An efficient and convenient synthesis of heterocycle-fused indazoles via the N-N bond forming reaction of nitroarenes induced by low-valent titanium reagent

Article abstract of DOI:10.1016/j.tet.2013.05.074

A mild and efficient one-pot protocol for the preparation of 8,13-dihydro-7H-indolo[2′,3′:3,4]pyrido[1,2-b]indazole and 5,6-dihydroindazolo[3,2-a]isoquinoline via the reductive cyclization of nitro-aryl substrates mediated by a low-valent titanium reagent has been developed. The attractive features of the current method include an N-N bond formation and the selective reduction of the CN bond and nitro group, both of which were easily achieved in one-pot by controlling the pH of the reaction mixture.

Full text of DOI:10.1016/j.tet.2013.05.074

Tetrahedron 69 (2013) 6721e6726
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient and convenient synthesis of heterocycle-fused
indazoles via the NeN bond forming reaction of nitroarenes
induced by low-valent titanium reagent
*
*
Wei Lin, Ming-Hua Hu, Xian Feng, Cheng-Pao Cao, Zhi-Bin Huang , Da-Qing Shi
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University,
Suzhou 215123, PR China
a r t i c l e i n f o
a b s t r a c t
A mild and efficient one-pot protocol for the preparation of 8,13-dihydro-7H-indolo[20,30:3,4]pyrido[1,2-
b]indazole and 5,6-dihydroindazolo[3,2-a]isoquinoline via the reductive cyclization of nitro-aryl sub-
strates mediated by a low-valent titanium reagent has been developed. The attractive features of the
current method include an NeN bond formation and the selective reduction of the C]N bond and nitro
group, both of which were easily achieved in one-pot by controlling the pH of the reaction mixture.
Ó 2013 Elsevier Ltd. All rights reserved.
Article history:
Received 8 March 2013
Received in revised form 11 May 2013
Accepted 20 May 2013
Available online 29 May 2013
Keywords:
Indolo[20,30:3,4]pyrido[1,2-b]indazole
5,6-Dihydroindazolo[3,2-a]isoquinoline
Nitro-aryl
Reductive cyclization
Low-valent titanium reagent
1. Introduction
(8) the treatment of (o-nitrobenzylidene)amines with either
P(OEt)3, PdCl2(PPh3)2/SnCl2/CO(g), or SnCl2/Et3N/PhSH followed by
Indazole derivatives are an important class of heterocyclic
pharmaceuticals because of their significant and broad spectrum of
biological properties, including antitumor,1 anti-HIV,2 antidepres-
sant,3 antimicrobial,4 anti-inflammatory,5 and contraceptive activ-
ities.6 Compared to 1H-indazoles, 2H-indazoles have been shown to
treatment with tosyl chloride.18 Unfortunately, however, there are
several drawbacks associated with the use of each of these existing
methods that have severely limited their application, including
poor levels of regioselectivity, low yields, the use of expensive li-
gands or reagents, the requirement for forcing reaction conditions
or specialized equipment. With these issues in mind, there is clearly
an urgent need for the development of a simple and efficient
method for the synthesis of 2H-indazoles using readily available
starting materials under mild reaction conditions.
Low-valent titanium reagents have attracted increasing levels of
interest in organic synthesis because of their pronounced ability to
promote the reductive coupling reactions of carbonyl compounds.19
In a recent publication, we described our work toward the synthesis
of heterocycles using low-valent titanium reagents.20 To the best of
our knowledge, there have been few reports about the synthesis of
heterocycle-fused indazoles.18d Herein, we will report the efficient
and convenient synthesis of heterocycle-fused indazole derivatives
via the reductive cyclization of nitro-aryl substrates mediated by
a low-valent titanium reagent.
possess potent levels of affinity for 5-HT1A receptors,7 estrogen
8
receptor a, and the imidazoline I2 receptor.9 Several different
^
synthetic methods have been developed for the construction of this
intriguing 2H-indazole scaffold involving the use of several differ-
ent starting materials, including (1) the direct N-arylation10 or N-
alkylation11 of an indazole; (2) the reductive cyclization of o-
nitrobenzylamines using Sn, Zn, Fe, SnCl2, low-valent titanium, or
an electrochemical method;12 (3) the Pd-catalyzed domino re-
action of 2-halophenyl acetylenes with hydrazines;13 (4) the Fe-
catalyzed NeN bond formation of 2-azidophenyl ketoximes;14
(5) the reaction of 2-chloromethylarylzinc reagents and aryldia-
zonium salts;15 (6) the [3þ2] cycloaddition of arynes and syd-
nones;16 (7) the copper-catalyzed three-component reaction of 2-
bromobenzaldehydes, primary amines, and sodium azide;17 and
2. Results and discussion
* Corresponding authors. Tel.: þ86 512 65880049; fax: þ86 512 65880095;
e-mail addresses: zbhuang@suda.edu.cn (Z.-B. Huang), dqshi@suda.edu.cn, dqshi@
263.net (D.-Q. Shi).
For our preliminary evaluation of the transformation, the re-
ductive cyclization of 1-(2-nitrophenyl)-4,9-dihydro-3H-pyrido
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.074

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W. Lin et al. / Tetrahedron 69 (2013) 6721e6726
[3,4-b]indole (1a), which were synthesized according to procedures
reported in the literature involving the conventional Bisch-
lereNapieralski reaction21 from 2-nitrobenzoic acids and trypt-
amine, was selected as a model reaction (Scheme 1). The reductive
cyclization reaction of 1a was then evaluated under a variety of
different conditions in the presence of several different low-valent
titanium reagents. The results are summarized in Table 1.
1-(2-nitrophenyl)-4,9-dihydro-3H-pyrido[3,4-b]indoles
subjected to the reaction conditions (Scheme 2) and the results are
summarized in Table 2.
1
were
Scheme 2. The synthesis of 8,13-dihydro-7H-indolo[20,30:3,4]pyrido[1,2-b]indazoles 2.
Scheme 1. Model reaction.
Table 2
Table 1
Synthesis of 8,13-dihydro-7H-indolo[20,30:3,4]pyrido[1,2-b]indazoles 2
Optimization of reaction conditions for the synthesis of 2a
Entry
R1
R2
R3
Compound
Isolated yield (%)
Entry
TiCl4/metal (M)
Ratio
Temp (ꢀC)
Base/pH value
Yielda/%
1
2
3
4
5
6
H
H
H
H
H
CH3
H
H
H
H
Cl
H
2a
2b
2c
2d
2e
2f
88
86
92
85
90
91
1
2
3
4
5
6
7
8
TiCl4/Zn
TiCl4/Zn
TiCl4/Fe
TiCl4/Mg
TiCl4/Sm
TiCl4/Fe
TiCl4/Fe
TiCl4/Fe
TiCl4/Fe
TiCl4/Fe
TiCl4/Fe
TiCl4/Fe
TiCl4/Fe
TiCl4/Fe
TiCl4/Fe
TiCl4/Fe
TiCl4/Fe
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:2
1:3
1:5
1:4
1:4
1:4
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
No base/2
TEA/8
TEA/8
TEA/8
TEA/8
TEA/4
TEA/5
TEA/6
TEA/7
TEA/9
TEA/10
TEA/8
TEA/8
TEA/8
TEA/8
TEA/8
TEA/8
10
78
90
89
87
75
78
86
87
89
87
70
87
87
37
45
80
Cl
CH3
H
H
H
CH3
9
10
11
12
13
14
15
16
17
To expand the scope of the current method, 1-(2-nitrophenyl)-
3,4-dihydroisoquinoline (3) was examined as a replacement for the
1-(2-nitrophenyl)-4,9-dihydro-3H-pyrido[3,4-b]indoles
(1)
(Scheme 3). The reductive cyclization products 5,6-dihydroindazolo
[3,2-a]isoquinoline (4) was obtained in isolated yields in excess of
90%. Furthermore, the substituents on the phenethylamine and 2-
nitrobenzoic acid moieties had no effect on the outcome of the
reaction. The results are summarized in Table 3.
40
60
a
Yield was determined by HPLC-MS.
As shown in Table 1, we examined the effect of different low-
valent titanium systems and pH values on the success of the cy-
clization step. When substrate 1a was reduced by TiCl4/Zn and no
base was added, only 10% desired product 2a was obtained (Table 1,
entry 1). When substrate 1a was reduced with different low-valent
titanium reagents in TEA and pH¼8 (Table 1, entries 2e5), TiCl4/Fe,
TiCl4/Mg, and TiCl4/Sm gave similar result of synthesis of 2a (90%,
89%, 87%, respectively) (Table 1, entries 3e5). Considering Fe is
cheaper, we used TiCl4/Fe to further research optimize conditions.
Similar test was carried out at pH value ranging from 4 to 10 with
an increment of 1 each time. The yield of product 2a was increased
as pH value was increased from 4 to 8 (Table 1, entries 6e9 and 3).
However, a further increase of pH value to 9 and 10 failed to im-
prove the yield of product 2a (Table 1, entries 10 and 11). To further
optimize reaction conditions, a similar test was carried out with
different ratio of 1a with low-valent titanium reagent from 1:2 to
1:4. The yield of product 2a was increased as ratio was increased
from 1:2 to 1:4 (Table 1, entries 3, 12, 13). However, a further in-
crease of ratio to 1:5 failed to improve the yield of product 2a (Table
1, entry 14). Moreover, we also try examined the effect of different
temperatures (Table 1, entries 3, 15e17), to our delight at refluxed
the reaction proceeded smoothly in high yield. Therefore, TEA and
pH¼8 was chosen as the reaction condition for all further synthesis
of 8,13-dihydro-7H-indolo[20,30:3,4]pyrido[1,2-b]indazole.
Scheme 3. The synthesis of 5,6-dihydroindazolo[3,2-a]isoquinoline 4.
Table 3
Synthesis of 5,6-dihydroindazolo[3,2-a]isoquinoline 4
Entry
R1
R2
R3
R4
R5
Compound
Isolated yield (%)
1
2
3
4
5
6
7
8
9
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2
CH2
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
CH3O
H
H
H
Cl
CH3
Cl
H
CH3O
CH3O
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
92
94
95
90
95
91
92
94
93
H
Cl
CH3
H
In order to apply this reaction to a library synthesis of
H
8,13-dihydro-7H-indolo[20,30:3,4]-pyrido[1,2-b]indazole 2, various

W. Lin et al. / Tetrahedron 69 (2013) 6721e6726
6723
The structures of all products 2 and 4 were characterized by IR,
1H NMR, 13C NMR spectral data as well as HRMS analysis. The
structure of 4h was further confirmed by X-ray diffraction analy-
sis.22 The molecular structure of 4h is shown in Fig. 1.
synthesized via the reductive cyclization of nitro-aryl substrates
induced by low-valent titanium reagent in the presence of TEA. This
method has several distinct advantages, in that the starting mate-
rials are readily available, the handling procedures required of the
reaction are relatively straightforward, and the substrate scope is
particularly broad.
4. Experimental section
4.1. General
Tetrahydrofuran (THF) was distilled from sodium-benzophenone
immediately prior to use. All the reactions were conducted under N2
atmosphere. Melting points are uncorrected. IR spectra were
recorded on Varian F-1000 spectrometer in KBr with absorptions in
cmꢁ1 1H NMR and 13C NMR were determined on Varian Invoa-
.
300 MHz or Invoa-400 MHz spectrometer in DMSO-d6 or CDCl3
solution. J values are in Hertz. Chemical shifts are expressed in parts
per million downfield from internal standard TMS. HRMS analyses
were carried out using TOF-MS or GCT-TOF instrument.
4.2. Characterization data of 1 and 3 are represented as
follows
Fig. 1. The crystal structure of compound 4h.
The synthesis of compounds 1 and 3 was according to the
literature.21e
4.2.1. 1-(2-Nitrophenyl)-4,9-dihydro-3H-pyrido[3,4-b]indole
(1a). Mp: 144e146 ꢀC (lit.18d 145e147 ꢀC). IR (KBr)
n
: 3397, 3025,
2984, 2874, 1621, 1525, 1445, 1345, 1319, 1291, 1172, 1082 cmꢁ1. 1H
NMR (300 MHz, CDCl3):
A plausible mechanistic pathway to products in Scheme 4, al-
though the details are still unclear. TiCl4 is reduced by iron dust to
give low-valent titanium species. In the initial step, 1-(2-
nitrophenyl)-4,9-dihydro-3H-pyrido[3,4-b]indole (1) was reduced
by low-valent titanium species to I. The nitroso compound I then
cyclized by the nucleophilic attack of the NH group onto the nitroso
group giving intermediate II. Finally, the expected product 2 was
produced by elimination of water promoted by ETA and low-valent
titanium species.
d
(ppm) 3.00 (t, J¼8.4 Hz, 2H, CH2), 4.02 (t,
J¼8.4 Hz, 2H, CH2), 7.13e7.17 (m, 1H, ArH), 7.24 (s, 2H, ArH), 7.55 (t,
J¼7.5 Hz, 1H, ArH), 7.61 (d, J¼7.8 Hz, 2H, ArH), 7.71 (t, J¼7.5 Hz, 1H,
ArH), 7.90 (s, 1H, NH), 8.07 (d, J¼8.1 Hz, 1H, ArH).
4.2.2. 1-(3-Chloro-2-nitrophenyl)-4,9-dihydro-3H-pyrido[3,4-b]in-
dole (1b). Mp: 149e150 ꢀC. IR (KBr)
n: 3067, 2942, 2837, 1593, 1528,
Scheme 4. Proposed mechanism for the synthesis of compound 2.
3. Conclusion
1341, 1320, 1307, 1279, 1174, 1155, 1080, 1042 cmꢁ1
.
1H NMR
(300 MHz, DMSO-d6): (ppm) 2.84e2.94 (m, 2H, CH2), 3.62e3.64
(m,1H, CHeH), 4.06e4.11 (m,1H, CHeH), 7.06 (t, J¼6.9 Hz,1H, ArH),
7.19 (t, J¼7.5 Hz, 1H, ArH), 7.30 (d, J¼7.8 Hz, 1H, ArH), 7.60 (d,
d
In summary, a series of 8,13-dihydro-7H-indolo[20,30:3,4]pyrido
[1,2-b]indazoles and 5,6-dihydroindazolo[3,2-a]isoquinolines were

6724
W. Lin et al. / Tetrahedron 69 (2013) 6721e6726
J¼7.5 Hz, 1H, ArH), 7.77 (t, J¼7.8 Hz, 1H, ArH), 7.98 (d, J¼7.8 Hz, 1H,
ArH), 8.19 (t, J¼8.1 Hz, 1H, ArH), 11.17 (s, 1H, NH).
2834, 1602, 1584, 1567, 1512, 1482, 1460, 1406, 1353, 1334, 1297,
1282, 1265, 1243, 1210, 1161, 1122, 1079, 1048, 1025, 882, 861, 835,
789 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d
(ppm) 2.77 (t, J¼7.6 Hz,
4.2.3. 1-(3-Methyl-2-nitrophenyl)-4,9-dihydro-3H-pyrido[3,4-b]in-
2H, CH2), 3.55 (s, 3H, OCH3), 3.73 (t, J¼7.2 Hz, 2H, CH2), 3.86 (s, 3H,
OCH3), 3.95 (s, 3H, OCH3), 6.36 (s, 1H, ArH), 7.03 (s, 1H, ArH), 7.07 (d,
J¼2.8 Hz, 1H, ArH), 7.26 (dd, J1¼2.8 Hz, J2¼9.2 Hz, 1H, ArH), 8.19 (d,
J¼9.2 Hz, 1H, ArH).
dole (1c). Mp: 138e140 ꢀC. IR (KBr)
n
: 3423, 3103, 2933, 2840,1592,
1517, 1342, 1315, 1305, 1281, 1173, 1154, 1073, 1037 cmꢁ1. 1H NMR
(300 MHz, CDCl3):
d
(ppm) 2.40 (s, 3H, CH3), 2.92 (t, J¼8.4 Hz, 2H,
CH2), 3.93 (t, J¼8.4 Hz, 2H, CH2), 7.11e7.15 (m, 1H, ArH), 7.23 (t,
J¼6.6 Hz, 2H, ArH), 7.36 (d, J¼7.2 Hz, 2H, ArH), 7.42e7.47 (m, 1H,
ArH), 7.59 (d, J¼8.1 Hz, 1H, ArH), 8.10 (s, 1H, NH).
4.2.11. 1-(4,5-Dimethoxy-2-nitrophenyl)-6,7-dimethoxy-3,4-
dihydroisoquinoline (3e). Mp: 176e178 ꢀC. IR (KBr)
n
: 3650, 3630,
3621, 1577, 1560, 1541, 1522, 1508, 1473, 1458, 1353, 1336, 1296,
1257, 1216, 1072, 875, 731, 669, 650 cmꢁ1 1H NMR (300 MHz,
DMSO-d6):
4.2.4. 1-(2-Chloro-6-nitrophenyl)-4,9-dihydro-3H-pyrido[3,4-b]in-
.
dole (1d). Mp: 218e220 ꢀC. IR (KBr)
n
: 3067, 2943, 2835, 1594,1528,
1341, 1321, 1307, 1278, 1175, 1153, 1081, 1044 cmꢁ1 1H NMR
(300 MHz, DMSO-d6): (ppm) 2.81e3.00 (m, 2H, CH2), 3.58e3.70
d
(ppm) 2.77 (t, J¼6.0 Hz, 2H, CH2), 3.56 (s, 3H, CH3O),
.
3.72 (t, J¼5.4 Hz, 2H, CH2), 3.87 (s, 3H, OCH3), 3.94 (s, 3H, OCH3),
3.97 (s, 3H, OCH3), 6.39 (s, 1H, ArH), 7.02 (s, 1H, ArH), 7.08 (s, 1H,
ArH), 7.72 (s, 1H, ArH).
d
(m, 1H, CHeH), 4.05e4.13 (m, 1H, CHeH), 7.07 (t, J¼7.2 Hz, 1H, ArH),
7.20 (t, J¼7.5 Hz, 1H, ArH), 7.31 (d, J¼8.1 Hz, 1H, ArH), 7.62 (d,
J¼7.8 Hz, 1H, ArH), 7.79 (t, J¼8.1 Hz, 1H, ArH), 8.01 (d, J¼8.1 Hz, 1H,
ArH), 8.20 (t, J¼8.1 Hz, 1H, ArH), 11.18 (s, 1H, NH).
4.2.12. 1-(3-Chloro-2-nitrophenyl)-6,7-dimethoxy-3,4-dihydroisoqui-
noline (3f). Mp: 142e143 ꢀC. IR (KBr)
n
: 3630, 3555, 3477, 3414,
2963, 1637, 1597, 1559, 1534, 123, 1508, 1474, 1458, 1375, 1358, 1333,
1262, 1099, 1022, 802, 669 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
d (ppm) 2.99e3.00 (m, 2H, CH2), 3.65 (s, 3H, OCH3), 3.93e3.95 (m,
4.2.5. 1-(5-Methyl-2-nitrophenyl)-4,9-dihydro-3H-pyrido[3,4-b]in-
.
dole (1e). Mp: 190e192 ꢀC (lit.18d 189e191 ꢀC). IR (KBr)
n
: 3424,
3102, 2935, 2841,1590,1516,1342,1315,1305,1281,1171,1152,1072,
1035 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
(ppm) 2.45 (s, 3H, CH3),
5H, OCH3þCH2), 6.67 (s,1H, ArH), 7.24 (s,1H, ArH), 7.93e7.94 (m, 2H,
d
ArH), 8.11e8.12 (m, 1H, ArH).
2.86e2.92 (m, 2H, CH2), 3.86 (t, J¼7.5 Hz, 2H, CH2), 7.03e7.08 (m,
1H, ArH), 7.16e7.20 (m, 1H, ArH), 7.31 (d, J¼8.1 Hz, 1H, ArH), 7.41 (s,
1H, ArH), 7.53e7.61 (m, 2H, ArH), 8.08 (d, J¼7.8 Hz, 1H, ArH), 11.02
(s, 1H, NH).
4.2.13. 6,7-Dimethoxy-1-(3-methyl-2-nitrophenyl)-3,4-dihydroisoqui-
noline (3g). Mp: 138e140 ꢀC. IR (KBr)
n: 3584, 3563, 3479, 3415,
1615,1602,1568, 1538,1524,1505,1463,1454,1357, 1321, 1275, 1235,
1214, 1123, 1024, 885, 875, 834, 808, 753 cmꢁ1. 1H NMR (400 MHz,
4.2.6. 1-(2-Methyl-6-nitrophenyl)-4,9-dihydro-3H-pyrido[3,4-b]in-
CDCl3):
d
(ppm) 2.45 (s, 3H, CH3), 2.76 (t, J¼7.6 Hz, 2H, CH2), 3.71 (s,
dole (1f). Mp: 206e208 ꢀC. IR (KBr)
n
: 3425, 3107, 2933, 2840, 1592,
1517, 1342, 1316, 1304, 1286, 1174, 1151, 1077, 1038 cmꢁ1 1H NMR
(300 MHz, DMSO-d6):
3H, OCH3), 3.80 (t, J¼7.6 Hz, 2H, CH2), 3.94 (s, 3H, OCH3), 6.56 (s, 1H,
ArH), 6.76 (s, 1H, ArH), 7.35e7.40 (m, 2H, ArH), 7.47 (t, J¼7.6 Hz,
1H, ArH).
.
d
(ppm) 2.35 (s, 3H, CH3), 2.83 (t, J¼8.4 Hz,
2H, CH2), 3.77 (t, J¼8.4 Hz, 2H, CH2), 7.05 (t, J¼7.5 Hz, 1H, ArH), 7.19
(t, J¼8.1 Hz, 1H, ArH), 7.35 (d, J¼8.4 Hz, 1H, ArH), 7.46 (d, J¼6.6 Hz,
1H, ArH), 7.60 (t, J¼7.2 Hz, 3H, ArH), 11.09 (s, 1H, NH).
4.2.14. 5-(2-Nitrophenyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquino-
line (3h). Mp: 100e101 ꢀC. IR (KBr)
n
: 3585, 3562, 2931, 2835, 1589,
1519, 1468, 1456, 1441, 1342, 1321, 1305, 1265, 1224, 1193, 1175,
1025, 950, 885, 719 cmꢁ1 1H NMR (400 MHz, CDCl3):
(ppm)
4.2.7. 6,7-Dimethoxy-1-(5-methyl-2-nitrophenyl)-3,4-
.
d
dihydroisoquinoline (3a). Mp: 138e140 ꢀC (lit.18d 137e139 ꢀC). IR
2.80e2.81 (m, 2H, CH2), 3.80e3.81 (m, 2H, CH2), 5.93 (s, 2H, CH2),
6.28 (s,1H, ArH), 6.74 (s,1H, ArH), 7.52e7.53 (m,1H, ArH), 7.60e7.61
(m, 1H, ArH), 7.70e7.71 (m, 1H, ArH), 8.11 (d, J¼7.6 Hz, 1H, ArH).
(KBr)
1464, 1455, 1356, 1322, 1277, 1236, 1215, 1124, 1025, 884, 874, 835,
809, 754 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
(ppm) 2.45 (s, 3H,
n: 3585, 3564, 3477, 3409, 1614, 1601, 1569, 1539, 1525, 1504,
d
CH3), 2.71 (t, J¼7.5 Hz, 2H, CH2), 3.50 (s, 3H, OCH3), 3.66 (t, J¼7.2 Hz,
2H, CH2), 3.82 (s, 3H, OCH3), 6.31 (s, 1H, ArH), 6.98 (s, 1H, ArH), 7.39
(s, 1H, ArH), 7.51 (d, J¼8.1 Hz, 1H, ArH), 8.01 (d, J¼8.4 Hz, 1H, ArH).
4.2.15. 5-(4-Chloro-2-nitrophenyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]
isoquinoline (3i). Mp: 220e222 ꢀC. IR (KBr)
n: 2959, 2941, 2898,
2857,1610,1594,1585,1510,1483,1446,1427,1401,1373,1339,1313,
100, 1266, 1240, 1213, 1166, 1076, 1037, 932, 874, 845, 828, 801, 756.
4.2.8. 1-(5-Chloro-2-nitrophenyl)-6,7-dimethoxy-3,4-dihydroisoqui-
1H NMR (300 MHz, DMSO-d6):
d (ppm) 3.13e3.14 (m, 2H, CH2),
noline (3b). Mp: 164e165 ꢀC. IR (KBr)
n: 3552, 3475, 3415, 2932,
3.92e3.93 (m, 2H, CH2), 6.17 (s, 2H, CH2), 6.82 (s, 1H, ArH), 7.22 (s,
1H, ArH), 7.87 (d, J¼7.8 Hz, 1H, ArH), 8.15 (d, J¼7.5 Hz, 1H, ArH), 8.49
(s, 1H, ArH).
2836,1605,1561,1525,1465,1455,1388,1354,1334,1318,1320,1291,
1268, 1233, 1213, 1175, 1123, 1101, 1078, 1025, 887, 874, 836, 809,
754 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d
(ppm) 2.73 (t, J¼6.8 Hz,
2H, CH2), 3.56 (s, 3H, OCH3), 3.70 (t, J¼6.8 Hz, 2H, CH2), 3.84 (s, 3H,
OCH3), 6.40 (s, 1H, ArH), 7.01 (s, 1H, ArH), 7.70 (s, 1H, ArH), 7.83 (d,
J¼8.8 Hz, 1H, ArH), 8.15 (dd, J1¼2.4 Hz, J2¼8.8 Hz, 1H, ArH).
4.3. General procedure for the synthesis of triazaindeno[1,2-
a]fluorene 2 and 5,6-dihydro-indazolo[3,2-a]isoquinoline 4
TiCl4 (0.44 mL, 4 mmol) was added a stirred suspension of iron
powder (0.23 g, 4 mmol) in freshly distilled anhydrous THF (10 mL)
at room temperature (rt) under a dry N2 atmosphere. After com-
pletion of the addition, the mixture was refluxed for 2 h. The sus-
pension of the low-valent titanium reagent formed was cooled to rt,
and then, 8 mL TEA was added; the pH was about 8. A solution of
nitro-aryl substrates (1 or 3) 1 mmol in THF (3 mL) was added
dropwise. The reaction mixture was then refluxed for 2 h under N2.
After this period, the thin layer chromatography (TLC) analysis of
the mixture showed the reaction to be complete. The reaction
mixture was quenched with 18% HCl (15 mL) and extracted with
CHCl3 (3ꢂ40 mL). The combined extracts were washed with water
4.2.9. 6,7-Dimethoxy-1-(2-nitrophenyl)-3,4-dihydroisoquinoline
(3c). Mp: 114e116 ꢀC (lit.18d 113e115 ꢀC). IR (KBr)
n: 3551, 3474, 3414,
1637, 1616, 1567, 1526, 1471, 1457, 1442, 1352, 1323, 1307, 1283, 1268,
1235, 1215, 1192, 1177, 1122, 1024, 948, 883, 808, 720, 618 cmꢁ1. 1H
NMR (400 MHz, DMSO-d6):
d
(ppm) 2.72 (t, J¼7.6 Hz, 2H, CH2), 3.52
(s, 3H, OCH3), 3.68 (t, J¼7.6 Hz, 2H, CH2), 3.83 (s, 3H, OCH3), 6.37 (s,
1H, ArH), 6.99 (s,1H, ArH), 7.59 (d, J¼7.6 Hz,1H, ArH), 7.71 (t, J¼7.6 Hz,
1H, ArH), 7.82 (t, J¼7.2 Hz, 1H, ArH), 8.08 (d, J¼8.0 Hz, 1H, ArH).
4.2.10. 6,7-Dimethoxy-1-(5-methoxy-2-nitrophenyl)-3,4-dihydroiso-
quinoline (3d). Mp: 126e128 ꢀC. IR (KBr)
n: 3552, 3480, 3414, 2937,

W. Lin et al. / Tetrahedron 69 (2013) 6721e6726
6725
(3ꢂ40 mL) and dried over anhydrous Na2SO4. After evaporation
of the solvent under reduced pressure, the crude product was pu-
rified by recrystallization from 95% ethanol to give the pure prod-
ucts 2 or 4.
132.2, 143.1, 153.1. HRMS: m/z (Mþ) calcd for C18H15N3: 273.1266;
found: 273.1266.
4.3.7. 2,3-Dimethoxy-11-methyl-5,6-dihydroindroindazolo[3,2-a]iso-
quinoline (4a). Mp: 150e152 ꢀC (lit.18d 152e154 ꢀC). IR (KBr)
n:
4.3.1. 8,13-Dihydro-7H-indolo[20,30:3,4]pyrido[1,2-b]indazole
3686, 3646, 2928, 2855, 2356, 2328, 1915, 1866, 1823, 1790, 1747,
1731, 1714, 1538, 1496, 1463, 1452, 1347, 1269, 1253, 1219, 1207,
(2a). Mp: 257e259 ꢀC (lit.18d 256e258 ꢀC). IR (KBr)
n
: 3191, 3060,
2927, 1624, 1505, 1436, 1394, 1345, 1311, 1295, 1230, 1175, 1145, 1116,
1090, 1005 cmꢁ1 1H NMR (300 MHz, CDCl3):
(ppm) 3.37 (t,
807 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d (ppm) 2.44 (s, 3H, CH3),
.
d
3.16 (t, J¼7.2 Hz, 2H, CH2), 3.82 (s, 3H, OCH3), 3.92 (s, 3H, OCH3),
4.51 (t, J¼6.8 Hz, 2H, CH2), 7.08 (s, 1H, ArH), 7.12 (d, J¼8.8 Hz, 1H,
ArH), 7.43 (s, 1H, ArH), 7.52 (d, J¼8.8 Hz, 1H, ArH), 7.84 (s, 1H, ArH).
J¼7.5 Hz, 2H, CH2), 4.76 (t, J¼7.5 Hz, 2H, CH2), 7.13e7.22 (m, 3H,
ArH), 7.32 (t, J¼7.2 Hz, 1H, ArH), 7.47 (d, J¼7.8 Hz, 1H, ArH), 7.59 (d,
J¼7.5 Hz, 1H, ArH), 7.74 (d, J¼9.0 Hz, 1H, ArH), 7.86 (d, J¼8.4 Hz, 1H,
ArH), 8.72 (s, 1H, NH).
13C NMR (100 MHz, DMSO-d6):
d (ppm) 27.2, 33.7, 53.1, 61.4, 61.7,
113.1, 118.1, 122.9, 122.9, 124.4,125.7, 130.8, 133.9,134.7, 136.3, 152.2,
153.8, 154.1.
4.3.2. 4-Chloro-8,13-dihydro-7H-indolo[20,30:3,4]pyrido[1,2-b]in-
dazole (2b). Mp: 175e177 ꢀC. IR (KBr)
n
: 3186, 3105, 2905, 1645,
1475,1445,1365,1335,1316,1233,1169, 1148,1115,1092,1057 cmꢁ1
1H NMR (300 MHz, CDCl3):
4.3.8. 11-Chloro-2,3-dimethoxy-5,6-dihydroindroindazolo[3,2-a]iso-
.
quinoline (4b). Mp: 162e164 ꢀC. IR (KBr)
n
: 3677, 36,430, 3589,
2938, 2366, 2328, 1905, 1876, 1813, 17,905, 1748, 1737, 1560, 1542,
1508, 1489, 1458, 1347, 1264, 1243, 1210, 1203, 802, 669 cmꢁ1 1H
NMR (400 MHz, DMSO-d6):
d
(ppm) 3.37 (t, J¼7.5 Hz, 2H, CH2), 4.75
(t, J¼7.5 Hz, 2H, CH2), 7.09e7.22 (m, 4H, ArH), 7.47 (d, J¼8.1 Hz, 1H,
ArH), 7.59 (d, J¼7.5 Hz, 1H, ArH), 7.64 (d, J¼8.4 Hz, 1H, ArH), 9.43 (s,
.
d
(ppm) 3.18 (t, J¼6.8 Hz, 2H, CH2), 3.82
1H, NH). 13C NMR (100 MHz, DMSO-d6):
d
(ppm) 25.5, 55.2, 115.2,
(s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.55 (t, J¼6.4 Hz, 2H, CH2), 7.10 (s,
1H, ArH), 7.27 (d, J¼9.2 Hz, 1H, ArH), 7.40 (s, 1H, ArH), 7.67 (d,
J¼9.2 Hz, 1H, ArH), 8.18 (s, 1H, ArH). 13C NMR (100 MHz, DMSO-d6):
118.6, 121.0, 122.4, 124.1, 125.5, 127.4, 128.1, 129.2, 130.3, 131.0, 131.9,
132.1, 143.1, 153.9. HRMS: m/z (Mþ) calcd for C17H1235ClN3:
293.0720; found: 293.0718.
d
(ppm) 33.5, 53.3, 61.4, 61.7, 113.3, 117.9, 122.9, 124.8, 125.0, 125.2,
131.1, 131.7, 132.2, 135.8, 151.6, 153.9, 154.6. HRMS: m/z [MþH]þ
4.3.3. 4-Methyl-8,13-dihydro-7H-indolo[20,30:3,4]pyrido[1,2-b]in-
calcd for C17H1635ClN2O2: 315.0900; found: 315.0890.
dazole (2c). Mp: 160e162 ꢀC. IR (KBr)
n
: 3192, 2932, 1632, 1590,
1512, 1444, 1395, 1345, 1310, 1292, 1229, 1174, 1142, 1119, 1082,
1007 cmꢁ1. 1H NMR (300 MHz, CDCl3):
(ppm) 2.65 (s, 3H, CH3),
4.3.9. 2,3-Dimethoxy-5,6-dihydroindroindazolo[3,2-a]isoquinoline
d
(4c). Mp: 181e182 ꢀC (lit.18d 180e182 ꢀC). IR (KBr)
n
: 3060, 2934,
2832, 1608, 1530, 1496, 1456, 1404, 1341, 1288, 1216, 1112, 1035,
1000, 858, 796, 741, 685, 645, 597, 577 cmꢁ1 1H NMR (400 MHz,
DMSO-d6):
3.32 (t, J¼7.5 Hz, 2H, CH2), 4.74 (t, J¼7.5 Hz, 2H, CH2), 7.04e7.07 (m,
2H, ArH), 7.18e7.23 (m, 2H, ArH), 7.42 (d, J¼8.4 Hz, 1H, ArH), 7.57 (d,
J¼6.9 Hz, 1H, ArH), 7.72 (d, J¼7.8 Hz, 1H, ArH), 9.14 (s, 1H, NH). 13C
.
d
(ppm) 3.18 (t, J¼6.4 Hz, 2H, CH2), 3.82 (s, 3H, OCH3),
NMR (75 MHz, CDCl3):
d
(ppm) 17.5, 21.2, 49.3, 108.5, 111.8, 116.4,
3.92 (s, 3H, OCH3), 4.55 (t, J¼6.8 Hz, 2H, CH2), 7.08 (s, 1H, ArH), 7.14
(t, J¼8.0 Hz, 1H, ArH), 7.29 (t, J¼7.6 Hz, 1H, ArH), 7.45 (s, 1H, ArH),
7.63 (d, J¼8.4 Hz, 1H, ArH), 8.13 (d, J¼8.4 Hz, 1H, ArH). 13C NMR
116.9,118.8,120.9,122.8, 123.1,125.8,126.4,126.8,127.3,128.1,137.8,
148.7. HRMS: m/z (Mþ) calcd for C18H15N3: 273.1266; found:
273.1264.
(100 MHz, DMSO-d6):
d (ppm) 33.6, 53.2, 61.4, 61.6, 113.0, 118.0,
122.7, 123.0, 125.4, 126.4, 127.3, 130.9, 131.3, 135.6, 153.3, 153.8,
154.3.
4.3.4. 1-Chloro-8,13-dihydro-7H-indolo[20,30:3,4]pyrido[1,2-b]in-
dazole (2d). Mp: 266e268 ꢀC. IR (KBr)
n
: 3187, 3105, 2911, 1635,
1509, 1465, 1385, 1340, 1310, 1290, 1231, 1171, 1142, 1115, 1092,
1002 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
4.3.10. 2,3,11-Trimethoxy-5,6-dihydroindroindazolo[3,2-a]isoquino-
d
(ppm) 3.28 (t, J¼7.2 Hz,
line (4d). Mp: 154e156 ꢀC. IR (KBr)
n
: 3552, 3480, 3414, 2890, 2829,
1637, 1618, 1585, 1540, 1499, 1465, 1438, 1362, 1351, 1322, 1297,
1285, 1253, 1223, 1203, 1179, 816, 622 cmꢁ1 1H NMR (400 MHz,
DMSO-d6):
2H, CH2), 4.68 (t, J¼7.5 Hz, 2H, CH2), 7.07e7.27 (m, 4H, ArH),
7.56e7.68 (m, 3H, ArH), 10.59 (s, 1H, NH). 13C NMR (100 MHz,
.
DMSO-d6):
d
(ppm) 25.6, 55.2, 115.2, 118.6, 121.1, 122.4, 124.1, 125.6,
d
(ppm) 3.17 (t, J¼6.8 Hz, 2H, CH2), 3.83 (s, 3H, CH3O),
127.4, 128.2, 129.3, 130.4, 131.1, 131.9, 132.1, 143.2, 154.0. HRMS: m/z
3.88 (s, 3H, CH3O), 3.93 (s, 3H, CH3O), 4.51 (t, J¼7.2 Hz, 2H, CH2),
6.98 (dd, J1¼2.0 Hz, J2¼9.2 Hz, 1H, ArH), 7.08 (s, 1H, ArH), 7.29 (d,
J¼4.0 Hz, 1H, ArH), 7.42 (s, 1H, ArH), 7.56 (d, J¼9.6 Hz, 1H, ArH).
HRMS: m/z [MþH]þ calcd for C18H19N2O3: 311.1396; found:
311.1401.
(Mþ) calcd for C17H1235ClN3: 293.0720; found: 293.0712.
4.3.5. 2-Methyl-8,13-dihydro-7H-indolo[20,30:3,4]pyrido[1,2-b]in-
dazole (2e). Mp: 255e257 ꢀC (lit.18d 254e257 ꢀC). IR (KBr)
n
: 3185,
3105, 2925, 1630, 1594, 1515, 1445, 1398, 1350, 1309, 1290, 1235,
1175, 1143, 1110, 1083, 1002 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
.
4.3.11. 2,3,10,11-Tetramethoxy-5,6-dihydroindroindazolo[3,2-a]iso-
quinoline (4e). Mp: 182e184 ꢀC. IR (KBr)
n: 2937, 2922, 1611, 1551,
d
(ppm) 2.44 (s, 3H, CH3), 3.27 (t, J¼7.2 Hz, 2H, CH2), 4.65 (t,
J¼6.9 Hz, 2H, CH2), 7.06e7.16 (m, 3H, ArH), 7.48e7.55 (m, 3H, ArH),
1499, 1458, 1449, 1436, 1398, 1371, 1320, 1303, 1290, 1260, 1229,
8.09 (s, 1H, ArH), 11.74 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6):
1191, 1169, 1156, 1112, 1028, 1011, 977, 860, 814, 784 cmꢁ1. 1H NMR
d
(ppm) 20.3, 21.5, 48.7, 106.9, 111.9, 116.3, 117.1, 118.4, 118.6, 119.7,
(400 MHz, DMSO-d6):
d
(ppm) 3.12 (t, J¼6.8 Hz, 2H, CH2), 3.80 (s,
122.0, 125.7, 125.8, 126.1, 128.6, 130.5, 137.7, 146.4.
6H, 2ꢂ CH3O), 3.86 (s, 3H, CH3O), 3.90 (s, 3H, CH3O), 4.42 (d,
J¼6.8 Hz, 2H, CH2), 6.97 (s, 1H, ArH), 7.05 (s, 1H, ArH), 7.24 (s, 1H,
4.3.6. 1-Methyl-8,13-dihydro-7H-indolo[20,30:3,4]pyrido[1,2-b]in-
ArH), 7.37 (s, 1H, ArH). 13C NMR (75 MHz, DMSO-d6):
d (ppm) 28.9,
dazole (2f). Mp: 261e263 ꢀC. IR (KBr)
n
: 3195, 2935, 1647, 1572,
1473, 1442, 1362, 1332, 1312, 1232, 1165, 1143, 1117, 1094,
1055 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
(ppm) 2.51 (s, 3H,
47.8, 56.0, 56.2, 56.3, 56.6, 96.9, 99.0, 107.9, 111.6, 113.0, 120.7, 125.6,
129.6, 144.7, 148.1, 148.6, 148.8, 151.2. HRMS: m/z (Mþ) calcd for
C19H20N2O4: 340.1423; found: 304.1431.
.
d
CH3), 3.29e3.30 (m, 2H, CH2), 4.70 (t, J¼6.0 Hz, 2H, CH2), 7.04e7.05
(m, 3H, ArH), 7.11e7.17 (m, 1H, ArH), 7.48 (d, J¼6.9 Hz, 1H, ArH),
7.56 (d, J¼6.6 Hz, 1H, ArH), 8.11 (s, 1H, ArH), 11.73 (s, 1H, NH). 13C
4.3.12. 9-Chloro-2,3-dimethoxy-5,6-dihydroindroindazolo[3,2-a]iso-
quinoline (4f). Mp: 174e176 ꢀC. IR (KBr)
n
: 3435, 3062, 1723, 1635,
1610, 1538, 1500, 1486, 1466, 1424, 1374, 1332, 1292, 1261, 1239,
1198, 1120, 1075, 1058, 1025, 800, 754, 681, 566 cmꢁ1 1H NMR
NMR (75 MHz, DMSO-d6):
d (ppm) 22.3, 25.7, 54.1, 112.6, 117.3,
121.2, 123.3, 123.9, 125.1, 127.2, 127.5, 130.3, 131.2, 131.4, 132.1,
.

6726
W. Lin et al. / Tetrahedron 69 (2013) 6721e6726
(400 MHz, CDCl3):
d
(ppm) 3.19 (t, J¼7.2 Hz, 2H, CH2), 3.94 (s, 3H,
College Graduate Research and Innovation Project of Jiangsu
Province Department of Education (CXZZ12_0809).
CH3O), 4.00 (s, 3H, CH3O), 4.65 (t, J¼6.8 Hz, 2H, CH2), 6.84 (s, 1H,
ArH), 7.06 (t, J¼8.0 Hz, 1H, ArH), 7.33 (d, J¼7.2 Hz, 1H, ArH), 7.40 (s,
1H, ArH), 7.84 (d, J¼8.4 Hz, 1H, ArH). 13C NMR (75 MHz, CDCl3):
References and notes
d
(ppm) 23.5, 42.9, 50.9, 51.1, 102.1, 106.3, 113.6, 113.9, 114.9, 117.0,
117.8, 119.9, 120.2, 126.9, 140.8, 143.3, 143.9. HRMS: m/z (Mþ) calcd
1. (a) Keppler, B. K.; Hartmann, M. Met.-Based Drugs 1994, 1, 145e150; (b) Baraldi,
P. G.; Balbonic, G.; Pavani, M. G.; Spalluto, G.; Tabrizi, M. A.; Clercq, E. D.; Bal-
zarini, J.; Bando, T.; Sugiyama, H.; Romagnoli, R. J. Med. Chem. 2001, 44,
2536e2543.
2. Rodgers, J. D.; Johnson, B. L.; Wang, H.; Greenberg, R. A.; Erickson-Viitanen, S.;
Klabe, R. M.; Cordova, B. C.; Rayer, M. M.; Lam, G. N.; Chang, C. H. Bioorg. Med.
Chem. Lett. 1996, 6, 2919e2924.
3. Ykeda, Y.; Takano, N.; Matsushita, H.; Shiraki, Y.; Koide, T.; Nagashima, R.; Fu-
jimura, Y.; Shindo, M.; Suzuki, S.; Iwasaki, T. Arzneim.-Forsch. 1979, 29, 511e520.
4. Li, X.; Chu, S.; Feher, V. A.; Khalili, M.; Nie, Z.; Margosiak, S.; Nikulin, V.; Levin, J.;
Sparankle, K. G.; Fedder, M. E.; Almassy, R.; Appelt, K.; Yager, K. M. J. Med. Chem.
2003, 46, 5663e5673.
for C17H1535ClN2O2: 314.0822; found: 314.0822.
4.3.13. 2,3-Dimethoxy-9-methyl-5,6-dihydroindroindazolo[3,2-a]iso-
quinoline (4g). Mp: 125e126 ꢀC. IR (KBr)
n: 3850, 3646, 1841, 1789,
1769,1731,1694,1681,1667,1660,1650,1639,1614,1582,1574,1550,
1538, 1519, 1505, 1455, 1359, 1308, 1264, 1236, 1195, 1160, 1065,
1059, 1029, 815, 734, 681, 576 cmꢁ1 1H NMR (400 MHz, CDCl3):
.
d
(ppm) 2.65 (s, 3H, CH3), 3.19 (t, J¼6.8 Hz, 2H, CH2), 3.93 (s, 3H,
CH3O), 4.01 (s, 3H, CH3O), 4.63 (t, J¼6.8 Hz, 2H, CH2), 6.83 (s, 1H,
ArH), 7.05e7.09 (m, 2H, ArH), 7.46 (s, 1H, ArH), 7.77e7.81 (m, 1H,
5. Picciola, G.; Ravenna, F.; Carenini, G.; Gentili, P.; Riva, M. Farmaco, Ed. Sci. 1981,
36, 1037e1056.
6. Corsi, G.; Palazzo, G.; Germani, C.; Barcellona, P. S.; Silvestrini, B. J. Med. Chem.
ArH). 13C NMR (100 MHz, DMSO-d6):
d (ppm) 22.6, 33.6, 53.1, 61.3,
1976, 19, 778e783.
61.5, 112.8, 118.0, 122.4, 123.7, 125.6, 127.6, 130.3, 130.8, 132.6, 135.8,
153.6, 153.8, 154.2. HRMS: m/z [MþNa]þ calcd for C18H18N2NaO2:
317.1266; found: 317.0227.
7. Andreonati, S.; Sava, V.; Makan, S.; Kolodeev, G. Pharmazie 1999, 54, 99e101.
8. Angelis, M. D.; Stossi, F.; Carlson, K. A.; Karzenellenbogen, B. S.; Katzenellenb-
ogen, J. A. J. Med. Chem. 2005, 48, 1132e1144.
9. Saczewski, F.; Saczewski, J.; Hudson, A. L.; Tyacke, R. J.; Nutt, D. J.; Man, J.; Tabin,
P. Eur. J. Pharm. Sci. 2003, 20, 201e208.
10. Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C. J. Org. Chem. 1995, 60,
5678e5682.
4.3.14. 5,6-Dihydro-[1,3]dioxolo[4,5-g]indazolo[3,2-a]isoquinoline
(4h). Mp: 158e160 ꢀC. IR (KBr)
n: 3855, 3822, 3775, 3745, 3726,
3691, 3650, 3620, 2912, 1560, 1542, 1523, 1508, 1499, 1478, 1458,
11. Claramunt, R. M.; Elguero, J.; Garceran, R. Heterocycles 1985, 23, 2895e2906.
12. (a) Paal, C.; Krecke, F. Chem. Ber. 1890, 23, 2640e2641; (b) Paal, C. Chem. Ber.
1891, 24, 959e966; (c) Busch, V.; Hartman, P. J. Prakt. Chem. 1895, 2, 404e406;
(d) Campi, E. M.; Habsuda, J.; Jackson, W. R.; Jonasson Cartrin, A. M.; McCubbin,
Q. J. Aust. J. Chem.1995, 48, 2023e2033; (e) Shi, D. Q.; Dou, G. L.; Ni, S. N.; Shi, J. W.;
Li, X. Y.; Wang, X. S.; Wu, H.; Ji, S. J. Synlett 2007, 2509e2512; (f) Sun, F.;
Feng, X.; Zhao, X.; Huang, Z. B.; Shi, D. Q. Tetrahedron 2012, 68, 3851e3855; (g)
Frontana-Uribe, B. A.; Moinet, C. Tetrahedron 1998, 54, 3197e3206.
1293, 1230, 1031, 958, 924, 909, 859, 841, 749, 669 cmꢁ1. 1H NMR
(400 MHz, DMSO-d6):
d
(ppm) 3.16 (t, J¼6.4 Hz, 2H, CH2), 4.55 (t,
J¼6.8 Hz, 2H, CH2), 6.09 (s, 2H, CH2), 7.07 (s, 1H, ArH), 7.13 (t,
J¼7.2 Hz, 1H, ArH), 7.30 (t, J¼8.0 Hz, 1H, ArH), 7.57 (s, 1H, ArH), 7.62
(d, J¼8.4 Hz, 1H, ArH), 8.12 (d, J¼8.4 Hz, 1H, ArH). 13C NMR
(100 MHz, DMSO-d6):
d (ppm) 33.6, 52.6, 106.8, 109.7, 114.6, 122.2,
ꢀ
13. Halland, N.; Nazare, M.; R’kyek, O.; Alonso, J.; Urmann, M.; Lindenschmidt, A.
Angew. Chem., Int. Ed. 2009, 48, 6879e6882.
14. Stokes, B. J.; Vogel, C. V.; Urnezis, L. K.; Pan, M.; Driver, T. G. Org. Lett. 2010, 12,
122.4, 125.8, 126.2, 127.3, 131.6, 132.5, 135.7, 152.2, 152.3, 152.5.
HRMS: m/z [MþH]þ calcd for C16H13N2O2: 265.0977; found:
265.1127.
2884e2887.
15. Haag, B.; Peng, Z.; Knochel, P. Org. Lett. 2009, 11, 4270e4273.
16. Wu, C.; Fang, Y.; Larock, R. C.; Shi, F. Org. Lett. 2010, 12, 2234e2237.
17. Kumar, M. R.; Park, A.; Park, N.; Lee, S. Org. Lett. 2011, 13, 3542e3545.
18. (a) Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.; Searle, R. J. G. J. Chem.
Soc. 1965, 4831e4837; (b) Varughese, D. J.; Manhas, M. S.; Bose, A. K. Tetrahe-
dron Lett. 2006, 47, 6795e6797; (c) Akazome, M.; Kondo, T.; Watanabe, Y. J. Org.
Chem. 1994, 59, 3375e3380; (d) Sawant, D.; Kumar, R.; Maulik, P. R.; Kundu, B.
Org. Lett. 2006, 8, 1525e1528.
4.3.15. 10-Chloro-5,6-dihydro[1,3]dioxolo[4,5-g]indazolo[3,2-a]iso-
quinoline (4i). Mp: 174e176 ꢀC. IR (KBr)
n
: 3215, 2905, 1619, 1516,
1502, 1491, 1477, 1445, 1417, 1402, 1377, 1336, 1299, 1279, 1257, 1241,
1204, 1160, 1051, 1038, 942, 929, 904, 848, 840, 796, 748, 695 cmꢁ1
1H NMR (400 MHz, DMSO-d6):
.
d
(ppm) 3.12 (t, J¼6.8 Hz, 2H, CH2),
19. (a) McMurry, J. E. Acc. Chem. Res. 1983, 16, 405e411; (b) McMurry, J. E. Chem.
€
4.49 (t, J¼6.8 Hz, 2H, CH2), 6.07 (s, 2H, CH2), 7.01e7.05 (m, 2H, ArH),
Rev. 1989, 89, 1513e1524; (c) Furstner, A.; Bogdanovi, B. Angew. Chem., Int. Ed.
7.49 (s, 1H, ArH), 7.66 (s, 1H, ArH), 8.10 (d, J¼9.2 Hz, 1H, ArH). 13C
1996, 35, 2442e2469.
20. (a) Shi, D. Q.; Rong, L. C.; Wang, J. X.; Zhuang, Q. Y.; Wang, X. S.; Hu, H. W.
Tetrahedron Lett. 2003, 44, 3199e3201; (b) Dou, G. L.; Wang, M. M.; Shi, D. Q. J.
Comb. Chem. 2009, 11, 151e154; (c) Shi, D. Q.; Dou, G. L.; Shi, C. L.; Li, Z. Y.; Ji, S. J.
Synthesis 2007, 3117e3124; (d) Dou, G. L.; Shi, D. Q. J. Comb. Chem. 2009, 11,
1073e1077; (e) Dou, G. L.; Shi, D. Q. Org. Biomol. Chem. 2011, 9, 7065e7070; (f)
Lin, W.; Dou, G. L.; Hu, M. H.; Cao, C. P.; Huang, Z. B.; Shi, D. Q. Org. Lett. 2013, 15,
1238e1241.
NMR (75 MHz, DMSO-d6):
d (ppm) 28.8, 48.0, 102.1, 104.9, 109.7,
116.2, 116.7, 120.7, 122.9, 123.3, 127.7, 131.1, 131.3, 147.5, 147.8, 148.3.
HRMS: m/z [M]þ, Calcd for C16H1135ClN2O2: M 298.0509; found:
298.0507.
ꢀ
ꢀ
21. (a) Sanchez-Sancho, F.; Mann, E.; Herradon, B. Synlett 2000, 509e516; (b)
Chern, M. S.; Shin, Y. K.; Dewang, P. M.; Li, W. R. J. Comb. Chem. 2004, 6,
855e858; (c) Wang, X. J.; Tan, J.; Grozinger, K. Tetrahedron Lett. 1998, 39,
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661e663; (e) Miklos, N. Synthesis 2006, 8, 1273e1278.
Acknowledgements
We acknowledge the financial support from the Foundation of
the Natural Science Foundation of China (No. 21072144), the Major
Basic Research Project of the Natural Science Foundation of the
Jiangsu Higher Education Institutions (No. 10KJA150049), A Project
Funded by the Priority Academic Project Development of Jiangsu
Higher Education Institutions, the Foundation of Key Laboratory of
Organic Synthesis of Jiangsu Province (No. JSK0812) and the Jiangsu
22. The single-crystal growth was carried out in ethanol solutions at rt. Intensity
data were collected on a Rigaku Mercury diffractometer with graphite mono-
ꢁ
chromated MoKa radiation (
l
¼0.71070 A) using the
u scan mode with 3.
08ꢀ<
q
<25.35ꢀ. Crystal data for 4 h: empirical formula C14H12N2O2, crystal di-
ꢁ
mension 0.65ꢂ0.58ꢂ0.55 mm, monoclinic, space group P-1, a¼8.057(3) A,
3
ꢁ
ꢀ
b¼15.736(5) A, c¼10.149(4) A,
a
¼90ꢀ,
b
¼110.414(6)ꢀ,
¼90 . V¼1206.1(7) A ,
g
ꢁ
ꢁ
Mr¼264.28, Z¼4, Dc¼1.455 Mg/m3,
m
(MoKa)¼0.098 mmꢁ1, F(000)¼552, S¼1.
047, R1¼0.0623, wR2¼0.1555.