungal activity against yeast,
whereas indazolo[2,3-c]quinazoline-11-sulfonamide [2] was
claimed to possess therapeutic activity against inflammation.
Nevertheless, the biological and physical properties of indazolo[3,2-
b]quinazoline derivatives have not yet been described. In light of the
potential biological activity associated with the indazole/
quinazoline-fused molecular structure, we envisage that an effi-
cient preparation of the indazolo[3,2-b]quinazoline derivatives may
facilitate the exploration of their properties.
iline moiety prompted us to examine the possibility of extending
this methodology to the preparation of indazoloquinazolines.
Herein, we describe our efforts to the facile synthesis of indazolo
[3,2-b]quinazoline derivatives by exposing 2-(2-nitrophenyl)-
1,2,3,4-tetrahydroquinazolines to UV light in acetonitrile. The scope
and limitation of this photochemical reaction as well as the prop-
erties of the target compounds were investigated.
2. Experimental
2.1. General
Melting points were determined on a Mel-Temp melting point
apparatus in open capillaries and are uncorrected. MS were per-
formed on JEOL JMS-SX/SX 102A spectrometer. Single crystal
structures were determined by a Bruker AXS SMART-1000 X-ray
single-crystal diffractometer. IR spectra were obtained using a
1725XFT-IR spectrophotometer. Absorption spectra were recorded
using an HP8453 spectrophotometer. Fluorescence spectra were
measured with a Hitachi F-4500 fluorescence spectrophotometer.
1H and 13C NMR spectra were recorded at 300 and 75 MHz on a
Varian VXR300 spectrometer as well as 600 and 150 MHz on a
Varian Unity Inova 600 spectrometer. Chemical shifts were re-
Recently we reported [8] an efficient route for the preparation of
indazolo[2,3-a]quinoline derivatives from 2-(2-nitrophenyl)-
1,2,3,4-tetrahydroquinolines via visible light photoredox catalysis,
* Corresponding author. Tel.: þ886 4 2359 7613; fax: þ886 4 2359 0426.
E-mail address: yang@thu.edu.tw (D.-Y. Yang).
ported in parts per million on the
d scale relative to an internal
http://dx.doi.org/10.1016/j.dyepig.2014.11.020
0143-7208/© 2014 Elsevier Ltd. All rights reserved.

260
S.-C. Li et al. / Dyes and Pigments 114 (2015) 259e266
N
N
N
N
N
N
N
N
N
indazolo[2,3- ]quinazoline
a
indazolo[2,3- ]quinazoline
indazolo[3,2- ]quinazoline
c
b
Fig. 1. Structures of indazoloquinazolines.
standard (tetramethylsilane, or appropriate solvent peaks) with
coupling constants given in hertz. 1H NMR multiplicity data are
denoted by s (singlet), d (doublet), t (triplet), q (quartet), and m
(multiplet). Analytical thin-layer chromatography (TLC) was carried
out on Merck silica gel 60G-254 plates (25 mm) and developed with
the solvents mentioned. Flash chromatography was performed in
columns of various diameters with Merck silica gel (230e400 mesh
ASTM 9385 kieselgel 60H) by elution with the solvent systems. The
visible light irradiation reaction was performed with a 23 W
household fluorescence lamp.
2.3.2. N,N-dimethyl-3-nitro-4-(1,2,3,4-tetrahydroquinazolin-2-yl)
aniline (4b)
Yellow solid; yield 97%; Rf ¼ 0.4 (40% EtOAc/hexanes); mp
115e116 ꢀC; IR nmax (KBr) 3400, 3332, 2871, 1605, 1531, 1483, 1266,
1071, 738 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
7.57 (d, J ¼ 8.7 Hz, 1H),
7.02e7.11 (m, 2H), 6.91 (d, J ¼ 7.2 Hz, 1H), 6.83 (dd, J ¼ 9.0, 3.0 Hz,
1H), 6.71 (t, J ¼ 7.5 Hz,1H), 6.61 (d, J ¼ 8.1 Hz,1H), 5.66 (d, J ¼ 1.8 Hz,
1H), 4.26 (s, 1H), 4.13, 3.85 (ABq, J ¼ 16.5 Hz, 1H each), 3.01 (s, 3H);
13C NMR (CDCl3, 75 MHz)
d 150.1, 150.0, 143.3, 129.1, 127.1, 126.1,
121.9, 121.3, 118.1, 115.4, 115.1, 106.9, 64.4, 45.5, 40.1; HRMS (EI)
calcd for C16H18N4O2 [Mþ] 298.1430, found 298.1435.
2.2. Calculation of fluorescence quantum yield
2.3.3. 2-(6-Nitrobenzo[d][1,3]dioxol-5-yl)-1,2,3,4-
tetrahydroquinazoline (4c)
Quinine hemisulfate salt monohydrate
(Ff
¼
0.546,
Yellow solid; yield 97%; Rf ¼ 0.6 (40% EtOAc/hexanes); mp
lmax ¼ 455 nm in aqueous H2SO4) was used as an external standard
for the measurement of fluorescence quantum yields of 1b and 24.
Fluorescence quantum yields were measured by comparing the
integrated area under the fluorescence curve for compounds 1b, 24,
and quinine sulfate dihydrate at equal absorbance at the same
excitation wavelength. The quantum yields were corrected for the
refractive index of the solvent.
104e105 ꢀC; IR nmax (KBr) 3332, 2779, 1716, 1612, 1501, 1478, 1328,
1251, 1036, 929, 751 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d 7.39 (s, 1H),
7.07 (t, J ¼ 8.1 Hz, 1H), 6.93 (d, J ¼ 7.5 Hz, 1H), 6.74 (td, J ¼ 7.5, 1.2 Hz,
1H), 6.63 (d, J ¼ 8.1 Hz, 1H), 6.12, 6.10 (ABq, J ¼ 1.2 Hz, 1H each), 5.86
(s, 1H), 4.28 (s, 1H), 4.11, 3.82 (ABq, J ¼ 16.5 Hz, 1H each); 13C NMR
(CDCl3, 75 MHz) d 150.4,146.7,143.4,142.7,133.1,126.9,125.8,120.5,
116.3, 114.2, 108.0, 105.4, 103.2, 63.1, 43.5; HRMS (EI) calcd for
C
15H13N3O4 [Mþ] 299.0906, found 299.0903.
2.3. General procedure for the preparation of compounds 4aee
2.3.4. 2-(4-Bromo-2-nitrophenyl)-1,2,3,4-tetrahydroquinazoline
(4d)
To a solution of o-aminobenzylamine (2, 4.1 mmol) in ethanol
(25 mL) was added o-nitrobenzaldehydes (3, 4.1 mmol) and a cat-
alytic amount of ammonium chloride (0.04 mmol) at room tem-
perature. The resulting mixture was stirred at room temperature
for 1e2 h. The precipitate was then filtered and washed with water
and hexanes to afford the desired product.
Yellow solid; yield 98%; Rf ¼ 0.4 (20% EtOAc/hexanes); mp
125e126 ꢀC; IR nmax (KBr) 3412, 3331, 1709, 1606, 1530, 1488, 1364,
1258, 1051, 744 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
7.94 (dd, J ¼ 1.8,
0.9 Hz, 1H), 7.67 (d, J ¼ 1.8 Hz, 2H), 7.08 (t, J ¼ 7.5 Hz, 1H), 6.90 (d,
J ¼ 7.2 Hz, 1H), 6.73 (td, J ¼ 7.5, 1.8 Hz, 1H), 6.66 (d, J ¼ 7.8 Hz, 1H),
5.90 (d, J ¼ 3.3 Hz, 1H), 4.32 (s, 1H), 3.96, 3.63 (ABq, J ¼ 16.8 Hz, 1H
each); 13C NMR (CDCl3, 75 MHz)
d 149.4, 141.9, 135.3, 135.0, 130.5,
2.3.1. 2-(2-Nitrophenyl)-1,2,3,4-tetrahydroquinazoline (4a)
127.5, 127.4, 126.2, 121.9, 121.3, 118.5, 115.2, 63.9, 43.9; HRMS (EI)
calcd for C14H12BrN3O2 [Mþ] 333.0113, found 333.0117.
Yellow solid; yield 95%; Rf ¼ 0.4 (20% EtOAc/hexanes); mp
80e81 ꢀC (lit.9 80e81 ꢀC); IR nmax (KBr) 3412, 3319, 1605, 1523,
1484, 1359, 1255, 1110, 1043, 748 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
7.79 (td, J ¼ 8.1, 1.5 Hz, 2H), 7.57 (td, J ¼ 7.8, 1.5 Hz, 1H), 7.45 (td,
2.3.5. 2-(1-Nitronaphthalen-2-yl)-1,2,3,4-tetrahydroquinazoline
(4e)
J ¼ 7.8, 1.5 Hz, 1H), 7.07 (td, J ¼ 7.5, 1.2 Hz, 1H), 6.91 (d, J ¼ 6.9 Hz,
1H), 6.73 (td, J ¼ 7.5, 1.2 Hz, 1H), 6.65 (dd, J ¼ 8.1, 0.9 Hz, 1H), 5.89 (s,
1H), 4.34 (s, 1H), 4.04, 3.73 (ABq, J ¼ 16.5 Hz, 1H each).
Yellow solid; yield 78%; Rf ¼ 0.4 (20% EtOAc/hexanes); mp
121e122 ꢀC; IR nmax (KBr) 3414, 3326, 1710, 1609, 1528, 1489, 1263,
1116, 1066, 748 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 8.00 (d,
J ¼ 9.0 Hz, 1H), 7.92 (dd, J ¼ 7.2, 2.4 Hz, 1H), 7.79e7.75 (m, 2H),
7.68e7.58 (m, 2H), 7.08 (t, J ¼ 8.7 Hz, 1H), 6.93 (d, J ¼ 7.5 Hz, 1H),
6.75 (td, J ¼ 7.5, 1.2 Hz, 1H), 6.65 (d, J ¼ 8.1 Hz, 1H), 5.62 (d,
J ¼ 1.8 Hz, 1H), 4.32 (bs, 1H), 4.16, 3.90 (ABq, J ¼ 16.5 Hz, 1H each);
OH
OH
O
O
1 mol% Ru(bpy)3Cl2
visible light
acetonitrile, rt
13C NMR (CDCl3, 150 MHz)
d 147.0, 142.6, 133.6, 131.0, 130.5, 128.8,
N
N
N
H
O2N
128.0, 127.6, 127.4, 126.3, 124.4, 124.0, 121.8, 121.3, 118.7, 115.3, 65.5,
45.4; HRMS (EI) calcd for C18H15N3O2 [Mþ] 305.1164, found
305.1160.
Fig. 2. Visible light-mediated preparation of indazolo[2,3-a]quinoline.

S.-C. Li et al. / Dyes and Pigments 114 (2015) 259e266
261
3
O
NO2
N
NO2
NH NO2
NH2
Et3N, CH3I
cat. NH4Cl
+
1
H
N
R
N
H
rt, 2 h
88%
NH2
EtOH, rt
1-2 h, 95-98%
H
R
2
6
4
3
hv (306 nm)
CH3CN
hv (306 nm)
CH3CN
7
N
N 5
N
No reaction
4
R
+
N
N
N
3
R
1
2
5
1
not observed
Scheme 1. Synthesis of the indazolo[3,2-b]quinazolines 1.
2.4. General procedure for the preparation of compounds 1aee, 15,
2.4.3. [1,3]Dioxolo[40,50:5,6]indazolo[3,2-b]quinazoline (1c)
17
Red solid; yield 84%; Rf ¼ 0.6 (40% EtOAc/hexanes); mp
256e257 ꢀC; IR nmax (KBr) 3050, 2910, 1708, 1649, 1492, 1449, 1365,
Photoreactions were performed in the Rayonet photochemical
reactor equipped with 306 nm lamps (8 watts each ꢂ 8). To a so-
lution of 4 (3 ꢂ 10ꢁ3 M) in acetonitrile (20 mL) was irradiated for
90 min. The solution was then concentrated in vacuo and the
product was purified by column chromatography (5e20% EtOAc
and benzene) to give the product.
1301, 1188, 1108, 1042, 954 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d 8.10
(dd, J ¼ 9.0, 0.9 Hz, 1H), 7.90 (d, J ¼ 8.4 Hz, 1H), 7.72e7.78 (m, 2H),
7.51 (td, J ¼ 7.8, 1.2 Hz, 1H), 7.18 (d, J ¼ 0.6 Hz, 1H), 6.12 (s, 2H); 13
C
NMR (CDCl3, 75 MHz) d 152.7, 151.8, 144.3, 144.1, 143.9, 131.3, 130.9,
128.1, 126.1, 125.8, 118.0, 105.7, 101.6, 97.8, 93.3; HRMS (EI) calcd for
C
15H9N3O2 [Mþ] 263.0695, found 263.0698.
2.4.1. Indazolo[3,2-b]quinazoline (1a)
2.4.4. 3-Bromoindazolo[3,2-b]quinazoline (1d)
Red solid; yield 86%; Rf ¼ 0.4 (20% EtOAc/hexanes); mp
Orange solid; yield 65%; Rf ¼ 0.4 (20% EtOAc/hexanes); mp
216e217 ꢀC; IR nmax (KBr) 3043, 1711, 1635, 1439, 1361, 1099, 906,
262e263 ꢀC; IR nmax (KBr) 3044, 1713, 1634, 1425, 1366, 1106, 1038,
741 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 9.66 (s, 1H), 8.54 (d,
918, 745 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 9.64 (s, 1H), 8.36 (d,
J ¼ 8.1 Hz, 1H), 8.22 (d, J ¼ 8.4 Hz, 1H), 7.98 (d, J ¼ 8.7 Hz, 1H),
J ¼ 8.7 Hz, 1H), 8.21 (d, J ¼ 8.7 Hz, 1H), 8.01e7.98 (m, 2H), 7.85 (td,
7.74e7.89 (m, 3H), 7.60 (t, J ¼ 8.1 Hz, 1H), 7.37 (td, J ¼ 8.1, 0.9 Hz,
J ¼ 7.8, 1.5 Hz, 1H), 7.64 (t, J ¼ 7.8 Hz, 1H), 7.42 (dd, J ¼ 8.7, 1.8 Hz,
1H); 13C NMR (CDCl3, 75 MHz)
d 153.8, 144.9, 143.8, 131.4, 131.3,
1H); 13C NMR (CDCl3, 150 MHz)
d 154.4, 144.7, 144.3, 131.9, 131.3,
128.4, 126.9, 125.7, 121.9, 119.9, 119.0, 115.1, 112.1; HRMS (EI) calcd
128.4, 127.2, 125.91, 125.86, 123.4, 123.0, 119.1, 117.7, 110.9; HRMS
for C14H9N3 [Mþ] 219.0796, found 219.0790.
(EI) calcd for C14H8BrN3 [Mþ] 296.9902, found 296.9908.
2.4.2. N,N-dimethylindazolo[3,2-b]quinazolin-3-amine (1b)
Orange solid; yield 62%; Rf ¼ 0.4 (40% EtOAc/hexanes); mp
200 ꢀC (dec.); IR nmax (KBr) 3047, 2900, 1715, 1634, 1435, 1121, 1098,
2.4.5. Benzo[6,7]indazolo[3,2-b]quinazoline (1e)
Red solid; yield 62%; Rf ¼ 0.5 (20% EtOAc/hexanes); mp
902, 770 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 9.44 (s, 1H), 8.29 (d,
264e265 ꢀC; IR nmax (KBr) 3033, 1711, 1614, 1422, 1395, 1325, 1110,
J ¼ 8.7 Hz, 1H), 9.00 (d, J ¼ 8.7 Hz, 1H), 7.87 (d, J ¼ 8.7 Hz, 1H), 7.72
(td, J ¼ 8.1, 1.8 Hz, 1H), 7.48 (t, J ¼ 8.1 Hz, 1H), 6.93 (dd, J ¼ 9.0 Hz,
1H), 6.84 (d, J ¼ 2.1 Hz, 1H), 3.15 (s, 6H); 13C NMR (CDCl3, 75 MHz)
745 cmꢁ1; 1H NMR (C6D6, 600 MHz)
d
9.28 (d, J ¼ 7.8 Hz,1H), 8.80 (s,
1H), 8.52 (d, J ¼ 8.4 Hz, 1H), 8.07 (d, J ¼ 8.4 Hz, 1H), 7.80 (d,
J ¼ 7.8 Hz, 1H), 7.52 (t, J ¼ 7.2 Hz, 1H), 7.47 (d, J ¼ 7.8 Hz, 1H), 7.45 (t,
J ¼ 7.2 Hz, 1H), 7.18e7.10 (m, 1H), 6.96 (d, J ¼ 8.4 Hz, 1H), 6.86 (t,
d
156.6, 153.5, 145.3, 143.7, 130.9, 129.8, 127.8, 125.8, 125.7, 122.4,
118.1, 109.9, 103.5, 92.6, 40.7; HRMS (EI) calcd for C16H14N4 [Mþ]
262.1218, found 262.1213.
J ¼ 6.6 Hz, 1H); 13C NMR (C6D6, 150 MHz)
d 153.4, 145.2, 145.1, 135.6,
131.9, 131.0, 130.3, 128.9, 128.3, 126.4, 126.2, 125.3, 124.8, 123.9,
Fig. 3. Structures of the prepared 1aee.

262
S.-C. Li et al. / Dyes and Pigments 114 (2015) 259e266
Fig. 5. X-ray crystal structures of 4a and 6.
Fig. 4. X-ray crystal structure of 1a.
121.6, 119.2, 118.0, 108.0; HRMS (EI) calcd for C18H11N3 [Mþ]
269.0953, found 269.0959.
resulting mixture was refluxed for 2 h. After cooled down to room
temperature, the precipitate was filtered, and washed with water
and hexanes to give a yellow solid; 91%, Rf ¼ 0.4 (40% EtOAc/
hexanes); mp 192e193 ꢀC; IR nmax (KBr) 3410, 3327, 2901, 1655,
2.4.6. N-(2-carbamoylphenyl)-6-nitrosobenzo[d][1,3]dioxole-5-
carboxamide (15)
1481, 1261, 1034, 879, 748 cmꢁ1 1H NMR (DMSO-d6, 300 MHz)
;
d
8.16 (s, 1H), 7.69 (s, 1H), 7.63 (dd, J ¼ 8.1, 1.8 Hz, 1H), 7.25 (td,
Dark green solid; yield 84%; Rf ¼ 0.6 (40% EtOAc/hexanes); mp
J ¼ 8.1, 1.5 Hz, 1H), 7.21 (s, 1H), 6.93 (s, 1H), 6.77 (d, J ¼ 7.5 Hz, 1H),
6.71 (td, J ¼ 8.1, 1.2 Hz, 1H), 6.30 (t, J ¼ 2.1 Hz, 1H), 6.25, 6.22 (ABq,
162e163 ꢀC; IR nmax (KBr) 3249, 1694, 1583, 1465, 1364, 1281, 1090,
1021, 920, 769 cmꢁ1; 1H NMR (DMSO-d6, 300 MHz)
d 13.00 (s, 1H),
J ¼ 0.9 Hz, 1H each); 13C NMR (DMSO-d6, 150 MHz)
d 163.8, 152.2,
8.19 (dd, J ¼ 8.1, 1.5 Hz, 1H), 7.87 (td, J ¼ 8.1, 1.5 Hz, 1H), 7.75 (d,
148.2, 147.7, 142.2, 134.0, 133.5, 127.7, 118.1, 115.2, 114.8, 107.6,
105.6, 104.1, 62.8; HRMS (EI) calcd for C15H11N3O5 [Mþ] 313.0699,
found 313.0694.
J ¼ 7.5 Hz, 1H), 7.65 (s, 1H), 7.58 (td, J ¼ 8.1, 1.2 Hz, 1H), 6.31 (s, 2H),
6.14 (s, 1H); 13C NMR (DMSO-d6, 150 MHz)
d 198.5, 191.6, 189.9,
187.6, 186.0, 176.4, 172.1, 165.0, 164.6, 163.3, 158.7, 147.1, 141.4, 124.6;
HRMS (EI) calcd for C15H11N3O5 [Mþ] 313.0699, found 313.0691.
2.5.2. 3-Methyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinazoline
(6)
2.4.7. 3-Methyl-2-(6-nitrosobenzo[d][1,3]dioxol-5-yl)quinazolin-
4(3H)-one (17)
To a solution of 4a (100 mg, 0.39 mmol) in methylene chloride
(10 mL) was added triethylamine (39.4 mg, 0.39 mmol) and methyl
iodide (111 mg, 0.47 mmol) at room temperature. The resulting
mixture was stirred at that temperature for 2 h. After completion of
the reaction, water (30 mL) was added to quench the reaction. The
product was then extracted with methylene chloride (20 mL) twice,
and the combined organic phase was dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by column
chromatography to give a yellow solid; yield 88%; Rf ¼ 0.5 (20%
EtOAc/hexanes); mp 56e57 ꢀC; IR nmax (KBr) 3429, 2865, 1709,
Light green solid; yield 85%; Rf ¼ 0.3 (20% EtOAc/hexanes); mp
226e227 ꢀC; IR nmax (KBr) 1674, 1567, 1472, 1346, 1265, 1068, 1014,
921, 771 cmꢁ1
;
1H NMR (DMSO-d6, 300 MHz)
d
8.23 (dd, J ¼ 8.1,
1.5 Hz,1H), 7.86 (ddd, J ¼ 8.7, 7.2, 1.5 Hz,1H), 7.70e7.65 (m, 3H), 7.60
(ddd, J ¼ 8.1, 7.2, 1.2 Hz, 1H), 6.33 (s, 2H), 3.32 (s, 3H); 13C NMR
(DMSO-d6, 150 MHz)
d 198.5, 198.4, 192.5, 191.3, 187.5, 184.3, 177.0,
172.0, 164.8, 164.6, 163.6, 158.0, 146.4, 141.6, 126.0, 70.7; HRMS (EI)
calcd for C16H11N3O4 [Mþ] 309.0750, found 309.0755.
2.5. Preparation of compounds 12, 6, 16, 21, 23, 24
1606, 1520, 1356, 1263, 1056, 834, 748 cmꢁ1
300 MHz)
;
1H NMR (CDCl3,
7.74 (dd, J ¼ 6.6, 1.5 Hz, 1H), 7.67 (d, J ¼ 7.8 Hz, 1H), 7.47
d
2.5.1. 2-(6-Nitrobenzo[d][1,3]dioxol-5-yl)-2,3-dihydroquinazolin-
4(1H)-one (12)
To a solution of 2-aminobenzamide (13, 500 mg, 3.67 mmol) in
ethanol (25 mL) was added 6-nitrobenzo[d][1,3]dioxole-5-
carbaldehyde (14, 716.5 mg, 3.67 mmol) and a catalytic amount
of ammonium chloride (0.18 mmol) at room temperature. The
(td, J ¼ 7.5, 1.5 Hz, 1H), 7.39 (td, J ¼ 7.2, 1.5 Hz, 1H), 7.09 (t, J ¼ 8.4 Hz,
1H), 8.85 (d, J ¼ 7.5 Hz, 1H), 6.72e6.67 (m, 2H), 5.71 (d, J ¼ 4.2 Hz,
1H), 4.38 (bs, 1H), 3.54, 3.37 (ABq, J ¼ 17.4 Hz, 1H each), 2.39 (s, 3H);
13C NMR (CDCl3, 150 MHz)
d 149.1, 140.8, 136.7, 132.0, 129.0, 128.5,
127.6, 127.5, 124.5, 118.4, 118.0, 113.8, 69.5, 49.7, 41.5; HRMS (EI)
calcd for C15H15N3O2 [Mþ] 269.1164, found 269.1159.
H
O
N
N
N
hv
O
N
OH
HO
N
4a
O
N
O
N
N
H
N
H
H
H
8
7
9
- H2O
O
N
N
N
N
- 1/2 O2
+ O2
- H2O
1a
N
N
H
H
11
Scheme 2. Proposed mechanism of the formation of 1a from 4a.
10

S.-C. Li et al. / Dyes and Pigments 114 (2015) 259e266
263
O
O
O
NO2
CH3I
O
N
NO2
O
NH NO2
NaOH
cat. NH4Cl
H
NH2
NH2
13
N
H
THF, rt
1 h, 80%
+
N
H
EtOH, reflux
2 h, 91%
O
O
O
O
16
14
12
O
hv (306 nm)
hv (306 nm)
CH3CN
1.5 h
CH3CN
1.5 h
85%
84%
O
O
NH2
N
NO
O
O
NO
O
N
N
H
O
O
17
15
Scheme 3. Synthesis of 15 and 17.
2.5.3. 3-Methyl-2-(6-nitrobenzo[d][1,3]dioxol-5-yl)-2,3-
2.5.4. 5-(2-Hydroxyethyl)-5H-indazolo[3,2-b]quinazolin-6-ium
dihydroquinazolin-4(1H)-one (16)
(23)
To a solution of 12 (100 mg, 0.32 mmol) in THF (10 mL) was
added sodium hydroxide (64 mg, 1.6 mmol) and methyl iodide
(54 mg, 0.38 mmol) at room temperature. The resulting mixture
was stirred at that temperature for 1 h. After completion of the
reaction, the solution was concentrated and the residue was
neutralized by hydrochloric acid to pH about 6. The product was
then extracted with ethyl acetate (20 mL) twice, and the com-
bined organic phase was dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography to give a yellow solid; yield 80%; Rf ¼ 0.5 (40%
EtOAc/hexanes); mp 211e212 ꢀC; IR nmax (KBr) 3386, 2924, 1737,
1608, 1498, 1260, 1039, 883, 753 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
To a solution of 1a (100 mg, 0.46 mmol) in toluene (5 mL) was
added 2-bromoethanol (85.7 mg, 0.69 mmol) at room temperature.
The resulting mixture was refluxed for 2 days. After cooled down to
room temperature, the precipitate was filtered, and washed with
ethyl acetate and hexanes to give a pink solid. To this solid was
added water (10 mL) and triethylamine to adjust the pH of the
solution to 8. The crude product was then extracted with ethyl
acetate (20 mL) twice, and the combined organic phase was dried
over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography to give a yellow solid; yield
45%; Rf ¼ 0.5 (40% EtOAc/hexanes); mp 81e83 ꢀC; IR nmax (KBr)
3178, 2946, 2351, 1739, 1599, 1451, 1343, 1187, 893, 736 cmꢁ1
;
1H
d
7.95 (d, J ¼ 7.8 Hz, 1H), 7.61 (s, 1H), 7.26e7.22 (m, 2H), 6.82 (t,
NMR (CDCl3, 300 MHz) d 11.10 (s, 1H), 9.98 (s, 1H), 8.32 (d,
J ¼ 7.5 Hz, 1H), 6.77 (s, 1H), 6.50 (d, J ¼ 8.1 Hz, 1H), 6.27 (d,
J ¼ 2.1 Hz, 1H), 6.13, 6.07 (ABq, J ¼ 18.6 Hz, 1H each), 5.39 (s, 1H),
J ¼ 8.7 Hz, 1H), 7.80 (dt, J ¼ 8.4, 1.2 Hz, 1H), 7.64 (dd, J ¼ 7.8, 1.5 Hz,
1H), 7.57 (ddd, J ¼ 9.0, 7.8, 1.8 Hz, 1H), 7.44 (ddd, J ¼ 8.7, 6.6, 1.2 Hz,
1H), 7.36 (d, J ¼ 8.4 Hz, 1H), 7.16 (ddd, J ¼ 8.1, 6.9, 1.2 Hz, 1H), 6.98
(td, J ¼ 7.8, 0.9 Hz,1H), 4.43 (t, J ¼ 5.1 Hz, 2H), 4.14 (q, J ¼ 6.0 Hz, 2H),
3.01 (s, 3H) 13C NMR (CDCl3, 150 MHz)
d 163.6, 153.2, 148.3, 144.0,
141.8, 133.9, 132.7, 128.4, 119.0, 114.5, 114.3, 106.6, 106.5, 103.4,
69.4, 33.2; HRMS (EI) calcd for C16H13N3O5 [Mþ] 327.0855, found
327.0849.
2.84 (t, J ¼ 6.3 Hz, 1H); 13C NMR (CDCl3, 150 MHz)
d 194.9, 145.1,
143.0, 140.6, 136.3, 136.2, 127.7, 119.9, 119.7, 119.4, 118.5, 116.1, 116.0,
O
O
O
HO
NH
HO
NH
O
O
N
N
NH
NO2
O
hv
H
N
N
N
H
H
H
O
O
O
O
19
O
O
18
12
O
NH2
O
H
O
H
N
OH
O
NO
OH
O
N
N
N
N
NH
H
NH
O
O
O
O
15
O
O
20
21
Scheme 4. Proposed mechanism for the formation of 15 from 12.

264
S.-C. Li et al. / Dyes and Pigments 114 (2015) 259e266
108.7, 62.1, 50.3; HRMS (EI) calcd for C16H15N3O2 [Mþ] 281.1164,
found 281.1165.
2.5.5. N,N-dimethyl-7,12-dihydroindazolo[3,2-b]quinazolin-3-
amine (24)
To a solution of 1b (100 mg, 0.46 mmol) in methanol (10 mL)
was added sodium borohydride (1.9 mg, 0.05 mmol) in one portion
at room temperature. After completion of the reaction within
5 min, the solvent was concentrated in vacuo. This mixture was
poured into water. The product was then extracted twice with
methylene chloride to give a white solid, yield 99%; Rf ¼ 0.3 (40%
EtOAc/hexanes); mp 227e229 ꢀC; IR nmax (KBr) 2854, 1709, 1636,
1494, 1363, 1264, 1157, 873, 751 cmꢁ1; 1H NMR (CD3OD, 300 MHz)
Fig. 6. X-ray crystal structures of 15 and 17.
d
7.51 (dd, J ¼ 9.3, 0.9 Hz, 1H), 7.24e7.19 (m, 2H), 6.99e6.93 (m, 2H),
6.70 (dd, J ¼ 9.0, 2.1 Hz,1H), 6.45 (d, J ¼ 2.1 Hz,1H), 5.44 (s, 2H), 2.95
(s, 6H); 13C NMR (CD3OD, 75 MHz)
151.52, 151.51, 136.7, 135.8,
tetrahydropyrimidine moiety adopted the envelope-like confor-
mation with the benzylamine nitrogen (N-3) atom protruding from
the plane. The o-nitrophenyl group of 4a was found to be situated at
the axial position of the envelope-like ring with the nitro group anti
to the aniline nitrogen (N-1) and syn to the benzylamine nitrogen
(N-3). This observation might explain the exclusive formation of 1
in preference to 5 upon UV irradiation of 4 since the benzylamine
nitrogen atom is closer to the o-nitro group to facilitate the
photoinduced electron transfer (the distance between the two ni-
trogen atoms was measured to be only 2.928 Å). Conversely, no
photogenerated product was observed upon UV irradiation of the
N-3-methylated 6 (Scheme 1), indicating that 6 is insensitive to the
applied irradiation conditions. Apparently, the extra methyl group
attached to the N-3 nitrogen blocks the indazole formation be-
tween the benzylamine and nitro group but fails to facilitate the
indazole formation between N-1 nitrogen and nitro group, pre-
sumably due to the fact that the distance between the N-1 nitrogen
and the o-nitrophenyl group remain the same after N-3 methyl-
ation (Fig. 5). Therefore, no photochemical reaction of 6 was
observed.
To further explore the scope and limitation of this photoreac-
tion, compound 12 with a carbonyl group incorporated at the 4-
position of the quinazoline ring was prepared and subsequently
subjected to UV irradiation. Scheme 3 shows the synthesis of 12,
which was prepared by condensation of 2-aminobenzamide (13)
and 6-nitrobenzo[d][1,3]dioxole-5-carbaldehyde (14) in the pres-
ence of NH4Cl in ethanol under conditions [12]. Upon irradiation of
12 in acetonitrile, the major product isolated was the unexpected o-
nitrosobenzamide 15, rather than the desired indazolo[3,2-b]qui-
nazolin-7(12H)-one. Scheme 4 depicts the proposed mechanism for
d
129.3, 128.1, 122.2, 121.1, 115.9, 115.5, 112.1, 102.4, 94.6, 49.5, 41.6;
HRMS (EI) calcd for C16H16N4 [Mþ] 264.1375, found 264.1369.
2.6. DDQ oxidation of compound 24
2.6.1. N,N-dimethylindazolo[3,2-b]quinazolin-3-amine (1b)
To a solution of 24 (66.0, 0.25 mmol) in methylene chloride
(10 mL) was added DDQ (61.0, 0.27 mmol) in one portion at room
temperature. After completion of the reaction within 30 min, the
solvent was concentrated in vacuo. This mixture was poured into
water. The product was then extracted twice with methylene
chloride. The resulting solid was recrystallized from methylene
chloride/hexane to give an orange red solid of 1b quantitatively.
3. Results and discussion
Scheme 1 shows the two-step synthesis of the indazolo[3,2-b]
quinazolines 1. The sequence commenced with NH4Cl-promoted
condensation of o-aminobenzylamine (2) and o-nitro-
benzaldehydes (3) to yield the tetrahydroquinazolines 4 [9e11].
The subsequent UV irradiation of 4 under aerobic conditions in
acetonitrile afforded the target compounds 1. Note that the for-
mation of the indazolo[2,3-a]quinazolines 5 was not observed.
Fig. 3 lists the structures and yields (from 4) of the prepared
compounds 1aee. The molecular structures of 1aee were verified
by 1H and 13C NMR spectroscopy. Among all proton NMR spectra, a
characteristic singlet absorption peak appearing at chemical shift of
9.66e9.44 ppm was observed and assigned to the C-7 hydrogen of
the indazolo[3,2-b]quinazoline moiety (see 1 in Scheme 1 for atom-
numbering). The structure of 1a (R ¼ H, CCDC-980236) was further
confirmed by single-crystal X-ray diffraction analysis as shown in
Fig. 4, explicitly revealing an indazole/quinazoline-fused molecular
skeleton.
HO
5
7
N
Br
N
N
2-bromoethanol
N
Scheme 2 depicts the proposed mechanism of the formation
of 1a from 4a via UV irradiation (306 nm). Presumably, it begins
with photoinduced intramolecular electron transfer from the
benzylamine nitrogen atom to the o-nitrophenyl group of 4a to
yield the biradical species 7. Compound 7 further undergoes
intramolecular proton transfer from the amine hydrogen atom to
the adjacent ortho nitro oxygen to give the nitrene 8. The sub-
sequent NeN bond formation between nitrene nitrogen and ni-
trogen atom of the protonated nitro group of 8 furnishes the N-
oxide 9 which is then dehydrated to the aromatized indazole N-
oxide 10 via 1,4-elimination. Final light-mediated deoxygenation
of 10 affords the 7,12-dihydroindazolo[3,2-b]quinazoline (11)
which is then oxidized in situ by molecular oxygen to give the
target compound 1a.
N
toluene, reflux
2 days
N
1a
22
Et3N
H2O
45%
HO
N
N
N
H
CHO
23
Fig. 5 shows the X-ray crystal structures of 4a (CCDC-980238)
and
6
(CCDC-980239). The former reveals that the 1,2,3,4-
Scheme 5. Synthesis of compound 23.

S.-C. Li et al. / Dyes and Pigments 114 (2015) 259e266
265
N
N
N
NaBH4
DDQ
N
N
N
N
N
H
24
1b
orange
colorless
non-fluorescent
fluoresecent
Scheme 6. Redox switch between 1b and 24.
was confirmed by single-crystal X-ray diffraction analysis as pre-
sented in Fig. 7.
The formation of the hydrolyzed 23 implies that 1a, in the
presence of a suitable nucleophile, is susceptible to 1,4-addition at
the C-7 position of the indazolo[3,2-b]quinazoline moiety. Indeed,
when treated with NaBH4 in methanol, the orange 1b was instantly
converted to the colorless 24. The reduced 24 can be reverted back
to 1b upon 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
oxidation. Fig. 8 shows the UVevis absorption spectra of 1b prior to
and after NaBH4 reduction in methanol. It displays two intense
bands at 252 and 346 nm, and two shoulder bands at 295 and
334 nm, along with a long wavelength broad absorption with
maximum at 465 nm before reduction. Presumably, the broad band
Fig. 7. X-ray crystal structure of 23.
the formation of the o-nitrosobenzamide 15 from 12. It presumably
begins with light-induced hydrogen transfer from the benzylic
hydrogen to nitro group to give the biradical species 18, which may
undergo electron delocalization to the structure 19. The nucleo-
philic attack from the nitro oxygen to the benzylic carbon of 19
yields the benzo[c]isoxazol-1(3H)-ol 20. The subsequent ring
opening of the isoxazolidine ring of 20 gives the 2-hydroxy-2,3-
dihydroquinazolin-4(1H)-one 21. Final ring opening of 2-hydroxy-
2,3-dihydroquinazolin-4(1H)-one moiety of 21 to expel the amide
leaving group affords the product o-nitrosobenzamide 15. A similar
photoconversion of o-nitrophenyl imine to the corresponding o-
nitrosobenzamide has been previously reported [13]. Interestingly,
when the amide nitrogen of 12 was selectively methylated by
methyl iodide in the presence of NaOH as a base in THF (Scheme 3),
the resulting N-methylated 16 was converted to the nitrosophenyl
imine 17 rather than undergoing ring opening reaction upon irra-
diation. The molecular structures of both 15 (CCDC-980240) and 17
(CCDC-980241) were confirmed by the X-ray crystal crystallog-
raphy as presented in Fig. 6.
at 465 nm is attributed to the increased
p delocalization of the
chromophore. The reduction of 1b to the indazole 24 resulted in the
complete disappearance of the long-wavelength absorbance
(465 nm) and the appearance of a short-wavelength band at around
326 nm, which resembles the absorption behavior of N,N-dime-
thylamino substituted indazole moiety.
Scheme 6 depicts the proposed redox switch between N,N-
dimethylindazolo[3,2-b]quinazolin-3-amine
(1b) and 7,12-
dihydroindazolo[3,2-b]quinazoline (24). In addition to color
change, compound 1b also exhibited a variation in emission as a
second output property upon reduction. Fig. 9 shows the emission
spectra of 1b prior to and after NaBH4 reduction. While compound
1b was essentially non-fluorescent in acetonitrile (Ff ¼ 0.007), the
fluorescence intensity at 455 nm increased substantially after
reduction, presumably due to the N,N-dimethylamino substituted
indazole fluorophore of 24. The reduced 24 is highly fluorescent in
acetonitrile (Ff ¼ 0.64) with up to a 91-fold increase in fluorescence
quantum yield after reduction.
With the availability of compounds 1aee, we then focused our
attention on their chemical properties. Upon alkylation of the N-5
position of 1a by 2-bromoethanol in toluene under reflux, the
resulting proposed N-5 alkylated 22 was found to be highly sus-
ceptible to base-mediated hydrolysis to afford the ring-opened 1H-
indazol-3-amine 23 (Scheme 5). The structure of 23 (CCDC-980242)
Fig. 8. UVevis spectra of 1b (3.0 ꢂ 10ꢁ5 M in MeOH) prior to and after NaBH4
Fig. 9. Emission spectra of 1b (3.0 ꢂ 10ꢁ5 M in MeOH) prior to and after NaBH4
reduction.
reduction.

266
S.-C. Li et al. / Dyes and Pigments 114 (2015) 259e266
[2] Bell, S. U. S. patent 3,505,315, 5,7-Dihydro-6-oxo-6h-indazolo(2,3-d)(1,4)
4. Conclusions
benzodiazepines-12-sulfonamides. Chem Abstr 1970, 72, 132808r.
[3] Stevens MFG. Triazines and related products. Part I. 1,3-di-O-cyanophenyl-
triazene. J Chem Soc C 1967:1096.
[4] Stevens HNE, Stevens MFG. Triazines and related products. Part IV. Methyl-
ation of 3-aryl-3,4-dihydro-4-imino-1,2,3-benzotriazines. J Chem Soc C 1970:
2284.
[5] Stevens HNE, Stevens MFG. Triazines and related products. Part V. The
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[6] Gescher A, Stevens MFG, Turnbull CP. Triazines and related products. Part 18.
Decomposition of 1,2,3-benzotriazines and related triazenes with sodium
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Trans 1977;1:103.
In summary, we have developed an efficient route for the con-
struction of indazolo[3,2-b]quinazoline skeleton by exposing
readily available 2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinazolines
to UV light. The prepared compounds were shown to exhibit
redox-switching behavior with color change and emission variation
as two easily detectable output properties. Further evaluation of
their potential to function as materials for organic thin film tran-
sistors is currently in progress.
[7] Yakaiah T, Lingaiah BPV, Narsaiah B, Pranaykumar K, Murthy USN. GdCl3
catalysed Grieco condensation: a facile approach for the synthesis of novel
pyrimidine and annulated pyrimidine fused indazole derivatives in single pot
under mild conditions and their anti-microbial activity. Eur J Med Chem
2008;43:341.
[8] Lin WC, Yang DY. Visible light photoredox catalysis: synthesis of indazolo[2,3-
a]quinolines from 2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinolines. Org Lett
2013;15:4862.
Acknowledgments
The authors thank the National Science Council Taiwan, for
financially supporting this research under Contract No. NSC 102-
2113-M-029-004-MY2.
[9] Correa WH, Papadopoulos S, Radnidge P, Roberts BA, Scott JL. Direct, efficient,
solvent-free synthesis of 2-aryl-1,2,3,4-tetrahydroquinazolines. Green Chem
2002;4:245.
Appendix A. Supplementary data
[10] Sinkkonen J, Zelenin KN, Potapov AA, Lagoda IV, Alekseyev VV, Pihlaja K. Ring-
chain tautomerism in 2-substituted 1,2,3,4-tetrahydroquinazolines A 1H, 13C
and 15N NMR study. Tetrahedron 2003;59:1939.
[11] Mobinikhaledi A, Foroughifar N, Basaki N. Zeolite catalyzed efficient synthesis
of perimidines at room temperature. Turk J Chem 2009;33:555.
[12] Shaabani A, Maleki A, Mofakham H. Click reaction: highly efficient synthesis of
2,3-dihydroquinazolin-4(1H)-ones. Synth Commun 2008;38:3751.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.dyepig.2014.11.020.
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