An efficient domino strategy for synthesis of novel spirocycloalkane fused pyrazolo[3,4-b]pyridine derivatives

Article abstract of DOI:10.1016/j.tet.2020.131727

A concise and efficient three-component domino strategy promoted by acetic acid has been established for the synthesis of novel spirocycloalkane fused pyrazolo[3,4-b]pyridine-dicarbonitrile derivatives in 73–90% yields. The domino reaction is easy to perform by mixing 1H-pyrazol-5-amines or isoxazol-5-amine, 2-arylidenemalononitriles, and cyclic ketones in the presence of acetic acid at 80 °C in 2–4 h. The present procedure shows attractive properties including inexpensive and easy starting materials, simple one-pot operation, large substrate scope, highly isolated yields, and easy purification process. This chemistry provides a promising synthetic strategy to construction of N-containing spirocycle skeleton with stereogenic centers.

Full text of DOI:10.1016/j.tet.2020.131727

Journal Pre-proof
An efficient domino strategy for synthesis of novel spirocycloalkane fused
pyrazolo[3,4-b]pyridine derivatives
Chunmei Li, Furen Zhang, Zhenlu Shen
PII:
S0040-4020(20)30947-9
https://doi.org/10.1016/j.tet.2020.131727
TET 131727
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 August 2020
Revised Date: 7 October 2020
Accepted Date: 27 October 2020
Please cite this article as: Li C, Zhang F, Shen Z, An efficient domino strategy for synthesis of novel
spirocycloalkane fused pyrazolo[3,4-b]pyridine derivatives, Tetrahedron, https://doi.org/10.1016/
j.tet.2020.131727.
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An efficient domino strategy for synthesis of
novel spirocycloalkane fused pyrazolo[3,4-
b]pyridine derivatives
Leave this area blank for abstract info.
Chunmei Li,a,b Furen Zhang,*a Zhenlu Shen*b
aSchool of Chemistry and Chemical Engineering, Zhejiang Key Laboratory of Alternative Technologies for Fine
Chemicals Process, Shaoxing University, Shaoxing, Zhejiang Province 312000, China
bCollege of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310032, P. R. China.

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An efficient domino strategy for synthesis of
novel spirocycloalkane fused pyrazolo[3,4-
b]pyridine derivatives
Leave this area blank for abstract info.
Chunmei Li,a,b Furen Zhang,*a Zhenlu Shen*b
aSchool of Chemistry and Chemical Engineering, Zhejiang Key Laboratory of Alternative Technologies for Fine
Chemicals Process, Shaoxing University, Shaoxing, Zhejiang Province 312000, China
bCollege of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310032, P. R. China.

1
Tetrahedron
journal homepage: www.elsevier.com
An efficient domino strategy for synthesis of novel spirocycloalkane fused
pyrazolo[3,4-b]pyridine derivatives
Chunmei Li,a,b Furen Zhang,*a Zhenlu Shen*b
a School of Chemistry and Chemical Engineering, Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Shaoxing University,
Shaoxing, Zhejiang Province 312000, China
bCollege of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310032, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A concise and efficient three-component domino strategy promoted by acetic acid has been
established for the synthesis of novel spirocycloalkane fused pyrazolo[3,4-b]pyridine-
dicarbonitrile derivatives in 73-90% yields. The domino reaction is easy to perform by mixing
1H-pyrazol-5-amines or isoxazol-5-amine, 2-arylidenemalononitriles, and cyclic ketones in the
o
Available online
presence of acetic acid at 80 C in 2-4 hours. The present procedure shows attractive properties
including inexpensive and easy starting materials, simple one-pot operation, large substrate
scope, highly isolated yields, and easy purification process. This chemistry provides a promising
synthetic strategy to construction of N-containing spirocycle skeleton with stereogenic centers.
Keywords:
Spirocycles
Synthesis
Domino reaction
One-pot method
Acetic acid
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
Compared to flat aromatic heterocycles, spirocycles are more
conformationally flexible and increasing the chances of finding
bioactive products.1 Thus, spirocycles usually exhibited lots of
unique activities in natural and synthetic products and occupied a
special place in medicinal chemistry.2 Since the first postulated
by Baeyer in 1900,3 the design and synthesis of structural
diversity spirocycles have become one of the most important task
in organic syhthetic chemistry.4 At present, they are considered to
be privileged structures in finding new biological and
pharmacological molecules.5
At the same time, N-containing spirocycles with stereogenic
centers were found in many natural and artificial synthesis
compounds and showed many special pharmacological
activities.6 Recently, with the development of asymmetric
organic synthesis, many N-containing spirocycles with
stereogenic centers have been prepared and studied (Figure 1).7
For instance, Bonne group reported the synthesis of spirolactams
(I) undergoing a Michael addition using 1,3-cyclic ketoamides
and unsaturated acyl cyanides as substrates.8 Du and Zhao
independently reported a oxo-Michael addition reaction for the
synthesis of II with excellent results.9 Shi et al. reported a
multicomponent Povarov-type reaction and afforded the
Figure 1. Some important N-containing spirocycles with stereogenic
centers.
[3+3] cyclization for the enantioselective synthesis of
spirooxindoles bearing tetrahydroquinolin-3-one scaffold
a
(IV).11 Recently, Ezzati and coworkers12 reported a four-
component reaction of arylglyoxals, malononitrile, 3-methyl-1-
phenyl-1H-pyrazol-5-amine, and acetone for the synthesis of
pyrazolo[3,4-b]pyridines. However, the inexpensive arylglyoxals
and limited substrate scope restricted the reaction and the author
did not explore the synthesis of N-containing spirocycles. The
selective synthesis of N-containing spirocycles with stereogenic
spirooxindoles
(III)
with
excellent
yields
and
diastereoselectivities.10 They also reported a multicomponent
————
Corresponding author. Tel.: +86 575 88345682; fax: +86 575
88345682; e-mail: frzhang@usx.edu.cn, zhenlushen@zjut.edu.cn

2
Tetrahedron
centers compounds has long been pursued by organic chemists.
Table 1 Optimization of conditions for the forming of product
4a.a
Despite these advances, most of these methodologies still have
one or more drawbacks, such as such as the limited substrate
scopes, and the use of highly complex substrates. Furthermore, it
is relatively difficult to develop N-containing spirocycloalkane
with stereogenic centers. Therefore, exploration of new and
simple method for the synthesis bioactive N-containing
spirocycles with stereogenic centers using inexpensive starting
materials is meaningful work.13
Recently, we have reported several domino reactions for the
synthesis of bioactive N-containing heterocyclic compounds.14
To the best of our knowledge, the synthesis of spirocycloalkane
fused pyrazolo[3,4-b]pyridine derivatives using inexpensive
starting materials undergoing easy one-pot multi-component
domino reaction has not been reported by other research groups.
In the recent, we reported a domino strategy for highly
diastereoselective synthesis of spirocycloalkane fused
pyrazolo[3,4-b]pyridine derivatives using recyclable solid acid as
catalyst.15 As an extension, we found an acetic acid promoted
one-pot three-component domino reaction of 1H-pyrazol-5-
amines, 2-arylidenemalononitriles, and cyclic ketones yielding
spirocycloalkane fused pyrazolo[3,4-b]pyridine derivatives.
Entry
Catalyst
(mol%)
-
Solvent
T (oC)
Time
(h)
Yield
(%)b
1
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
H2O
80
80
80
80
80
80
80
80
80
65
80
66
80
rt
12
3
0
2
H2SO4 (10)
TFA (10)
35
46
77
86
53
57
59
88
66
67
50
63
0
3
3
4
TsOH (10)
HOAc (10)
Y(OTf)3 (10)
Sc(OTf)3 (10)
HOAc (5)
3
5
3
2. Results and disscussion
6
3
Initially, we chose 3-methyl-1-phenyl-1H-pyrazol-5-amine
(1a), 2-benzylidenemalononitrile (2a), and cyclohexanone (3a) as
model substrates to optimize reaction conditions. This reaction
did not give any product when it was carried out under catalyst-
free conditions even in 12 hours. Thus, different acidic catalysts
were investigated and the representative data were summarized in
Table 1. Firstly, from 35% to 86% yields of product 4a were
obtained when different Brønsted acids, such as sulfuric acid
(H2SO4), trifluoroacetic acid (TFA), toluenesulfonic acid (TsOH),
and acetic acid (HOAc) were used to promote the model reaction
(Table 1, entries 2-5). The acetic acid exhibited the best catalytic
activity and gave the product 4a with 86% yield (Table 1, entry
5). Subsequently, the Lewis acids, such as yttrium(III)
7
3
8
3
9
HOAc (20)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
3
10
11
12
13
14
15
16
17
3
3
THF
3
DMSO
EtOH
EtOH
EtOH
EtOH
3
12
3
trifluoromethanes,
and
scandium(III)
40
60
100
27
49
85
trifluoromethanesulfonate (Table 1, entries 6-7) were used
respectively to catalyze the model reaction. The results indicated
that no catalyst was more suitable for the one-pot three-
component reaction and gave higher yield than acetic acid. The
following catalyst loading screening indicated that acetic acid (10
mol%) was enough to put the reaction forward smoothly (Table 1,
entries 5, 8-9). Next, the model reaction was performed in the
presence of acetic acid (10 mol%) as catalyst in various solvents
including ethanol (EtOH), methanol (MeOH), water (H2O),
tetrahydrofuran (THF), and dimethyl sulfoxide (DMSO). As
shown in Table 1, the protic solvents exhibited better adaptability
than aprotic solvents. Ethanol was proven to be the best solvent
for the reaction. Subsequently, the model reaction was performed
in ethanol using acetic acid as catalyst and repeated many times
in different reaction temperatures. The best yield (86%) was
obtained as the temperature was increased from room
3
3
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5
mmol), acidic catalyst (x mol%), and solvent (3.0 mL) were
introduced in a heated 10 mL sealed tube for given time.
b Isolated yield.
different 2-arylidenemalononitriles were explored under
optimized conditions when 3-methyl-1-phenyl-1H-pyrazol-5-
amine (1a) and cyclohexanone (3a) were used as model
substrates. A variety of functional groups in substituted 2-
arylidenemalononitriles were well tolerated to give 77-89%
yields
of
3'-methyl-1'-phenyl-4'-(aryl)-4',7'-dihydrospiro
[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-5',5'(1'H)-dicarbo
nitriles (4a-4o). When the p-substituents on aromatic ring of 2-
arylidenemalononitriles were electron-withdrawing groups such
as Cl, Br, CF3, and NO2, they showed similar reactivity to
electron-neutral group but are higher reactivity than those
o
temperature to 80 C. A further increase in reaction temperature
did not deliver higher yield of the model product 4a obviously
(Table 1, entries 5, 14-17).
i
With the above results in hand, we went on to study the scope
of the domino reaction. Using above optimized conditions, we
then proceeded to probe the substrate diversity of this one-pot
three-component reaction by using various starting materials and
a series of structurally diverse novel spirocycloalkane fused
pyrazolo[3,4-b]pyridine derivatives were afforded in good to
excellent yields. The results were summarized in Table 2. Firstly,
containing electron-donating groups such as Me, Pr, and OMe.
Additionally, slightly lower yields of desired products were
obtained when there are ortho and meta substituents on the
aromatic ring of 2-arylidenemalononitriles, which may be
attributed to the large steric effect of such 2-
arylidenemalononitriles. Additionally, we also noted that the
reactions of 2-(naphthalen-1-ylmethylene)malononitrile (2n) and

3
2-(thiophen-2-ylmethylene)malononitrile (2o), derived from
inactive fused and heterocyclic aldehydes, with 3-methyl-1-
phenyl-1H-pyrazol-5-amine (1a) and cyclohexanone (3a) worked
well in this transformation to afford the desired products in good
yields. In addition, different substrates 2, such as (E)-2-cyano-3-
phenylacrylamide (2p), 3-benzylidene-2,4-dioxopentanedioic
acid (2q), or diethyl 3-benzylidene-2,4-dioxopentanedioate (2r)
also were selected to react with compound 1a and 3a respectively.
Unfortunately, none of the desired product was obtained which
might be attributed to the poor electron-withdrawing of amide,
acid or ester groups bearing substrate 2.
To expand the scope of the reaction, various of 1H-pyrazol-
5-amines and isoxazol-5-amines such as 1,3-dimethyl-1H-
pyrazol-5-amine (1b), 3-methyl-1H-pyrazol-5-amine (1c), 5-
amino-1H-pyrazol-3-ol (1d), and 3-methylisoxazol-5-amine (1e)
were explored to react with 2-benzylidenemalononitrile (2a) and
cyclohexanone (3a). To our delight, all the 1H-pyrazol-5-amine
and isoxazol-5-amine substrates tolerated the domino reaction
and gave corresponding products with good to excellent yields. It
is worth mentioning that the high active isoxazol-5-amine
substrate exhibited good adaptability and gave desired products
with excellent yields.
Table 2 Range of the substrates for the synthesis of 4.a
Entry
1
4
Ar
X
Y
n
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
2
2
2
1
1
1
1
1
1
1
R
Time (h)
Yield %
86
83
77
81
89
88
84
85
78
80
82
83
81
79
76
74
73
73
88
84
90
75
81
74
73
79
85
81
89
83
85
88
76
4a
4b
4c
C6H5
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NMe
NMe
NH
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OH
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4
4
4
4
3
3
3
3
4
4
4
4
4
4
4
4
4
4
2
2
2
4
4
4
4
4
3
3
3
3
3
3
3
2
4-CH3C6H4
4-iPrC6H4
4-OMeC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
4-NO2C6H4
2-ClC6H4
3-ClC6H4
2-NO2C6H4
3-NO2C6H4
2,4-Cl2C6H3
1-Naphthyl
2-Thienyl
C6H5
3
4
4d
4e
5
6
4f
7
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
4j
4k
4l
4m
4n
4o
4p
4q
4r
4-CH3C6H4
4-CH3C6H4
C6H5
4s
O
4t
4-CH3C6H4
4-ClC6H4
C6H5
O
4u
4v
4w
4x
4y
4z
O
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
4-ClC6H4
C6H5
4-CH3C6H4
4-ClC6H4
C6H5
4aa
4bb
4cc
4dd
4ee
4ff
4gg
4-CH3C6H4
4-ClC6H4
C6H5
O
O
S
4-CH3C6H4
4-ClC6H4
C6H5
S
S
NMe

4
Tetrahedron
a
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), acetic acid (10 mol%), and EtOH (3.0 mL) were introduced in a
heated 10 mL sealed tube for 2-4 hours.
b Isolated yield.
To further investigate the scope of the reaction, various cyclic
ketones such as cyclopentanone, and cycloheptanone and
heterocyclic ketones such as tetrahydro-4H-pyran-4-one,
tetrahydro-4H-thiopyran-4-one, and 1-methylpiperidin-4-one
were respectively used to react with 3-methyl-1-phenyl-1H-
pyrazol-5-amine (1a) and different 2-arylidenemalononitrile (2).
Similar to above domino processes, all the cyclic ketones can
enable the reaction to occur smoothly. Reactions involving
electron-deficient 2-arylidenemalononitrile still exhibited higher
feasibility in the domino reaction than those bearing electron-
donating groups under similar conditions. Both the
cyclopentanone and cycloheptanone showed weaker reactivity
than cyclohexanone in this one-pot three-component reaction
which maybe attribute to the poor stability of five-member or
seven-member rings. In addition, owing to the electronic effects,
the heterocyclic ketones exhibited slightly higher reactivity than
cyclohexanone when the same 3-methyl-1-phenyl-1H-pyrazol-5-
amine (1a) and 2-arylidenemalononitrile (2) were used in the
domino reaction.
On the basis of literature reports12,15 and taking our
experimental outcomes into consideration, a possible mechanism
for the formation of 4a is outlined in Scheme 2. Initially, the
intermediate A was generated from the Michael addition reaction
of
3-methyl-1-phenyl-1H-pyrazol-5-amine
(1a)
and
benzylidenemalononitrile (2a) in the presence of acetic acid.
Next, the slightly less reactive cyclohexanone (3a) reacts with
amino group of 1-phenyl-1H-pyrazol-5-amine (1a) to form
intermediate B. With the departure of water molecule, the imine
intermediate C formed. Subsequently, under the attraction of
methenyl to carbon of imine, the final product 4a was obtained
through proton transfer of intermediate C.
In all cases the domino reaction was very fast and complete
within 2-4 hours. The water is the sole byproduct and the vast
majority of products were obtained directly from the
concentration of reaction mixture. The structural elucidation was
determined by NMR spectroscopic analysis and HRMS analysis.
To explore the mechanism of the domino reaction, some
control experiments were conducted (Scheme 1). When the
substrates 3-methyl-1-phenyl-1H-pyrazol-5-amine (1a) and 2-
benzylidenemalononitrile (2a) were treated using above
optimized conditions, the compound 5 was obtained with 65%
yield. The compound 6 was given with 44% yield when the
mixture of 3-methyl-1-phenyl-1H-pyrazol-5-amine (1a) and
cyclohexanone (3a) was stirred under above conditions. No
compound 7 was detected under above reaction conditions. The
above results indicated that the competition between
benzylidenemalononitrile (2a) and cyclohexanone (3a) to 3-
methyl-1-phenyl-1H-pyrazol-5-amine (1a) were existence and
the former exhibited higher reactivity than the latter under above
conditions.
Scheme 2. Probable mechanism for forming of products 4a.
3. Conclusion
In summary, we have discovered a novel three-component
domino reaction for the synthesis N-containing spirocycloalkanes
with stereogenic center. The one-pot three-component domino
reaction is easy to perform simply by mixing inexpensive starting
materials using acetic acid as catalyst in ethanol. After the
completion of the reaction, the vast majority of spirocycloalkane
fused pyrazolo[3,4-b]pyridine-dicarbonitrile derivatives were
obtained with good to excellent yields through simple filter
without further purification. The reaction is fast and can be
finished within 2-4 hours with water as sole byproduct. It should
be noted that the reaction had good feasibility and tolerated
various
1H-pyrazol-5-amine
or
isoxazol-5-amine,
2-
arylidenemalononitrile, and cyclic ketone substrates.
4. Experimental section
All the concerned reagents and solvents were purchased from
commercial suppliers and were used without further purification.
The reactions were monitored by thin-layer chromatography
(TLC) analysis using silica gel (GF254) plates and the Advion
1
CMS instrument. H NMR spectra were recorded on a 400 MHz
instrument (Bruker Avance 400 Spectrometer). Chemical shifts
(δ) are given in ppm relative to TMS as the internal reference,
with coupling constants (J) in Hz. 13C NMR spectra were
recorded at 100 MHz. Chemical shift were reported in ppm with
the internal chloroform (or DMSO-d6) signal at 77.7 (or 39.9)
ppm as a standard. HRMS (ESI) was measured with a
Waters XEVO G2-XS QTOF/H-CLASS instrument.
4.1. Typical procedure for the preparation of 3'-methyl-1',4'-
diphenyl-4',7'-dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-
b]pyridine]-5',5'(1'H)-dicarbonitrile (4a)
Scheme 1. Control experiments.

5
The mixture of 3-methyl-1-phenyl-1H-pyrazol-5-amine (1a,
0.5 mmol), 2-benzylidenemalononitrile (2a, 0.5 mmol),
cyclohexanone (3a, 0.5 mmol), and acetic acid (0.05 mmol) was
= 7.2 Hz, 2H, ArH), 4.38 (s, 1H, CH), 3.94 (s, 1H, NH), 2.06-
2.13 (m, 2H, CH2), 1.96-1.99 (m, 1H, CH2), 1.80-1.86 (m, 2H,
CH2), 1.61-1.85 (m, 7H, CH2 + CH3), 1.31-1.36 (m, 1H, CH2);
13C NMR (100 MHz, CDCl3): δ = 146.7, 140.4, 138.6, 135.4,
132.8, 130.3, 129.5, 129.1, 126.9, 122.0, 114.7, 112.8, 97.9, 61.8,
50.2, 44.1, 34.4, 28.4, 24.9, 21.5, 21.1, 13.9; HRMS (ESI) m/z
MH+, found 442.1795. C26H25ClN5+ requires 442.1793.
o
submitted in 3.0 mL ethanol and stirred at 80 C for about 4
hours. After completion of the reaction as detected by TLC, the
reaction was cooled to room temperature and a great deal of
suspension was formed. After the solid being filtered, the product
4a was collected without further purification (175 mg, yield 86%,
mp: 287-288 oC).
Pale yellow power, mp: 287-288 oC; 1H NMR (400 MHz,
CDCl3): δ = 7.74 (d, J = 8.0 Hz, 2H, ArH), 7.49-7.55 (m, 7H,
ArH), 7.37 (t, J = 7.2 Hz, 1H, ArH), 4.4 (s, 1H, CH), 3.84 (s, 1H,
NH), 2.10-2.16 (m, 2H, CH2), 2.00-2.03 (m, 1H, CH2), 1.63-1.86
(m, 10H, CH2 + CH3), 1.35-1.39 (m, 1H, CH2); 13C NMR (100
MHz, CDCl3): δ = 147.0, 140.4, 138.7, 134.1, 129.5, 129.4,
128.9, 126.8, 122.0, 114.9, 113.0, 98.5, 61.7, 50.4, 44.6, 34.5,
28.4, 24.9, 21.5, 21.2, 13.8; HRMS (ESI) m/z MH+, found
408.2189. C26H26N5+ requires 408.2183.
4.6. 4'-(4-bromophenyl)-3'-methyl-1'-phenyl-4',7'-
dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4f)
o
1
White solid, mp: 255-256 C; H NMR (400 MHz, CDCl3): δ =
7.72 (d, J = 6.8 Hz, 2H, ArH), 7.62 (s, 2H, ArH), 7.54 (t, J = 7.2
Hz, 2H, ArH), 7.35-7.40 (m, 3H, ArH), 4.37 (s, 1H, CH), 3.86 (s,
1H, NH), 2.11-2.16 (m, 2H, CH2), 1.97-2.00 (m, 1H, CH2), 1.86-
1.89 (m, 2H, CH2), 1.65-1.76 (m, 8H, CH2 + CH3), 1.32-1.36 (m,
1H, CH2); 13C NMR (100 MHz, CDCl3): δ = 146.8, 140.4, 138.5,
133.3, 132.1, 129.6, 127.0, 123.7, 122.0, 114.7, 112.8, 97.8, 61.8,
50.1, 44.1, 34.5, 28.4, 24.9, 21.5, 21.1, 14.0; HRMS (ESI) m/z
MH+, found 486.1289. C26H25BrN5+ requires 486.1288.
4.2. 3'-methyl-1'-phenyl-4'-(p-tolyl)-4',7'-dihydrospiro[cyclo
hexane-1,6'-pyrazolo[3,4-b]pyridine]-5',5'(1'H)-dicarbonitrile
(4b)
4.7. 3'-methyl-1'-phenyl-4'-(4-(trifluoromethyl)phenyl)-4',7'-
dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4g)
White crystal, mp: 268-270 oC; 1H NMR (400 MHz, CDCl3): δ =
7.74 (d, J = 8.0 Hz, 2H, ArH), 7.52 (t, J = 8.0 Hz, 2H, ArH),
7.33-7.41 (m, 3H, ArH), 7.28-7.30 (m, 2H, ArH), 4.37 (s, 1H,
CH), 3.91 (s, 1H, NH), 2.43 (s, 1H, CH3), 2.09-2.14 (m, 2H,
CH2), 1.98-2.00 (m, 1H, CH2), 1.65-1.84 (m, 10H, CH2 + CH3),
1.33-1.38 (m, 1H, CH2); 13C NMR (100 MHz, CDCl3): δ = 147.1,
140.4, 139.2, 138.7, 131.1, 129.5, 126.7, 122.0, 115.0, 113.1,
98.7, 61.7, 50.6, 44.3, 34.5, 28.4, 25.0, 21.5, 21.3, 21.2, 13.9;
o
1
White solid, mp: 146-148 C; H NMR (400 MHz, CDCl3): δ =
7.68-7.74 (m, 4H, ArH), 7.52-7.56 (m, 2H, ArH), 7.52-7.56 (m,
2H, ArH), 7.36-7.40 (m, 1H, ArH), 4.47 (s, 1H, CH), 3.93 (s, 1H,
NH), 2.11-2.16 (m, 2H, CH2), 1.98-2.01 (m, 1H, CH2), 1.86-1.89
(m, 2H, CH2), 1.62-1.80 (m, 7H, CH2 + CH3), 1.35-1.39 (m, 1H,
CH2); 13C NMR (100 MHz, CDCl3): δ = 146.6, 140.5, 138.4 (1JCF
+
= 13.0 HZ), 131.8, 131.5, 129.6, 127.0, 125.8, 122.0, 114.5,
HRMS (ESI) m/z MH+, found 422.2342. C27H28N5 requires
112.6, 97.5, 61.9, 50.0, 44.4, 34.5, 28.4, 24.9, 21.5, 21.1, 13.9;
422.2339.
HRMS (ESI) m/z MH+, found 476.2055. C27H25F3N5 requires
+
4.3. 4'-(4-isopropylphenyl)-3'-methyl-1'-phenyl-4',7'-
dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4c)
476.2057.
4.8. 3'-methyl-4'-(4-nitrophenyl)-1'-phenyl-4',7'-
dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4h)
o
1
White solid, mp: 214-216 C; H NMR (400 MHz, CDCl3): δ =
7.74 (d, J = 8.0 Hz, 2H, ArH), 7.53 (t, J = 8.0 Hz, 2H, ArH), 7.43
(s, 2H, ArH), 7.29-7.38 (m, 3H, ArH), 4.37 (m, 1H, CH), 3.81 (s,
1H, NH), 2.12-2.16 (m, 2H, CH2), 1.99-2.02 (m, 1H, CH2), 1.86-
1.88 (m, 2H, CH2), 2.95-3.02 (m, 1H, CH), 2.00-2.16 (m, 3H,
CH3), 1.61-1.80 (m, 8H, CH2 + CH3), 1.25-1.38 (m, 7H, CH2 +
CH3); 13C NMR (100 MHz, CDCl3): δ = 150.1, 147.1, 140.3,
138.7, 131.2, 129.5, 126.8, 122.0, 115.0, 113.1, 98.8, 61.7, 50.5,
44.3, 34.5, 33.8, 28.4, 25.0, 23.9, 21.5, 21.2, 13.8; HRMS (ESI)
m/z MH+, found 450.2648. C29H32N5+ requires 450.2652.
o
1
Yellow crystal, mp: 215-216 C; H NMR (400 MHz, CDCl3): δ
= 8.35 (s, 2H, ArH), 7.70-7.74 (m, 4H, ArH), 7.54 (s, 2H, ArH),
7.39 (s, 1H, ArH), 4.53 (s, 1H, CH), 4.01 (s, 1H, NH), 2.12-2.16
(m, 2H, CH2),1.96-1.99 (m, 1H, CH2), 1.85-1.90 (m, 2H, CH2),
1.72-1.86 (m, 7H, CH2 + CH3), 1.32-1.36 (m, 1H, CH2); 13C
NMR (100 MHz, CDCl3): δ = 148.6, 146.4, 141.7, 140.6, 138.4,
131.7, 129.6, 127.1, 124.0, 122.1, 114.3, 112.5, 97.0, 62.0, 49.7,
44.3, 34.4, 28.5, 24.8, 21.5, 21.1, 14.0; HRMS (ESI) m/z MH+,
found 453.2028. C26H25N6O2+ requires 453.2034.
4.4. 4'-(4-methoxyphenyl)-3'-methyl-1'-phenyl-4',7'-
dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4d)
4.9. 4'-(2-chlorophenyl)-3'-methyl-1'-phenyl-4',7'-
dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4i)
Pale yellow solid, mp: 275-276 oC; 1H NMR (400 MHz, CDCl3):
δ = 7.73 (s, 2H, ArH), 7.30-7.53 (m, 5H, ArH), 7.01 (s, 2H,
ArH), 4.37 (s, 1H, CH), 3.89 (s, 3H, OMe), 3.79 (s, 1H, NH),
1.99-2.15 (m, 3H, CH2), 1.67-1.86 (m, 10H, CH2 + CH3), 1.35-
1.38 (m, 1H, CH2); 13C NMR (100 MHz, CDCl3): δ = 160.4,
147.1, 140.4, 138.7, 130.0, 129.5, 126.8, 126.0, 122.0, 115.0,
114.5, 114.0, 113.1, 98.7, 61.6, 55.3, 50.7, 44.0, 34.5, 28.4, 25.0,
21.5, 21.7, 13.8; HRMS (ESI) m/z MH+, found 438.2291.
C27H28N5O+ requires 438.2288.
o
1
Yellow crystal, mp: 190-192 C; H NMR (400 MHz, CDCl3): δ
= 7.70 (d, J = 8.0 Hz, 2H, ArH), 7.57-7.62 (m, 2H, ArH), 7.50-
7.54 (m, 2H, ArH), 7.34-7.43 (m, 3H, ArH), 5.34 (s, 1H, CH),
3.90 (s, 1H, NH), 2.14-2.18 (m, 2H, CH2), 2.06-2.10 (m, 1H,
CH2), 1.79-1.89 (m, 4H, CH2), 1.66-1.70 (m, 5H, CH2 +CH3),
1.35-1.42 (m, 1H, CH2); 13C NMR (100 MHz, CDCl3): δ = 146.5,
140.4, 138.6, 135.4, 132.0, 131.2, 130.4, 130.2, 129.6, 127.3,
126.9, 122.0, 114.1, 113.2, 98.4, 77.4, 77.3, 77.1, 76.8, 62.2,
48.5, 38.7, 34.2, 28.4, 24.9, 21.6, 21.2, 13.5; HRMS (ESI) m/z
MH+, found 442.1795. C26H25ClN5+ requires 442.1793.
4.5. 4'-(4-chlorophenyl)-3'-methyl-1'-phenyl-4',7'-
dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4e)
4.10. 4'-(3-chlorophenyl)-3'-methyl-1'-phenyl-4',7'-
dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4j)
White crystal, mp: 251-252 oC; 1H NMR (400 MHz, CDCl3): δ =
7.72 (d, J = 8.0 Hz, 2H, ArH), 7.45-7.54 (m, 6H, ArH), 7.36 (d, J

6
Tetrahedron
White crystal, mp: 224-226 oC; 1H NMR (400 MHz, CDCl3): δ
126.8, 126.7, 126.1, 125.3, 122.3, 122.0, 114.9, 113.4, 99.7, 62.4,
49.7, 37.2, 34.3, 28.5, 25.0, 21.6, 21.2, 13.8; HRMS (ESI) m/z
MH+, found 458.2340. C30H28N5+ requires 458.2339.
= 7.73 (d, J = 7.6 Hz, 2H, ArH), 7.34-7.54 (m, 7H, ArH), 4.37 (s,
1H, CH), 3.92 (s, 1H, NH), 2.09-2.13 (m, 2H, CH2), 1.95-1.98
(m, 1H, CH2), 1.80-1.85 (m, 2H, CH2), 1.60-1.74 (m, 7H, CH2 +
CH3), 1.33-1.37 (m, 1H, CH2); 13C NMR (100 MHz, CDCl3): δ =
146.7, 140.5, 138.6, 136.4, 130.2, 129.7, 129.6, 129.0, 126.9,
122.0, 114.6, 112.7, 97.8, 61.9, 50.0, 44.2, 34.4, 28.4, 24.9, 21.5,
4.15. 3'-methyl-1'-phenyl-4'-(thiophen-2-yl)-4',7'-
dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4o)
21.1, 13.9; HRMS (ESI) m/z MH+, found 442.1789. C26H25ClN5
+
Brown crystal, mp: 244-246 oC; 1H NMR (400 MHz, CDCl3): δ =
7.71 (d, J = 8.0 Hz, 2H, ArH), 7.51 (t, J = 8.0 Hz, 2H, ArH), 7.42
(d, J = 4.8 Hz, 1H, ArH), 7.32-7.42 (m, 2H, ArH), 7.11-7.14 (m,
1H, ArH), 4.73 (s, 1H, CH), 3.91 (s, 1H, ArH), 2.06-2.18 (m, 3H,
CH2), 1.92-1.98 (m, 1H, CH2), 1.80-1.82 (m, 5H, CH2 + CH3),
1.57-1.76 (m, 4H, CH2), 1.30-1.39 (m, 1H, CH2); 13C NMR (100
MHz, CDCl3): δ = 147.1, 139.9, 138.6, 136.7, 129.5, 129.0,
127.3, 126.9, 126.7, 122.0, 114.8, 113.1, 98.9, 61.9, 50.9, 40.4,
34.5, 28.4, 24.9, 21.5, 21.1, 13.4; HRMS (ESI) m/z MH+, found
414.1751. C24H24N5S+ requires 414.1747.
requires 442.1793.
4.11. 3'-methyl-4'-(2-nitrophenyl)-1'-phenyl-4',7'-
dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4k)
Brown yellow solid, mp: 131-132 oC; 1H NMR (400 MHz,
CDCl3): δ = 8.11 (dd, J = 8.0, 1.2 Hz, 1H, ArH), 7.82 (dd, J = 7.6,
1.2 Hz, 1H, ArH), 7.67-7.74 (m, 3H, ArH), 7.64 (t, J = 7.6 Hz,
1H, ArH), 7.54 (t, J = 8.0 Hz, 2H, ArH), 7.38 (t, J = 7.2 Hz, 1H,
ArH), 5.74 (s, 1H, CH), 3.95 (s, 1H, NH), 2.06-2.18 (m, 2H,
CH2), 2.00-2.03 (m, 1H, CH2), 1.76-1.88 (m, 4H, CH2), 1.73 (m,
3H, CH3), 1.61-1.70 (m, 2H, CH2), 1.30-1.36 (m, 1H, CH2); 13C
NMR (100 MHz, CDCl3): δ = 150.4, 146.3, 140.6, 138.5, 133.2,
131.8, 130.3, 129.6, 129.1, 127.1, 125.7, 122.1, 114.0, 113.0,
97.6, 77.4, 77.1, 76.8, 62.3, 49.0, 37.4, 34.4, 28.5, 24.8, 21.5,
4.16. 1',3'-dimethyl-4'-phenyl-4',7'-dihydrospiro[cyclohexane-
1,6'-pyrazolo[3,4-b]pyridine]-5',5'(1'H)-dicarbonitrile (4p)
White crystal, mp: 271-272 C; 1H NMR (400 MHz, DMSO-d6):
o
δ = 7.44 (s, 5H, ArH), 6.25 (s, 1H, CH), 4.53 (s, 1H, NH), 3.58
(s, 1H, CH3), 2.13-2.15 (m, 1H, CH2), 1.81-1.88 (m, 2H, CH2),
1.71-1.74 (m, 3H, CH2), 1.46-1.50 (m, 3H, CH2), 1.44 (s, 3H,
CH3), 1.23-1.24 (m, 1H, CH2); 13C NMR (100 MHz, DMSO-d6):
δ = 143.4, 142.0, 135.9, 129.3, 128.8, 116.0, 114.1, 95.3, 61.8,
50.3, 43.8, 34.4, 34.1, 29.0, 25.2, 21.1, 21.0, 13.8; HRMS (ESI)
m/z MH+, found 346.2025. C21H24N5+ requires 346.2026.
21.2, 13.7; HRMS (ESI) m/z MH+, found 453.2030. C26H25N6O2
requires 453.2034.
+
4.12. 3'-methyl-4'-(3-nitrophenyl)-1'-phenyl-4',7'-
dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4l)
4.17. 1',3'-dimethyl-4'-(p-tolyl)-4',7'-dihydrospiro[cyclohexane-
1,6'-pyrazolo[3,4-b]pyridine]-5',5'(1'H)-dicarbonitrile (4q)
o
Yellow solid, mp: 178-180 C; 1H NMR (400 MHz, CDCl3): δ =
8.42 (s, 1H, ArH), 8.36 (dd, J = 8.0, 0.8 Hz, 2H, ArH), 7.90 (s,
1H, ArH), 7.70-7.74 (m, 3H, ArH), 7.54 (t, J = 8.4 Hz, 2H, ArH),
7.38 (t, J = 7.6 Hz, 1H, ArH), 4.55 (s, 1H, CH), 3.98 (s, 1H, NH),
2.11-2.15 (m, 2H, CH2), 1.98-2.01 (m, 1H, CH2), 1.86-1.89 (m,
2H, CH2), 1.77-1.81 (m, 2H, CH2), 1.70 (s, 3H, CH3), 1.62-1.65
(m, 2H, CH2), 1.32-1.36 (m, 1H, CH2); 13C NMR (100 MHz,
CDCl3): δ = 148.5, 146.3, 140.6, 138.4, 136.7, 130.0, 129.6,
127.1, 124.6, 122.2, 114.3, 112.5, 96.9, 61.9, 49.9, 44.3, 34.5,
28.5, 24.8, 21.5, 21.1, 14.0; HRMS (ESI) m/z MH+, found
453.2033. C26H25N6O2+ requires 453.2034.
Pale yellow solid, mp: 258-260 oC; 1H NMR (400 MHz, DMSO-
d6): δ = 7.41-7.54 (m, 4H, ArH), 6.39 (s, 1H, CH), 4.64 (s, 1H,
NH), 3.75 (s, 3H, CH3), 2.52 (s, 3H, CH3), 2.22-2.24 (m, 1H,
CH2), 2.01-2.04 (m, 2H, CH2), 1.85-1.89 (m, 3H, CH2), 1.71-1.74
(m, 2H, CH2), 1.63 (s, 3H, CH3), 1.30-1.37 (m, 1H, CH2); 13C
NMR (100 MHz, DMSO-d6): δ = 144.0, 142.1, 138.6, 132.8,
132.0, 129.4, 129.3, 129.0, 120.8, 95.4, 82.0, 61.7, 50.8, 50.5,
43.5, 43.4, 34.3, 34.1, 29.0, 27.4, 25.3, 25.2, 21.4, 21.2, 21.1,
13.9; HRMS (ESI) m/z MH+, found 360.2178. C22H26N5+ requires
360.2183.
4.13. 4'-(2,4-dichlorophenyl)-3'-methyl-1'-phenyl-4',7'-
dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4m)
4.18. 3'-hydroxy-4'-(p-tolyl)-4',7'-dihydrospiro[cyclohexane-1,6'-
pyrazolo[3,4-b]pyridine]-5',5'(1'H)-dicarbonitrile (4r)
White crystal, mp: 230-232 oC; 1H NMR (400 MHz, CDCl3): δ =
7.70 (d, J = 7.6 Hz, 2H, ArH), 7.61 (s, 1H, ArH), 7.51-7.56 (m,
3H, ArH), 7.37 (t, J = 7.6 Hz, 2H, ArH), 5.28 (s, 1H, CH), 3.93
(s, 1H, NH), 2.13-2.16 (m, 2H, CH2), 2.04-2.07 (m, 1H, CH2),
1.80-1.89 (m, 4H, CH2), 1.70-1.72 (m, 5H, CH2 + CH3), 1.35-
1.42 (m, 1H, CH2); 13C NMR (100 MHz, CDCl3): δ = 146.3,
140.5, 138.5, 136.0, 135.8, 132.1, 130.7, 130.1, 129.6, 127.8,
127.0, 122.1, 113.9, 113.1, 97.8, 62.2, 48.4, 38.5, 34.1, 28.4,
24.9, 21.5, 21.1, 13.6; HRMS (ESI) m/z MH+, found 476.1399.
C26H24Cl2N5+ requires 476.1403.
o
White crystal, mp: 251-252 C; 1H NMR (400 MHz, DMSO-d6):
δ = 7.24 (d, J = 7.6 Hz, 2H, ArH), 7.17 (d, J = 7.6 Hz, 2H, ArH),
7.07 (s, 1H, NH), 4.31 (s, 1H, CH), 2.39 (d, J = 8.4 Hz, 1H, CH2)
2.34 (s, 3H, CH3), 2.03-2.05 (m, 1H, CH2), 1.80-1.85 (m, 3H,
CH2), 1.68-1.71 (m, 2H, CH2), 1.48-1.50 (m, 2H, CH2), 1.32-1.37
(m, 1H, CH2); 13C NMR (100 MHz, DMSO-d6): δ = 163.1, 162.3,
145.7, 140.7, 128.3, 127.8, 126.7, 106.3, 99.6, 77.4, 45.0, 40.2,
38.9, 21.7, 19.9, 11.2; HRMS (ESI) m/z MH+, found 348.1821.
C20H22N5O+ requires 348.1819.
4.19. 3'-methyl-4'-phenyl-4',7'-dihydro-5'H-spiro[cyclohexane-
1,6'-isoxazolo[5,4-b]pyridine]-5',5'-dicarbonitrile (4s)
4.14. 3'-methyl-4'-(naphthalen-1-yl)-1'-phenyl-4',7'-
dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4n)
Pale yellow crystal, mp: 240-242 oC; 1H NMR (400 MHz, CDCl3
+ DMSO-d6): δ = 7.96 (s, 1H, NH), 7.45 (s, 5H, ArH), 4.34 (s,
1H, CH), 2.18-2.21 (m, 1H, CH2), 1.87-1.97 (m, 2H, CH2), 1.77-
1.84 (m, 2H, CH2), 1.64-1.68 (m, 2H, CH2), 1.61 (s, 3H, CH3),
1.24-1.29 (m, 1H, CH2); 13C NMR (100 MHz, CDCl3 + DMSO-
d6): δ = 169.6, 163.2, 138.3, 134.3, 133.5, 119.4, 117.5, 91.0,
66.7, 55.1, 48.4, 38.3, 34.5, 29.5, 25.6, 25.4, 16.2; HRMS (ESI)
m/z MH+, found 333.1707. C20H21N4O+ requires 333.1710.
Pale yellow solid, mp: 213-214 oC; 1H NMR (400 MHz, CDCl3):
δ = 8.39 (d, J = 8.4 Hz, 1H, ArH), 8.00 (t, J = 6.4 Hz, 2H, ArH),
7.90 (d, J = 7.6 Hz, 3H, ArH), 7.53-7.69 (m, 5H, ArH), 7.38 (t, J
= 7.2 Hz, 2H, ArH), 5.62 (s, 1H, CH), 3.93 (s, 1H, NH), 2.20-
2.26 (m, 3H, CH2), 1.67-1.99 (m, 7H, CH2), 1.56 (s, 3H, CH3),
1.31-1.35 (m, 1H, CH2); 13C NMR (100 MHz, CDCl3): δ = 146.9,
140.7, 138.7, 134.2, 132.1, 130.0, 129.9, 129.6, 129.4, 128.6,

7
1
4.20. 3'-methyl-4'-(p-tolyl)-4',7'-dihydro-5'H-spiro[cyclohexane-
Yellow oil; H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 7.6
1,6'-isoxazolo[5,4-b]pyridine]-5',5'-dicarbonitrile (4t)
Hz, 2H, ArH), 7.67-7.72 (m, 2H, ArH), 7.59 (s, 1H, ArH), 7.53-
7.56 (m, 1H, ArH), 7.40-7.52 (m, 2H, ArH), 4.51 (s, 1H, CH),
4.03 (s, 1H, NH), 2.60 (s, 3H, CH3), 2.27-2.31 (m, 1H, CH2),
2.15-2.21 (m, 1H, CH2), 1.95-2.07 (m, 5H, CH2), 1.92 (s, 3H,
CH3), 1.74-1.76 (m, 1H, CH2), 1.71-1.73 (m, 2H, CH2); 13C NMR
(100 MHz, CDCl3): δ = 147.1, 140.6, 139.3, 138.7, 138.6, 130.9,
130.8, 129.9, 129.5, 129.0, 126.8, 122.2, 115.1, 113.8, 112.3,
98.7, 64.8, 50.3, 45.0, 38.8, 32.3, 29.2, 28.5, 22.1, 22.0, 21.3,
Pale yellow crystal, mp: 248-250 oC; 1H NMR (400 MHz, CDCl3
+ DMSO-d6): δ = 7.85 (s, 1H, NH), 7.32 (s, 2H, ArH), 7.25 (d, J
= 6.8 Hz, 2H, ArH), 4.28 (s, 1H, CH), 2.40 (s, 1H, CH3), 2.20-
2.23 (m, 1H, CH2), 1.87-1.96 (m, 6H, CH2), 1.64-1.68 (m, 5H,
CH2 + CH3), 1.27-1.32 (m, 1H, CH2); 13C NMR (100 MHz,
CDCl3 + DMSO-d6): δ = 169.6, 163.3, 144.1, 135.0, 134.2, 134.1,
119.5, 117.6, 91.1, 66.6, 55.2, 48.2, 38.4, 34.5, 29.5, 26.0, 25.6,
25.4, 16.3; HRMS (ESI) m/z MH+, found 347.1870. C21H23N4O+
requires 347.1866.
+
21.2, 13.9; HRMS (ESI) m/z MH+, found 436.2499. C28H30N5
requires 436.2496.
4.26. 4'-(4-chlorophenyl)-3'-methyl-1'-phenyl-4',7'-
dihydrospiro[cycloheptane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4z)
4.21. 4'-(4-chlorophenyl)-3'-methyl-4',7'-dihydro-5'H-
spiro[cyclohexane-1,6'-isoxazolo[5,4-b]pyridine]-5',5'-
dicarbonitrile (4u)
Yellow oil; 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.4, 0.8
Hz, 2H, ArH), 7.47-7.51 (m, 2H, ArH), 7.43 (s, 4H, ArH), 7.32-
7.36 (m, 1H, ArH), 4.32 (s, 1H, CH), 3.82 (s, 1H, NH), 2.41-2.47
(m, 1H, CH2), 2.05-2.09 (m, 1H, CH2), 1.93-1.99 (m, 1H, CH2),
1.77-1.87 (m, 5H, CH2), 1.74 (s, 3H, CH3), 1.63-1.66 (m, 1H,
CH2), 1.50-1.54 (m, 2H, CH2); 13C NMR (100 MHz, CDCl3): δ =
146.7, 140.6, 138.5, 135.5, 132.6, 129.6, 129.1, 127.0, 122.3,
114.8, 113.4, 98.0, 64.9, 50.2, 44.8, 38.9, 32.3, 29.1, 28.5, 22.1,
o
1
White power, mp: 269-270 C; H NMR (400 MHz, CDCl3 +
DMSO-d6): δ = 8.06 (s, 1H, NH), 7.55 (s, 4H, ArH), 4.46 (s, 1H,
CH), 2.31 (s, 1H, CH2), 2.07-2.11 (m, 1H, CH2), 1.91-1.96 (m,
5H, CH2), 1.74-1.78 (m, 5H, CH2 + CH3), 1.25-1.31 (m, 1H,
CH2); 13C NMR (100 MHz, CDCl3 + DMSO-d6): δ = 165.0,
158.3, 135.3, 132.2, 130.0, 129.1, 129.0, 114.4, 85.7, 61.9, 50.2,
43.2, 33.6, 29.7, 24.7, 20.8, 20.6, 11.6; HRMS (ESI) m/z MH+,
found 367.1325. C20H20ClN4O+ requires 367.1320.
+
22.0, 13.9; HRMS (ESI) m/z MH+, found 456.1950. C27H27ClN5
requires 456.1950.
4.22. 3'-methyl-1',4'-diphenyl-4',7'-dihydrospiro[cyclopentane-
1,6'-pyrazolo[3,4-b]pyridine]-5',5'(1'H)-dicarbonitrile (4v)
4.27. 3'-methyl-1',4'-diphenyl-2,3,4',5,6,7'-
hexahydrospiro[pyran-4,6'-pyrazolo[3,4-b]pyridine]-5',5'(1'H)-
dicarbonitrile (4aa)
Brown yellow solid, mp: 129-130 oC; 1H NMR (400 MHz,
CDCl3): δ = 7.69 (dd, J = 8.8, 1.2 Hz, 2H, ArH), 7.49-7.53 (m,
5H, ArH), 7.41-7.44 (m 1H, ArH), 7.33-7.36 (m, 2H, ArH), 4.38
(s, 1H, CH), 3.94 (s, 1H, NH), 1.94-1.99 (m, 8H, CH2), 1.72 (s,
3H, CH3); 13C NMR (100 MHz, CDCl3): δ = 146.9, 140.8, 138.6,
134.2, 133.0, 129.5, 129.3, 129.1, 128.9, 128.8, 126.8, 122.1,
115.0, 113.6, 112.2, 99.4, 70.2, 48.2, 46.3, 38.4, 36.7, 36.2, 26.0,
25.0, 24.4, 24.2, 13.8; HRMS (ESI) m/z MH+, found 394.2022.
C25H24N5+ requires 394.2026.
o
1
Brown solid, mp: 288-290 C; H NMR (400 MHz, CDCl3): δ =
7.74 (dd, J = 8.4, 1.2 Hz, 2H, ArH), 7.49-7.56 (m, 7H, ArH),
7.38 (t, J = 7.2 Hz, 1H, ArH), 4.38 (s, 1H, CH), 3.97-4.06 (m, 2H,
CH2), 3.93 (s, 1H, NH), 3.78-3.87 (m, 2H, CH2), 2.47-2.55 (m,
1H, CH2), 2.14-2.21 (m, 1H, CH2), 1.94-1.98 (m, 1H, CH2), 1.79-
1.81 (m, 1H, CH2), 1.72 (s, 3H, CH3); 13C NMR (100 MHz,
CDCl3: δ = 147.0, 139.7, 138.5, 133.6, 129.6, 129.5, 129.0, 127.1,
122.1, 114.3, 112.5, 99.2, 63.1, 62.4, 59.9, 50.0, 44.3, 34.3, 29.0,
13.8; HRMS (ESI) m/z MH+, found 410.1977. C25H24N5O+
requires 410.1975.
4.23. 4'-(4-chlorophenyl)-3'-methyl-1'-phenyl-4',7'-
dihydrospiro[cyclopentane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4w)
o
Yellow solid, mp: 131-132 C; 1H NMR (400 MHz, CDCl3): δ =
4.28. 3'-methyl-1'-phenyl-4'-(p-tolyl)-2,3,4',5,6,7'-
hexahydrospiro[pyran-4,6'-pyrazolo[3,4-b]pyridine]-5',5'(1'H)-
dicarbonitrile (4bb)
7.84 (dd, J = 8.4, 1.2 Hz, 2H, ArH), 7.63-7.70 (m, 5H, ArH),
7.50 (t, J = 8.4 Hz, 1H, ArH), 7.45 (d, J = 7.6 Hz, 1H, ArH), 4.54
(s, 1H, CH), 4.12 (s, 1H, NH), 2.11-2.14 (m, 7H, CH2), 1.91 (s,
3H, CH3); 13C NMR (100 MHz, CDCl3): δ = 146.6, 140.8, 138.5,
135.5, 132.8, 131.3, 130.6, 130.0, 129.5, 129.2, 129.0, 126.9,
122.1, 121.5, 114.8, 113.3, 98.9, 70.1, 48.0, 45.7, 38.4, 36.0, 24.9,
24.4, 24.2, 13.9; HRMS (ESI) m/z MH+, found 428.1645.
C25H23ClN5+ requires 428.1636.
o
1
White solid, mp: 249-250 C; H NMR (400 MHz, CDCl3 +
DMSO-d6): δ = 7.72 (d, J = 8.0 Hz, 2H, ArH), 7.36 (t, J = 7.6 Hz,
3H, ArH), 7.13-7.17 (m, 4H, ArH), 6.57 (s, 1H, NH), 4.37 (s, 1H,
CH), 3.67-3.79 (m, 3H, CH2), 3.57-3.65 (m, 1H, CH2), 2.25 (s,
3H, CH3), 2.01-2.03 (m, 2H, CH2), 1.72-1.78 (m, 1H, CH2), 1.58-
1.61 (m, 1H, CH2), 1.44 (s, 3H, CH3); 13C NMR (100 MHz,
CDCl3 + DMSO-d6): δ = 151.2, 146.1, 144.2, 143.6, 136.7, 134.2,
134.1, 130.8, 126.1, 130.1, 84.2, 83.9, 83.6, 67.5, 64.8, 54.4, 47.9,
45.3, 45.1, 44.3, 44.1, 38.3, 26.0, 18.8; HRMS (ESI) m/z MH+,
found 424.2130. C26H26N5O+ requires 424.2132.
4.24. 3'-methyl-1',4'-diphenyl-4',7'-dihydrospiro[cycloheptane-
1,6'-pyrazolo[3,4-b]pyridine]-5',5'(1'H)-dicarbonitrile (4x)
Brown crystal, mp: 240-242 oC; 1H NMR (400 MHz, CDCl3): δ =
7.71 (d, J = 6.8 Hz, 2H, ArH), 7.49-7.53 (m, 6H, ArH), 7.38 (t, J
= 7.6 Hz, 1H, ArH), 4.38 (s, 1H, CH), 3.88 (s, 1H, NH), 2.45-
2.51 (m, 1H, CH2), 2.12-2.14 (m, 1H, CH2), 1.98-2.02 (m, 1H,
CH2), 1.87-1.89 (m, 4H, CH2), 1.73 (s, 3H, CH3), 1.51-1.57 (m,
2H, CH2); 13C NMR (100 MHz, CDCl3): δ = 147.0, 140.6, 138.6,
134.0, 131.0, 129.5, 129.4, 128.8, 126.9, 122.2, 114.9, 113.7,
98.5, 64.9, 50.3, 45.3, 38.8, 32.3, 29.2, 28.5, 22.1, 22.0, 13.8;
4.29. 4'-(4-chlorophenyl)-3'-methyl-1'-phenyl-2,3,4',5,6,7'-
hexahydrospiro[pyran-4,6'-pyrazolo[3,4-b]pyridine]-5',5'(1'H)-
dicarbonitrile (4cc)
o
1
White solid, mp: 282-284 C; H NMR (400 MHz, CDCl3): δ =
7.89 (d, J = 6.8 Hz, 2H, ArH), 7.56-7.71 (m, 7H, ArH), 4.54 (s,
1H, CH), 4.19-4.22 (m, 2H, CH2), 4.13 (s, 1H, NH), 3.97-4.02 (m,
2H, CH2), 2.65-2.69 (m, 1H, CH2), 2.30-2.35 (m, 2H, CH2), 2.11-
2.15 (m, 1H, CH2), 1.91-1.99 (m, 5H, CH2 + CH3); 13C NMR
(100 MHz, CDCl3): δ = 146.8, 139.8, 138.4, 135.7, 132.3, 129.6,
129.3, 127.2, 122.1, 114.1, 112.3, 98.7, 63.1, 62.4, 59.9, 49.8,
HRMS (ESI) m/z MH+, found 422.2341. C27H28N5 requires
+
422.2339.
4.25. 3'-methyl-1'-phenyl-4'-(p-tolyl)-4',7'-
dihydrospiro[cycloheptane-1,6'-pyrazolo[3,4-b]pyridine]-
5',5'(1'H)-dicarbonitrile (4y)

8
Tetrahedron
43.8, 34.3, 28.9, 13.9; HRMS (ESI) m/z MH+, found 444.1585.
White crystal; Mp: 180-188 oC; 1H NMR (400 MHz, CDCl3): δ =
C25H23ClN5O+ requires 444.1586.
7.58 (d, J = 7.6 Hz, 2H, ArH), 7.47 (t, J = 7.6 Hz, 2H, ArH), 7.32
(t, J = 7.6 Hz, 1H, ArH), 5.68-5.71 (m, 1H, CH), 3.83 (br, 2H,
NH2), 2.26 (s, 5H, CH2 + CH3), 2.19-2.23 (m, 2H, CH2), 1.72-
1.79 (m, 2H, CH2), 1.66-1.71 (m, 2H, CH2).
4.30. 3-methyl-1,4-diphenyl-2',3',4,5',6',7-
hexahydrospiro[pyrazolo[3,4-b]pyridine-6,4'-thiopyran]-
5,5(1H)-dicarbonitrile (4dd)
Brown power, mp: 287-288 oC; 1H NMR (400 MHz, CDCl3): δ =
7.72 (d, J = 8.0 Hz, 2H, ArH), 7.59-7.57 (m, 7H, ArH), 7.39 (t, J
= 8.0 Hz, 1H, ArH), 4.41 (s, 1H, CH), 3.76 (s, 1H, NH), 3.07-
3.14 (m, 2H, CH2), 2.47-2.67 (m, 4H, CH2), 2.29-2.32 (m, 1H,
CH2), 2.17-2.21 (m, 1H, CH2), 1.73 (s, 3H, CH3); 13C NMR (100
MHz, CDCl3): δ = 147.0, 139.6, 138.5, 133.6, 130.8, 129.6,
128.9, 127.1, 122.1, 114.2, 112.6, 99.1, 61.4, 50.3, 44.3, 35.6,
29.5, 23.8, 23.1, 13.8; HRMS (ESI) m/z MH+, found 426.1753.
C25H24N5S+ requires 426.1747.
Acknowledgments
We are grateful for financial support from the National
Natural Science Foundation of China (No. 21776260) and the
help of undergraduate of Shaoxing University for this research
work.
References and notes
1. Zheng, Y.; Tice, C. M.; Singh, S. B. Bioorg. Med. Chem. Lett.
2014, 24, 3673–3682.
4.31. 3-methyl-1-phenyl-4-(p-tolyl)-2',3',4,5',6',7-
hexahydrospiro[pyrazolo[3,4-b]pyridine-6,4'-thiopyran]-
5,5(1H)-dicarbonitrile (4ee)
2. (a) Rios, R. Chem. Soc. Rev. 2012, 41, 1060–1074; (b) Heathcock,
C. L.; Graham, S. L.; Pirrung, M. C.; Plavac, F.; White, C. T. The
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& Sons, New York, 1983, Vol. 5, pp. 264–313; (c) Smith, L. K.;
Baxendale, I. R. Org. Biomol. Chem. 2015, 13, 9907–9933; (d)
Undheim, K. Synthesis 2014, 46, 1957–2006.
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4. Kotha, S.; Panguluri, N. R.; Ali, R. Eur. J. Org. Chem. 2017,
5316–5342
5. (a) Molvi, K. I.; Haque, N.; Awen, B. Z. S.; Zameeruddin, M.;
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1643–1664; (c) Zheng, Y.; Tice, C. M.; Singh, S. B. Bioorg. Med.
Chem. Lett. 2014, 24, 3673–3682.
o
1
White solid, mp: 277-278 C; H NMR (400 MHz, CDCl3): δ =
7.71 (d, J = 8.0 Hz, 2H, ArH), 7.53 (t, J = 7.6 Hz, 2H, ArH), 7.38
(t, J = 7.2 Hz, 3H, ArH), 7.29 (s, 3H, ArH), 4.37 (s, 1H, CH),
3.77 (s, 1H, NH), 3.04-3.12 (m, 2H, CH2), 2.53-2.64 (m, 4H,
CH2), 2.44 (s, 3H, CH3), 2.26-2.30 (m, 1H, CH2), 2.11-2.17 (m,
1H, CH2), 1.74 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ =
147.1, 139.6, 139.5, 138.5, 130.5, 129.6, 129.5, 127.0, 122.1,
114.3, 112.7, 99.3, 77.4, 77.1, 76.8, 61.1, 50.5, 44.0, 35.6, 29.5,
23.8, 23.1, 21.3, 13.9; HRMS (ESI) m/z MH+, found 440.1900.
C26H26N5S+ requires 440.1903.
6. (a) Liu, J.; Tian, Y.; Shi, J.; Zhang S.; Cai, Q. Angew. Chem., Int.
Ed. 2015, 54, 10917–10920; (b) Li, M.; Hawkins, A.; Barber, D.
M.; Bultinck, P.; Herrebout, W.; Dixon, D. J. Chem. Commun.
2013, 49, 5265–5267.
4.32. 4-(4-chlorophenyl)-3-methyl-1-phenyl-2',3',4,5',6',7-
hexahydrospiro[pyrazolo[3,4-b]pyridine-6,4'-thiopyran]-
5,5(1H)-dicarbonitrile (4ff)
7.
(a) Chupakhin, E.; Babich, O.; Prosekov, A.; Asyakina, L.;
Krasavin, M. Molecules 2019, 24, 4165–4202; (b) Ding, A.;
Meazza, M.; Guo, H.; Yang, J. W.; Rios, R. Chem. Soc. Rev.
2018, 47, 5946–5996; (c) Bartolo, N. D.; Read, J. A.; Valentin, E.
M.; Woerpel, K. A. Chem. Rev. 2020, 120, 1513–1619; (d) Li, H.;
Shakaroun, R. M.; Guillaume, S. M.; Carpentier, J.-F. Chem. Eur.
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2019, 52, 2349–2360; (f) Ligny, R.; Hanninen, M. M.; Guillaume
S. M.; Carpentier, J.-F. Chem. Commun. 2018, 54, 8024–8031; (g)
Liu, X.; Zheng, H.; Xia, Y.; Lin L.; Feng, X. Acc. Chem. Res.
2017, 50, 2621–2631; (h) Qi, J.; Teng, Q.; Thirupathi, N.; Tung,
C.-H.; Xu, Z. Org. Lett. 2019, 21, 692–695; (i) Liang, M.; Zhang,
S.; Jia, J.; Tung, C.-H.; Wang, J.; Xu, Z. Org. Lett. 2017, 19,
2526–2529; (j) Wang, B.; Liang, M.; Tang, J.; Deng, Y.; Zhao, J.;
Sun, H.; Tung, C.-H.; Jia, J.; Xu, Z. Org. Lett. 2016, 18, 4614–
4619; (k) Mao, W.; Lin, S.; Zhang, L.; Lu, H.; Jia, J.; Xu, Z.
Org. Chem. Front. 2020, 7, 856–861.
o
1
White solid, mp: 261-262 C; H NMR (400 MHz, CDCl3): δ =
7.70 (d, J = 8.0 Hz, 2H, ArH), 7.54 (t, J = 7.6 Hz, 2H, ArH), 7.46
(s, 3H, ArH), 7.39 (t, J = 7.2 Hz, 2H, ArH), 4.38 (s, 1H, CH),
3.89 (s, 1H, NH), 3.02-3.10 (m, 2H, CH2), 2.43-2.63 (m, 4H,
CH2), 2.24-2.27 (m, 1H, CH2), 2.09-2.15 (m, 1H, CH2), 1.74 (s,
3H, CH3); 13C NMR (100 MHz, CDCl3): δ = 146.8, 139.7, 138.4,
135.7, 132.2, 129.6, 129.2, 127.2, 122.1, 114.0, 112.4, 98.5, 61.2,
50.1, 43.8, 35.6, 29.5, 23.7, 23.1, 13.9; HRMS (ESI) m/z MH+,
found 460.1362. C25H23ClN5S+ requires 460.1357.
4.33. 1,3'-dimethyl-1',4'-diphenyl-4',7'-dihydrospiro[piperidine-
4,6'-pyrazolo[3,4-b]pyridine]-5',5'(1'H)-dicarbonitrile (4gg)
o
1
Brown power, mp: 246-248 C; H NMR (400 MHz, CDCl3 +
DMSO-d6): δ = 7.57 (s, 1H, ArH), 7.39-7.46 (m, 6H, ArH), 7.29
(s, 1H, ArH), 7.04 (s, 2H, ArH), 5.69 (s, 1H, CH), 3.19-3.22 (m,
1H, ArH), 3.07-3.11 (m, 2H, CH2), 2.68-2.72 (m, 2H, CH2), 2.46-
2.52 (m, 2H, CH2), 2.16 (s, 3H, CH3), 1.65-1.69 (m, 1H, CH2);
13C NMR (100 MHz, CDCl3 + DMSO-d6): δ = 143.9, 133.4,
132.2, 129.6, 129.0, 127.1, 126.8, 118.5, 115.9, 112.3, 81.8, 78.8,
78.5, 78.2, 55.3, 54.6, 50.0, 45.4, 43.0, 40.6, 40.4, 40.2, 40.0,
39.8, 39.5, 39.3, 34.8; HRMS (ESI) m/z MH+, found 423.2286.
C26H27N6+ requires 423.2292.
8. Goudedranche, S.; Bugaut, X.; Constantieux, T.; Bonne, D.;
Rodriguez, J. Chem. Eur. J. 2014, 20, 410–415.
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15, 128–131.
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F. J. Org. Chem. 2016, 81, 7898–7907.
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Chem. 2018, 71, 435–441.
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Zhang, F. R. Synlett. 2020, 31, 1313–1317.
6-Amino-3-methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-
carbonitrile (5)16
o
1
White solid, mp: 207-208 C; H NMR (400 MHz, CDCl3): δ =
8.09 (d, J = 8.4 Hz, 2H, ArH), 7.33-7.64 (m, 7H, ArH), 7.28-7.35
(m, 1H, ArH), 5.40 (s, 2H, NH2), 2.02 (s, 3H, CH3).
4-(cyclohex-1-en-1-yl)-3-methyl-1-phenyl-1H-pyrazol-5-amine
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2456–2466.
(6)17

9
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7618.
Supplementary Material
Supplementary material related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2020.xx.xxx.
17. Moree, W. J.; Goldman, P.; Demaggio, A. J.; Christenson, E.;
Herendeen, D.; Eksterowicz, J.; Kesicki, E. A.; McElligott, D. L.;
Beaton, G. Bioorg. Med. Chem. Lett. 2008, 18, 5126–5129.

Table 1 Optimization of conditions for the forming of product 4a.a
Entry
Catalyst
(mol%)
-
Solvent
T (oC)
Time
(h)
Yield
(%)b
1
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
H2O
80
80
80
80
80
80
80
80
80
65
80
66
80
rt
12
3
0
2
H2SO4 (10)
TFA (10)
35
46
77
86
53
57
59
88
66
67
50
63
0
3
3
4
TsOH (10)
HOAc (10)
Y(OTf)3 (10)
Sc(OTf)3 (10)
HOAc (5)
3
5
3
6
3
7
3
8
3
9
HOAc (20)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
HOAc (10)
3
10
11
12
13
14
15
16
17
3
3
THF
3
DMSO
EtOH
EtOH
EtOH
EtOH
3
12
3
40
60
100
27
49
85
3
3
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol), acidic catalyst (x mol%), and solvent
(3.0 mL) were introduced in a heated 10 mL sealed tube for given time.
b Isolated yield.

Table 2 Range of the substrates for the synthesis of 4.a
Entry
1
4
Ar
X
Y
n
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
2
2
2
1
1
1
1
1
1
1
R
Time (h)
Yield %
86
83
77
81
89
88
84
85
78
80
82
83
81
79
76
74
73
73
88
84
90
75
81
74
73
79
85
81
89
83
85
88
76
4a
4b
4c
C6H5
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NMe
NMe
NH
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OH
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4
4
4
4
3
3
3
3
4
4
4
4
4
4
4
4
4
4
2
2
2
4
4
4
4
4
3
3
3
3
3
3
3
2
4-CH3C6H4
4-iPrC6H4
4-OMeC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
4-NO2C6H4
2-ClC6H4
3-ClC6H4
2-NO2C6H4
3-NO2C6H4
2,4-Cl2C6H3
1-Naphthyl
2-Thienyl
C6H5
3
4
4d
4e
5
6
4f
7
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
4j
4k
4l
4m
4n
4o
4p
4q
4r
4-CH3C6H4
4-CH3C6H4
C6H5
4s
O
4t
4-CH3C6H4
4-ClC6H4
C6H5
O
4u
4v
4w
4x
4y
4z
O
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
4-ClC6H4
C6H5
4-CH3C6H4
4-ClC6H4
C6H5
4aa
4bb
4cc
4dd
4ee
4ff
4gg
4-CH3C6H4
4-ClC6H4
C6H5
O
O
S
4-CH3C6H4
4-ClC6H4
C6H5
S
S
NMe
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), acetic acid (10 mol%), and EtOH (3.0 mL)
were introduced in a heated 10 mL sealed tube for 2-4 hours.
b Isolated yield.

Figure 1. Some important N-containing spirocycles with stereogenic centers.
Scheme 1. Control experiments.
Scheme 2. Probable mechanism for forming of products 4a.

Highlights
1. A reaction for synthesis of spirocycloalkane fused pyrazolo[3,4-b]pyridines has been established.
2. The reaction can be finished within 2-4 hours with water as sole byproduct.
3. This chemistry provides a strategy to construction of N-containing spirocycles with stereogenic
center.

The authors declare no conflict of interest.