Regioselective Ring Expansion of 3-Ylideneoxindoles with Tosyldiazomethane (TsDAM): A Metal-Free and Greener Approach for the Synthesis of Pyrazolo-[1,5- c]quinazolines

Article abstract of DOI:10.1021/acs.joc.0c00078

An efficient, metal-free approach to access pyrazolo-[1,5-c]quinazolines with 3-ylideneoxindoles and tosyldiazomethane (TsDAM) under mild aqueous reaction conditions has been developed and the solvent involvement in the present reaction has also been explored for the first time. This greener approach involves 1,3-dipolar cycloaddition, regioselective ring expansion, followed by the elimination of tosyl group with aqueous base in a single operation, and the product can be isolated in high purity without column chromatographic separation. The method is also compatible with a large variety of functional groups, providing good to excellent yields in water, thus resulting in a decrease of environmental impact in the pharmaceutical industry.

Full text of DOI:10.1021/acs.joc.0c00078

Subscriber access provided by University of Victoria Libraries
Article
Regioselective ring expansion of 3-ylideneoxindoles with
tosyldiazomethane (TsDAM) : A metal-free and greener
approach for the synthesis of pyrazolo-[1,5-c]quinazolines
Gopathi Ramu, Yellaiah Tangella, Srinivas Ambala, and BATHINI NAGENDRA BABU
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00078 • Publication Date (Web): 31 Mar 2020
Downloaded from pubs.acs.org on April 4, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Regioselective ring expansion of 3-ylideneoxindoles with tosyldiazomethane
(TsDAM) : A metal-free and greener approach for the synthesis of pyrazolo-
[1,5-c]quinazolines
9
Gopathi Ramu,a,b Yellaiah Tangella,a,b Srinivas Ambala,a and Bathini Nagendra Babu*a,b
aDepartment of Fluoro-Agrochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad-500
007, India.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
bAcademy of Scientific and Innovative Research (AcSIR), New Delhi-110025, India
EtOOC
O
Ts
Ar
O
N2
N
H
Metal free
EtOOC
Mild reaction condition
Broad substrate scope
Greener approach
N
N
Water as a solvent
[3+2] cyclo addition
N
O
H
Regio selective ring expansion
Good to excellent yields
Gram scale synthesis
H2O
ABSTRACT:
An efficient, metal free approach to access the pyrazolo-[1,5-c]quinazolines with 3-ylideneoxindoles and
tosyldiazomethane (TsDAM) under mild aqueous reaction conditions has been developed and also the
solvent involvement in the present reaction has been explored for the first time. This greener approach
involves 1,3-dipolar cycloaddition, regioselective ring expansion followed by the elimination of tosyl
group with aqueous base in a single operation and the product can be isolated in high purity without
column chromatographic separation. The method is also compatible with a large variety of functional
groups, providing good to excellent yields in water, thus offering the decrease of environmental impact in
the pharmaceutical industry.
INTRODUCTION
The development of facile strategies to construct diverse complex heterocyclic compounds has
intrigued as an important theme in synthetic organic chemistry over the years due to the extensive
applications in various fields of science.1 Among the several synthetic methods to these ends,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 21
1
2
3
4
5
6
7
8
9
those that exploit the use of easily accessible starting materials under domino conditions are
highly desirable for their atom and step economy.2 For instance, quinazolines and pyrazoles are
the most significant heterocyclic compounds, widely found in plethora of drug-related molecules,
functional materials and natural products.3 Owing to their unique biological activity and
pharmacological properties, they occupy an important position in the family of heterocycles.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CO2H
CO2Et
CO2Et
HO2C
EtO2C
CO2H
N
N
N
Cl
N
N
N
O
Cl
O
N
O
Cl
N
N
O
H
H
H
Gly/NMDA antagonist
AMPA receptors
Benzodiazepine receptor
Me
CO2H
Cl
CO2Et
N
N
Cl
N
O
N
N
N
N
N
Ph
Cl
N
N
O
N
H
H
Me
Phosphodiesterase 10 A inhibitors
Kinase CK2 inhibitor
Adenosine receptors
Figure 1. Some Important biologically active molecules
In particular, pyrazolo[1,5- ]quinazolines, belonging to a class of N-fused heterocyclic
c
compounds containing quinazoline and pyrazole frameworks, have drawn a great deal of attention
from both medicinal as well as synthetic chemists due to their significant biological activities
Figure 1), such as benzodiazepine/adenosine receptor,5 Gly/NMDA antagonist,6 AMPA
receptors,7 γ-aminobutyric acid type A receptors (GABA),8 phosphodiesterase 10 A inhibitors,9
non-nucleoside HIV-1 reverse transcriptase inhibitor,10 kinase CK2 inhibitor,11 excitatory amino
acid antagonists.12 They also serve as versatile synthons for the synthesis of various other
bioactive molecules.13
(
Accordingly, considerable effort has been devoted to the development of new and novel
synthetic approaches to the construction of pyrazolo[1,5-
synthetic analogues would serve as the versatile synthons in the synthesis of pyrazolo[1,5-
]quinazoline derivatives. In the past few years, several methods have been developed by
employing complex starting materials, which includes a reactions of 3-diazoindolin-2-ones with
electron-deficient alkynes14 or, enaminones15 2-(1 -pyrazol-5-yl)anilines with carbonates,16 2-
c]quinazoline derivatives. Isatin and its
c
H
aminoacetophenone hydrazones with triphosgene,17 1-(2-halophenyl)-3-akylprop-2-yn-1-ones
with hydrazine hydrochloride and amidine hydrochlorides,18 alkyne ketones with
sulfonylhydrazones,19 arynes with 3-diazoindolin-2-ones,20 3-aryl/alkylideneoxindoles with
Bestmann–Ohira reagent21 and 3-ylideneoxindoles with diazomethane derivatives.22 However,
ACS Paragon Plus Environment

Page 3 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
these protocols offer certain limitations, some of them involves the use of metal salts, expensive
and complex reagents which require multi step synthesis, harsher reaction conditions, lower
yields, and poor chemo selectivity. In view of these aspects as well as from the standpoint of step
economy, the development of efficient and practical methods for the construction of pyrazolo-
9
[1,5-c]quinazolines via an elegant domino strategy with easily accessible precursors is still
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
desirable (Figure 2).
Over the past decade, 3-ylideneoxindole core has evolved as an important synthetic
intermediate for organic chemists. They have been widely used in the development of several
novel methodologies, total synthesis of natural products due to the high reactivity as an
electrophile and easy accessibility.23 On the other hand; substituted diazomethane intermediate is
an interesting building block in domino reactions due to its unusual reactivity in the generation of
multiple bonds in a single operation.
Previous reports:
Flavia Varano et al.,6d,19
Daniela Catarzi et al.,5a
R2
N
COOEt
N
EtOOC
O
NO2
O
CHO
+
N
O
N
R2
N
H
N
O
N
O
H
H
Kishor et al.,21
Wen-Yong Han et al.,22
O
C
O
PO(OEt)2
N
R2OOC
R1
C
R1
KOH, MeOH
o
N
25 C,1 h
O
CHF2
N
O
R2OOC
O
O
N
N
H
N
O
O2
P OEt
OEt
H
R
+
PO(OEt)2
N
Ph
O
Et2O, rt
14 d
N2
N
N
CHF2
N2
in situ
N
O
Ph
O
KOH, MeOH
25 oC,1.5 h
R
N
H
N
H
Our work:
R1
N
EtOOC
EtOOC
N
N
O
H
O
R1 = -COCH3, -COPh, -Ts
expected
N
K2CO3
H
H2O:Acetone
60 oC, 4 h
EtOOC
O
Ts
R
N
N
N2
R = -CH3, -Ph
N
O
observed
H
Figure 2. Literature precedents for the synthesis of pyrazoloquinazolines
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 21
1
2
3
4
RESULTS AND DISCUSSION
5
6
7
8
In our recent studies, we have developed efficient strategies via an in situ generated
diazomethanes with substituted 3-ylideneoxindoles and isatins under metal-free conditions with
excellent regio/diastereoselectivity to access the biologically interesting pyrazolo-[1,5-
9
]quinazolines, viridicatin derivatives and marinoquinolines.24 Inspired by the literature as well as
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
c
our own work in regioselective ring expansion, 3-ylideneoxindole (1) with tosyldiazomethane
(TsDAM) (2) were chosen for the synthesis of either benzoyl/acylated or tosylated pyrazolo-[1,5-
c
]quinazolines via an anticipated 1,3-dipolar cycloaddition followed by a ring expansion under
mild reaction conditions. After the X-ray analysis of the resulting product, we concluded that the
reaction ended with the formation of unexpected product pyrazolo-[1,5- ]quinazoline by the
elimination of both benzoyl/acyl and tosyl substituents through regioselective ring expansion.
c
Table 1
:
Optimization of the Reaction Conditionsa
EtOOC
EtOOC
O
N
O
Ts
N
O
+
N2
N
N
H
H
2a
1a
3a
Entry
1
Base
K2CO3
Solvent
Temp(oC)
rt
Time(in h)
Yield (%)b
EtOH
EtOH
EtOH
MeOH
H2O
8 h
70
78
-
2
K2CO3
-
80
1 h
3
80
4 h
4
K2CO3
K2CO3
K2CO3
Cs2CO3
tBuOK
DBU
80
1 h
73
-
5
100
60
24 h
4 h
6
H2O/Acetone
H2O/Acetone
H2O/Acetone
H2O/Acetone
H2O/Acetone
H2O/Acetone
H2O/DCM
H2O/THF
H2O/CH3CN
CH3CN
88
80
78
75
68
60
70
65
66
-
7
60
4 h
8
60
4 h
9
60
4 h
10
11
12
13
14
15
16
17
18
19
Et3N
60
4 h
Pyridine
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
60
4 h
60
4 h
60
4 h
60
4 h
80
24 h
24 h
24 h
24 h
24 h
DMF
100
85
-
DCE
-
toluene
100
70
-
THF
-
aReaction conditions: 1a (1 mmol), 2a (1 mmol), and base (2 mmol) stirred in
open air atmosphere. bIsolated yield.
ACS Paragon Plus Environment

Page 5 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
This unusual observation prompted us to further investigate the model reaction between 1a and
2a by changing various parameters including the use of bases, solvents, and temperature to evaluate the
optimal conditions. We started our studies by treating 1a (1 mmol) with 2a (1 mmol) in the presence of
K2CO3 (2 mmol) in ethanol at room/elevated temperature, the reaction proceeded smoothly and yielded
the product 3a in 70 and 78%, respectively (Table 1, entries 1-2). Notably, no desired product formation
was observed in the absence of base (Table 1, entry 3). Further, when the reaction was performed in
methanol (Table 1, entry 4), the trans-esterification product was observed in 73% (3l, Table 2). Next, to
avoid the alcoholic solvent and to make the reaction much greener, we performed the reaction in H2O at
100 oC. Unfortunately, due to insolubility of the starting materials the reaction failed to yield the product
3a (Table 1, entry 5). However, to avoid the solubility problem we performed the reaction in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
H2O/Acetone (2:1) mixture at 60 C. To our delight, the reaction proceeded smoothly, and the excellent
improvement of the yield was observed (Table 1, entry 6). Next, a series of experiments were conducted
t
with different bases viz., Cs2CO3, BuOK, DBU, Et3N and pyridine to increase the product formation, no
significant results were obtained (Table 1, entries 7-11). Attempts were also made to improve the product
formation by performing the reaction in mixed solvents, none of these were found effective (Table 1,
entries 12-14). Additionally, we also screened the aprotic solvents, and found to be incompetent (Table 1,
entries 15-19). It is noteworthy to mention that only protic solvents effected the formation of the products
in good to excellent yields. Remarkably, the choice of solvent was crucial for this transformation and
affected the yields significantly. Therefore, after careful screening the optimized reaction conditions are
the following: 3- ylideneoxindole 1 (1 mmol), tosyldiazomethane (TsDAM) 2 (1 mmol) and K2CO3 (2
mmol) H2O/Acetone (2:1) at 60 °C.
With the optimal conditions in hand, we explored the generality and substrate scope of the
reaction by screening different 3-ylideneoxindoles (Table 2). Initially, a variety of ethyl 2-(2-oxoindolin-
3-ylidene)acetate with different functional groups was screened under the optimized conditions, which
provided the corresponding pyrazolo-[1,5-c]quinazoline derivatives in good to excellent yields (60−90%).
From the results it was clear that, slightly higher yields were obtained with the substrates on
benzene ring bearing electron-donating groups than the electron-withdrawing groups. The methyl
ester and the halogen-substituted 3-ylideneoxindoles were also applied to the reactions, delivering
the desired products in good yields. The
N-protected 3-ylideneoxindoles resulted in the desired
products 3j and 3k in 75% and 72% yields. Further, various benzylideneindolin-2-ones and 2-
oxo-2-phenylethylideneindolin-2-ones were synthesized from the corresponding 3-
ylideneoxindoles. They reacted smoothly with diazomethane substrate
2 and provided the
corresponding pyrazolo-[1,5- ]quinazoline in moderate to good yield (Table 2). The electronic
c
feature of both substrates influenced the reaction yields. The substrates with electron donating
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 21
1
2
3
4
groups on
1
at -R3 position delivered the corresponding products in slightly higher yields than
their counterparts. However, naphthyl substituted 2-oxoethylideneindolin-2-one afforded the
corresponding pyrazolo-quinazoline in moderate yield. All the compounds (3a-u) were isolated
by simple filtration, which did not require any column chromatography technique for purification.
5
6
7
8
9
Table 2
:
Synthesis of pyrazolo-[1,5-
c]quinazolines
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R3
R3
O
N
O
K2CO3
Ts
N
+
R1
O
R1
H2O:Acetone (2:1)
60 oC, 4 h
N
N2
N
R2
2a
R
2
1
3a-s
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
N
N
O
N
N
O
N
O
F
Cl
Br
O
N
N
N
N
N
N
O
N
N
O
N
N
H
H
H
H
H
3d, 81%
3c
3a
, 78%
, 88%
3e, 80%
3b
, 90%
EtOOC
EtOOC
Cl
EtOOC
EtOOC
EtOOC
N
N
O
N
N
N
O
Me
O2N
Me
N
N
N
N
N
N
O
N
N
O
N
N
O
H
H
H
H
Cl
3h
Me
Me
3i
3f
3g
, 86%
, 75%
, 78%
O
3j
, 75%
, 85%
O2N
Cl
EtOOC
MeOOC
N
N
O
N
N
N
N
N
N
O
N
O
N
O
N
N
N
N
H
N
O
Bz
H
3l
, 84%
N
O
N
N
3k, 72%
H
3m, 70%
(MeOH as solvent)
H
H
3n,
77%
O
3o, 73%
3p,
63%
O2N
O
O
EtOOC
Br
EtOOC
MeO
N
N
N
N
N
N
Cl
N
N
N
N
N
O
Br
N
H
O
N
H
O
H
N
O
N
H
O
H
3q, 65%
3t
, 78%
3u
, 76%
3r, 60%
3s
, 62%
aReaction conditions:1 (1 mmol), 2a (1 mmol) and K2CO3 (2 mmol), in H2O:Acetone
(2:1), 80 °C, 1 h. bIsolated yields
On the other hand, to extend the synthetic feasibility as well as our curiosity, we also
examined the reaction between the electronically varied α-benzoyl-TsDAM 2a-d with ethyl 2-(2-
oxoindolin-3-ylidene)acetate . It is to be noted that the electron withdrawing groups (-NO2, -Cl)
1
on the 2a delivered the desired product 3a with the better yields in shorter reaction times than the
ACS Paragon Plus Environment

Page 7 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
electron donating groups (-Me) (Scheme 1). Next, our curiosity further extended to examine the
nature of the solvent, systematic comparative experiments were performed in ethanol. Reaction in
ethanol displayed faster reaction times than the water with almost same efficacy (Scheme 2),
which provided the desired product 3a in 78% yield along with the by-products ethyl 4-
9
methylbenzenesulfonate (6) and ethyl benzoate (7), which are useful synthetic precursors in the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
organic synthesis.
Scheme 1. Examination of various tosyldiazomethanes (TsDAM) with ethyl 2-(2-oxoindolin-3-
ylidene)acetates
EtOOC
EtOOC
O
N
O
K2CO3
Ts
N
+
O
R
H2O:Acetone (2:1)
60 oC
N
N2
2a-d
N
H
H
1
3a
Substrate 2
2a, R= H
Time (h)
4 h
Yield %
88
2b, R= 4-NO2
2c, R= 4-Cl
2d, R= 4-Me
2.5 h
2.5 h
8 h
86
80
65
Scheme 2. Synthesis of 3a in ethanol
EtOOC
O
EtOOC
O
EtO S O
O
N
O
K2CO3
Ts
N
+
+
OEt
+
O
EtOH, 80 oC
1 h
N2
N
N
H
H
3a, 78%
6
7
1a
2a
Scheme 3. Synthetic utility of ethyl benzoyl/acyl diazomethane
COOEt
O
EtOOC
K2CO3
OEt
N
+
N
O
EtOH,
80 oC,1 h
EtOOC
MeO
COOEt
N
O
OMe
H
+
5e
O
N2
9, 78%
No reaction
MeO
N
H
K2CO3
OMe
8a
1a
EtOOC
H2O:Acetone,
(2:1), 60 oC, 4 h
O
COOEt
EtOOC
COOEt
+
O
N
O
K2CO3
EtOH,
N2
8b
N
N
H
1a
N
o
80 C,1 h
H
9,
72%
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 21
1
2
3
4
5
6
7
8
9
Inspired by the above results, we attempted to synthesize the biologically important
dicarboxylates (Figure 1) with ethyl 2-diazo-3-(3,4-dimethoxyphenyl)-3-oxopropanoate (8a) and
3-diazo-4-ethoxy-2,4-dioxobutan-1-ylium (8b) with optimized reaction conditions. Unfortunately,
the present base mediated reaction did not work; the lower nucleophilic strength of H2O and the
acyl/donating group containing benzoyl functionality could not be eliminated to produce the key
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
cycloaddition intermediate. Surprisingly, the replacement of H2O with ethanol in the presence of
o
base at 80 C afforded the desired product diethyl 5-oxo-5,6-dihydropyrazolo[1,5-
c
]quinazoline-
1,2-dicarboxylate
9 in both the cases (8a and 8b) with good yields (Scheme 3).
Scheme 4. Gram scale synthesis of 3a
O
O
O
O
EtO
K2CO3
Ts
N
O
+
H2O:Acetone (2:1),
N
O
N2
2a (6.91g)
o
60 C, 4 h, 86%
N
H
(5 g)
N
H
1a
3a
(5.1 g, 86%)
To demonstrate the synthetic utility of the reaction, a gram-scale synthesis was executed
using 1a (5 g, 23.03 mmol) and 2a (6.9 g, 23.03 mmol) to give the corresponding product 3a in
86% (5.1 g, Scheme 4).
O
O
Scheme 5. Applications and Control experiments
Ts
N
Ph
Ph
K2CO3
N
O
+
N
H2O:Acetone
(2:1), 60 oC, 1 h
N
Ph
N
H
N
H
8
O
O
O
3q
Ts
+
(i)
O
N2
O
N
H
Ph
1q
2a
N
K2CO3
N
H2O:Acetone
(2:1), 60 oC, 4 h
N
O
H
3q
EtOOC
D
N
EtOOC
O
K2CO3
Ts
N
+
O
D2O:acetone
(2:1), 60 oC, 4 h
(ii)
N2
N
N
O
H
H
1a
2a
11,
81%
Our results prompted us to perform several control experiments to verify the reaction
mechanism and the role of the solvents. We could observe the time dependent product formation
by isolating the reaction intermediate
8 and the desired product 3a at different time (Scheme 5,
ACS Paragon Plus Environment

Page 9 of 21
The Journal of Organic Chemistry
1
2
3
4
5
eq. i). Attempts were also made to understand the role of protic solvent by performing the
experiments in the acetone- D2O system, wherein the deuterated product 11 was achieved in good
6
7
1
yield (Scheme 5, eq. ii). The disappearance of the peak at 8.18ppm in the H NMR and the mass
8
9
of the deuterated compound 11 in HRMS were clear evidence for the product formation as well as
the solvent involvement in the reaction (Figure 3 and ESI).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EtOOC
N
N
N
O
3a
H
D
EtOOC
N
O
N
N
11
H
Figure 3. Stacked plot of 1H NMR spectra of 3a and 11
Ts
Ts
Ts
R
N
H
R1
N
N
O
N
ring
1,3
O
R1
R1
K2CO3
N
H
O
NH expansion
K2CO3
N2
-ArCO2H
N H-shift
N
N
N
Ar
H2O
O
O
Ts
N
R
N
R
II
1
R1
Ts
R
IV
III
I
1,5
H-shift
Ts
Ts
R1
R1
R1
N
O
N
O
N
O
N
N
N
-TsOH
N
N
R
V
N
R
VI
O
R
VII
Figure 4: Plausible reaction mechanism
On the basis of deuterated experimental results, by-products formed in Scheme 2 and the
relevant literature reports, a plausible mechanism for this transformation is outlined in Figure 4
First, the reaction of 2-diazo-1-aryl-2-tosylethanone with H2O in the presence of base forms the
intermediate (
),25 which undergoes a 1,3-dipolar cycloaddition with alkene partner, 3-
.
I
ylideneoxindole (1), leading to the formation of an intermediate (II), Next, 1,3-H shift occurred to
give the spiro intermediate (III). The spiro-Intermediate (III) further undergone rearrangement
via ring expansion to afford the intermediate (IV), which was further encountered 1,5- H shift to
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 21
1
2
3
4
5
yield the intermediate (
tosylpyrazolo[1,5-
V
), undergone oxidative aromatization and afforded the
2-
c
]quinazolin-5(6H)-ones (VI), which was isolated and confirmed by NMR and
6
7
HRMS. Finally, the formation of the desired product pyrazolo-[1,5-c]quinazolines (VII) was
8
obtained by the replacement of tosyl group (Figure 4).
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
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSION
In summary, we developed an efficient, environmentally benign method for the synthesis of
pyrazolo-[1,5- ]quinazolines via regioselective ring expansion of 3-ylidene oxindoles with
c
tosyldiazomethane (TsDAM) in water/protic solvent. The solvent involvement in the present
reaction has been explored for the first time. The mild nucleophilic solvent would participate in
the reaction and facilitate to generate the key cycloaddition intermediate as well as the
replacement of the tosyl group by donating the proton. A wide array of 3-ylideneoxindoles were
tolerated in the reaction and afforded pyrazolo-[1,5-c]quinazolines in good to excellent yields.
The product could be easily isolated in high-purity with simple extraction. Moreover, present
protocol is amicable for the scale up synthesis. Further, the current approach is explored for the
direct synthesis of biologically important compounds and also having scope for late stage C-H
functionalization on pyrazole ring which could facilitate to generate the large library of the
pyrazolo-[1,5-c]quinazolines.
EXPERIMENTAL SECTION
General Information:
General Procedures.
Unless otherwise noted, all reagents were used as received from commercial sources. All air and moisture
sensitive reactions were conducted under a nitrogen or argon atmosphere using flame-dried or oven-dried
glassware with magnetic stirring. Tetrahydrofuran (THF) was dried over Na, benzophenone and distilled
prior to use. Reactions were monitored by thin-layer chromatography carried out on silica plates (silica
gel 60 F254, Merck) using UV-light, iodine and p-anisaldehyde for visualization. Column
chromatography was carried out using silica gel (60-120 mesh or 100- 200 mesh) packed in glass
columns. Technical grade EtOAc and petroleum ether used for column chromatography and were distilled
prior to use. Organic solutions were concentrated under reduced pressure using a rotary evaporator. Room
temperature (r.t.) is 23-25 °C.
Materials. Commercial reagents were purchased from Merck, Alfa, Spectrochem or TCI, and used as
received with the following exceptions. Tetrahydrofuran (THF), ethylene glycol dimethyl ether (DME),
toluene and 1,4-dioxane were dried over Na with benzophenone-ketyl intermediate as indicator.
ACS Paragon Plus Environment

Page 11 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Dichloroethane (DCE) and Dichloromethane DCM) were distilled over CaH2 and acetonitrile (CH3CN)
was distilled over P2O5. N,N-Dimethylformamide (DMF) was distilled under reduced pressure. Other
commercially available reagents and solvents were used without further purification.
Instrumentation. 1H NMR and 13C NMR spectra were recorded in CDCl3 or DMSO as solvent on Bruker
AVANCE 400, INOVA instruments with 400, 300 and 500 MHz frequencies spectrometers. The
coupling constant J is given in Hz. Chemical shifts (δ) were reported in ppm relative to the residual
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
13
solvent signal (CDCl3 δ = 7.26 for H NMR and δ = 77.0 for C NMR), DMSO (1H NMR: δ = 2.54and
13C NMR: δ = 39.52 ppm). Chemical shifts (ppm) were recorded with tetramethylsilane (TMS) as the
internal reference standard, or TMS (δ = 0.0) as internal standard and signal patterns are indicated as
follows: s = singlet, d = doublet, dd = doublet of doublet, dt = doublet of triplet, t = triplet, q = quartet, qd
= quartet of doublet, m = multiplet, br = broad, tt = triplet of triplet. IR spectra were recorded on a Bruker
Infrared spectrophotometer and are reported as cm-1. High-resolution mass spectra (HRMS) were
recorded on a Waters- spectrometer-TOF.
General procedure for the preparation of substituted- pyrazolo-[1,5-c]quinazolines (3a-u):
R3
R3
O
K2CO3
N
O
Ts
N
R1
O
R1
H2O : Acetone(2:1)
60 oC, 4 h
N
N2
N
R2
R2
3a-s
1
2
The 3-ylideneoxindoles 1 (0.50 mmol), Substituted 2-diazo-1-phenyl-2-tosylethan-1-ones 2a (0.50mmol)
o
and K2CO3 (1.0 mmol) were stirred in 5.0 mL of (H2O: Acetone (2:1)) was stirred at 60 C for 4 h in an
oil bath. Upon the completion of the reaction (monitored by TLC), the reaction mixture was cooled to
room temperature and the product got precipitated, which was isolated by the simple filtration after (3 x
50 ml) water washing (3a-s).
Ethyl 5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3a): Compound 3a was obtained by
o
1
the simple filtration as a creamy white solid (103mg, 88%). Mp 287 – 289 C. H NMR (300 MHz,
CDCl3+ DMSO-d6) δ 11.89 (s, 1H), 9.18 (d, J = 8.1 Hz, 1H), 8.18 (s, 1H), 7.35 – 7.26 (m, 1H), 7.18 (d, J
= 8.0 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 1.21 (t, J = 7.0 Hz, 3H). 13C{1H} NMR
(75 MHz, CDCl3+ DMSO-d6) δ 167.3, 151.1, 149.3, 146.8, 140.5, 136.6, 132.4, 128.0, 120.8, 116.8,
115.5, 65.6, 19.2. HRMS (ESI) m/z: [M + H]+ Calcd for C13 H12 N3 O3 258.0873; Found 258.0874.
Ethyl 9-methoxy-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3b): Compound 3b was
obtained by the simple filtration as a creamy white solid (100 mg, 90%). Mp 275 – 278 C.1H NMR (300
o
MHz, DMSO-d6) δ 12.16 (s, 1H), 8.92 (d, J = 2.3 Hz, 1H), 8.42 (s, 1H), 7.32 – 7.23 (m, 2H), 4.35 (q, J =
7.1 Hz, 2H), 3.82 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 163.0, 155.2,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 21
1
2
3
4
5
146.3, 144.1, 142.0, 130.1, 120.7, 117.5, 112.6, 110.4, 109.8, 61.2, 55.9, 14.6. HRMS (ESI) m/z: [M +
H]+ Calcd for C14 H14 N3 O4 288.0978; Found 288.0979.
6
7
8
Ethyl 9-fluoro-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3c): Compound 3c was
o
obtained by the simple filtration as a creamy white solid (91 mg, 78%). Mp 297 – 302 C. 1H NMR (400
9
MHz, DMSO-d6) δ 12.30 (s, 1H), 9.10 – 8.99 (m, 1H), 8.41 (s, 1H), 7.51 (dd, J = 11.4, 5.5 Hz, 1H), 7.38
(dd, J = 8.9, 4.9 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz,
DMSO-d6) δ 167.5, 162.3(d, JC-F = 238.2 Hz), 151.0, 148.7, 146.0, 137.6, 124.7(d, JC-F = 24.4 Hz), 122.8,
117.6, 117.3, 115.6, 66.0, 19.3. 19F NMR (376 MHz, DMSO-d6) δ -118.4. HRMS (ESI) m/z: [M + H]+
Calcd for C13 H11 O3 N3 F 276.07790; Found 258.1074; found: 276.0779.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 9-chloro-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3d): Compound 3d was
o
obtained by the simple filtration as a creamy white solid (93 mg, 81%). Mp 280 – 282 C. 1H NMR (400
MHz, DMSO-d6) δ 12.38 (s, 1H), 9.35 (s, 1H), 8.45 (s, 1H), 7.70 – 7.64 (m, 1H), 7.39 (d, J = 8.8 Hz, 1H),
4.37 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.8, 146.4,
144.1, 141.0, 135.0, 132.1, 127.3, 126.4, 118.1, 113.3, 111.0, 61.4, 14.6. HRMS (ESI) m/z: [M + H]+
Calcd for C13 H11 O3 N3 Cl 292.0483; found: 292.0483.
Ethyl 9-bromo-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3e): Compound 3e was
o
obtained by the simple filtration as a creamy white solid (90mg, 80%). Mp 285 – 289 C. 1H NMR (300
MHz, CDCl3+ DMSO-d6) δ 12.10 (s, 1H), 9.48 (d, J = 2.0 Hz, 1H), 8.26 (s, 1H), 7.45 (dd, J = 8.7, 2.0 Hz,
1H), 7.15 (d, J = 8.7 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz,
CDCl3+DMSO-d6) δ 168.7, 149.4, 148.9, 143.3, 142.6, 136.4, 133.7, 124.6, 120.3, 119.1, 117.4, 66.0,
18.8. HRMS (ESI) m/z: [M + H]+ Calcd for C13 H11 O3 N3 Br 335.9978; found: 335.9982.
Ethyl 9-methyl-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3f): Compound 3f was
o
obtained by the simple filtration as a creamy white solid (100 mg, 86%). Mp 270 – 275 C. 1H NMR (300
MHz, CDCl3+ DMSO-d6) δ 11.53 (s, 1H), 8.71 (s, 1H), 7.92 (s, 1H), 6.85 – 6.72 (m, 2H), 3.94 (q, J = 7.1
Hz, 2H), 1.99 (s, 3H), 0.98 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3+ DMSO-d6) δ 167.5,
151.3, 149.6, 146.8, 138.1, 137.7, 137.6, 132.1, 120.6, 116.7, 115.3, 65.6, 25.9, 19.1. HRMS (ESI) m/z:
[M + H]+ Calcd for C14 H14 O3 N3 272.1029; found: 272.1030.
Ethyl 9-nitro-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3g): Compound 3g was
o
1
obtained by the simple filtration as a pale yellow solid (86 mg, 75%). Mp 300 – 304 C. H NMR (500
MHz, DMSO-d6) δ 12.76 (s, 1H), 10.25 (d, J = 2.3 Hz, 1H), 8.49 (s, 1H), 8.42 – 8.36 (m, 1H), 7.56 – 7.45
(m, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 162.7,
146.5, 144.0, 142.5, 141.1, 140.9, 126.9, 123.7, 117.4, 112.1, 111.4, 61.6, 14.5. HRMS (ESI) m/z: [M +
H]+ Calcd for C13 H11 O5 N4 303.0724; found: 303.0729.
ACS Paragon Plus Environment

Page 13 of 21
The Journal of Organic Chemistry
1
2
3
4
5
Ethyl 7, 10-dichloro-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3h): Compound 3h was
o
obtained by the simple filtration as a creamy white solid (88 mg, 78%). Mp 260 – 264 C. 1H NMR (400
6
7
8
9
MHz, CDCl3) δ 8.85 (s, 1H), 8.30 (s, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 4.39 (q, J =
7.1 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 163.6, 145.7, 143.1, 136.3,
132.7, 131.0, 130.6, 126.2, 118.3, 116.1, 112.7, 61.7, 14.1. HRMS (ESI) m/z: [M + H]+ Calcd for C13 H10
O3 N3 Cl2 326.0093; found: 326.0095.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 7,9-dimethyl-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3i): Compound 3i was
o
obtained by the simple filtration as a creamy white solid (98 mg, 85%). Mp 250 – 254 C. 1H NMR (300
MHz, CDCl3+ DMSO-d6) δ 10.81 (s, 1H), 8.99 (s, 1H), 8.30 (s, 1H), 7.14 (s, 1H), 4.32 (q, J = 7.1 Hz,
2H), 2.39 (s, 3H), 2.32 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.8, 147.5,
144.7, 142.3, 134.6, 133.6, 130.6, 126.0, 122.5, 112.3, 111.3, 61.1, 21.2, 17.0, 14.4. HRMS (ESI) m/z: [M
+ H]+ Calcd for C15 H16 O3 N3 286.1186; found: 286.1187.
Ethyl 6-methyl-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3j): Compound 3j was
o
obtained by the simple filtration as a creamy white solid (87 mg, 75%). Mp 240 – 242 C. 1H NMR (400
MHz, CDCl3) δ 9.60 (dd, J = 8.1, 1.4 Hz, 1H), 8.44 (s, 1H), 7.70 – 7.64 (m, 1H), 7.45 – 7.36 (m, 2H),
4.47 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
162.8, 147.0, 145.3, 140.9, 136.4, 132.1, 128.8, 123.8, 114.3, 113.0, 111.0, 61.1, 31.5, 14.3. HRMS (ESI)
m/z: [M + H]+ Calcd for C14 H14 O3 N3 272.1029; found: 272.1029.
Ethyl 6-benzyl-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3k): Compound 3k was
o
obtained by the simple filtration as a creamy white solid (81 mg, 72%). Mp 257 – 259 C. 1H NMR (500
MHz, CDCl3) δ 9.61 (d, J = 8.0 Hz, 1H), 8.49 (s, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H),
7.35 – 7.26 (m, 6H), 5.63 (s, 2H), 4.44 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 162.9, 147.3, 145.9, 141.1, 135.8, 135.0, 132.0, 129.0, 128.9, 127.8, 126.6, 123.9, 115.3,
113.3, 111.2, 61.1, 48.0, 14.3. HRMS (ESI) m/z: [M + H]+ Calcd for C20 H18 O3 N3 348.1342; found:
348.1345.
Methyl 5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3l): Compound 3l was obtained by
o
1
the simple filtration as a creamy white solid (100 mg, 84%). Mp 280 – 285 C. H NMR (400 MHz,
DMSO-d6) δ 12.28 (s, 1H), 9.28 (dd, J = 8.2, 1.1 Hz, 1H), 8.48 (s, 1H), 7.65 (dd, J = 8.4, 7.3, 1.4 Hz, 1H),
7.42 – 7.34 (m, 2H), 3.90 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 163.3, 146.4, 144.3, 142.2,
136.1, 132.4, 127.4, 123.5, 116.2, 112.0, 110.2, 52.5. HRMS (ESI) m/z: [M + H]+ Calcd for C12 H10 O3
N3 244.0716; found: 244.0718.
1-phenylpyrazolo[1,5-c]quinazolin-5(6H)-one(3m): Compound 3m was obtained by the simple filtration
as a creamy white solid (82mg, 70%). Mp 302 – 304 oC. 1H NMR (300 MHz, CDCl3+ DMSO-d6) δ 11.97
(s, 1H), 8.29 – 8.22 (m, 1H), 8.07 (s, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.36 (d, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 21
1
2
3
4
5
6
7
7.7 Hz, 2H), 7.10 (t, J = 7.6 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3+ DMSO-d6) δ 149.8, 149.6, 140.4,
139.7, 138.1, 136.4, 135.9, 135.4, 134.1, 128.0, 127.6, 122.9, 121.3, 117.6. HRMS (ESI) m/z: [M + H]+
Calcd for C16 H12 O N3 262.0974; found: 262.0978.
8
9
1-(4-methoxyphenyl)pyrazolo[1,5-c]quinazolin-5(6H)-one(3n): Compound 3n was obtained by the
simple filtration as a creamy white solid (89 mg, 77%). Mp 290 – 292 oC. 1H NMR (500 MHz, DMSO-d6)
δ 11.90 (s, 1H), 8.05 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.48 – 7.39 (m, 3H), 7.35 (d, J = 8.0 Hz, 1H), 7.12
– 7.05 (m, 3H), 3.84 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 159.5, 145.4, 144.9, 135.3, 134.9,
131.2, 130.5, 124.2, 123.2, 122.7, 119.2, 116.4, 114.8, 113.2, 55.7. HRMS (ESI) m/z: [M + H]+ Calcd for
C17 H14 O2 N3 292.1080; found: 292.1085.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(4-chlorophenyl)pyrazolo[1,5-c]quinazolin-5(6H)-one(3o): Compound 3o was obtained by the simple
o
filtration as a creamy white solid (84 mg, 73%). Mp 287 – 289 C. 1H NMR (400 MHz, CDCl3+ DMSO-
d6) δ 8.14 (s, 1H), 7.99 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.43 – 7.38 (m, 2H), 7.34 (d, J = 8.2 Hz, 2H),
7.08 – 7.01 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3+DMSO-d6) δ 144.5, 144.4, 135.0, 134.4, 131.7,
129.7, 129.2, 128.6, 127.8, 122.4, 122.4, 118.9, 115.9, 112.6. HRMS (ESI) m/z: [M + H]+ Calcd for C16
H11 O N3 Cl 296.0585; found: 296.0588.
1-(4-nitrophenyl)-6,10b-dihydropyrazolo[1,5-c]quinazolin-5(1H)-one(3p): Compound 3p was obtained
o
1
by the simple filtration as a pale yellow solid (72 mg, 63%). Mp 310 – 312 C. H NMR (400 MHz,
DMSO-d6) δ 11.94 (s, 1H), 8.11 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 4.3 Hz, 3H), 7.51 – 7.45
(m, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 145.3,
144.9, 135.4, 135.0, 132.3, 130.6, 129.9, 129.4, 128.6, 123.2, 122.8, 119.5, 116.5, 113.0. HRMS (ESI)
m/z: [M + H]+ Calcd for C16 H11 N4 O3 [M + H]+: 307.0825; found: 307.0829.
1-benzoylpyrazolo[1,5-c]quinazolin-5(6H)-one(3q): Compound 3q was obtained by the simple filtration
o
1
as a creamy white solid (75 mg, 65%). Mp 267 – 269 C. H NMR (300 MHz, CDCl3+ DMSO-d6) δ
12.30 (s, 1H), 8.77 (d, J = 8.1 Hz, 1H), 8.07 (s, 1H), 7.79 (d, J = 10.6 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H),
7.54 – 7.48 (m, 3H), 7.38 (d, J = 8.1 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3+
DMSO-d6) δ 193.1, 151.5, 149.3, 147.1, 145.6, 140.7, 139.3, 137.5, 137.0, 135.1, 133.9, 132.6, 131.3,
128.0, 122.1, 121.0, 116.8. HRMS (ESI) m/z: [M + H]+ Calcd for C17 H12 O2 N3 290.0924; found:
290.0927.
1-(3-methoxy-4-nitrobenzoyl)pyrazolo[1,5-c]quinazolin-5(6H)-one(3r): Compound 3r was obtained by
o
the simple filtration as a pale yellow solid (67 mg, 60%). Mp 286 – 288 C. 1H NMR (400 MHz, DMSO-
d6) δ 12.34 (s, 1H), 8.60 (d, J = 7.4 Hz, 1H), 8.38 -8.32 (m, 2H), 8.18 (dd, J = 8.8, 2.2 Hz, 1H), 7.66 –
7.60 (m, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 4.06 (s, 3H).
13C{1H} NMR (126 MHz, DMSO-d6) δ 187.2, 155.8, 146.7, 144.4, 142.0, 139.4, 136.1, 136.1, 132.5,
ACS Paragon Plus Environment

Page 15 of 21
The Journal of Organic Chemistry
1
2
3
4
5
131.1, 127.1, 126.2, 123.4, 117.2, 116.4, 115.0, 112.0, 57.8. HRMS (ESI) m/z: [M + H]+ Calcd for C18
H13 O5 N4 365.0880; found: 365.0892.
6
7
8
9
1-(2-naphthoyl)-9-chloropyrazolo[1,5-c]quinazolin-5(6H)-one(3s): Compound 3s was obtained by the
o
1
simple filtration as a creamy white solid (69mg, 62%). Mp 274 – 276 C. H NMR (500 MHz, CDCl3+
DMSO-d6) δ 12.35 (s, 1H), 9.03 – 8.95 (m, 1H), 8.36 (d, J = 8.1 Hz, 1H), 8.25 – 8.21 (m, 1H), 8.05 – 7.98
(m, 2H), 7.99 – 7.91 (m, 2H), 7.69 – 7.63 (m, 1H), 7.59 (dd, J = 15.4, 8.3 Hz, 1H), 7.49 (dd, J = 13.3, 5.3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
Hz, 1H), 7.42 (dd, J = 14.2, 7.2 Hz, 1H). C{1H} NMR (75 MHz, CDCl3+ DMSO-d6) δ 194.95, 152.0,
148.9, 145.7, 141.0, 140.2, 139.7, 137.1, 136.9, 136.7, 134.8, 133.9, 133.7, 132.9, 132.2, 132.0, 130.2,
130.0, 123.2, 123.0, 118.2. HRMS (ESI) m/z: [M + H]+ Calcd for C21 H13 O2 N3 Cl 374.0690; found:
374.0704.
Ethyl 10-bromo-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3t): Compound 3t was
obtained by the simple filtration as a creamy white solid (87mg, 78%). Mp 286 – 288 C. 1H NMR (300
o
MHz, CDCl3+DMSO-d6) δ 12.17 (s, 1H), 8.14 (s, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.36 – 7.24 (m, 2H), 4.27
(q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3+DMSO-d6) δ 168.7, 149.4,
148.9, 143.3, 142.6, 136.4, 133.7, 124.6, 120.3, 119.1, 117.4, 66.0, 18.8. HRMS (ESI) m/z: [M + H]+
Calcd for C13 H11 O3 N3 Br 335.9978; found: 335.9982.
Ethyl 8-bromo-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate(3u): Compound 3u was
obtained by the simple filtration as a creamy white solid (85mg, 76%). Mp 290 – 292 C. 1H NMR (300
o
MHz, CDCl3+DMSO-d6) δ 12.34 (s, 1H), 9.24 (d, J = 8.7 Hz, 1H), 8.32 (s, 1H), 7.52 (s, 1H), 7.37 (d, J =
8.6 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3+DMSO-d6) δ
167.4, 151.1, 148.8, 146.2, 142.0, 134.0, 130.9, 129.9, 123.3, 116.0, 115.6, 65.9, 19.3. HRMS (ESI) m/z:
[M + H]+ Calcd for C13 H11 O3 N3 Br 335.9978; found: 335.9982.
1-benzoyl-2-tosylpyrazolo[1,5-c]quinazolin-5(6H)-one(8): Compound 8 was obtained by the simple
filtration as a creamy white solid (84 mg, 42%). Mp 256 – 258 oC.1H NMR (300 MHz, CDCl3+DMSO) δ
12.37 (s, 1H), 7.81 (d, J = 7.4 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.61 (t, J = 6.9 Hz, 1H), 7.50 (d, J = 7.3
Hz, 1H), 7.46 – 7.41 (m, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 4.6 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H),
7.17 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 2.34 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3+DMSO-
d6) δ 194.7, 158.7, 150.1, 148.6, 144.5, 141.7, 141.3, 140.0, 139.3, 136.3, 134.6, 134.5, 133.8, 133.2,
128.7, 128.6, 121.6, 120.4, 115.9, 26.4. HRMS (ESI) m/z: [M + H]+ Calcd for C24 H18 N3 O4 S 444.1018;
found: 444.1021.
Ethyl 5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate-2-d(11): Compound 11 was obtained
by the simple filtration as a creamy white solid (96 mg, 81%). Mp 290 – 292 C.1H NMR (300 MHz,
o
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 21
1
2
3
4
5
6
7
8
CDCl3+DMSO-d6) δ 12.11 (s, 1H), 9.30 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.9 Hz,
1H), 7.22 (t, J = 7.7 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz,
CDCl3+DMSO-d6) δ 167.4, 149.4, 146.8, 140.4, 136.6, 132.4, 128.0, 120.8, 116.8, 65.6, 19.1. HRMS
(ESI) m/z: [M + H]+ Calcd for C13 H11 D N3 O3 259.0941; found: 259.0948.
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
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the preparation of substituted- pyrazolo-[1,5-c]quinazolines (9):
The 3–ylideneoxindoles 1 (0.50 mmol), Substituted 2-diazo-1-phenyl-2-tosylethan-1-ones 2a (0.50mmol)
o
and K2CO3 (1.0 mmol) were stirred in 5.0 mL of ethanol was stirred at 80 C for 1 h in an oil bath.. Upon
the completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature
and diluted with 10 ml of water and extracted with EtOAc (3X10 ml). The organic layers were combined
and washed with brine, dried over anhydrous Na2SO4. After the solvent was removed under reduced
pressure, the crude product was purified by flash column chromatography on silica gel (petroleum
ether/EtOAc) to afford the desired products (9)
Diethyl 5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1,2-dicarboxylate(9): Compound 9 was obtained
o
1
after column chromatography as a creamy white solid (118 mg, 78%). Mp 242 – 244 C. H NMR (400
MHz, CDCl3) δ 11.07 (s, 1H), 8.78 – 8.74 (m, 1H), 7.62 – 7.56 (m, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.39 –
7.34 (m, 1H), 4.48 – 4.43 (m, 4H), 1.43 (td, J = 7.1, 4.1 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ
162.6, 161.9, 149.0, 145.5, 141.3, 134.2, 132.2, 126.4, 124.7, 116.5, 111.9, 110.8, 62.3, 62.0, 14.2, 14.0.
HRMS (ESI) m/z: [M + H]+ Calcd for C16 H16 N3 O5330.1084; found: 330.1094.
Ethyl 4-methylbenzenesulfonate(6): Compound 6 was obtained after column chromatography as a
colorless liquid (32mg, 60%).1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0 Hz,
2H), 4.11 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
144.6, 133.3, 129.8, 127.8, 66.8, 21.6, 14.7. HRMS (ESI) m/z: [M + H]+ Calcd for C9 H13 O3 S 201.0585;
found: 201.0571.
Ethyl benzoate(7): Compound 7 was obtained after column chromatography as a colorless liquid(32 mg,
60%). 1H NMR (500 MHz, CDCl3) δ 8.06 – 8.03 (m, 2H), 7.57 – 7.53 (m, 1H), 7.46 – 7.41 (m, 2H), 4.38
(q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.6, 132.8, 130.5,
129.5, 128.3, 60.9, 14.3. HRMS (ESI) m/z: [M + H]+ Calcd for C9 H11 O2151.0754; found: 151.0760.
ethyl 3,4-dimethoxybenzoate(5e): Compound 5e was obtained after column chromatography as a colorless
liquid (40 mg, 70%).1H NMR (400 MHz, CDCl3) δ 7.72 – 7.68 (m, 1H), 7.54 (d, J = 6.4 Hz, 1H), 6.94 –
ACS Paragon Plus Environment

Page 17 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
6.83 (m, 1H), 4.45 (q, J = 7.1 Hz, 2H), 3.94 (s, 6H), 1.39 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 166.4, 152.9, 148.6, 123.5, 123.0, 112.0, 110.2, 60.8, 56.0, 14.4. HRMS (ESI) m/z: [M + H]+
Calcd for C11 H15 O4 [M + H] +: 211.0965; found: 211.0976.
8
9
ASSOCIATED CONTENT
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Experimental details and characterization data (PDF)
Accession Codes
The CCDC 1942896 contains the supplementary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing da-
ta_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
* E-mail: bathini@iict.res.in.
ORCID
Bathini Nagendra Babu: 0000-0001-7378-0878
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors thank Council of Scientific and Industrial Research (CSIR), and Dr. J. B. Nanubolu for
crystal support (IICT Comm. No. IICT/Pubs./2019/388).
REFERENCES
1. (a) Domling, A.; Wang, W.; Wang, K. Chemistry and biology of multicomponent reactions.
Chem. Rev. 2012, 112, 3083–3135. (b) Shiri, M. Indoles in multicomponent processes (MCPs).
Chem. Rev. 2012, 112, 3508–3549.
2. (a) Denmark, S, E.; Dappen, M, S.; Cramer C, J. Intramolecular [4 + 2] cycloadditions of
nitroalkenes with olefins. J. Am. Chem. Soc. 1986, 108, 1306–1307. (b) Denmark, S,E.;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 21
1
2
3
4
5
6
7
8
9
Thorarensen, A. Tandem [4+ 2]/[3+ 2] cycloadditions of nitroalkenes. Chem. Rev. 1996, 96, 137–
165. (c) Lu, L, Q.; Chen, J, R.; Xiao, W, J. Development of cascade reactions for the concise
construction of diverse heterocyclic architecture. Acc. Chem. Res. 2012, 45, 1278–1293.
3. (a) Indrasena Reddy, K.; Aruna, C.; Manisha, M.; Srihari, K.; Sudhakar Babu, K.; Vijayakumar,
V.; Sarveswari, S.; Priya, R.; Amrita, A.; Siva, R. Synthesis, DNA binding and in-vitro
cytotoxicity studies on novel bis-pyrazoles . J. Photochem. Photobiol. 2017, 168, 89–97. (b) Do,
K.; Wilsker, D.; Ji, J.; Zlott, J.; Freshwater, T.; Kinders, R. J.; Collins, J.; Chen, A. P.; Doroshow,
J. H.; Kummar, S. Phase I study of single-agent AZD1775 (MK-1775), a Wee1 kinase inhibitor,
in patients with refractory solid tumors. J. Clin. Oncol. 2015, 33, 3409–3415. (c) Kumar, V.;
Kaur, K.; Gupta, G. K.; Sharma, A. K. Pyrazole containing natural products: synthetic preview
and biological significance. Eur. J. Med. Chem. 2013, 69, 735–753.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4. (a) Ameta, K. L.; Pawar, R. P.; Domb, A. J. Bioactive Heterocycles: Synthesis and Biological
Evaluation; Nova Science Publishers: New York, 2012, p 217. (b) Pozharskii, A. F.; Soldatenkov,
A. T.; Katritzky, A. R. Heterocycles in Life and Society; John Wiley & Sons, Ltd.: Chichester,
2011, p 1.
5. (a) Catarzi, D.; Colotta, V.; Varano, F.; Poli, D.; Squarcialupi, L.; Filacchioni, G.; Varani, K.;
Vincenzi, F.; Borea, P. A.; Ben, D. D.; Lambertucci, C.; Cristalli, G. Pyrazolo[1,5-c]quinazoline
derivatives and their simplified analogues asadenosine receptor antagonists: Synthesis, structure–
affinity relationships and molecular modeling studies. Bioorg. Med. Chem. 2013, 21, 283−294.
(b) Colotta, V.; Catarzi, D.; Varano, F.; Filacchioni, G.; Cecchi, L. Synthesis and binding activity
of some pyrazolo[1,5-c]quinazolines as tools to verify an optional binding site of a
benzodiazepine receptor ligand. J. Med. Chem. 1996, 39, 2915−2921.
6. (a) Varano, F.; Catarzi, D.; Colotta, V.; Poli, D.; Filacchioni, G.; Galli, A.; Costagli, C. Synthesis
and biological evaluation of a new set of pyrazolo[1,5-c]quinazolines as glycine/N-methyl-D-
aspartic acid receptor antagonists. Chem. Pharm. Bull. 2009, 57, 826−829. (b) Bacilieri, M.;
Varano, F.; Deflorian, F.; Marini, M.; Catarzi, D.; Colotta, V.; Filacchioni, G.; Galli, A.; Costagli,
C.; Kaseda, C.; Moro, S. Tandem 3D-QSARs approach as a valuable tool to predict binding
affinity data:ꢀ design of new Gly/NMDA receptor antagonists as a key study. J. Chem. Inf. Model.
2007, 47, 1913−1922. (c) Catarzi, D.; Colotta, V.; Varano, F. Competitive Gly/NMDA receptor
antagonists. Curr. Top. Med. Chem. 2006, 6, 809−821. (d) Varano, F.; Catarzi, D.; Colotta, V.;
Calabri, F. R.; Lenzi, O.; Filacchioni, G.; Galli, A.; Costagli, C.; Deflorian, F.; Moro, S. 1-
Substituted pyrazolo[1,5-c]quinazolines as novel Gly/NMDA receptor antagonists: Synthesis,
biological evaluation, and molecular modeling study. Boorg. Med. Chem. 2005, 13, 5536−5549.
ACS Paragon Plus Environment

Page 19 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7. (a) McQuaid, L. A.; Smith, E. C. R.; South, K. K.; Mitch, C. H.; Schoepp, D. D.; True, R. A.;
Calligaro, D. O.; O’Malley, P. J.; Lodge, D.; Ornstein, P. L. Synthesis and excitatory amino acid
pharmacology of a series of heterocyclic-fused quinoxalinones and quinazolinones. J. Med.
Chem. 1992, 35, 3319−3324. (b) Nikam, S. S.; Kornberg, B. E. AMPA receptor antagonists.
Curr. Med. Chem. 2001, 8, 155−170. (c) Varano, F.; Catarzi, D.; Colotta, V.; Lenzi, O.;
Filacchioni, G.; Galli, A.; Costagli, C. Novel AMPA and kainate receptor antagonists containing
the pyrazolo [1, 5-c] quinazoline ring system: Synthesis and structure–activity relationships.
Bioorg. Med. Chem. 2008, 16, 2617− 2626.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8. (a) Guerrini, G.; Ciciani, G.; Costanzo, A. Synthesis of novel cognition enhancers with pyrazolo
[5, 1-c] [1, 2, 4] benzotriazine core acting at γ-aminobutyric acid type A (GABAA) receptor.
Bioorg Med Chem. 2013, 21, 2186–2198. (b) Guerrini, G.; Ciciani, G.; Bruni, F.; Selleria, S.;
Martini, C.; Daniele, S.; Ghelardini. C.; Mannelli, L, D, C.; Costanzo, A. Development of ligands
at γ-aminobutyrric acid type A (GABAA) receptor subtype as new agents for pain relief. Bioorg.
Med. Chem. 2011, 19, 7441–7452.
9. Asproni, B.; Murineddu, G.; Pau, A.; Pinna, G. A.; Langgård, M.; Christoffersen, C. T.; Nielsen,
J.; Kehler, J. Synthesis and SAR study of new phenylimidazole-pyrazolo [1, 5-c] quinazolines as
potent phosphodiesterase 10A inhibitors. Bioorg. Med. Chem. 2011, 19, 642−649.
10. Campiani, G.; Aiello, F.; Fabbrini, M.; Morelli, E.; Ramunno, A.; Armaroli, S.; Nacci, V.;
Garofalo, A.; Greco, G.; Novellino, E.; Maga, G.; Spadari, S.; Bergamini, A.; Ventura, L.;
Bongiovanni, B.; Capozzi, M.; Bolacchi, F.; Marini, S.; Coletta, M.; Guiso, G.; Caccia, S.
Quinoxalinylethylpyridylthioureas (QXPTs) as potent non-nucleoside HIV-1 reverse transcriptase
(RT) inhibitors. Further SAR studies and identification of a novel orally bioavailable hydrazine-
based antiviral agent. J. Med. Chem. 2001, 44, 305–315.
11. Stefano, M.; Flavia, V.; Giorgio, C.; Mario A, P.; Giuseppe, Z.; Adriana, C.; Adriano, G.;
Daniela, C.; Vittoria, C.; Lorenzo A, P.; Meggio. F. Pyrazoloquinazoline tricyclic system as novel
scaffold to design new kinase CK2 inhibitors. Lett. Drug Des. Discov. 2006, 3, 281–284.
12. McQuaid, L, A.; Smith, R, E, C.; South, K, K.; Mitch, C, H.; Schoepp, D, D.; True, R, A.;
Calligaro, D, O., O'Malley, P, J.; Lodge, D.; Ornstein, P, L. Synthesis and excitatory amino acid
pharmacology of a series of heterocyclic-fused quinoxalinones and quinazolinones. J. Med.
Chem. 1992, 35, 3319–3324.
13. Beaulieu, F.; Ouellet, C.; Ruediger, E, H.; Belema, M.; Qiu, Y.; Yang, X.; Banville, J.; Burke, J,
R.; Gregor, K, R.; MacMaster, J, F.; Martel, A.; McIntyre, K, W.; Pattoli, M, A.; Zusi, F, C.;
Vyas, D. Synthesis and biological evaluation of 4-amino derivatives of benzimidazoquinoxaline,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 21
1
2
3
4
5
benzimidazoquinoline, and benzopyrazoloquinazoline as potent IKK inhibitors. Bioorg. Med.
Chem. Lett. 2007, 17, 1233–1237.
6
7
8
14. Vogt, B, R.; Yardley, P. Pyrazolo[1,5-c]quinazoline derivatives and related compounds. U.S. Pat.
4,112, 096, 1978.
9
15. Augusti, R.; Kascheres, C. Reactions of 3-Diazo-1,3-dihydro-2ff-indol-2-one derivatives with
enaminones. A novel synthesis of 1,2,3-Triazoles. J. Org. Chem. 1993, 58, 7079-7083.
16. Wolfe, R, T.; Greenbush, N.; Surrey, A, R. 8- chloropyrazolo-[1,5-c]quinazoline derivatives and
methods of preparng same. U.S. Pat. 3,313,815, 1967; Chem. Abstr., 1967, 67(13), 64428m.
17. Alkhathlan, H, Z.; Al-Saad, M, A.; Al-Hazimi, H, M.; Al-Farhan, K, A.; Mousa, A, A.
Quinazoline, Pyrazolo[1,5-c]Quinazoline and Spiro Quinazoline dimers from the reaction of 2-
aminoacetophenone hydrazones with triphosgene. J. Chem. Res. 2002, 587−588.
18. Yang, X.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Easy and efficient one-pot synthesis of pyrazolo[1,5-
c]quinazolines under mild copper-catalyzed conditions. RSC Adv. 2012, 2, 11061−11066.
19. Chen, Q.; Li, K.; Lu, T.; Zhou, Q. Phosphine-catalyzed domino reactions of alkynyl ketones with
sulfonylhydrazones: construction of diverse pyrazoloquinazoline derivatives. RSC Adv. 2016, 6,
24792− 24796.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20. Cheng, B.; Zu, B.; Bao, B.; Li, Y.; Wang, R.; Zhai, H. Synthesis of Spiro[indazole-3,3′-indolin]-
2′-ones via [3 + 2] dipolar cycloaddition of arynes with 3-diazoindolin-2-ones and Indazolo[2,3-
c]quinazolin-6(5H)-ones by subsequent thermal isomerization. J. Org. Chem. 2017, 82,
8228−8233.
21. Gupta, A, K.; Ahamad, S.; Gupta, E.; Kant, R.; Mohanan, K. Substrate-controlled product-
selectivity in the reaction of the Bestmann–Ohira reagent with N-unprotected isatin-derived
olefins. Org. Biomol. Chem. 2015, 13, 9783–9788.
22. Han, W, Y.; Wang, J, S.; Zhao, J.; Long, L.; Cui, B, D.; Wan, N, W.; Chen, Y, Z. A Protocol for
the Synthesis of CF2H-Containing Pyrazolo[1,5-c]quinazolines from 3-Ylideneoxindoles and in
Situ Generated CF2HCHN2. J. Org. Chem. 2018, 83, 6556−6565.
23. Ball-Jones, N, R.; Badillo, J, J.; Franz, A, K. Strategies for the enantioselective synthesis of
spirooxindoles. Org. Biomol. Chem. 2012, 10, 5165−5181.
24. (a) Ramu, G.; Krishna, N, H.; Pawar, G.; Sastry, K, N, V.; Nanubolu, J, B.; Babu, B, N. Solvent-
controlled, tunable domino reaction of 3-ylideneoxindoles with in situ-generated α-
aryldiazomethanes: a facile access to 3-spirocyclopropyl-2-oxindole and pyrazoloquinazolinone
scaffolds. ACS Omega. 2018, 3, 12349-12360. (b) Tangella, Y.; Manasa, K, L.; Krishna, N, H.;
Sridhar, B. Regioselective ring expansion of isatins with in situ generated α-aryldiazomethanes:
direct access to viridicatin alkaloids. Org. Lett. 2018, 20, 3639−3642. (c) Ramu, G.; Ambala, S.;
ACS Paragon Plus Environment

Page 21 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
Nanubolu, J, B.; Babu, B, N. Regioselective ring expansion followed by H-shift of 3-ylidene
oxindoles: a convenient synthesis of N-substituted/un-substituted pyrrolo[2,3-c] quinolines and
marinoquinolines. RSC Adv. 2019, 9, 35068−35072.
7
8
9
25. Deepa, N.; Prashant, P.; Namboothiri, I. N. N. 1, 3-Dipolar cycloaddition of chalcones and
arylidene-1, 3-dicarbonyls with diazosulfone for the regioselective synthesis of functionalized
pyrazoles and pyrazolines. Tetrahedron 2018, 74, 2716-2724.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment