An efficient metal-free cascade process for the synthesis of 4-arylpyrimido[1,2-b]indazole-3-carbonitrile derivatives

Article abstract of DOI:10.1016/j.tet.2017.07.035

An efficient metal-free cascade reaction to synthesize novel pyrimido[1,2-b]indazole-3-carbonitrile derivatives was reported. The reaction starts from aromatic aldehydes, 1H-indazol-3-amine (4-chloro-1H-indazol-3-amine), and 3-(1H-indol-3-yl)-3-oxopropane

Full text of DOI:10.1016/j.tet.2017.07.035

Accepted Manuscript
An efficient metal-free cascade process for the synthesis of 4-
arylpyrimido[1,2-b]indazole-3-carbonitrile derivatives
Lei Li, Hui Xu, Lei Dai, Junhua Xi, Lingli Gao, Liangce Rong
PII:
S0040-4020(17)30777-9
10.1016/j.tet.2017.07.035
TET 28867
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 April 2017
Revised Date: 18 July 2017
Accepted Date: 21 July 2017
Please cite this article as: Li L, Xu H, Dai L, Xi J, Gao L, Rong L, An efficient metal-free cascade process
for the synthesis of 4-arylpyrimido[1,2-b]indazole-3-carbonitrile derivatives, Tetrahedron (2017), doi:
10.1016/j.tet.2017.07.035.
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ACCEPTED MANUSCRIPT
An efficient metal-free cascade process for the synthesis of
4-arylpyrimido[1,2-b]indazole-3-carbonitrile derivatives
Lei Li, Hui Xu, Lei Dai, Junhua Xi, Lingli Gao, Liangce Rong*
Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials; School of
Chemistry and Materials Science, Jiangsu Normal University, Xuzhou, 221116, Jiangsu, P. R.
China
E-mail: lcrong@jsnu.edu.cn
An efficient metal-free cascade process for the synthesis of
4-arylpyrimido[1,2-b]indazole-3-carbonitrile derivatives
Lei Li, Hui Xu, Lei Dai, Junhua Xi, Lingli Gao, Liangce Rong*
Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials; School of
Chemistry and Materials Science, Jiangsu Normal University, Xuzhou, 221116, Jiangsu, P. R.
China
E-mail: lcrong@jsnu.edu.cn

ACCEPTED MANUSCRIPT
An
efficient
metal-free
cascade
process
for
the
synthesis
of
4-arylpyrimido[1,2-b]indazole-3-carbonitrile derivatives
Lei Li, Hui Xu, Lei Dai, Junhua Xi, Lingli Gao, Liangce Rong*
Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials; School of
Chemistry and Materials Science, Jiangsu Normal University, Xuzhou, 221116, Jiangsu, P. R.
China
Telephone Number: 86-516-83500349
Fax Number: 86-516-83403164
E-mail: lcrong@jsnu.edu.cn
1

ACCEPTED MANUSCRIPT
An
efficient
metal-free
cascade
process
for
the
synthesis
of
4-arylpyrimido[1,2-b]indazole-3-carbonitrile derivatives
Lei Li, Hui Xu, Lei Dai, Junhua Xi, Lingli Gao, Liangce Rong*
Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials; School of
Chemistry and Materials Science, Jiangsu Normal University, Xuzhou, 221116, Jiangsu, P. R.
China
Telephone Number: 86-516-83500349
Fax Number: 86-516-83403164
E-mail: lcrong@jsnu.edu.cn
Abstract
pyrimido[1,2-b]indazole-3-carbonitrile derivatives was reported. The reaction starts from aromatic
aldehydes, 1H-indazol-3-amine (4-chloro-1H-indazol-3-amine), and
An
efficient
metal-free
cascade
reaction
to
synthesize
novel
3-(1H-indol-3-yl)-3-oxopropanenitrile or 3-oxo-3-arylpro-panenitrile in the presence of ethanol
and triethylamine under plain laboratory conditions. The reaction was easy to operate with good
tolerance to substrates in high yield.
Keywords Pyrimido[1,2-b]indazole, Indole, 1H-indazol-3-amine, Triethylamine, Multicomponent
reactions
1. Introduction
Multicomponent reactions (MCRs) mean that the three or more reactants react and convert them
into the diversity molecules with one-pot process.1-7 More attention has been paid on this synthetic
method because of simple set-up, atom economy, and high yield. Recently, various MCRs have
efficiently constructed nitrogen-bearing heterocyclic compounds which have biological and
pharmacoligical activities.8-10 The nucleus structure of 3-substituted indole is prevalent in natural
products and is very important in medicinal chemistry also.11,12 Compounds with these structures
have many important bioactivities, such as anticancer, anti-tumour,13 anti-inflammatory,
decreasing
hypoglycemic,
analgesic
effective
and
anti-pyretic
effects.14
The
pyrazolo[1,5-a]pyrimidine derivatives show antimicrobial, antibacterial, antitrichomonal,
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antischistosomal, anticancer, and antitumor properties.15 Several marketed drugs, such as divaplon,
taniplon, and fasiplon, have pyrazolo[1,5-a]pyrimidine motifs in their main core structure (Fig.
1)16.
Figure 1. The active compounds with pyrazolo[1,5-a]pyrimidine nucleus.
Pyrimido[1,2-b]indazole scaffolds being like pyrazolo[1,5-a]pyrimidine nucleus in their central
motifs are the important nitrogen-bearing heterocyclic compounds. These compounds also have
some interesting biological properties, for examples, they can be used as anticancer and protein
kinase inhibitors. Some medicines with the main structures of pyrimido[1,2-b] indazole can treat a
variety of ailments.17
It was found that 1H-indazol-3-amine was an efficient reagent for the synthesis of
pyrimido[1,2-b]indazole derivatives. As far as we know, only two research groups have
synthesized some pyrimido[1,2-b]indazole derivatives from 1H-indazol-3-amine, successfully.
Jeong's group has synthesized pyrimido[1,2-b]indazole derivatives from a three-component
reaction of 1H-indazol-3-amine, aldehydes, and malononitrile.18 They used 1H-indazol-3-amine,
aldehydes and 1,3-dicarbonyl staring material to give the similar compounds.19 Recently, the
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reaction of 4-hydroxy-2H-chromen-2-one, isatin, and 1H-indazole-3-amine was also reported by
this group.20 Palaniraja's group published three papers about the reaction making
pyrimido[1,2-b]indazole derivatives.21 Considering the importance of 3-substituted indole and
pyrimido[1,2-b]indazole, we plan to synthesize novel compounds with both
pyrimido[1,2-b]indazole and 3-substituted indole scaffolds from aromatic aldehydes,
1H-indazol-3-amine, and 3-(1H-indol-3-yl)-3-oxopropanenitrile.
2. Results and Discussion
At the beginning of this research, we employed benzaldehyde (1a), 1H-indazol-3-amine (2),
and 3-(1H-indol-3-yl)-3-oxopropanenitrile 3 as the substrates to optimize this reaction conditions
(Scheme 1). First, proton acid hydrated p-toluene sulphonic acid (PTSA·H2O) and Lewis acid
(FeCl3) were selected to evaluate the acidic catalysts on the model reaction. Showing different
from the reported methods,19 acidic catalysts have no catalytic effect (Table 1, entries 1-2). Next,
we tested the base catalysts. Organic base (DBU, piperidine, DMAP, Et3N) and inorganic base
(such as KOH, NaOH, K2CO3, and Na2CO3) was used. The results showed that the organic alkalis
had a good catalytic effect (Table 1, entries 3-6), while the inorganic strong bases (KOH, NaOH)
had a weak catalytic effect (Table 1, entries 7-8). However, the inorganic weak bases (K2CO3,
Na2CO3) could not provide target product (Table 1, entries 9-10). Of all the catalysts,
triethylamine had the best catalytic capacity. Next, the influence of the reaction time, temperature,
and catalyst loading were investigated (Table 1, entries 11-18). Finally, the optimum condition
o
was obtained as follows: EtOH as solvent, 20 mol % catalyst loading, 80 C, and about 5 h
reaction time (Table 1, entry 16). The results were listed in Table 1.
Scheme 1. The model reaction of benzaldehyde, 1H-indazol-3-amine, and
3-(1H-indol-3-yl)-3-oxopropanenitrile.
Table 1 Condition optimization for the reaction between benzaldehyde, 1H-indazol-3-amine, and
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3-(1H-indol-3-yl)-3-oxopropanenitrilea.
Entry
1
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3OH
EtOH
Catalyst (mol%)
PTSA H2O (30)
FeCl3 (30)
DBU (30)
Temp. oC
80
Time (h)
Yields (%)b
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
5
7
7
0
0
2
80
3
80
30
41
15
76
25
28
trace
trace
56
85
42
82
67
91
90
52
4
Piperidine (30)
DMAP (30)
Et3N (30)
80
5
80
6
80
7
KOH (30)
NaOH (30)
K2CO3 (30)
Na2CO3 (30)
Et3N (30)
80
8
80
9
80
10
11
12
13
14
15
16
17
18
80
80
Et3N(30)
80
THF
Et3N (30)
80
EtOH
Et3N (20)
80
EtOH
Et3N (10)
80
EtOH
Et3N (20)
80
EtOH
Et3N (20)
80
EtOH
Et3N (20)
60
aReaction condition: Reagent: benzaldehyde 1a (1 mmol), 1H-indazol-3-amine 2 (1 mmol), and
3-(1H-indol-3-yl)-3-oxopropanenitrile 3 (1 mmol), solvent (8 mL).
bIsolated Yields
With the optimized reaction conditions in hand, we next expanded the model reaction of
different aromatic aldehydes with 1H-indazol-3-amines and 3-(1H-indol-3-yl)-3-oxopropanenitrile
(Scheme 2). It was found that both electron-donating (OH, Me, MeO) and electron-withdrawing
(F, Cl, Br, NO2) substituents of aromatic aldehydes worked well, giving the desired compounds
4a−4l in good yields. 4-Pyridylformaldehyde could be applied to this method too, and the
corresponding product 4m was obtained in 85% yield. In addition, 4-chloro-1H-indazol-3- amine
was also explored, and the corresponding products 4n-4q were obtained with high yields. The
results were summarized in Table 2.
Scheme 2. The reactions of aromatic aldehydes, (substituted) 1H-indazol-3-amine, and
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3-(1H-indol-3-yl)-3-oxopropanenitrile.
Table 2 Three-component reactions of aromatic aldehydes, (substituted) 1H-indazol-3-amine, and
3-(1H-indol-3-yl)-3-oxopropanenitrilea.
Entry
R1
R2
Compounds
Yields (%)b
1
1-H
H
4a
4b
4c
4d
4e
4f
91
2
4-F
H
90
3
4-Cl
H
89
4
3,4-Cl2
4-Br
H
90
5
H
88
6
4-NO2
4-OH
H
92
7
H
4g
4h
4i
91
8
4-CH3
3-CH3O
4-CH3O
3,4-OCH2O
3,4,5-(CH3O)3
4-pyridyl
4-F
H
87
9
10
H
89
H
4j
90
11
H
4k
4l
86
12
H
87
13
H
4m
4n
4o
4p
4q
85
14
Cl
82
15
4-OH
Cl
89
16
4-CH3
4-CH3O
method:
Cl
85
17
aReaction
Cl
88
aromatic
aldehydes
(1
mmol),
1H-indazol-3-amine
(4-chloro-1H-indazol-3-amine) (1 mmol), and 3-(1H-indol-3-yl)-3-oxopropanenitrile (1 mmol),
EtOH (8 mL), Et3N (0.2 mmol), 80 oC, reaction time (3-5 h) (monitored reactions by TLC).
bIsolated Yields
In order to obtain more pyrimido[1,2-b]indazole derivatives, 3-oxo-3-arylpropanenitrile was
also applied in our synthesis. Under screened conditions, the reactions of different aromatic
aldehydes,1H-indazol-3-amine and 3-oxo-3-arylpropanenitrile were performed very well and the
2,4-diaryl-3,4-dihydropyrimido[1,2-b]indazole-3-carbonitrile products 6a-6p were obtained with
high yields (Scheme 3). Simultaneously, this reaction was also effective to the staring material of
4-chloro-1H-indazol-3-amine, and the corresponding products 6q-6s were synthesized under
screened conditions. The results were listed in Table 3.
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Scheme 3. The reactions of aromatic aldehydes, (substituted) 1H-indazol-3-amine, and
3-oxo-3-arylpropanenitrile.
Table 3 Three-component reactions of aromatic aldehydes, (substituted) 1H-indazol-3-amine, and
3-oxo-3-arylpropanenitrilea
Entry
R1
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
X
H
H
H
H
H
H
H
H
F
Compounds
Yields (%)b
1
H
6a
6b
6c
6d
6e
6f
86
2
3-CH3
89
3
4-CH3
87
4
3,4-(CH3)2
4-OH
83
5
90
6
4-CH3O
3,4,5-(CH3O)3
3,4-Cl2
4-OH
89
7
6g
6h
6i
86
8
83
9
10
88
4-CH3
F
6j
81
11
4-OH
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
6k
6l
87
12
3-CH3
80
13
4-CH3
6m
6n
6o
6p
6q
6r
6s
84
14
3-CH3O
4-CH3O
3,4,5-(CH3O)3
4-OH
88
15
83
16
80
17
91
18
4-CH3
88
89
19
4-CH3O
aReaction
method:
aromatic
aldehydes
(1
mmol),
1H-indazol-3-amine
(4-chloro-1H-indazol-3-amine) (1 mmol), and 3-oxo-3-arylpropanenitrile (1 mmol), EtOH (8 mL),
Et3N (0.2 mmol), 80 oC, reaction time (3-5 h) (monitored reactions by TLC).
bIsolated Yields
1
The products structures were determined by IR, HNMR, and 13C NMR, and HRMS analysis
(see in Supporting Information). In their IR, the signal of cyano group (-CN) were found, but the
signal of amino group (-NH2) (Supporting information, Fig. 75) disappeared, which means the
products are different from that data of literature.18 In accordance with the result, a possible
mechanism was provided in Figure 2. Firstly, the Knoevenagel product A of aldehyde and
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3-(1H-indol-3-yl)-3-oxopropanenitrile was formed in EtOH with Et3N as a catalyst. Then, it
maybe has two approaches to reacting with 1H-indazol-3-amine. In path a, the amino group of
1H-indazol-3-amine reacted with the carbonyl group of A to give imine intermediate B.
Intermediate C is the tautomer of B, and then, D was formed from the intramolecular cyclization
of intermediate C. At last, products 4 were obtained after an oxidation reaction. If the reaction was
operated as path b, it could give a structure similar to that of the literature.18 However, we did not
find this structure.
In order to test our hypothesis, the reaction of benzaldehyde 4a and
3-(1H-indol-3-yl)-3-oxopropanenitrile 3 were first performed and the condensation product 7
(Supporting information, Fig. 73, 74) was obtained. Then, the reaction of 7 and
1H-indazol-3-amine was carried out under screened condition. As expected, the product 4a could
be successfully obtained with 90% yield (Scheme 4). The results fully proved our proposed
mechanism.
Figure 2. The possible reaction mechanism.
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Scheme 4. The controlled reaction of 4a.
3. Conclusion
In conclusion, we have reported a facile and efficient cascade reactions for the synthesis of
pyrimido[1,2-b]indazole-3-carbonitrile derivatives from aromatic aldehyde, 1H-indazol-3-amine
(4-chloro-1H-indazol-3-amine),
and
3-(1H-indol-3-yl)-3-oxopropanenitrile
or
3-oxo-3-arylpropanenitrile under metal-free conditions. It was a very successful process for the
construction of pyrimido[1,2-b]indazole compounds under plain laboratory conditions. This
synthetic path was novel as compared to the reported literature. This reaction has the advantages
of simple operation, high yields, easy isolation and wide scope substrates.
4. Experimental
4.1 General methods
All reagents were purchased from the Merck and Sigma-Aldrich chemical companies and used
without further purification. Melting points were determined on XT-5 microscopic melting-point
apparatus and were uncorrected. IR spectra were recorded on a FT Bruker Tensor 27 spectrometer.
1H NMR and 13C NMR spectra were obtained from solution in DMSO-d6 (or CDCl3 or DMSO-d6 :
CDCl3 = 9:1) using a Bruker-400 spectrometer. HRMS spectra were obtained with a Bruker
microTOF-Q 134 instrument.
4.2 General procedure for the synthesis of pyrimido[1,2-b]indazole-3-carbonitrile dericatives
The
mixture
of
aromatic
aldehyde
(1
mmol),
1H-indazol-3-amine
(4-chloro-1H-indazol-3-amine) (1 mmol), and 3-(1H-indol-3-yl)-3-oxopropanenitrile or
3-oxo-3-arylpropanenitrile (1 mmol), 95% EtOH (8 mL), Et3N (0.2 mmol) was put in a reaction
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o
flask under 80 C about 3–5 h (monitored by TLC). After the completion of the reaction, the
reaction mixture was cooled to room temperature and the products could be precipitated out from
solvent. Then, compound 4 and 6 were recrystallized from DMF or EtOH.
4.2.1 2-(1H-indol-3-yl)-4-phenylpyrimido[1,2-b]indazole-3-carbonitrile (4a)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.42 (s, 1H), 8.62 (s, 1H),
8.33 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 1,2 Hz, 1H), 7.83 (d, J = 8.8 Hz,
1H), 7.76 – 7.60 (m, 6H), 7.37 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H);
13C NMR (100 MHz, DMSO-d6) (δ, ppm): 154.5, 151.9 147.5, 143.2, 136.8, 136.2, 133.4, 131.0,
130.4, 129.4, 128.5, 125.2, 122.6, 122.2, 121.8, 121.1, 120.6, 117.4, 116.8, 113.4, 112.6, 103.5,
95.6; IR (KBr): 3362, 2923, 2226, 1636, 1541, 1522, 1458, 1401, 1260, 1158, 1079, 1028, 938,
859, 755, 733, 699, 610, 580, 530 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for
C25H15N5Na: 408.1225, found: 408.1231.
4.2.2 4-(4-fluorophenyl)-2-(1H-indol-3-yl)pyrimido[1,2-b]indazole-3-carbonitrile (4b)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.43 (s, 1H), 8.62 (s, 1H),
8.31 (d, J = 8.4 Hz, 1H), 8.17 (dd, J = 8.0, 5.6 Hz, 2H), 7.82 (d, J = 8.8 Hz, 1H), 7.79 – 7.64 (m,
3H), 7.51 (t, J = 8.8 Hz, 2H), 7.40 – 7.29 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) (δ, ppm): 162.2, 153.5, 151.9, 147.4, 143.1, 136.2, 133.5, 133.3, 131.8 (d, JC-F = 8.9
Hz), 131.0, 125.1, 122.6, 122.3, 121.8, 121.1, 120.7, 117.4, 116.8, 115.6 (d, JC-F = 11.8 Hz), 113.4,
112.6, 103.4, 95.5; IR (KBr): 3405, 2924, 2223, 1639, 1541, 1518, 1507, 1401, 1239, 1159, 1079,
1028, 948, 839, 755, 738, 708, 669, 577, 528 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for
C25H14FN5Na: 426.1131, found: 426.1148.
4.2.3 4-(4-chlorophenyl)-2-(1H-indol-3-yl)pyrimido[1,2-b]indazole-3-carbonitrile (4c)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.44 (s, 1H), 8.62 (s, 1H),
8.31 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.8 Hz,
1H), 7.78 – 7.71 (m, 3H), 7.58 (d, J = 8.4 Hz, 1H), 7.39 – 7.29 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H);
13C NMR (100 MHz, DMSO-d6) (δ, ppm): 160.6, 153.3, 151.9, 147.4, 143.1, 136.2, 135.6, 135.4,
133.5, 132.6, 131.2, 130.0, 129.1, 128.7, 125.1, 122.3, 120.7, 116.8, 113.5, 112.6, 103.4, 95.5; IR
(KBr):3422, 2925, 2224, 1645, 1604, 1568, 1550, 1488, 1400, 1370, 1160, 1079, 1029, 976, 930,
845, 730, 734, 670, 585, 529 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C25H14ClN5Na:
442.0835, found: 442.0828.
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4.2.4 4-(3,4-dichlorophenyl)-2-(1H-indol-3-yl)pyrimido[1,2-b]indazole-3-carbonitrile (4d)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.47 (s, 1H), 8.65 (s, 1H),
8.37-8.35 (m, 2H), 8.10 (dd, J = 2.4 Hz, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.8
Hz, 1H), 7.76 – 7.66 (m, 3H), 7.40 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.25 (t, J = 8.0 Hz,
1H); 13C NMR (100 MHz, DMSO-d6 : CDCl3 = 9:1) (δ, ppm): 151.8, 147.3, 143.0, 137.1, 136.2,
133.6, 133.3, 131.4, 131.1, 130.8, 129.5, 125.1, 122.6, 122.3, 122.0, 121.1, 120.7, 117.2, 116.8,
113.6, 112.6, 103.3, 95.3; IR (KBr): 3421, 2925, 2222, 1636, 1522, 1458, 1400, 1241, 1158, 1080,
1029, 939, 903, 856, 755, 737, 610, 577, 530 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for
C25H13Cl2N5Na: 476.0446, found: 476.0470.
4.2.5 4-(4-bromophenyl)-2-(1H-indol-3-yl)pyrimido[1,2-b]indazole-3-carbonitrile (4e)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.43 (s, 1H), 8.62 (s, 1H),
8.31 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.8 Hz,
1H), 7.73 – 7.68 (m, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.39 – 7.29 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H);
13C NMR (100 MHz, DMSO-d6) (δ, ppm): 153.4, 151.9, 147.4, 143.1, 136.3, 135.9, 133.6, 132.0,
131.6, 131.5, 131.0, 130.2, 125.1, 124.2, 122.7, 122.3, 121.9, 121.1, 120.7, 117.4, 116.8, 113.5,
112.6, 103.4, 95.4; IR (KBr): 3420, 2924, 2230, 1636, 1541, 1522, 1399, 1242, 1158, 1079, 1028,
947, 755, 739, 669, 577, 530 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C25H14BrN5Na:
486.0330, found: 486.0351.
4.2.6 2-(1H-indol-3-yl)-4-(4-nitrophenyl)pyrimido[1,2-b]indazole-3-carbonitrile (4f)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.46 (s, 1H), 8.64 (s, 1H),
8.51 (d, J = 8.4 Hz, 2H), 8.41 – 8.32 (t, J = 9.2 Hz, 3H), 7.87 (d, J = 8.8 Hz, 1H), 7.76 – 7.70 (m,
2H), 7.66 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz,
1H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 152.3, 152.0, 148.4, 147.4, 143.0, 142.7, 136.3,
133.7, 131.2, 130.9, 129.6, 125.1, 124.1, 123.7, 122.7, 122.3, 121.1, 120.7, 117.2, 116.9, 113.7,
112.7, 103.3, 95.6; IR (KBr):3400, 2924, 2222, 1649, 1534, 1518, 1507, 1397, 1230, 1150, 1079,
1028, 930, 830, 755, 737, 708, 670, 550, 535 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for
C25H14N6NaO2: 453.1076, found: 453.1062.
4.2.7 4-(4-hydroxyphenyl)-2-(1H-indol-3-yl)pyrimido[1,2-b]indazole-3-carbonitrile (4g)
11

ACCEPTED MANUSCRIPT
1
Yellow solid; m.p. > 280°C; H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.39 (s, 1H), 10.14 (s,
1H), 8.59 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.71
– 7.61 (m, 3H), 7.34 – 7.29 (m, 2H), 7.22 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6) (δ, ppm): 159.8, 154.5, 151.9, 147.5, 143.3, 136.2, 133.4, 131.2, 130.9,
127.4, 125.2, 122.6, 122.2, 121.4, 121.2, 120.6, 117.8, 116.6, 115.4, 113.2, 112.6, 103.5, 95.1; IR
(KBr): 3405, 2925, 2234, 1634, 1568, 1539, 1488, 1401, 1369, 1158, 1079, 1029, 948, 841, 749,
734, 669, 578 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C25H15N5NaO: 424.1174,
found: 424.1189.
4.2.8 2-(1H-indol-3-yl)-4-(p-tolyl)pyrimido[1,2-b]indazole-3-carbonitrile (4h)
Yellow solid; m.p. >280 °C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.40 (s, 1H), 8.60 (s, 1H),
8.30 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.72 – 7.62 (m, 3H),
7.46 (d, J = 8.0 Hz, 2H), 7.38 – 7.28 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H), 2.45 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) (δ, ppm): 154.5, 151.9, 147.4, 143.2, 140.3, 136.2, 133.9, 133.4, 130.9,
129.3, 129.1, 125.2, 122.6, 122.2, 121.6, 121.1, 120.6, 117.5, 116.7, 113.3, 112.6, 103.5, 95.5,
21.0; IR (KBr): 3405, 2923, 2223, 1637, 1522, 1401, 1242, 1158, 1080, 1028, 948, 847, 754, 737,
669, 650, 610, 577, 530 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C26H17N5Na:
422.1382, found: 422.1380.
4.2.9 2-(1H-indol-3-yl)-4-(3-methoxyphenyl)pyrimido[1,2-b]indazole-3-carbonitrile (4i)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.41 (s, 1H), 8.61 (s, 1H),
8.31 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.73 – 7.62 (m, 5H), 7.57 (t, J = 8.0 Hz, 1H),
7.39 – 7.28 (m, 2H), 7.22 (t, J = 8.0 Hz, 2H), 3.90 (s, 3H); 13C NMR (100 MHz, DMSO-d6) (δ,
ppm): 159.1, 154.2, 151.9, 147.4, 143.1, 138.0, 136.2, 133.4, 131.0, 129.7, 125.2, 122.6, 122.3,
121.8, 121.7, 121.2, 120.6, 117.4, 116.8, 115.8, 115.0, 113.4, 112.6, 103.5, 95.7, 55.4; IR (KBr):
3405, 2925, 2219, 1634, 1527, 1488, 1402, 1385, 1246, 1158, 1080, 1029, 948, 853, 750, 705, 577,
530 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C26H17N5NaO: 438.1331, found:
438.1345.
4.2.10 2-(1H-indol-3-yl)-4-(4-methoxyphenyl)pyrimido[1,2-b]indazole-3-carbonitrile (4j)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.40 (s, 1H), 8.60 (s, 1H),
8.29 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.0 Hz,
12

ACCEPTED MANUSCRIPT
1H), 7.67 – 7.61 (m, 2H), 7.34 -7.34 (m, 2H), 7.25 - 7.20 (m, 3H), 3.89 (s, 3H); 13C NMR (100
MHz, DMSO-d6) (δ, ppm): 161.1, 154.1, 151.9, 147.5, 143.2, 136.2, 133.4, 131.1, 130.9, 129.0,
125.2, 122.6, 122.2, 121.5, 121.1, 120.6, 117.7, 116.6, 114.0, 113.2, 112.6, 103.5, 95.2, 55.5; IR
(KBr): 3343, 2926, 2223, 1637, 1609, 1567, 1548, 1519, 1486, 1465, 1437, 1377, 1297, 1256,
1178, 1159, 1128, 1080, 1033, 939, 900, 832, 754, 678, 654, 617, 594, 518, 438, 426 cm-1; HRMS
(ESI-TOF) m/z [M+Na]+ calculated for C26H17N5NaO: 438.1331, found: 438.1339.
4.2.11 4-(benzo[d][1,3]dioxol-5-yl)-2-(1H-indol-3-yl)pyrimido[1,2-b]indazole-3-carbonitrile (4k)
Yellow solid; m.p. >280 °C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.43 (s, 1H), 8.61 (s, 1H),
8.27 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.67 – 7.67 (m, 4H),
7.33 -7.30 (m, 2H), 7.23 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 6.19 (s, 2H); 13C NMR (100
MHz, DMSO-d6) (δ, ppm): 153.9, 151.9, 149.3, 147.5, 143.1, 136.2, 133.5, 130.6, 125.2, 124.3,
122.6, 122.3, 121.2, 120.7, 116.7, 113.3, 112.6, 109.4, 108.4, 103.5, 101.8, 95.4; IR (KBr): 3420,
2924, 2225, 1668, 1636, 1528, 1489, 1441, 1385, 1339, 1246, 1211, 1157, 1079, 1030, 935, 912,
858, 746, 709, 619, 576, 520 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C26H15N5NaO2:
452,1123, found: 452.1136.
4.2.12 2-(1H-indol-3-yl)-4-(3,4,5-trimethoxyphenyl)pyrimido[1,2-b]indazole-3-carbonitrile (4l)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.40 (s, 1H), 8.60 (s, 1H),
8.33 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.70 -7.64 (m, 3H), 7.44 (s, 2H), 7.39 – 7.34 (t,
J = 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.2 Hz, 1H), 3.93 (s, 6H), 3.80 (s, 3H); 13
C
NMR (100 MHz, DMSO-d6 : CDCl3 = 9:1) (δ, ppm): 153.8, 152.7, 151.9, 147.4, 142.9, 139.4,
136.2, 133.1, 131.7, 130.8, 125.1, 122.4, 122.3, 121.5, 121.1, 120.5, 117.4, 116.6, 113.3, 112.5,
107.0, 103.5, 95.4, 60.2, 56.1; IR (KBr):3407, 2924, 2219, 1634, 1527, 1488, 1452 1402, 1385,
1246, 1210, 1158, 1080, 1053 1029, 948, 923 853, 750, 732, 705, 577, 530 cm-1; HRMS
(ESI-TOF) m/z [M+Na]+ calculated for C28H21N5NaO3: 498.1542, found: 498.1561.
4.2.13 2-(1H-indol-3-yl)-4-(pyridin-4-yl)pyrimido[1,2-b]indazole-3-carbonitrile (4m)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.47 (s, 1H), 8.89 (d, J =
5.6 Hz, 2H), 8.63 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 5.2 Hz, 2H), 7.87 (d, J = 8.8 Hz,
1H), 7.72 (t, J = 7.6 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.2 Hz,
1H), 7.23 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6 : CDCl3 = 9:1) (δ, ppm): 162.2,
13

ACCEPTED MANUSCRIPT
151.8, 150.0, 147.4, 143.8, 143.0, 136.3, 133.5, 131.0, 125.1, 123.4, 122.6, 122.2, 121.0, 120.7,
116.9, 113.6, 112.6, 103.3, 95.2; IR (KBr):3240, 2924, 2221, 1635, 1507, 1490, 1400, 1262, 1158,
1080, 1028, 948, 842, 755, 736, 708, 611, 580, 531 cm-1; HRMS (ESI-TOF) m/z [M+Na]+
calculated for C24H14N6Na: 409.1178, found: 409.1175.
4.2.14 10-chloro-4-(4-fluorophenyl)-2-(1H-indol-3-yl)pyrimido[1,2-b]indazole-3-carbonitrile (4n)
Yellow solid; m.p. > 280 °C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.48 (s, 1H), 8.61 (d, J =
2.4 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.22 – 8.15 (m, 2H), 8.12 (d, J = 0.8 Hz, 1H), 7.73 (d, J =
8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 2H), 7.45 (dd, J = 8.8, 1.6 Hz, 1H), 7.32
(t, J = 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 154.6,
152.3, 147.7, 143.4, 136.2, 133.6, 133.1, 132.0, 131.9, 125.0 (d, JCF = 14.0 Hz), 124.5, 123.2,
122.7, 122.3, 120.7, 118.9, 117.3, 115.6 (d, JCF = 14.0 Hz), 112.6, 112.2, 103.3, 96.1; IR
(KBr):3413, 3222, 2225, 1703, 1636, 1567, 1521, 1482, 1456, 1384, 1221, 1162, 1030, 958, 783,
732, 640 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C25H13ClFN5Na: 460.0741, found:
460.0752.
4.2.15 10-chloro-4-(4-hydroxyphenyl)-2-(1H-indol-3-yl)pyrimido[1,2-b]indazole-3-carbonitrile
(4o)
1
Yellow solid; m.p. > 280 °C; H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.41 (s, 1H), 10.19 (s,
1H), 8.59 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.64 (ddd, J =
15.9, 11.1, 7.6 Hz, 3H), 7.37 (d, J = 7.2 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H),
7.04 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 160.0, 154.8, 152.5, 147.7,
142.8, 136.2, 133.4, 131.2, 131.0, 127.2, 126.9, 125.2, 122.6, 122.2, 121.3, 120.4, 117.6, 115.6,
115.4, 112.5, 110.6, 103.4, 95.4; IR (KBr): 3448, 2923, 2225, 1653, 1636, 1559, 1541, 1522, 1507,
1498, 1474, 1458, 1399, 1385, 1339, 1160,1029 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated
for C25H14ClN5NaO: 458.0785, found: 458.0783.
4.2.16 10-chloro-2-(1H-indol-3-yl)-4-(p-tolyl)pyrimido[1,2-b]indazole-3-carbonitrile (4p)
Yellow solid; m.p. > 280 °C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.43 (s, 1H), 8.59 (s, 1H),
8.05 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.72 – 7.57 (m, 3H), 7.48 (d, J = 8.0 Hz, 2H),
7.38 (d, J = 7.2 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 2.46 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) (δ, ppm): 155.0, 152.5, 147.7, 142.7, 140.6, 136.2, 133.9, 133.5, 131.1,
14

ACCEPTED MANUSCRIPT
129.3, 129.2, 126.8, 125.2, 122.6, 122.3, 121.6, 120.7, 117.5, 115.7, 112.6, 110.8, 103.4, 95.9,
21.1; IR (KBr): 3448, 3227, 2223, 1636, 1567, 1542, 1521, 1482, 1384, 1162, 1029, 958, 786, 733,
669 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C26H16ClN5Na: 456.0992, found:
456.0983.
4.2.17 10-chloro-2-(1H-indol-3-yl)-4-(4-methoxyphenyl)pyrimido[1,2-b]indazole-3-carbonitrile
(4q)
Yellow solid; m.p. > 280 °C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.41 (s, 1H), 8.59 (s, 1H),
8.18 – 8.12 (m, 2H), 7.75 (d, J = 8.8 Hz, 1H), 7.70 -7.59 (m, 3H), 7.37 (d, J = 7.2 Hz, 1H), 7.31 (t,
J = 7.2 Hz, 1H), 7.24 -7.21 (m, 3H), 3.90 (s, 3H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm):
161.3, 154.6, 152.6, 147.8, 142.8, 136.2, 133.4, 131.1, 128.9, 126.8, 125.2, 122.6, 122.2, 121.5,
120.7, 117.6, 115.7, 114.1, 112.6, 110.6, 103.4, 95.6, 55.5; IR (KBr): 3448, 2224, 1637, 1560,
1517, 1482, 1384, 1252, 1036, 736 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for
C26H16ClN5NaO: 472.0941, found: 472.0950.
4.2.18 2,4-diphenylpyrimido[1,2-b]indazole-3-carbonitrile (6a)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, CDCl3) (δ, ppm): 8.38 (d, J = 8.4 Hz, 1H), 8.16
– 8.09 (m, 2H), 8.01 (t, J = 3.6 Hz, 2H), 7.84 (d, J = 8.8 Hz, 1H), 7.72(d, J = 2.0 Hz, 2H), 7.71 (s,
1H), 7.66 (t J = 7.6 Hz, 1H), 7.62-7.60 (m, 3H), 7.37 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) (δ, ppm): 154.4, 153.5, 151.5, 144.1, 136.4, 132.5, 131.6, 130.9, 130.3, 129.4, 129.2,
129.0, 128.7, 122.5, 121.5, 117.3, 116.2, 114.2, 97.1; IR (KBr): 3422, 2926, 2220, 1636, 1482,
1458, 1401, 1158, 1079, 1028, 948, 856, 757, 734, 692, 668, 609, 578, 532 cm-1; HRMS
(ESI-TOF) m/z [M+Na]+ calculated for C23H14N4NaO: 369.1116, found: 369.1127.
4.2.19 2-phenyl-4-(m-tolyl)pyrimido[1,2-b]indazole-3-carbonitrile (6b)
1
Yellow solid; m.p. 276 - 278°C; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.35 (d, J = 8.0 Hz,
1H), 8.05 – 7.98 (m, 2H), 7.87 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.74 – 7.69 (m, 4H), 7.54 (t, J =
7.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 2.47 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) (δ, ppm): 154.1, 152.3, 151.3, 143.2, 138.0, 136.3, 131.7, 131.1, 130.2, 129.6, 129.0,
128.6, 128.5, 126.3, 122.1, 121.1, 116.7, 116.2, 113.2, 97.8, 21.0; IR (KBr): 3421, 2924, 2222,
1636, 1507, 1401, 1158, 1080, 1028, 947, 757, 692, 587, 531 cm-1; HRMS (ESI-TOF) m/z
[M+Na]+ calculated for C24H16N4NaO2: 383.1273, found: 383.1289.
15

ACCEPTED MANUSCRIPT
4.2.20 2-phenyl-4-(p-tolyl)pyrimido[1,2-b]indazole-3-carbonitrile (6c)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, CDCl3) (δ, ppm): 8.37 (d, J = 8.4 Hz, 1H), 8.03
(s, 1H), 8.01 – 7.89 (m, 3H), 7.83 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 2.0 Hz, 2H), 7.70 (s, 1H), 7.65
(t, J = 8.4 Hz, 1H), 7.41 (d, J = 7.6 Hz, 2H), 7.35 (t, J =7.6 Hz, 1H), 2.48 (s, 3H); 13C NMR (100
MHz, CDCl3) (δ, ppm): 154.5, 153.5, 151.5, 144.1, 141.3, 133.7, 132.4, 131.5, 130.3, 129.7, 129.3,
129.2, 128.7, 122.4, 121.6, 117.3, 116.3, 114.1, 97.0, 21.7; IR (KBr): 3416, 2924, 2218, 1637,
1401, 1158, 1080, 1028, 758, 733, 642, 577, 531 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated
for C24H16N4NaO: 383.1273, found: 383.1299.
4.2.21 4-(3,4-dimethylphenyl)-2-phenylpyrimido[1,2-b]indazole-3-carbonitrile (6d)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, CDCl3) (δ, ppm): 8.38 (d, J = 8.4 Hz, 1H), 8.00
(t, J = 3.6 Hz, 2H), 7.88 (s, 1H), 7.84 (t, J = 9.2 Hz, 2H), 7.71 (d, J = 2.4 Hz, 2H), 7.70 (s, 1H),
7.64 (d, J = 8.2 Hz, 1H), 7.35 (t, J = 8.0 Hz, 2H), 2.42 (s, 3H), 2.38 (s, 3H); 13C NMR (100 MHz,
CDCl3) (δ, ppm): 154.7, 153.5, 151.4, 144.1, 140.0, 137.4, 134.0, 132.4, 131.5, 130.4, 130.3,
130.2, 129.2, 128.7, 126.8, 122.3, 121.6, 117.2, 116.4, 114.1, 97.1, 20.1, 20.0; IR (KBr): 3412,
2924, 2218, 1636, 1566, 1481, 1401, 1373, 1158, 1079, 1029, 948, 758, 730, 695, 669, 610, 581,
528 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C25H18N4Na: 397.1429, found:
397.1451.
4.2.22 4-(4-hydroxyphenyl)-2-phenylpyrimido[1,2-b]indazole-3-carbonitrile (6e)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 10.19 (s, 1H), 8.29 (d, J =
8.0 Hz, 1H), 8.01-7.95 (m, 4H), 7.78 (d, J = 8.8 Hz, 1H), 7.73 – 7.70 (m, 3H), 7.66 (t, J = 8.4 Hz
1H), 7.34 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm):
159.9, 153.8, 152.3, 151.3, 143.3, 131.6, 131.1, 131.0, 130.3, 129.2, 128.6, 127.0, 121.7, 121.1,
116.6, 116.5, 115.5, 113.0, 97.2; IR (KBr): 3420, 2925, 2220, 1636, 1611, 1567, 1550, 1513, 1401,
1371, 1281, 1242, 1157, 1080, 1029, 948, 834, 757, 735, 617, 577, 531 cm-1; HRMS (ESI-TOF)
m/z [M+Na]+ calculated for C23H14N4NaO: 385.1065, found: 385.1078.
4.2.23 4-(4-methoxyphenyl)-2-phenylpyrimido[1,2-b]indazole-3-carbonitrile (6f)
1
Yellow solid; m.p. > 280°C; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.33 (d, J = 8.4 Hz, 1H),
8.08 (d, J = 8.8 Hz, 2H), 8.03 – 8.01 (m, 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.74 – 7.72 (m, 3H), 7.69
(d, J =8.8 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 3.92 (s, 3H); 13C NMR (100
16

ACCEPTED MANUSCRIPT
MHz, DMSO-d6) (δ, ppm): 161.7, 153.9, 152.8, 143.8, 132.1, 131.7, 131.3, 130.7, 129.6, 129.1,
122.4, 121.6, 117.2, 117.0, 114.6, 113.5, 97.9, 56.0; IR (KBr):3416, 2924, 2220, 1636, 1512, 1402,
1384, 1298, 1253, 1158, 1079, 1028, 948, 840, 755, 689, 612, 578, 532 cm-1; HRMS (ESI-TOF)
m/z [M+Na]+ calculated for C24H16N4NaO: 399.1222, found: 399.1243.
4.2.24 2-phenyl-4-(3,4,5-trimethoxyphenyl)pyrimido[1,2-b]indazole-3-carbonitrile (6g)
1
Yellow solid; m.p. > 280°C; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.36 (d, J = 8.4 Hz, 1H),
8.04 - 8.02 (m, 2H), 7.84 (d, J = 8.8 Hz, 1H), 7.74 - 7.69 (m, 4H), 7.42 – 7.42 (m, 3H), 3.91 (s,
6H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3-d) (δ, ppm): 153.9, 153.6, 153.5, 151.6, 143.9,
140.5, 132.5, 131.6, 131.4, 130.2, 129.2, 128.6, 122.5, 121.6, 117.3, 116.4, 114.1, 106.9, 96.9,
61.2, 56.5; IR (KBr): 3419, 2927, 2222, 1635, 1506, 1458, 1404, 1384, 1244, 1158, 1122, 1080,
1028, 947, 853, 743, 705, 577, 528 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for
C26H20N4NaO3: 459.1433, found: 459.1427.
4.2.25 4-(3,4-dichlorophenyl)-2-phenylpyrimido[1,2-b]indazole-3-carbonitrile (6h)
Yellow solid; m.p. > 280°C; 1H NMR (400 MHz, CDCl3) (δ, ppm): 8.37 (d, J = 8.4 Hz, 1H), 8.08
(d, J = 8.4 Hz, 2H), 7.99 (t, J = 3.6 Hz, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.72 – 7.71 (m, 2H), 7.68 (t,
J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.39 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6 : CDCl3 : = 9:1) (δ, ppm): 152.8, 152.1, 150.7, 143.2, 136.3, 134.2, 131.8, 131.0, 130.1,
129.6, 128.4, 127.9, 122.0, 120.7, 116.6, 115.4, 113.5, 96.1; IR (KBr): 3420, 2923, 2220, 1636,
1399, 1339, 1158, 1029, 938, 753, 687, 610, 578, 529 cm-1; HRMS (ESI-TOF) m/z [M+Na]+
calculated for C23H12Cl2N4Na: 437.0337, found: 437.0351.
4.2.26 2-(4-fluorophenyl)-4-(4-hydroxyphenyl)pyrimido[1,2-b]indazole-3-carbonitrile (6i)
Yellow solid; m.p. > 280 °C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 10.22 (s, 1H), 8.31 (d, J =
8.4 Hz, 1H), 8.16 – 8.06 (m, 2H), 8.03 – 7.91 (m, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.68 (t, J = 5.2 Hz,
1H), 7.59 (t, J = 8.8 Hz, 2H), 7.35 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H); 13C NMR (100
MHz, DMSO-d6) (δ, ppm): 159.9, 153.7, 152.3, 150.4, 143.3, 133.1 (d, JC-F = 9.0 Hz), 130.9,
126.9, 125.5, 121.8, 121.1, 116.6, 116.5, 115.8 (d, JC-F = 22.0 Hz), 115.5, 113.0, 97.3; IR (KBr):
3448, 2921, 2226, 1643, 1601, 1507, 1454, 1428, 1384, 1333,1265, 1238, 1165, 1108, 918, 861,
762 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C23H13FN4NaO: 403.0971, found:
403.0975.
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4.2.27 2-(4-fluorophenyl)-4-(p-tolyl)pyrimido[1,2-b]indazole-3-carbonitrile (6j)
Yellow solid; m.p. > 280 °C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.33 (d, J = 8.4 Hz, 1H),
8.14 -8.10 (m, 2H), 7.96 (dd, J = 17.6, 8.0 Hz, 2H), 7.83 (d, J = 8.8 Hz, 1H), 7.73 – 7.67 (m, 1H),
7.63 – 7.45 (m, 4H), 7.38 (d, J = 8.0 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, DMSO-d6) (δ,
ppm): 153.8, 152.3, 150.4, 143.3, 140.6, 133.5, 133.2 (d, JC-F = 9.0 Hz), 131.7, 131.3, 130.3, 129.2,
129.1, 125.4, 122.1, 121.1, 116.7, 116.3, 116.0, 115.7 (d, JC-F = 22.0 Hz), 113.2, 97.7, 21.0; IR
(KBr): 3447, 2923, 2224, 1637, 1559, 1522, 1507, 1489, 1458, 1384, 1236, 1163, 1030, 743 cm-1;
HRMS (ESI-TOF) m/z [M+Na]+ calculated for C24H15FN4Na: 401.1178, found: 401.1185.
4.2.28 2-(4-chlorophenyl)-4-(4-hydroxyphenyl)pyrimido[1,2-b]indazole-3-carbonitrile (6k)
Yellow solid; m.p. > 280 °C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 10.21 (s, 1H), 8.30 (d, J =
8.4 Hz, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.83 -7.78 (m, 3H), 7.67 (d, J = 8.0
Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) (δ,
ppm): 159.9, 153.7, 152.3, 150.2, 143.3, 136.5, 132.3, 131.2, 130.9, 128.8, 128.0, 126.9, 121.8,
121.1, 116.6, 116.5, 115.5, 113.0, 97.2; IR (KBr): 3439, 2227, 1637, 1611, 1592, 1592, 1576,
1551, 1509, 1478, 1368, 1169, 1114, 1095, 1027, 830, 743 cm-1; HRMS (ESI-TOF) m/z
calculated for C23H13ClN4NaO: 419.0676, found [M+Na]+: 419.0679.
4.2.29 2-(4-chlorophenyl)-4-(m-tolyl)pyrimido[1,2-b]indazole-3-carbonitrile (6l)
1
Yellow solid; m.p. 274 -276 °C; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.34 (d, J = 8.4 Hz,
1H), 8.10 – 8.03 (m, 2H), 7.86 - 7.82 (m, 5H), 7.71 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H),
7.46 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 2.47 (s, 3H); 13C NMR (100 MHz, DMSO-d6) (δ,
ppm): 153.9, 152.3, 150.2, 143.2, 138.0, 136.6, 136.2, 132.3, 131.3, 131.2, 129.6, 128.9, 128.6,
127.9, 126.3, 122.2, 121.1, 116.7, 116.2, 113.2, 97.8, 21.1; IR (KBr): 3447, 2923, 2223, 1638,
1636, 1593, 1507, 1479, 1457, 1398, 1373, 1167, 1095, 1030, 829, 757, 742, 701, 646, 582 cm-1;
HRMS (ESI-TOF) m/z [M+Na]+ calculated for C24H15ClN4Na: 417.0883, found: 417.0896.
4.2.30 2-(4-chlorophenyl)-4-(p-tolyl)pyrimido[1,2-b]indazole-3-carbonitrile (6m)
1
Yellow solid; m.p. >280 °C; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.34 (d, J = 8.4 Hz, 1H),
8.06 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.4 Hz, 3H), 7.71 (t, J = 7.6 Hz, 1H),
7.48 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 7.6 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, DMSO-d6 :
CDCl3 = 9:1) (δ, ppm): 153.6, 152.3, 150.0, 143.2, 140.4, 136.7, 133.3, 132.1, 131.1, 129.1, 129.0,
18

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128.7, 127.6, 121.9, 120.9, 116.6, 113.2, 97.4, 21.0; IR (KBr):3348, 2224, 1637, 1593, 1479, 1369,
1187, 1170, 1116, 1094, 827, 774, 744, 669, 649, 618 cm-1; HRMS (ESI-TOF) m/z [M+Na]+
calculated for C24H15ClN4Na: 417.0883, found: 417.0886.
4.2.31 2-(4-chlorophenyl)-4-(3-methoxyphenyl)pyrimido[1,2-b]indazole-3-carbonitrile (6n)
1
Yellow solid; m.p. 254 - 256 °C; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.35 (d, J = 8.4 Hz,
1H), 8.08 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 3H), 7.72 (t, J = 7.6 Hz, 1H), 7.66 – 7.55 (m,
3H), 7.40 (t, J = 7.6 Hz, 1H), 7.23 (dd, J = 8.0, 2.0 Hz, 1H), 3.89 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) (δ, ppm): 159.2, 153.4, 152.3, 150.1, 143.1, 137.5, 136.7, 132.3, 131.3, 129.9, 128.9,
127.8, 122.2, 121.4, 121.1, 116.7, 116.1, 114.7, 113.2, 97.8, 55.4; IR (KBr): 3347, 2923, 2226,
1637, 1483, 1425, 1384, 1252, 1169, 1116, 1092, 1032, 851, 828, 773, 738, 698 cm-1; HRMS
(ESI-TOF) m/z [M+Na]+ calculated for C24H15ClN4NaO: 433.0832, found: 433.0840.
4.2.32 2-(4-chlorophenyl)-4-(4-methoxyphenyl)pyrimido[1,2-b]indazole-3-carbonitrile (6o)
1
Yellow solid; m.p. >280 °C; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.32 (d, J = 8.4 Hz, 1H),
8.08 – 8.04 (m, 4H), 7.84 (s, 1H), 7.83 – 7.78 (m, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 7.6 Hz,
1H), 7.22 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 161.3,
153.4, 152.3, 150.2, 143.3, 136.6, 132.3, 131.3, 130.9, 128.8, 128.5, 127.9, 122.0, 121.1, 116.7,
116.4, 114.2, 113.1, 97.4, 55.5; IR (KBr):3334, 2225, 1637, 1608, 1593, 1550, 1511, 1479, 1370,
1306, 1258, 1170, 1134, 1115, 1092, 1040, 1024, 1012, 904, 830, 802, 742, 620, 555, 531 cm-1;
HRMS (ESI-TOF) m/z [M+Na]+ calculated for C24H15ClN4NaO: 433.0832, found: 433.0846.
4.2.33 2-(4-chlorophenyl)-4-(3,4,5-trimethoxyphenyl)pyrimido[1,2-b]indazole-3-carbonitrile (6p)
Yellow solid; m.p. > 280 °C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.37 (d, J = 8.4 Hz, 1H),
8.09 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.8 Hz, 3H), 7.73 (t, J = 8.8 Hz, 1H), 7.45 – 7.38 (m, 3H),
3.92 (s, 6H), 3.81 (s, 3H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 153.4, 152.9, 152.3, 150.1,
143.1, 139.6, 136.7, 132.3, 131.4, 131.3, 128.9, 127.8, 122.2, 121.2, 116.7, 116.3, 113.2, 106.9,
97.8, 60.3, 56.2; IR (KBr): 3347, 2920, 2220, 1717, 184, 1669, 1653, 1647, 1636, 1559, 1540,
1457, 1399, 1029, 743, 569 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for
C26H19ClN4NaO3: 493.1043, found: 493.1051.
4.2.34 10-chloro-4-(4-hydroxyphenyl)-2-phenylpyrimido[1,2-b]indazole-3-carbonitrile (6q)
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Yellow solid; m.p. > 280 °C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 10.25 (s, 1H), 8.06 – 8.01
(m, 2H), 8.00 – 7.95 (m, 2H), 7.79 – 7.69 (m, 4H), 7.64 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.2 Hz,
1H), 7.07 – 7.01 (m, 2H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 160.1, 154.2, 152.9, 151.7,
142.8, 131.6, 131.3, 131.0, 130.2, 129.1, 128.6, 126.9, 126.8, 121.7, 116.4, 115.6, 115.6, 110.4,
97.5; IR (KBr): 3348, 2229, 1735, 1654, 1636, 1560, 1544, 1534, 1508, 1447, 1458, 1437, 1399,
1375, 1158, 1030, 737,698 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C23H13ClN4NaO:
419.0676, found: 419.0686.
4.2.35 10-chloro-2-phenyl-4-(p-tolyl)pyrimido[1,2-b]indazole-3-carbonitrile (6r)
1
Yellow solid; m.p.165–167 °C; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.02 (dd, J = 8.0, 1.6
Hz, 2H), 7.89 – 7.84 (m, 2H), 7.69 – 7.59 (m, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz,
2H), 7.26 (d, J = 8.0 Hz, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 160.1,
145.4, 139.0, 136.5, 135.6, 133.1, 131.9, 129.7, 129.4, 128.9, 128.4, 126.6, 126.1, 125.4, 113.7,
95.7, 20.9; IR (KBr):3348, 2923, 2237, 1654, 1648, 1559, 1542, 1501, 1447, 1385, 1030, 899, 734,
692, 678, 603 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C24H15ClN4Na: 417.0883,
found: 417.0895.
4.2.36 10-chloro-4-(4-methoxyphenyl)-2-phenylpyrimido[1,2-b]indazole-3-carbonitrile (6s)
1
Yellow solid; m.p. 163–165 °C; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.04 – 7.98 (m, 2H),
7.88 – 7.82 (m, 2H), 7.70 – 7.59 (m, 3H), 7.51 -7.46 (m, 3H), 7.03 – 6.97 (m, 2H), 3.80 (s, 3H);
13C NMR (100 MHz, DMSO-d6) (δ, ppm): 160.1, 145.2, 136.6, 135.6, 133.0, 131.9, 131.1, 129.7,
129.4, 128.4, 126.6, 126.1, 120.3, 113.8, 95.7, 55.3; IR (KBr): 3448, 2923, 2235, 1647, 1502,
1384, 1253, 1027, 850, 830, 742 cm-1; HRMS (ESI-TOF) m/z [M+Na]+ calculated for
C24H15ClN4NaO: 433.0832, found: 433.0836.
4.2.37 2-(1H-indole-3-carbonyl)-3-phenylacrylonitrile (7)
Yellow solid; m.p. 233-235 °C; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.32 (s, 1H, NH), 8.47
(s, 1H, CH), 8.25 (s, 1H, CH), 8.19 (d, J = 12.0 Hz, 1H), 8.07 – 8.05 (m, 2H), 7.62-7.61 (m, 3H),
7.56 (d, J = 8.0 Hz, 1H), 7.29 (q, J = 6.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm):
181.4, 152.1, 136.7, 136.1, 132.5, 132.3, 130.3, 129.1, 126.1, 123.6, 122.4, 121.3, 117.6, 113.6,
112.5, 111.5; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C18H12N2NaO: 295.0847, found:
295.0849.
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Acknowledgment
We are grateful to National Natural Science Foundation of China (NSFC) (51174201, 21571087),
the Open Foundation of Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional
Materials (No. K201312), the Major Projects of Natural Science Research in Jiangsu Province
(15KJA150004), the Priority Academic Program Development of Jiangsu Higher Education
Institutions for financial support, and this work was also sponsored by TAPP. In addition, we are
very grateful to Professor Changsheng Cao for his important help on revising our paper.
Supplementary Material 1H NMR and 13C NMR spectra for all compounds are available free of
charge via the Internet.
References and notes
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Figure 1. The active compounds with pyrazolo[1,5-a]pyrimidine nucleus.
Scheme 1. The model reaction of benzaldehyde, 1H-indazol-3-amine, and
3-(1H-indol-3-yl)-3-oxopropanenitrile.
Table 1 Condition optimization for the reaction between benzaldehyde, 1H-indazol-3-amine, and
3-(1H-indol-3-yl)-3-oxopropanenitrilea
.
Entry
Solvent
CH3CN
CH3CN
Catalyst (mol%)
PTSA·H2O (30)
FeCl3 (30)
Temp. oC
Time (h)
Yields (%)b
1
2
80
80
3
3
0
0
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3
4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3OH
EtOH
DBU (30)
Piperidine (30)
DMAP (30)
Et3N (30)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
3
3
3
3
3
3
3
3
3
3
3
3
3
5
7
7
30
41
5
15
6
76
7
KOH (30)
NaOH (30)
K2CO3 (30)
Na2CO3 (30)
Et3N (30)
25
8
28
9
trace
10
11
12
13
14
15
16
17
18
trace
56
Et3N(30)
85
THF
Et3N (30)
42
EtOH
Et3N (20)
82
EtOH
Et3N (10)
67
EtOH
Et3N (20)
91
EtOH
Et3N (20)
90
52
EtOH
Et3N (20)
aReaction condition: Reagent: benzaldehyde 1a (1 mmol), 1H-indazol-3-amine
3-(1H-indol-3-yl)-3-oxopropanenitrile 3 (1 mmol), solvent (8 mL).
bIsolated Yields
2
(1 mmol), and
Scheme 2. The reactions of aromatic aldehydes, (substituted) 1H-indazol-3-amine, and
3-(1H-indol-3-yl)-3-oxopropanenitrile.
Table 2 Three-component reactions of aromatic aldehydes, (substituted) 1H-indazol-3-amine, and
3-(1H-indol-3-yl)-3-oxopropanenitrilea.
Entry
R1
R2
H
H
H
H
H
H
H
H
H
Compounds
Yields (%)b
1
2
3
4
5
6
7
8
9
1-H
4a
4b
4c
4d
4e
4f
91
90
89
90
88
92
91
87
89
4-F
4-Cl
3,4-Cl2
4-Br
4-NO2
4-OH
4-CH3
3-CH3O
4g
4h
4i
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10
11
12
13
14
15
16
17
4-CH3O
3,4-OCH2O
3,4,5-(CH3O)3
4-pyridyl
4-F
H
4j
4k
4l
90
86
87
85
82
89
85
88
H
H
H
4m
4n
4o
4p
4q
Cl
Cl
Cl
Cl
4-OH
4-CH3
4-CH3O
aReaction method: aromatic aldehydes (1 mmol), 1H-indazol-3-amine (4-chloro-1H-indazol-3-amine
) (1 mmol),
and 3-(1H-indol-3-yl)-3-oxopropanenitrile (1 mmol), EtOH (8 mL), Et3N (0.2 mmol), 80 oC, reaction time (3-5 h)
(monitored reactions by TLC).
bIsolated Yields
Scheme 3. The reactions of aromatic aldehydes, (substituted) 1H-indazol-3-amine, and
3-oxo-3-arylpropanenitrile.
Table 3 Three-component reactions of aromatic aldehydes, (substituted) 1H-indazol-3-amine, and
3-oxo-3-arylpropanenitrilea
Entry
1
R1
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
X
H
H
H
H
H
H
H
H
F
Compounds
Yields (%)b
H
6a
6b
6c
6d
6e
6f
86
89
87
83
90
89
86
83
88
81
87
80
84
88
83
2
3-CH3
3
4-CH3
4
3,4-(CH3)2
4-OH
5
6
4-CH3O
3,4,5-(CH3O)3
3,4-Cl2
4-OH
7
6g
6h
6i
8
9
10
11
12
13
14
15
4-CH3
F
6j
4-OH
Cl
Cl
Cl
Cl
Cl
6k
6l
3-CH3
4-CH3
6m
6n
6o
3-CH3O
4-CH3O
25

ACCEPTED MANUSCRIPT
16
17
18
19
3,4,5-(CH3O)3
4-OH
H
Cl
Cl
Cl
Cl
H
H
H
6p
6q
6r
6s
80
91
88
89
4-CH3
4-CH3O
aReaction method: aromatic aldehydes (1 mmol), 1H-indazol-3-amine (4-chloro-1H-indazol-3-amine) (1 mmol),
and 3-oxo-3-arylpropanenitrile (1 mmol), EtOH (8 mL), Et3N (0.2 mmol), 80 oC, reaction time (3-5 h) (monitored
reactions by TLC).
bIsolated Yields
Figure 2. The possible reaction mechanism.
Scheme 4. The controlled reaction of 4a.
26