Temperature-dependent regioselective synthesis of 1,2,4-triazino[2,3-b] indazoles and 3H-1,4-benzodiazepines by domino-Staudinger/aza-Wittig/ isomerization reaction

Article abstract of DOI:10.1002/ejoc.201100710

o-Azidobenzaldimine 8 reacted with triphenylphosphane at 0 °C with warming to room temperature to give 1,2,4-triazino[2,3-b]indazoles 12 by a domino-Staudinger/aza-Wittig/isomerization reaction. However, when heated to 80 °C the same reaction mixture affo

Full text of DOI:10.1002/ejoc.201100710

FULL PAPER
DOI: 10.1002/ejoc.201100710
Temperature-Dependent Regioselective Synthesis of 1,2,4-Triazino[2,3-
b]indazoles and 3H-1,4-Benzodiazepines by Domino-Staudinger/Aza-Wittig/
Isomerization Reaction
Hai Xie,[a,b] Jian-Bo Yu,[a] and Ming-Wu Ding*[a]
Keywords: Nitrogen heterocycles / Fused ring systems / Aza-Wittig reaction / Isomerization / Azides
o-Azidobenzaldimine 8 reacted with triphenylphosphane at
0 °C with warming to room temperature to give 1,2,4-triaz-
ino[2,3-b]indazoles 12 by a domino-Staudinger/aza-Wittig/
isomerization reaction. However, when heated to 80 °C the
same reaction mixture afforded 3H-1,4-benzodiazepines 14
by a tandem-Staudinger/aza-Wittig reaction.
in the synthesis of many nitrogen-containing heterocy-
cles.[11,12] We envisioned that a domino-Staudinger/aza-Wit-
tig reaction of suitably functionalized o-azidobenzaldimines
1 would provide access to fused indazoles in only one step.
In support of our continued interest in the synthesis of N-
heterocycles by application of the aza-Wittig reaction,[13] we
report here a temperature-dependent regioselective synthe-
sis of previously unreported 1,2,4-triazino[2,3-b]indazole
ring systems and 3H-1,4-benzodiazepines by a domino-
Staudinger/aza-Wittig/isomerization reaction.
Introduction
Domino reactions have attracted significant attention
from the synthetic organic chemistry community because of
their utility in the creation of structurally diverse and com-
plex molecules from simple precursors in an efficient man-
ner.[1] The value of domino processes can be greatly en-
hanced when divergence from an intermediate is made pos-
sible with different reaction conditions.
Indazoles play an increasingly important role in drug dis-
covery because of their structural similarity with indoles
and benzimidazoles.[2] Many indazole derivatives have ex-
hibited anti-HIV,[3] antiplatelet,[4] anticancer,[5] antimicro-
bial,[6,7] and antifungal activities.[8,9] Much effort has been
invested in the synthesis of derivatives of these compounds
to deduce structure–activity relationships and to discover
new analogues with improved properties, especially in me-
dicinal chemistry.
There are several regioselective methods for the prepara-
tion of 2H-indazoles.[10] Among them, a simple but effective
route for the synthesis of indazoles was provided by Molina
et al. (Scheme 1).[10b] The (indazolylimino)phosphorane de-
rivative 3 was directly obtained from Staudinger reaction of
o-azidobenzaldimines 1 through the intermediacy of phos-
phazide 2 instead of the expected o-(triphenylphosphor-
anylidene)aminobenzaldimine 4. Further aza-Wittig reac-
tions of 3 with isocyanates or acyl chlorides gave various
fused indazoles in good yields. Aza-Wittig reactions have
recently received increased attention in view of their utility
Scheme 1. Literature preparation of the (indazolylimino)phos-
phorane 3 by abnormal Staudinger reaction.
Results and Discussion
Vinyl azides 6, obtained easily from condensation of
azides 5 with aromatic aldehydes in the presence of piper-
idinium acetate,[14] reacted with triphenylphosphane or
methyldiphenyl phosphane to give iminophosphoranes 7.
Initially, aza-Wittig reactions of (triphenylimino)phos-
phorane 7 (R = Ph) with 2-azidobenzaldehyde were exam-
ined in ethanol, but low yields (32–35%) of 8 were obtained
due to the low reactivity of 7 (R = Ph) with 2-azidobenzal-
dehyde. However, when more reactive (methyldi-
[a] Key Laboratory of Pesticide & Chemical Biology of Ministry
of Education, Central China Normal University,
Wuhan, 430079, P. R. China
Fax: +86-27-67862041
E-mail: ding5229@yahoo.com.cn
[b] College of Chemistry & Chemical Engineering, Shanxi Datong
University,
Shanxi 037009, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100710.
Eur. J. Org. Chem. 2011, 6933–6938
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6933

H. Xie, J.-B. Yu, M.-W. Ding
FULL PAPER
phenylimino)phosphorane 7 (R = Me) was used at 50 °C,
good yields (82–92%) of condensed o-azidobenzaldimines
8 were obtained (Scheme 2, Table 1).
Scheme 2. Preparation of o-azidobenzaldimine 8.
Table 1. Preparation of o-azidobenzaldimine 8.
Scheme 3. Preparation of 1,2,4-triazino[2,3-b]indazoles 12 by a
domino-Staudinger/aza-Wittig/isomerization reaction.
Entry
R
Ar1
Ar2
Conditions Yield (%)[a]
1
2
3
4
5
6
7
8
9
10
8a Ph
Me
8b Ph
Me
8c Me Ph
8d Me Ph
8e Me 4-ClC6H4 Ph
8f Me 4-ClC6H4 4-ClC6H4
8g Me 4-ClC6H4 4-FC6H4
8h Me 4-ClC6H4 4-CH3C6H4
Ph
Ph
50 °C/8 h
50 °C/4 h
50 °C/7 h
50 °C/4 h
50 °C/6 h
50 °C/4 h
50 °C/4 h
50 °C/5 h
50 °C/6 h
50 °C/4 h
35
90
32
92
75
88
86
84
83
90
Table 2. Preparation of 1,2,4-triazino[2,3-b]indazoles 12.
Ph
4-ClC6H4
Entry
Ar1
Ar2
Yield (%)[a]
4-FC6H4
4-CH3C6H4
1
2
3
4
5
6
7
8
9
12a
12b
12c
12d
12e
12f
12g
12h
12i
Ph
Ph
Ph
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
4-ClC6H4
4-FC6H4
4-CH3C6H4
Ph
4-ClC6H4
4-FC6H4
4-CH3C6H4
4-CH3OC6H4
4-CF3C6H4
91
90
84
86
89
86
88
87
89
90
[a] Isolated yields.
When o-azidobenzaldimines 8 were treated with tri-
phenylphosphane in CH2Cl2 at 0 °C for 2 h, and then at
room temperature for another 2 h, previously unreported
1,2,4-triazino[2,3-b]indazoles 12 were isolated directly in
high yields (84–91%) (Scheme 3, Table 2). The domino for-
mation of 1,2,4-triazino[2,3-b]indazoles 12 can be viewed as
an initial Staudinger reaction between o-azidobenzaldimine
8 and triphenylphosphane to create phosphazide intermedi-
ate 9, which cyclizes to give iminophosphorane 10. Further
intramolecular aza-Wittig reaction of 10 produces cyclized
compound 11, in which an isomerization reaction takes
place to give 1,2,4-triazino[2,3-b]indazole 12. It is note-
worthy that the reaction proceeds under mild conditions to
give various substituted 1,2,4-triazino[2,3-b]indazoles, and
the overall transformation is run in a simple one-pot pro-
cedure from azides 8.
10
12j
[a] Isolated yields.
It is interesting to note that 3H-1,4-benzodiazepines 14
were obtained instead when o-azidobenzaldimines 8 were
allowed to react with triphenylphosphane in toluene at
80 °C for 8 h (Scheme 4, Table 3). The formation of 3H-1,4-
benzodiazepines 14 can be viewed as an initial Staudinger
reaction between o-azidobenzaldimine 8 and triphenylphos-
Scheme 4. Preparation of 3H-1,4-benzodiazepines 14 by a tandem-
Staudinger/aza-Wittig reaction.
phane to give the iminophosphorane 13, through loss of N2 imino)phosphorane 10. Notably, 1,4-benzodiazepine skel-
from phosphazide intermediate 9 under higher temperature. etons are one of the most important and central building
Further intramolecular aza-Wittig reaction of 13 produces blocks in medicinal and pharmaceutical chemistry. Many
3H-1,4-benzodiazepine 14. It is deduced that phosphazide 1,4-benzodiazepines are found in a wide variety of biolo-
intermediate 9 tends to decompose at higher temperature gically active substances, which show sedative, anxiolytic,
to give the iminophosphorane 13 instead of the (indazolyl- anticonvulsant, hypnotic, raf protein kinase and cysteine
6934
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Eur. J. Org. Chem. 2011, 6933–6938

1,2,4-Triazino[2,3-b]indazoles and 3H-1,4-benzodiazepines
protease inhibitory activities.[15–17] The above tandem- and 14j were obtained from the CH2Cl2 solution of 12i and
Staudinger/aza-Wittig reaction provides an efficient synthe- 14j and X-ray structure analysis verified the proposed struc-
sis of 3H-1,4-benzodiazepines under mild reaction condi- tures (Figures 1 and 2).
tions. Analogous 1,4-benzodiazepin-5-ones have also been
prepared previously by application of the tandem-Staud-
inger/aza-Wittig reaction by other groups.[18]
Conclusions
Table 3. Preparation of 3H-1,4-benzodiazepines 14.
In conclusion, we report here a new temperature-depend-
ent regioselective synthesis of 1,2,4-triazino[2,3-b]indazoles
or 3H-1,4-benzodiazepines, by using a domino-Staudinger/
aza-Wittig/isomerization reaction or tandem-Staudinger/
aza-Wittig reaction. Due to the availability of the synthetic
approach and the neutral ring closure conditions, this new
synthetic approach has potential applications in the synthe-
sis of various 1,2,4-triazino[2,3-b]indazoles and 3H-1,4-
benzodiazepines, which are of considerable interest as bio-
logically active compounds or pharmaceuticals.
Entry
Ar1
Ar2
Yield (%)[a]
1
2
3
4
5
6
7
8
9
14a
14b
14c
14d
14e
14f
14g
14h
14i
Ph
Ph
Ph
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
4-ClC6H4
4-FC6H4
4-CH3C6H4
Ph
4-ClC6H4
4-FC6H4
4-CH3C6H4
4-CH3OC6H4
4-CF3C6H4
91
90
84
86
89
86
88
87
82
90
10
14j
[a] Isolated yields.
Experimental Section
The structures of the 1,2,4-triazino[2,3-b]indazoles 12
and 3H-1,4-benzodiazepines 14 were confirmed on the ba-
sis of spectroscopic data. Furthermore, single crystals of 12i
General: All reactions were performed in round-bottom flasks. Col-
umn chromatography purifications were performed under “flash“
conditions using 400–630 mesh silica gel, except where otherwise
noted. Analytical thin-layer chromatography (TLC) was carried out
on silica gel 60 F254 plates, which were visualized by exposure to
ultraviolet light.
Instrumentation: Melting points were determined with an X-4
model apparatus (Beijing Taike Company, Beijing, People’s Repub-
lic of China). IR spectra were recorded with a PE-983 infrared
spectrometer (Perkin–Elmer) as KBr pellets with absorption
in cm–1. MS were measured with a Finnigan Trace MS spectrome-
ter (Thermo Fisher Scientific Company). 1H NMR spectra were
recorded in CDCl3 with a Varian Mercury Plus 600 (600 MHz)
spectrometer and chemical shifts (δ) are reported in ppm using
(CH3)4Si as an internal reference (δ = 0 ppm). Elemental analyses
were obtained with a Vario EL III elementary analysis instrument.
General Procedure for Preparation of Azides 8: To a well-stirred
solution of azide 6 (4 mmol) in absolute ethanol (15 mL) was added
methyldiphenylphosphane (0.80 g, 4 mmol) in ethanol (5 mL) at
room temp. After the mixture was stirred for 3 h, 2-azidobenzalde-
hyde (0.59 g, 4 mmol) was added and the mixture was stirred at
50 °C for 4–8 h. The solvent was partly removed under reduced
pressure and the yellow precipitated solid was collected by filtration
and recrystallized from CH2Cl2/ethanol to give azide 8.
Figure 1. ORTEP diagram of the crystal structure of 14j (30% ther-
mal ellipsoids).
2-(Azidobenzylideneamino)-1,3-diphenylprop-2-en-1-one (8a): Yel-
low crystals (1.27 g, 90%), m.p. 84–85 °C. IR (KBr): ν = 3069,
˜
2134, 1652, 1592, 1448, 1251, 1126 cm–1. 1H NMR (600 MHz,
CDCl3): δ = 8.82 (s, 1 H, N=CH), 8.28–7.23 (m, 14 H, Ar-H), 6.71
(s, 1 H, =CH) ppm. 13C NMR (150 MHz, CDCl3): δ = 193.8, 158.9,
145.2, 140.9, 137.5, 134.6, 132.7, 132.3, 131.3, 131.2, 129.8, 129.7,
129.3, 128.7, 128.3, 128.2, 127.7, 127.6, 127.1, 124.8, 118.5 ppm.
C22H16N4O (352.39): calcd. C 74.98, H 4.58, N 15.90; found C
75.19, H 4.88, N 16.12.
2-(Azidobenzylideneamino)-3-(4-chlorophenyl)-1-phenylprop-2-
en-1-one (8b): Yellow crystals (1.42 g, 92%), m.p. 148–149 °C. IR
(KBr): ν = 3095, 2133, 1651, 1448, 1250, 1069 cm–1 1H NMR
.
˜
(600 MHz, CDCl3): δ = 8.81 (s, 1 H, N=CH), 8.23–7.22 (m, 13 H,
Ar-H), 6.64 (s, 1 H, =CH) ppm. 13C NMR (150 MHz, CDCl3): δ
= 193.8, 159.2, 159.1, 145.5, 141.1, 137.4, 134.6, 133.2, 132.9, 132.5,
129.9, 129.8, 128.6, 128.4, 128.0, 127.8, 127.7, 127.1, 124.9,
Figure 2. ORTEP diagram of the crystal structure of 12i (30% ther-
mal ellipsoids).
Eur. J. Org. Chem. 2011, 6933–6938
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6935

H. Xie, J.-B. Yu, M.-W. Ding
FULL PAPER
118.6 ppm. C22H15ClN4O (386.84): calcd. C 68.31, H 3.91, N 14.48;
found C 68.52, H 4.08, N 14.22.
NMR (150 MHz, CDCl3): δ = 192.6, 160.3, 158.9, 143.3, 140.9,
138.4, 136.3, 133.3, 132.7, 131.1, 130.6, 128.5, 127.6, 127.3, 127.2,
124.9, 118.6, 114.0, 55.2 ppm. C23H17ClN4O2 (416.87): calcd. C
66.27, H 4.11, N 13.44; found C 66.39, H 4.28, N 13.66.
2-(Azidobenzylideneamino)-3-(4-fluorophenyl)-1-phenylprop-2-en-1-
one (8c): Yellow crystals (1.11 g, 75%), m.p. 112–114 °C. IR (KBr):
ν = 3072, 2133, 1655, 1594, 1450, 1296, 1127, 1069 cm–1. 1H NMR
2-(Azidobenzylideneamino)-1-(4-chlorophenyl)-3-[4-(trifluoro-
˜
(600 MHz, CDCl3): δ = 8.83 (s, 1 H, N=CH), 8.24–7.03 (m, 13 H, methyl)phenyl]prop-2-en-1-one (8j): Yellow crystals (1.49 g, 82%),
Ar-H), 6.67 (s, 1 H, =CH) ppm. 13C NMR (150 MHz, CDCl3): δ
m.p. 174–176 °C. IR (KBr): ν = 3116, 2125, 1647, 1585, 1328, 1278,
˜
= 193.7, 163.5, 161.8, 159.0, 144.6, 140.8, 137.4, 133.2, 132.7, 132.3,
1069 cm–1. 1H NMR (600 MHz, CDCl3): δ = 8.77 (s, 1 H, N=CH),
130.8, 129.7, 128.4, 128.2, 127.5, 126.9, 124.8, 118.5, 115.4, 8.22–7.22 (m, 12 H, Ar-H), 6.64 (s, 1 H, =CH) ppm. 13C NMR
115.2 ppm. C22H15FN4O (370.38): calcd. C 71.34, H 4.08, N 15.13;
found C 71.19, H 4.28, N 15.22.
(150 MHz, CDCl3): δ = 192.6, 159.5, 146.8, 141.3, 139.3, 137.9,
135.2, 133.3, 131.4, 131.2, 129.9, 128.8, 127.7, 126.7, 126.4, 125.2,
125.1, 125.0, 124.9, 118.8, 118.7 ppm. C23H14ClF3N4O (454.84):
calcd. C 60.74, H 3.10, N 12.32; found C 60.49, H 3.28, N 12.47.
2-(Azidobenzylideneamino)-1-phenyl-3-(p-tolyl)prop-2-en-1-one (8d):
Yellow crystals (1.29 g, 88%), m.p. 134–136 °C. IR (KBr): ν = 3124,
˜
2132, 1653, 1575, 1449, 1123, 1069 cm–1 1H NMR (600 MHz, General Procedure for Preparation of 1,2,4-Triazino[2,3-b]indazoles
.
CDCl3): δ = 8.82 (s, 1 H, N=CH), 8.28–7.16 (m, 13 H, Ar-H), 6.71
(s, 1 H, =CH), 2.35 (s, 3 H, CH3) ppm. 13C NMR (150 MHz,
CDCl3): δ = 193.8; 158.8, 144.5, 140.9, 139.1, 137.8, 132.6, 132.2,
131.8, 131.4, 130.1, 129.7, 129.1, 128.2, 127.7, 127.2, 124.9, 118.5,
12: A solution of triphenylphosphane (1.5 mmol, 0.39 g) in dry
CH2Cl2 (10 mL) was added dropwise under nitrogen to a well-
stirred solution of azides 8 (1.5 mmol) in CH2Cl2 (10 mL) at 0 °C.
After the stirring was continued for 2 h, the mixture was slowly
21.4, 21.2 ppm. C23H18N4O (366.42): calcd. C 75.39, H 4.95, N warmed to room temp. while the stirring was continued for 2 h. The
15.29; found C 75.49, H 4.88, N 15.42.
solvent was evaporated under reduced pressure, and the residue was
chromatographed on a silica gel column using petroleum ether and
ether (10:1) as eluent to give 1,2,4-triazino[2,3-b]indazoles 12 as
yellow solids.
2-(Azidobenzylideneamino)-1-(4-chlorophenyl)-3-phenylprop-2-
en-1-one (8e): Yellow crystals (1.33 g, 86 %), m.p. 90–92 °C. IR
(KBr): ν = 3128, 2126, 1649, 1583, 1278, 1070 cm–1 1H NMR
.
˜
(600 MHz, CDCl3): δ = 8.78 (s, 1 H, N=CH), 8.26–7.22 (m, 13 H, 2-Benzyl-3-phenyl-1,2,4-triazino[2,3-b]indazole (12a): Yellow crys-
1
Ar-H), 6.68 (s, 1 H, =CH) ppm. 13C NMR (150 MHz, CDCl3): δ
= 192.6, 159.0, 145.1, 141.0, 138.7, 135.8, 134.4, 132.8, 131.3, 131.2,
tals (0.46 g, 91%); m.p.168–169 °C. H NMR (600 MHz, CDCl3):
δ = 8.37–7.02 (m, 14 H, Ar-H), 4.40 (s, 2 H, CH2) ppm. 13C NMR
129.3, 128.9, 128.6, 128.4, 127.7, 127.0, 124.9, 118.6 ppm. (150 MHz, CDCl3): δ = 150.9, 148.9, 147.4, 137.1, 135.8, 134.3,
C22H15ClN4O (386.84): calcd. C 68.31, H 3.91, N 14.48; found C
68.59, H 3.99, N 14.22.
130.0, 129.8, 129.4, 128.7, 126.5, 128.4, 128.3, 126.7, 122.5, 120.6,
117.3, 112.3, 41.3 ppm. MS: m/z (%) = 336 (100) [M+], 204 (39),
102 (26), 91 (32), 77 (18). C22H16N4 (336.40): calcd. C 78.55, H
4.79, N 16.66; found C 78.64, H 4.68, N 16.69.
2-(Azidobenzylideneamino)-1,3-bis(4-chlorophenyl)prop-2-en-1-one
(8f): Yellow crystals (1.41 g, 84%), m.p. 169–170 °C. IR (KBr): ν =
˜
3126, 2126, 1648, 1583, 1483, 1281, 1084 cm–1
.
1H NMR
2-(4-Chlorobenzyl)-3-phenyl-1,2,4-triazino[2,3-b]indazole (12b): Yel-
1
(600 MHz, CDCl3): δ = 8.77 (s, 1 H, N=CH), 8.22–7.22 (m, 12 H, low crystals (0.49 g, 90%); m.p. 141–142 °C. H NMR (600 MHz,
Ar-H), 6.62 (s, 1 H, =CH) ppm. 13C NMR (150 MHz, CDCl3): δ
= 192.6, 159.3, 145.4, 141.1, 139.0, 135.5, 134.8, 133.1, 132.5, 131.3,
128.7, 128.6, 127.9, 127.7, 126.9, 125.0, 118.7 ppm. C22H14Cl2N4O
(421.28): calcd. C 62.72, H 3.35, N 13.30; found C 62.59, H 3.49,
N 13.12.
CDCl3): δ = 8.34–6.94 (m, 13 H, Ar-H), 4.35 (s, 2 H, CH2) ppm.
13C NMR (150 MHz, CDCl3): δ = 150.7, 148.9, 146.7, 135.7, 135.6,
134.2, 132.6, 130.1, 129.9, 129.3, 128.6, 125.5, 122.6, 120.6, 117.3,
112.3, 40.6 ppm. MS: m/z (%) = 370 (100) [M+], 204 (36), 125 (45),
102 (32), 88 (17). C22H15ClN4 (370.84): calcd. C 71.25, H 4.08, N
15.11; found C 71.54, H 3.94, N 15.23.
2-(Azidobenzylideneamino)-1-(4-chlorophenyl)-3-(4-fluorophenyl)-
prop-2-en-1-one (8g): Yellow crystals (1.34 g, 83 %), m.p. 142–
2-(4-Fluorobenzyl)-3-phenyl-1,2,4-triazino[2,3-b]indazole (12c): Yel-
low crystals (0.45 g, 84%); m.p. 141–142 °C. H NMR (600 MHz,
CDCl3): δ = 8.36–6.87 (m, 13 H, Ar-H), 4.36 (s, 2 H, CH2) ppm.
13C NMR (150 MHz, CDCl3): δ = 162.4, 160.8, 150.7, 148.9, 147.1,
135.7, 134.2, 132.7, 130.3, 130.0, 129.8, 129.3, 128.6, 122.5, 120.5,
117.2, 115.3, 115.2, 112.3, 40.5 ppm. MS: m/z (%) = 354 (100) [M+],
1
144 °C. IR (KBr): ν = 3130, 2131, 1648, 1584, 1247, 1129,
˜
1070 cm–1. 1H NMR (600 MHz, CDCl3): δ = 8.79 (s, 1 H, N=CH),
8.23–7.04 (m, 12 H, Ar-H), 6.66 (s, 1 H, =CH) ppm. 13C NMR
(150 MHz, CDCl3): δ = 192.7,163.7, 162.0, 159.3, 144.6, 141.1,
138.8, 135.7, 133.3, 133.0, 131.2, 130.8, 128.7, 128.4, 127.6, 126.9,
125.0, 118.7, 115.6, 115.4 ppm. C22H14ClFN4O (404.83): calcd. C 222 (40), 109 (52), 102 (21), 88 (9). C22H15FN4 (354.39): calcd. C
65.27, H 3.49, N 13.84; found C 65.43, H 3.58, N 13.92.
74.56, H 4.27, N 15.81; found C 74.42, H 4.38, N 15.53.
2-(Azidobenzylideneamino)-1-(4-chlorophenyl)-3-(p-tolyl)prop-2-en-
1-one (8h): Yellow crystals (1.44 g, 90 %), m.p. 130–132 °C, IR
2-(4-Methylbenzyl)-3-phenyl-1,2,4-triazino[2,3-b]indazole (12d): Yel-
low crystals (0.45 g, 86%); m.p. 175–177 °C. H NMR (600 MHz,
1
1
(KBr): ν = 3128, 2124, 1646, 1602, 1505, 1247, 1069 cm–1. H CDCl3): δ = 8.37–6.91 (m, 13 H, Ar-H), 4.35 (s, 2 H, CH2), 2.28
˜
NMR (600 MHz, CDCl3): δ = 8.79 (s, 1 H, N=CH), 8.26–7.16 (m, (s, 3 H, CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 150.9, 148.9,
12 H, Ar-H), 6.68 (s, 1 H, =CH), 2.35 (s, 3 H, CH3) ppm. 13C 147.7, 136.3, 135.9, 134.4, 134.1, 130.0, 129.7, 129.4, 129.2, 128.6,
NMR (150 MHz, CDCl3): δ = 192.6, 158.9, 144.4, 140.9, 139.3,
138.6, 136.0, 132.7, 131.7, 131.4, 131.2, 130.0, 129.2, 128.6, 127.7,
127.1, 124.9, 118.6, 21.4 ppm. C23H17ClN4O (400.87): calcd. C
68.91, H 4.27, N 13.98; found C 69.14, H 4.16, N 14.11.
128.5, 122.4, 120.7, 120.6, 119.5, 117.3, 117.2, 112.3, 40.8,
20.9 ppm. MS: m/z (%) = 350 (100) [M+], 218 (11), 204 (17), 105
(18), 102 (9). C23H18N4 (350.42): calcd. C 78.83, H 5.18, N 15.99;
found C 78.91, H 5.08, N 15.63.
2-(Azidobenzylideneamino)-1-(4-chlorophenyl)-3-(4-methoxyphenyl)-
2-Benzyl-3-(4-chlorophenyl)-1,2,4-triazino[2,3-b]indazole (12e): Yel-
low crystals (0.49 g, 89%); m.p. 145–147 °C. H NMR (600 MHz,
CDCl3): δ = 8.37–7.03 (m, 13 H, Ar-H), 4.38 (s, 2 H, CH2) ppm.
1
prop-2-en-1-one (8i): Yellow crystals (1.43 g, 86 %), m.p. 112–
113 °C. IR (KBr): ν = 3130, 2126, 1647, 1582, 1279, 1069 cm–1. 1H
˜
NMR (600 MHz, CDCl3): δ = 8.81 (s, 1 H, N=CH), 8.27–6.89 (m, 13C NMR (150 MHz, CDCl3): δ = 149.8, 149.0, 146.9, 137.0, 136.2,
12 H, Ar-H), 6.70 (s, 1 H, =CH), 3.82 (s, 3 H, OCH3) ppm. 13C
135.8, 132.7, 130.7, 130.2, 128.7, 128.6, 126.8, 122.7, 120.6, 117.3,
6936
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6933–6938

1,2,4-Triazino[2,3-b]indazoles and 3H-1,4-benzodiazepines
112.3, 41.3 ppm. MS: m/z (%) = 370 (100) [M+], 204 (58), 102 (60), 308 (100) [M+], 231 (45), 192 (25), 165 (84), 89 (11). C22H16N2
91 (89), 77 (30). C22H15ClN4 (370.84): calcd. C 71.25, H 4.08, N
15.11; found C 71.32, H 4.03, N 15.39.
(308.38): calcd. C 85.69, H 5.23, N 9.08; found C 85.75, H 5.28, N
9.26.
2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-1,2,4-triazino[2,3-b]indazole 3-(4-Chlorobenzylidene)-2-phenyl-3H-1,4-benzodiazepine (14b): Yel-
1
(12f): Yellow crystals (0.52 g, 86%); m.p. 142–144 °C. 1H NMR
(600 MHz, CDCl3): δ = 8.35–6.97 (m, 12 H, Ar-H), 4.34 (s, 2 H,
CH2) ppm. 13C NMR (150 MHz, CDCl3): δ = 149.5, 149.0, 146.2,
136.3, 135.8, 135.4, 132.7, 132.6, 130.6, 130.2, 130.0, 128.9, 128.7,
122.8, 120.6, 117.3, 112.2, 40.6 ppm. MS: m/z (%) = 404 (100) [M+],
low crystals (0.46 g, 90%), m.p. 199–201 °C. H NMR (600 MHz,
CDCl3): δ = 8.54 (s, 1 H, N=CH), 8.21–7.26 (m, 13 H, Ar-H), 5.75
(s, 1 H, =CH) ppm. 13C NMR (150 MHz, CDCl3): δ = 162.3, 160.5,
148.8, 139.6, 137.4, 137.1, 132.5, 131.2, 131.1, 129.9, 129.5, 129.0,
128.9, 128.7, 128.4, 127.5, 125.0, 124.9, 118.2, 118.1 ppm. MS: m/z
238 (19), 204 (32), 125 (64), 102 (57), 88 (19). C22H14Cl2N4 (%) = 342 (75) [M+], 231 (45), 192 (17), 165 (100), 89 (11).
(405.29): calcd. C 65.20, H 3.48, N 13.82; found C 65.37, H 3.53,
N 13.99.
C22H15ClN2 (342.83): calcd. C 77.08, H 4.41, N 8.17; found C
77.31, H 4.29, N 8.23.
3-(4-Chlorophenyl)-2-(4-fluorobenzyl)-1,2,4-triazino[2,3-b]indazole
(12g): Yellow crystals (0.51 g, 88%); m.p. 177–178 °C. 1H NMR
(600 MHz, CDCl3): δ = 8.36–6.90 (m, 12 H, Ar-H), 4.35 (s, 2 H,
CH2) ppm. 13C NMR (150 MHz, CDCl3): δ = 162.5, 160.8, 149.6,
149.0, 146.6, 136.2, 135.8, 132.6, 132.5, 130.6, 130.2, 128.9, 122.7,
120.6, 117.2, 115.5, 115.3, 112.2, 40.4 ppm. MS: m/z (%) = 388
3-(4-Fluorobenzylidene)-2-phenyl-3H-1,4-benzodiazepine (14c): Yel-
low crystals (0.41 g, 84%), m.p. 166–167 °C. H NMR (600 MHz,
1
CDCl3): δ = 8.54 (s, 1 H, N=CH), 8.22–6.98 (m, 13 H, Ar-H), 5.77
(s, 1 H, =CH) ppm. 13C NMR (150 MHz, CDCl3): δ = 162.7, 161.9,
161.1, 160.9, 148.7, 139.8, 137.3, 131.4, 131.3, 131.2, 130.0, 129.8,
128.8, 128.5, 127.4, 125.1, 125.0, 117.0, 116.9, 115.2, 115.1 ppm.
(100) [M+], 222 (30), 109 (43), 102 (11). C22H14ClFN4 (388.83): MS: m/z (%) = 326 (100) [M+], 231 (42), 192 (29), 165 (95), 89 (13).
calcd. C 67.96, H 3.63, N 14.41; found C 68.07, H 3.69, N 14.38.
C22H15FN2 (326.37): calcd. C 80.96, H 4.63, N 8.58; found C 80.77,
H 4.88, N 8.74.
3-(4-Chlorophenyl)-2-(4-methylbenzyl)-1,2,4-triazino[2,3-b]indazole
(12h): Yellow crystals (0.50 g, 87%); m.p. 170–171 °C. 1H NMR
(600 MHz, CDCl3): δ = 8.37–6.92 (m, 12 H, Ar-H), 4.33 (s, 2 H,
3-(4-Methylbenzylidene)-2-phenyl-3H-1,4-benzodiazepine (14d): Yel-
1
low crystals (0.42 g, 86%), m.p. 136–138 °C. H NMR (600 MHz,
CH2), 2.29 (s, 3 H, CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = CDCl3): δ = 8.54 (s, 1 H, N=CH), 8.23–7.11 (m, 13 H, Ar-H), 5.78
149.7, 148.9, 147.1, 136.4, 136.1, 135.8, 133.9, 132.8, 130.7, 130.1,
129.3, 128.8, 128.5, 122.6, 120.6, 117.2, 112.2, 40.8, 20.9 ppm. MS:
(s, 1 H, =CH), 2.32 (s, 3 H, CH3) ppm. 13C NMR (CDCl3,
150 MHz): δ = 162.2, 160.6, 160.5, 148.8, 139.6, 137.4, 137.0, 132.4,
m/z (%) = 384 (100) [M+], 218 (20), 105 (34), 102 (23). C23H17ClN4 131.2, 131.1, 129.9, 129.5, 128.9, 128.7, 128.4, 127.5, 124.9, 118.1,
(384.87): calcd. C 71.78, H 4.45, N 14.56; found C 71.59, H 4.39,
N 14.53.
21.2 ppm. MS: m/z (%) = 322 (100) [M+], 231 (44), 192 (22), 165
(76), 130 (28), 89 (12). C23H18N2 (322.41): calcd. C 85.68, H 5.63,
N 8.69; found C 85.83, H 5.74, N 8.79.
3-(4-Chlorophenyl)-2-(4-methoxybenzyl)-1,2,4-triazino[2,3-b]-
1
indazole (12i): Yellow crystals (0.53 g, 89%); m.p. 150–152 °C. H
3-Benzylidene-2-(4-chlorophenyl)-3H-1,4-benzodiazepine (14e): Yel-
1
NMR (600 MHz, CDCl3): δ = 8.37–6.75 (m, 12 H, Ar-H), 4.31 (s,
low crystals (0.46 g, 89%), m.p. 146–148 °C. H NMR (600 MHz,
2 H, CH2), 3.76 (s, 3 H, OCH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 8.55 (s, 1 H, N=CH), 8.18–7.21 (m, 13 H, Ar-H), 5.78
CDCl3): δ = 158.4, 149.8, 149.0, 147.3, 136.1, 135.8, 132.8, 130.7,
130.1, 129.7, 128.9, 128.8, 122.6, 120.6, 117.2, 114.0, 112.3, 55.2,
40.4 ppm. MS: m/z (%) = 400 (100) [M+], 121 (41), 102 (17), 96 (4).
C23H17ClN4O (400.87): calcd. C 68.91, H 4.27, N 13.98; found C
68.74, H 4.12, N 14.24.
(s, 1 H, =CH) ppm. 13C NMR (150 MHz, CDCl3): δ = 160.8, 160.7,
148.6, 139.8, 137.4, 135.8, 135.1, 131.4, 131.2, 130.1, 129.6, 128.8,
128.7, 128.3, 127.5, 127.4, 125.3, 118.3, 118.2 ppm. MS: m/z (%) =
342 (100) [M+], 265 (43), 199 (94), 152 (44), 89 (54). C22H15ClN2
(342.83): calcd. C 77.08, H 4.41, N 8.17; found C 76.81, H 4.68, N
8.25.
3-(4-Chlorophenyl)-2-[4-(trifluoromethyl)benzyl]-1,2,4-triazino-
[2,3-b]indazole (12j): Yellow crystals (0.59 g, 90 %); m.p. 176–
3-(4-Chlorobenzylidene)-2-(4-chlorophenyl)-3H-1,4-benzodiazepine
177 °C. 1H NMR (600 MHz, CDCl3): δ = 8.33–7.18 (m, 12 H, Ar- (14f): Yellow crystals (0.49 g, 86%), m.p. 180–181 °C. 1H NMR
H), 4.43 (s, 2 H, CH2) ppm. 13C NMR (150 MHz, CDCl3): δ =
149.4. 148.9, 145.6, 141.0, 136.3, 135.7, 132.4, 130.6, 130.2, 129.1,
(600 MHz, CDCl3): δ = 8.54 (s, 1 H, N=CH), 8.15–7.26 (m, 12 H,
Ar-H), 5.73 (s, 1 H, =CH) ppm. 13C NMR (150 MHz, CDCl3): δ
128.9, 128.7, 125.4, 124.8, 123.0, 122.7, 120.5, 117.1, 112.1, = 160.9, 160.4, 148.5, 140.2, 137.5, 135.6, 133.6, 133.5, 133.1, 131.6,
40.9 ppm. MS: m/z (%) = 438 (100) [M+], 272 (27), 159 (56), 102
131.1, 130.7, 130.1, 128.9, 128.8, 128.4, 127.3, 125.4, 117.0 ppm.
(67), 88 (53), 75 (22). C23H14ClF3N4 (438.84): calcd. C 62.95, H MS: m/z (%) = 376 (100) [M+], 265 (65), 199 (100), 152 (21), 89
3.22, N 12.77; found C 63.02, H 3.34, N 12.59.
(26). C22H14Cl2N2 (377.27): calcd. C 70.04, H 3.74, N 7.43; found
C 69.89, H 3.88, N 7.64.
General Procedure for Preparation of 3H-1,4-Benzodiazepines 14:
To a well-stirred solution of triphenylphosphane (0.39 g, 1.5 mmol)
in dry toluene (10 mL) at 80 °C, was added dropwise a solution of
azides 8 (1.5 mmol) in toluene (5 mL). After the stirring was con-
tinued for 8 h at 80 °C, the solvent was evaporated under reduced
pressure. The obtained residue was chromatographed on a silica gel
column using petroleum ether and ether (7:1) as eluent to give 3H-
1,4-benzodiazepines 14 as yellow solids.
2-(4-Chlorophenyl)-3-(4-fluorobenzylidene)-3H-1,4-benzodiazepine
(14g): Yellow crystals (0.48 g, 88%), m.p. 150–152 °C. 1H NMR
(600 MHz, CDCl3): δ = 8.54 (s, 1 H, N=CH), 8.16–6.99 (m, 12 H,
Ar-H), 5.75 (s, 1 H, =CH) ppm. 13C NMR (150 MHz, CDCl3): δ
= 162.8, 161.2, 161.1, 161.0, 160.6, 148.5, 139.4, 137.5, 135.8, 131.5,
131.3, 131.2, 131.1, 130.1, 128.9, 128.7, 127.4, 125.3, 117.3, 115.3,
115.2 ppm. MS: m/z (%) = 360 (100) [M+], 265 (44), 199 (78), 134
(13), 102 (6). C22H14ClFN2 (360.82): calcd. C 73.23, H 3.91, N
7.76; found C 73.36, H 4.07, N 7.92.
3-Benzylidene-2-phenyl-3H-1,4-benzodiazepine (14a): Yellow crys-
1
tals (0.42 g, 91%), m.p. 170–172 °C. H NMR (600 MHz, CDCl3):
δ = 8.55 (s, 1 H, N = CH), 8.24–7.20 (m, 14 H, Ar-H), 5.80 (s, 1
H, =CH) ppm. 13C NMR (150 MHz, CDCl3): δ = 162.0, 160.7,
160.6, 148.8, 140.2, 137.3, 135.3, 131.3, 131.2, 130.0, 129.9, 129.5,
128.8, 128.5, 128.2, 127.4, 127.2, 125.0, 118.0 ppm. MS: m/z (%) =
2-(4-Chlorophenyl)-3-(4-methylbenzylidene)-3H-1,4-benzodiazepine
(14h): Yellow crystals (0.46 g, 87%), m.p. 189–191 °C. 1H NMR
(600 MHz, CDCl3): δ = 8.53 (s, 1 H, N=CH), 8.16–7.11 (m, 12 H,
Ar-H), 5.76 (s, 1 H, =CH), 2.32 (s, 3 H, CH3) ppm. 13C NMR
Eur. J. Org. Chem. 2011, 6933–6938
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6937

H. Xie, J.-B. Yu, M.-W. Ding
FULL PAPER
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1
diazepine (14j): Yellow crystals (0.55 g, 90%), m.p. 176–178 °C. H
NMR (600 MHz, CDCl3): δ = 8.56 (s, 1 H, N=CH), 8.17–7.26 (m,
12 H, Ar-H), 5.78 (s, 1 H, =CH) ppm. 13C NMR (150 MHz,
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131.1, 130.1, 129.6, 129.0, 128.8, 127.2, 125.5, 125.1, 116.4 ppm.
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Acknowledgments
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (NSFC) (grant
number 21032001), the Program for Changjiang Scholars and In-
novative Research Team in University (grant number IRT0953),
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Received: May 20, 2011
Published Online: October 10, 2011
6938
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6933–6938