Intramolecular Cycloaddition Approach to Fused Pyrazoles: Access to 4,5-Dihydro-2 H -pyrazolo[4,3- c ]quinolines, 2,8-Dihydroindeno[2,1- c ]pyrazoles, and 4,5-Dihydro-2 H -benzo[ e ]indazoles

Article abstract of DOI:10.1055/s-0036-1591737

A straightforward and efficient method for the synthesis of pyrazoles fused with 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1 H -indene, or 1,2,3,4-tetrahydronaphthalene involves the formation of the tosylhydrazone from an aromatic substrate carrying aldehy

Full text of DOI:10.1055/s-0036-1591737

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–J
paper
A
en
M. Jash et al.
Paper
Synthesis
Intramolecular Cycloaddition Approach to Fused Pyrazoles: Access
to 4,5-Dihydro-2H-pyrazolo[4,3-c]quinolines, 2,8-Dihydroinde-
no[2,1-c]pyrazoles, and 4,5-Dihydro-2H-benzo[e]indazoles
Moumita Jash
Bimolendu Das
R
O
Suparna Sen
R
O
Chinmay Chowdhury*
R
H
N
Organic & Medicinal Chemistry Divi-
sion, CSIR-Indian Institute of Chemi-
cal Biology, 4, Raja S. C. Mullick
Road, Kolkata-700032, India
chinmay@iicb.res.in
N
N
H
N
NH
n
Ts
R
MeCN, rt, 2 h
MeCN, rt, 3 h
Ts
N
N
H
H
N
then Cs2CO3,1,4-dioxane,
100 °C, 2–3.5 h
then Cs2CO3, 1,4-dioxane,
100 °C, 1–2 h
n
Ts
up to 95% yield
n = 1, 2
up to 87% yield
R = H, akyl, aryl, heteroaryl
Received: 26.09.2017
Accepted after revision: 10.11.2017
Published online: 12.12.2017
(HIF)-1 inhibitor,6b displaying the highest activity at IC50 of
0.014 μM, while PF-3882845 (compound 4, Figure 1) is re-
ported as an orally efficacious mineralocorticoid receptor
(MR) antagonist for hypertension and nephropathy.6e In
view of the immense biological activities of fused
pyrazoles, convenient syntheses of novel scaffolds of this
class are of interest. Thus, in continuation of our studies in
heterocycles synthesis,7 we became interested in the con-
struction of novel fused pyrazoles 5–7 (Figure 2).
Among the fused pyrazoles, those attached to different
heterocycles, particularly quinoline frameworks,4e,8 have
been studied to a larger extent; but pyrazoles fused with
saturated quinolines (like those in Figure 2), particularly
DOI: 10.1055/s-0036-1591737; Art ID: ss-2017-z0621-op
Abstract A straightforward and efficient method for the synthesis of
pyrazoles fused with 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-
indene, or 1,2,3,4-tetrahydronaphthalene involves the formation of the
tosylhydrazone from an aromatic substrate carrying aldehyde and acet-
ylenic functionalities at appropriate positions, followed by base-pro-
moted generation of the diazo compound and subsequent intramolec-
ular 1,3-dipolar cycloaddition. A number of functional groups were
found to be compatible for this reaction sequence and yields were mod-
erate to very good (44–95%). A plausible reaction mechanism support-
ed by DFT calculations has been provided to explain the formation of
products.
Key words cycloaddition, pyrazole, indazole, dihydroquinoline, quino-
line
NH
N
F
Pyrazoles, considered as privileged structural motif in
medicinal chemistry,1 are prevalent in core structures of
natural products2 and in a variety of commercial drugs.3
More specifically, fused pyrazoles like pyrazolo[4,3-c]quin-
olines are associated with a broad range of biological ef-
fects.4 Mention may be made of compound 1 (Figure 1), a
well-known anti-inflammatory agent and interleukin 1
inhibitor,5a and compounds 2a,b (ELND006 and ELND007)
that are potent metabolically stable γ-secretase inhibitors
that selectively inhibit the production of amyloid-β over
Notch.5b
R
N
N
N
O
S
O
F3C
X
2
Cl
N
N
CN
H
2a, X = CH, R = F (ELND006)
2b, X = N, R = H (ELND007)
1
H
N
O
N
N
N
N
N
HO2C
O
H
In addition, pyrazoles fused with carbocycles are also
used as attractive building blocks for many pharmacologi-
cally active compounds.6 For example, indenopyrazole
compound 3 (Figure 1) acts as a hypoxia inducible factor
4
Cl
(PF-3882845)
3
Figure 1 Biologically active fused polycyclic pyrazoles
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

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M. Jash et al.
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Synthesis
1). This disappointing result prompted us to carry out the
reaction at higher temperature. To our delight, when the re-
action was performed in refluxing acetonitrile, consider-
able improvement in the yield (68%, entry 2) along with sig-
nificant reduction of reaction time (2.5 h) was achieved. Re-
placing DBU by an inorganic base (i.e., K2CO3/Cs2CO3)
caused a reduction in the yield of 5a (entries 3, 4). We
therefore pursued with DBU as a base but chose the higher-
boiling solvent 1,4-dioxane instead of acetonitrile. To our
disappointment, the yield of the product 5a was still not
encouraging (entry 5). Pleasingly, employment of Cs2CO3 as
base and 1,4-dioxane as solvent afforded product 5a within
1 hour in excellent yield (88%, entry 6). However, the use of
CsOAc lowered the yield to 64% (entry 7), suggesting the ne-
cessity of Cs2CO3 in this reaction. The use of Cs2CO3 in either
NH
R
N
R
NH
N
N
O
n
S
O
6; n = 1
7; n = 2
5
R = H, alkyl, aryl, heteroaryl
Figure 2 Fused pyrazoles 5–7 as synthetic targets
pyrazolo[4,3-c]dihydroquinolines (i.e., 5), are less known.4f,9
While the syntheses of 2,8-dihydroindeno[2,1-c]pyrazoles
6 and 4,5-dihydrobenzo[e]indazoles 7 are not yet reported,
though few methods exist for their structural isomers10,11a
and related molecules.11b,c Therefore, development of alter-
native, efficient, and straightforward procedures for the
generation of fused pyrazoles 5–7 appeared relevant. We
therefore took up the synthesis of dihydro-2H-pyrazolo-
[4,3-c]quinolines 5 (Scheme 1, a), 2,8-dihydroindeno[2,1-c]-
Present work:
NH
N
a)
R
O
R
TsNHNH2,
MeCN, rt, 2 h
pyrazoles
6
and 4,5-dihydro-2H-benzo[e]indazoles
7
N
then Cs2CO3, 1,4-dioxane,
100 °C, 1–2 h
N
(Scheme 1, b) adopting a straightforward method, in which
intramolecular [3+2] cycloaddition of alkyne-tethered to-
sylhydrazones was conceived to be the key step. Incidental-
ly, during the course of this study, Suja et al.9 (Scheme 1, c)
published the synthesis of two tautomers of 5 by perform-
ing the reaction for prolonged periods (12 h) and using a
strong base (i.e., NaOH). In another publication,10a Xu et al.
(Scheme 1, d) carried out the synthesis of 6,5,5-tricyclic
fused pyrazoles, structural isomers of 6 by executing the re-
action at 60 °C for 12 hours using the costly reagent t-BuO-
Li. Importantly, both of these reactions require a strong
base, which may affect sensitive functional groups. Besides
these, Valdés and co-workers11a developed a cascade proto-
col comprising intermolecular [3+2]-cycloaddition/[1,5]-
sigmatropic rearrangement for the synthesis of tautomers
of 7. The limitations are poor yields (42–57%) and long reac-
tion time (12 h).
Ts
8
Ts
5
R = H, aryl, heteroaryl
R
b)
R
TsNHNH2,
MeCN, rt, 3 h
NH
N
then Cs2CO3, 1,4-dioxane,
100 °C, 2–3.5 h
n
O
n
6, 7
9, 10
6; n = 1 (2,8-dihydroindeno[2,1-c]pyrazoles)
7; n = 2 (4,5-dihydro-2H-benzo[e]indazoles)
R = akyl, aryl, heteroaryl
Previous works:
c)
R2
O
N
HN
R2
TsNHNH2
EtOH, 25 °C, 3 h
R1 = H, alkyl
R2 = H, Et, Ph
then 5 N NaOH,
50 °C, 12 h
N
R1
R1
N
Ts
We commenced our investigation with the substrate
N-(2-formylphenyl)-4-methyl-N-[3-(naphthalen-1-yl)prop-2-
yn-1-yl]benzenesulfonamide (8a), which can easily be ob-
tained through N-tosylation of 2-aminobenzaldehyde fol-
lowed by N-propargylation and Sonogashira coupling with
naphthyl iodide (see Supporting Information). To check the
prospect of cycloaddition reaction in the synthesis, the req-
uisite tosylhydrazone 11a was smoothly prepared from al-
dehyde 8a through reaction with p-toluenesulfonyl hydra-
zide (NH2NHTs) in acetonitrile at room temperature. There-
after, an optimization study was carried out on hydrazone
11a by performing a series of experiments with variation of
the reaction parameters such as base, solvent, temperature,
etc. for the model conversion into 5a. Selected results are
summarized in Table 1. Initial exposure of 11a to DBU in
acetonitrile at room temperature for 24 hours afforded the
desired fused pyrazole 5a in only 38% yield (Table 1, entry
Ts
Suja and co-workers9
(only two examples)
H
N
d)
NNHTs
Ar
N
tBuOLi, 60 °C
R
Ar
R
1,4-dioxane, 12 h
Xu and co-workers10a
NNHTs
Ar
e)
N
NH
K2CO3, 1,4-dioxane,
110 °C, 12 h
Ar
R
R
Valdes and co-workers11a
Scheme 1 Synthesis of pyrazole-fused heterocycles 5 and carbocycles
6, 7 using intramolecular [3+2]-cycloaddition reactions
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M. Jash et al.
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a less polar solvent (i.e., THF) or a more polar solvent (i.e.,
DMF) was not found to encouraging (entries 8, 9). Besides, a
couple of reactions were conducted in 1,4-dioxane using
stronger base (NaH/t-BuOK) but yields were found to be
within the range of 52–67% (entries 10, 11). Thus, the reac-
tion conditions of entry 6 of Table 1 were considered as op-
timal for further exploration.
strate having a terminal alkyne moiety (instead of an inter-
nal alkyne) worked best, furnishing the product 5j (95%)
within 1 hour; this experiment suggested that the steric in-
teractions play an important role during cycloaddition.
Based on previous reports9,12 and our own observations,
a plausible reaction mechanism is outlined in Scheme 3 to
explain the formation of products 5. Initially, the reaction
between 4-methylbenzenesulfonohydrazide and aldehyde
8 forms hydrazone 11, which is then converted into the
diazo species A in presence of the base.10a,11a,12b,c Intramo-
lecular 1,3-dipolar cycloaddition of the diazo compound
forms a transient intermediate B, which in the presence of
base undergoes deprotonation–reprotonation leading to
pyrazole 5. The possibility of 1,5-hydrogen shift, which is
thermally allowed but would lead to the formation of 5′ is
ruled out in this case. Incidentally, DFT calculations reveal
that structure 5d is stabler than 5d′ by about 4.22 kJ/mol
(see Supporting Information).
Having established the optimized reaction conditions,
we next sought to extend the scope and generality of the
procedure employing a variety of substituents R at the
alkyne moiety of substrate 8 as shown in Scheme 2. Indeed,
a series of products 5a–j could easily be synthesized within
1–2 hours and in good to excellent yields (64–95%). Intro-
duction of the phenyl ring as substituent (R = Ph) as in sub-
strate 8, yielded 76% of the desired product 5b (Scheme 2).
Thereafter, the reactions also proceeded smoothly when
electron-donating or -withdrawing group at the para posi-
tion of the phenyl ring was present and the results are pre-
sented in Scheme 2. Electron-donating groups (viz., Me,
OMe) afforded 5c,d in 64–70% yields, while electron-with-
drawing groups (viz., CF3, NO2, CO2Me) furnished products
5e,f,g in somewhat higher yields (72–90%). Furthermore,
the reaction times were found to be shorter (1.2–1.5 h) in
the case of electron-withdrawing groups compared to elec-
tron-donating groups (2 h). The substituents (R = pyridyl,
thiophenyl) in substrate 8 and afforded the corresponding
products 5h,i in good yields (68–78%). Notably, the sub-
The structures of products 513 were determined by
spectroscopic (1H and 13C NMR, and HRMS) and analytical
data. In addition, single crystal X-ray14 analysis of 5d and 5e
gave further support (Figure 3).
After successfully establishing an expedient strategy for
synthesizing pyrazolo[4,3-c]dihydroquinolines 5, we fo-
cused our attention to investigate the synthesis of products
6 and 7 under the optimized reaction conditions using the
substrates 9 and 10 (Scheme 4). Accordingly, the alkyne
Table 1 Optimization of the Reaction Conditions for the One-Pot Synthesis of 5aa
Ts
NH
N
NH
O
TsNHNH2,
MeCN, rt, 2 h
N
base, solvent,
temperature
N
Ts
N
N
Ts
Ts
8a
11a
5a
Entry
Base
DBU
Solvent
Temp (°C)
Time (h)
Yield (%)b
1
2
MeCN
r.t.
24
38
68
38
55
60
88
64
75
48
67
52
DBU
MeCN
reflux
reflux
reflux
100
2.5
3.0
2.0
1.5
1.0
1.5
2.0
1.5
1.5
2.0
3
K2CO3
Cs2CO3
DBU
MeCN
4
MeCN
5
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
6
Cs2CO3
CsOAc
Cs2CO3
Cs2CO3
t-BuOK
NaH
100
7
100
8
reflux
100
9
DMF
10
11
1,4-dioxane
1,4-dioxane
100
100
a Reaction conditions: 8a (0.25 mmol), NH2NHTs (0.5 mmol, 2 equiv) in MeCN (2 mL) at r.t. for 2 h; the resulting crude intermediate obtained (upon removal of
MeCN) was then heated in the presence of base (1.5 equiv) in solvent (2 mL) under an atmosphere of argon at indicated temperature.
b Isolated yield of pure product after chromatography.
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tethered aldehydes 9 (n = 1) were treated with p-toluene-
sulfonyl hydrazide for 3 hours and thereafter, the resulting
crude hydrazones were exposed to the optimized reaction
conditions to obtain 2,8-dihydroindeno[2,1-c]pyrazoles 6.
In the case of substrate 9a (R = naphthyl), the correspond-
ing product 6a was formed within 2 hours in 60% isolated
yield, whereas substrate 9b (R = Ph) required 3 hours to fur-
nish the product 6b in 85% yield. Employment of a
heteroaryl substituent (e.g., R = pyridyl) in substrate 9c ne-
N
R
TsHN
R
N
R
N
O
Cs2CO3
NH2NHTs
N
N
N
Ts
A
Ts
11
Ts
8
1,3-dipolar
cycloaddition
N
HN
NH
N
N
N
R
H
R
R
base
N
N
deprotonation–
reprotonation
1,5-H shift
N
Ts
5'
Ts
5
Ts
B
not detected
Figure 3 ORTEP diagram of compound 5d and 5e (drawn at 50% prob-
ability level)
Scheme 3 Plausible mechanism for the formation of products 5
Ts
R
NH
NH
N
O
R
Cs2CO3,
1,4-dioxane
TsNHNH2,
MeCN
N
R
rt, 2 h
N
N
100 °C, 1–2 h
N
Ts
Ts
R = H, aryl, heteroaryl
Ts
8
5
11
NH
N
NH
NH
N
N
Me
N
N
N
Ts
5c, 2 h, 64%
Ts
5a, 1 h, 88%
NH
Ts
5b, 1 h, 76%
NH
N
N
NH
N
NO2
OMe
CF3
N
N
N
Ts
Ts
5d, 2 h, 70%
Ts
5e, 1.5 h, 74%
5f, 1.2 h, 72%
NH
N
NH
N
NH
N
S
CO2Me
N
N
N
N
Ts
Ts
Ts
5g, 1.5 h, 90%
NH
5i, 1.5 h, 78%
5h, 1.5 h, 68%
N
N
Ts
5j, 1 h, 95%
Scheme 2 One-pot synthesis of pyrazolo[4,3-c]dihydroquinolines 5. Reagents and conditions: 8 (0.25 mmol), NH2NHTs (0.5 mmol, 2 equiv) in MeCN (2
mL) at r.t. for 2 h; the resulting crude intermediate obtained (upon removal of MeCN) was then heated in 1,4-dioxane (2 mL) at 100 °C for 1–2 h in the
presence of Cs2CO3 (0.38 mmol, 1.5 equiv). Yields of isolated pure products are shown.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

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cessitated longer reaction time period (3 h), yet diminished
the yield of the product 6c to 62%. Interestingly, incorpora-
tion of an electron-donating group (e.g., OMe) in the het-
eroaryl moiety as in substrate 9d (R = 2,4-dimethoxypyrim-
idine) proved beneficial for product 6d formation (82%).
Electron-withdrawing substituents (F, CO2Me) at the para-
position of the phenyl ring facilitated this reaction by re-
ducing the reaction time to 2 hours, though the desired
products 6e,f were isolated in somewhat lower (60–75%)
yields. To our disappointment, when an alkyl chain (R = Bu)
was employed at the terminal position of the acetylene
moiety as in substrate 9g, the reaction required longer time
period (3.5 h) and yield of the product 6g dropped signifi-
cantly to 44%.
The structures of products 6 and 7 were concluded from
1H and 13C NMR supported by mass spectral analysis. Al-
though two tautomeric forms are possible, we prefer the
structures shown based on X-ray crystallographic analysis
of products 6b and 6d (Figure 4).
Figure 4 ORTEP diagram of 6b and 6d (drawn at 50% probability level)
We also anticipated that 6,6,5-tricyclic-fused pyrazoles
7, a higher homologue of products 6, could also be easily ac-
cessed utilizing the substrate 10 (Scheme 4). Indeed, when
the hydrazones derived from the substrates 10 (n = 2,
R = Ph, Bu) were exposed to our optimized conditions, the
results were in tune with the previous reactions, providing
the 4,5-dihydrobenzo[e]indazoles 7a,b in 46–87% yields.
In order to extend the synthetic utility of the products
prepared, we decided to check the viability of a simple and
straightforward transformation of products 5 into pyrazolo-
[4,3-c]quinolines 12 through a base-promoted tosyl elimi-
nation as shown in Scheme 5. Towards this objective, 5b
R
R
R
Cs2CO3,
NH
TsNHNH2,
MeCN
1,4-dioxane
N
N
NH Ts
rt, 3 h
100 °C, 2–3.5 h
n
n
O
n
9; n = 1
10; n = 2
6; n = 1
7; n = 2
MeO
N
N
N
OMe
NH
N
NH
NH
N
NH
N
N
6c, 3 h, 62%
6d, 3 h, 82%
6b, 3 h, 85%
MeO2C
6a, 2 h, 60%
F
NH
NH
NH
N
N
N
6g, 3.5 h, 44%
6f, 2 h, 75%
6e, 2 h, 60%
NH
NH
N
N
7b, 3 h, 46%
7a, 3 h, 87%
Scheme 4 Synthesis of carbocycle fused pyarazoles 6, 7. Reagents and conditions: 9/10 (0.25 mmol), NH2NHTs (0.5 mmol, 2 equiv) in MeCN (2 mL) for
3 h; the resulting crude intermediate was heated at 100 °C for 2–3.5 h in the presence of Cs2CO3 (0.38 mmol, 1.5 equiv) and 1,4-dioxane (2 mL). Yields
of isolated pure products are shown.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

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Synthesis
was treated with different bases (i.e., Cs2CO3, K2CO3, Na2CO3,
NaH, NaHDMS, or t-BuOK) in DMSO; to our disappoint-
ment, no reaction took place even after heating these reac-
tions for several hours at 100–120 °C. Surprisingly, when
potassium hydroxide was used as a base, the reaction was
found to be complete within 3 hours, furnishing the expect-
ed product 12b in 90% yield (Scheme 5). This transforma-
tion was then extended to the synthesis of 12a (92%) and
12c (95%) using the compounds 5a and 5d, respectively
(Scheme 5).
were recorded on 300 or 600 MHz spectrometer using TMS as inter-
nal standard. Chemical shifts (δ) are given from TMS (δ = 0.00) in
parts per million (ppm) with reference to the residual nuclei of the
deuterated solvent used [CDCl3: 1H NMR 7.26 ppm (s); 13C NMR 77.0
ppm; DMSO-d6: 1H NMR 2.54 ppm (s); 13C NMR 39.5 ppm]. Coupling
constants (J) are expressed in hertz (Hz) and standard abbreviations
are used to denote spin multiplicities. All 13C NMR spectra were ob-
tained with complete proton decoupling. Mass spectra were per-
formed using ESI-TOF, EI, or FAB ionization mode.
3-Aryl-5-tosyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolines 5; Gen-
eral Procedure
NH
N
To a well stirred solution of 8 (0.25 mmol, 1 equiv) in anhyd MeCN (2
mL) was added p-toluenesulfonyl hydrazide (95 mg, 0.5 mmol, 2.0
equiv) and the mixture was stirred at r.t. for 2 h. After completion of
the reaction (monitored by TLC), MeCN was removed under reduced
pressure to obtain a crude material that was then dissolved in 1,4-di-
oxane (2 mL), and Cs2CO3 (123 mg, 0.38 mmol, 1.5 equiv) was added.
The mixture was allowed to stir at 100 °C for a few hours (see Scheme
2 in text) until the completion of reaction (TLC). Next, the solvent was
evaporated under reduced pressure and the crude mixture was ex-
tracted with EtOAc (3 × 30 mL). The combined extracts were washed
with brine (25 mL), dried (anhyd Na2SO4), filtered, and concentrated
in vacuo. The residue was purified by silica gel (100–200 mesh)
column chromatography using EtOAc–PE to furnish 5.
N
HN
R
R
DMSO, 120 °C, 2–3 h
– TsH
KOH,
N
H
N
Ts
5
12
5a: R = 1-naphthyl
5b: R = Ph
5d: R = 4-MeOC6H4
12a: R = 1-naphthyl (92%)
12b: R = Ph (90%)
12c: R = 4-MeOC6H4 (95%)
Scheme 5 Base-promoted transformation of 5 to pyrazolo[4,3-c]quin-
olines 12
The structures of the products 12 were established from
spectroscopic (1H and 13C NMR) and analytical data. Nota-
bly, pyrazolo[4,3-c]quinolines are well known for their bio-
logical relevance;4 consequently, several synthetic proce-
dures have been reported using either multistep and/or
costly reagents/starting materials.8 Therefore, our present
approach may serve as an alternative for an easy access of
pyrazolo[4,3-c]quinolines.
In conclusion, we have developed a facile method for ac-
cessing pyrazole-fused polycyclic scaffolds 5–7 starting
from low cost and easily available starting materials. The
method relies on a base-promoted generation of diazo com-
pounds which underwent intramolecular 1,3-dipolar
cycloaddition with a tethered alkyne moiety. The reactions
were complete within few hours and a range of functional
groups were compatible. The pyrazolo[4,3-c]quinolines 12
could also be easily prepared through a simple base (KOH)
treatment of products 5. We believe that this method will
find applications in organic and medicinal chemistry as
well.
3-(Naphthalen-1-yl)-5-tosyl-4,5-dihydro-2H-pyrazolo[4,3-c]quin-
oline (5a)
Yield: 99.2 mg (88%); pale yellow solid; mp 160–162 °C.
1H NMR (CDCl3, 300 MHz): δ = 8.02–7.98 (m, 2 H), 7.87–7.85 (m, 1 H),
7.77–7.74 (m, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.63–7.55 (m, 3 H), 7.45–
7.37 (m, 4 H), 7.02 (d, J = 8.1 Hz, 2 H), 6.92 (d, J = 8.1 Hz, 2 H), 4.87 (s,
2 H), 2.33 (s, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 143.2, 135.3, 135.1, 133.9, 131.2, 129.9,
128.8, 128.5, 127.6, 127.2, 127.0, 126.9, 126.5, 126.3, 125.6, 125.3,
124.6, 122.5, 111.8, 43.4, 21.5.
HRMS (EI): m/z calcd for
C
27H21N3O2S [M]+: 451.1354; found:
451.1345.
3-Phenyl-5-tosyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (5b)
Yield: 76 mg (75%); white solid; mp 146–148 °C.
1H NMR (CDCl3, 300 MHz): δ = 7.85 (d, J = 7.8 Hz, 1 H), 7.65 (d, J = 7.2
Hz, 1 H), 7.57–7.50 (m, 3 H), 7.48–7.43 (m, 3 H), 7.38–7.33 (m, 1 H),
7.01 (d, J = 8.1 Hz, 2 H), 6.83 (d, J = 8.1 Hz, 2 H), 5.07 (s, 2 H), 2.21 (s,
3 H).
13C NMR (CDCl3, 75 MHz): δ = 144.3, 143.2, 139.9, 135.2, 134.7, 129.4,
129.3, 128.8, 128.6, 128.5, 127.6, 126.9, 126.3, 125.3, 122.4, 109.6,
43.4, 21.3.
All solvents were distilled prior to use. Petroleum ether (PE) refers to
the fraction boiling in the range 60–80 °C. CH2Cl2 was dried over P2O5,
distilled, and stored over 3Å molecular sieves in a sealed container.
1,4-Dioxane and THF were distilled over sodium and benzophenone.
MeCN was dried over P2O5, distilled, and stored under 4 Å molecular
sieves in a sealed container. Commercial grade anhyd DMF was used
as such. All the reactions were carried out under argon atmosphere
and anhydrous conditions unless otherwise noted. Analytical TLC was
performed on silica gel 60 F254 aluminum TLC sheets. Visualization of
the developed chromatogram was performed by UV absorbance or I2
exposure. For purification, column chromatography was performed
using 60–120 or 100–200 mesh silica gel. 1H and 13C NMR spectra
HRMS (EI): m/z calcd for
401.1199.
C
23H19N3O2S [M]+: 401.1198; found:
3-(p-Tolyl)-5-tosyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (5c)
Yield: 66.4 mg (64%); pale yellow gum.
1H NMR (CDCl3, 300 MHz): δ = 7.84 (d, J = 8.1 Hz, 1 H), 7.64 (d, J = 7.2
Hz, 1 H), 7.45–7.40 (m, 1 H), 7.37–7.35 (m, 1 H), 7.33 (s, 4 H), 6.99 (d,
J = 8.1 Hz, 2 H), 6.82 (d, J = 8.1 Hz, 2 H), 5.05 (s, 2 H), 2.46 (s, 3 H), 2.21
(s, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 143.2, 139.1, 135.3, 134.7, 130.1, 128.8,
128.6, 128.5, 127.6, 126.9, 126.2, 122.5, 109.4, 43.4, 21.4, 21.3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

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HRMS (EI): m/z calcd for C24H21N3O2S [M]+: 415.1354; found:
415.1364.
1H NMR (CDCl3 + DMSO-d6, 600 MHz): δ = 8.80 (s, 1 H), 8.54 (s, 1 H),
7.90 (s, 1 H), 7.67 (d, J = 7.8 Hz, 1 H), 7.53–7.48 (m, 2 H), 7.29–7.22 (m,
2 H), 6.85 (d, J = 8.4 Hz, 2 H), 6.71 (d, J = 8.4 Hz, 2 H), 4.96 (s, 2 H), 2.14
(s, 3 H).
3-(4-Methoxyphenyl)-5-tosyl-4,5-dihydro-2H-pyrazolo[4,3-
c]quinoline (5d)
13C NMR (CDCl3 + DMSO-d6, 150 MHz): δ = 143.3, 134.7, 128.6, 128.5,
128.3, 127.6, 126.7, 122.4, 110.1, 43.5, 21.4.
Yield: 75.4 mg (70%); pale white solid; mp 180–182 °C.
HRMS (EI+): m/z calcd for C22H18N4O2S [M]+: 402.1150; found:
402.1147.
1H NMR (CDCl3, 300 MHz): δ = 7.82 (d, J = 7.8 Hz, 1 H), 7.64–7.61 (m,
1 H), 7.41 (td, J = 7.7, 1.7 Hz, 1 H), 7.36–7.32 (m, 3 H), 7.04 (d, J = 8.7
Hz, 2 H), 6.98 (d, J = 8.1 Hz, 2 H), 6.81 (d, J = 8.1 Hz, 2 H), 5.02 (s, 2 H),
3.90 (s, 3 H), 2.21 (s, 3 H).
3-(Thiophen-2-yl)-5-tosyl-4,5-dihydro-2H-pyrazolo[4,3-c]quino-
13C NMR (CDCl3, 75 MHz): δ = 160.0, 144.3, 143.2, 139.6, 135.2, 134.8,
128.8, 128.6, 128.4, 127.6, 127.5, 126.9, 125.5, 122.4, 121.8, 114.8,
109.0, 55.4, 43.4, 21.3.
HRMS (ESI): m/z calcd for C24H21N3O3SNa [M + Na]+: 454.1201; found:
454.1202.
line (5i)
Yield: 79.4 mg (78%); white solid; mp 134–136 °C.
1H NMR (CDCl3, 300 MHz): δ = 7.87–7.84 (m, 1 H), 7.59–7.56 (m, 1 H),
7.48–7.42 (m, 2 H), 7.36 (td, J = 7.4, 1.0 Hz, 1 H), 7.24–7.18 (m, 2 H),
7.05 (d, J = 8.4 Hz, 2 H), 6.85 (d, J = 8.1 Hz, 2 H), 5.06 (s, 2 H), 2.23 (s, 3
H).
13C NMR (CDCl3, 75 MHz): δ = 143.4, 135.0, 134.8, 132.0, 128.9, 128.7,
128.0, 127.4, 126.8, 125.8, 124.9, 123.9, 122.2, 109.4, 43.2, 21.3.
5-Tosyl-3-[4-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazo-
lo[4,3-c]quinoline (5e)
HRMS (EI+): m/z calcd for C21H17N3O2S2 [M]+: 407.0762; found:
Yield: 86.7 mg (74%); white solid; mp 244–246 °C.
1H NMR (CDCl3, 300 MHz): δ = 7.84 (d, J = 7.8 Hz, 1 H), 7.76 (d, J = 8.1
Hz, 2 H), 7.59–7.52 (m, 3 H), 7.43 (td, J = 7.8, 1.1 Hz, 1 H), 7.35–7.31
(m, 1 H), 6.98 (d, J = 8.4 Hz, 2 H), 6.81 (d, J = 8.1 Hz, 2 H), 5.07 (s, 2 H),
2.21 (s, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 143.4, 135.1, 134.7, 128.9, 128.7, 127.7,
126.9, 126.6, 126.4, 126.3, 124.3, 122.2, 110.6, 43.4, 21.4.
407.0763.
5-Tosyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (5j)
Yield: 77.2 mg (95%); white solid; mp 136–138 °C.
1H NMR (CDCl3, 300 MHz): δ = 7.86–7.83 (m, 1 H), 7.63 (dd, J = 7.5, 1.5
Hz, 1 H), 7.41 (td, J = 7.7, 1.6 Hz, 1 H), 7.34 (td, J = 7.4, 1.2 Hz, 1 H),
7.23 (s, 1 H), 7.11 (d, J = 8.1 Hz, 2 H), 6.88 (d, J = 7.8 Hz, 2 H), 4.96 (s, 2
H), 2.21 (s, 3 H).
HRMS (EI): m/z calcd for C24H18F3N3O2S [M]+: 469.1072; found:
469.1081.
13C NMR (CDCl3, 75 MHz): δ = 143.3, 135.3, 134.9, 128.7, 128.6, 128.4,
127.5, 127.1, 125.3, 122.3, 112.5, 43.2, 21.3.
3-(4-Nitrophenyl)-5-tosyl-4,5-dihydro-2H-pyrazolo[4,3-c]quino-
line (5f)
HRMS (EI+): m/z calcd for C17H15N3O2S [M]+: 325.0885; found:
325.0878.
Yield: 80.2 mg (72%); brown solid; mp 268–270 °C.
1H NMR (CDCl3 + DMSO-d6, 600 MHz): δ = 8.25 (d, J = 8.4 Hz, 2 H),
7.69 (dd, J = 8.1, 0.9 Hz, 1 H), 7.66 (d, J = 9.0 Hz, 2 H), 7.56 (d, J = 6.6
Hz, 1 H), 7.31–7.28 (m, 1 H), 7.26–7.25 (m, 1 H), 6.85 (d, J = 8.4 Hz, 2
H), 6.71 (d, J = 7.8 Hz, 2 H), 4.99 (s, 2 H), 2.14 (s, 3 H).
13C NMR (CDCl3 + DMSO-d6, 150 MHz): δ = 146.9, 143.3, 134.7, 134.5,
128.6, 128.5, 128.4, 127.6, 126.8, 126.7, 124.3, 122.5, 110.5, 43.7, 21.4
2,8-Dihydroindeno[2,1-c]pyrazoles 6 and 4,5-Dihydro-2H-ben-
zo[e]indazoles 7; General Procedure
To a well stirred solution of substrate 9/10 (0.25 mmol, 1 equiv) in
anhyd MeCN (2 mL) was added p-toluenesulfonyl hydrazide (95 mg,
0.5 mmol, 2.0 equiv) and the mixture was stirred at r.t. for 3 h. After
complete consumption of the starting material (monitored by TLC),
MeCN was removed under reduced pressure. The crude product was
then dissolved in anhyd 1,4-dioxane (2 mL), and Cs2CO3 (123 mg, 0.38
mmol, 1.5 equiv) was added. The mixture was allowed to stir at
100 °C for a few hours (see Scheme 2) until completion of the reaction
(TLC). The solvent was evaporated under reduced pressure and the
crude mixture was extracted with EtOAc (3 × 30 mL). The combined
extracts were washed with brine (25 mL), dried (anhyd Na2SO4), fil-
tered, and concentrated in vacuo. The residue was purified through
silica gel (100–200 mesh) column chromatography using EtOAc–PE to
give 6/7.
HRMS (EI): m/z calcd for
C
23H18N4O4S [M]+: 446.1049; found:
446.1051.
Methyl 4-(5-Tosyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-3-
yl)benzoate (5g)
Yield: 103.2 mg (90%); white solid; mp 198–200 °C.
1H NMR (CDCl3, 300 MHz): δ = 8.20 (d, J = 8.1 Hz, 2 H), 7.87–7.85 (m, 1
H), 7.61 (d, J = 7.5 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 2 H), 7.45 (td, J = 7.7, 1.6
Hz, 1 H), 7.35–7.00 (m, 1 H), 6.99 (d, J = 8.4 Hz, 2 H), 6.82 (d, J = 8.1 Hz,
2 H), 5.09 (s, 2 H), 4.01 (s, 3 H), 2.24 (s, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 166.5, 143.4, 135.1, 134.7, 134.0, 130.5,
129.9, 128.7, 128.6, 127.6, 126.9, 126.1, 124.4, 122.3, 110.5, 52.4, 43.4,
21.3.
3-(Naphthalen-1-yl)-2,8-dihydroindeno[2,1-c]pyrazole (6a)
Yield: 42.3 mg (60%); yellow solid; mp 184–186 °C.
HRMS (EI+): m/z calcd for C25H21N3O4S [M]+: 459.1253; found:
1H NMR (CDCl3, 300 MHz): δ = 8.06–7.98 (m, 3 H), 7.69 (s, 1 H), 7.60–
459.1255.
7.51 (m, 4 H), 7.16–7.13 (m, 2 H), 6.97–6.95 (m, 1 H), 3.89 (s, 2 H).
13C NMR (CDCl3, 75 MHz): δ = 146.5, 136.0, 133.8., 130.8, 129.4, 128.5,
127.9, 127.2, 127.0, 126.7, 126.5, 125.7, 125.4, 125.3, 124.9, 121.3,
30.1.
3-(Pyridin-3-yl)-5-tosyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline
(5h)
Yield: 68.3 mg (68%); pale yellow solid; mp 244–246 °C.
HRMS (EI): m/z calcd for C20H14N2 [M]+: 282.1157; found: 282.1148.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

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M. Jash et al.
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Synthesis
Phenyl-2,8-dihydroindeno[2,1-c]pyrazole (6b)
HRMS (EI): m/z calcd for C14H16N2 [M]+: 212.1313; found: 212.1301.
Yield: 49.3 mg (85%); yellow solid; mp 188–190 °C.
1-Phenyl-4,5-dihydro-2H-benzo[e]indazole (7a)
1H NMR (CDCl3, 300 MHz): δ = 7.77–7.74 (m, 2 H), 7.70 (d, J = 7.5 Hz, 1
H), 7.57–7.55 (m, 1 H), 7.52–7.50 (m, 1 H), 7.48–7.42 (m, 2 H), 7.34–
7.27 (m, 1 H), 7.24–7.19 (m, 1 H), 3.81 (s, 2 H).
13C NMR (CDCl3, 75 MHz): δ = 145.5, 136.1, 130.5, 129.1, 128.5, 126.9,
125.7, 125.1, 120.1, 30.2.
Yield: 53.5 mg (87%); pale yellow solid; mp 168–170 °C.
1H NMR (CDCl3, 600 MHz): δ = 7.63–7.61 (m, 2 H), 7.48–7.44 (m, 3 H),
7.30 (dd, J = 7.8, 1.2 Hz, 1 H), 7.25–7.23 (m, 1 H), 7.09 (td, J = 7.4, 1.4
Hz, 1 H), 7.04 (td, J = 7.5, 1.6 Hz, 1 H), 3.01 (t, J = 7.2 Hz, 2 H), 2.83 (t,
J = 7.2 Hz, 2 H).
HRMS (EI): m/z calcd for C16H12N2 [M]+: 232.1000; found: 232.0992.
13C NMR (CDCl3, 150 MHz): δ = 135.3, 131.3, 130.6, 128.9, 128.8,
128.5, 128.4, 126.5, 125.8, 123.0, 113.8, 30.2, 21.9.
HRMS (EI): m/z calcd for C17H14N2 [M]+: 246.1157; found: 246.1142.
3-(Pyridin-3-yl)-2,8-dihydroindeno[2,1-c]pyrazole (6c)
Yield: 36.1 mg (62%); pale yellow solid; mp 192–194 °C.
1H NMR (CDCl3, 300 MHz): δ = 9.09 (s, 1 H), 8.67 (d, J = 3.9 Hz, 1 H),
8.08 (d, J = 7.8 Hz, 1 H), 7.66 (d, J = 7.5 Hz, 1 H), 7.51–7.45 (m, 2 H),
7.34–7.21 (m, 3 H), 3.80 (s, 2 H).
1-Butyl-4,5-dihydro-2H-benzo[e]indazole (7b)
Yield: 24.8 mg (46%); pale yellow gum.
1H NMR (CDCl3, 600 MHz): δ = 7.43 (d, J = 7.2 Hz, 1 H), 7.27–7.24 (m, 2
H), 7.14–7.12 (m, 1 H), 2.99 (t, J = 6.9 Hz, 2 H), 2.96 (t, J = 7.8 Hz, 2 H),
2.88 (t, J = 6.9 Hz, 2 H), 1.77–1.74 (m, 2 H), 1.49–1.45 (m, 2 H), 0.97 (t,
J = 7.5 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 159.9, 149.1, 147.8, 145.4, 135.5, 134.0,
127.3, 127.0, 125.9, 125.5, 124.7, 123.9, 120.0, 30.9.
HRMS (EI): m/z calcd for C15H11N3 [M]+: 233.0953; found: 233.0954.
13C NMR (CDCl3, 75 MHz): δ = 134.9, 128.6, 126.9, 125.6, 122.8, 30.5,
30.1, 29.6, 22.6, 21.7, 13.8.
HRMS (EI): m/z calcd for C15H18N2 [M]+: 226.1470; found: 226.1472.
3-(2,4-Dimethoxypyrimidin-5-yl)-2,8-dihydroindeno[2,1-c]pyra-
zole (6d)
Yield: 60.3 mg (82%); brown solid; mp 212–216 °C.
1H NMR (CDCl3, 300 MHz): δ = 8.89 (s, 1 H), 7.65 (d, J = 7.5 Hz, 1 H),
7.51 (d, J = 7.5 Hz, 1 H), 7.32 (t, J = 7.4 Hz, 1 H), 7.23–7.21 (m, 1 H),
4.19 (s, 3 H), 4.10 (s, 3 H), 3.81 (s, 2 H).
13C NMR (CDCl3, 75 MHz): δ = 166.9, 164.5, 157.4, 145.6, 135.6, 128.1,
126.9, 125.8, 125.4, 120.4, 106.1, 55.2, 54.6, 30.2.
Pyrazolo[4,3-c]quinolines 12; General Procedure
To a well stirred solution of 5 (0.15 mmol, 1 equiv) in DMSO (3.0 mL)
was added KOH (42 mg, 0.75 mmol, 5 equiv) and the mixture was
heated at 120 °C for 2–3 h. After completion of the reaction (TLC), the
mixture was diluted with H2O and extracted with EtOAc (3 × 25 mL).
The combined extracts were washed with brine, dried (anhyd
Na2SO4), filtered, and concentrated in vacuo. The crude material was
purified by silica gel (100–200 mesh) column chromatography using
EtOAc–PE to afford 12.
HRMS (EI): m/z calcd for
C
16H14N4O2 [M]+: 294.1117; found:
294.1114.
3-(4-Fluorophenyl)-2,8-dihydroindeno[2,1-c]pyrazole (6e)
Yield: 37.5 mg (60%); yellow solid; mp 180–182 °C.
1H NMR (CDCl3, 300 MHz): δ = 7.70–7.65 (m, 2 H), 7.56 (d, J = 7.2 Hz, 1
H), 7.42 (d, J = 7.2 Hz, 1 H), 7.25–7.14 (m, 4 H), 3.72 (s, 2 H).
3-(Naphthalen-1-yl)-1H-pyrazolo[4,3-c]quinoline (12a)
Yield: 40.7 mg (92%); white solid; mp >300 °C.
13C NMR (CDCl3, 150 MHz): δ = 162.8 (d, J = 247.6 Hz), 145.4, 135.9,
128.7 (d, J = 7.7 Hz), 127.0, 126.8, 125.8, 125.3, 123.7, 119.9, 116.3 (d,
J = 21.7 Hz), 30.2.
1H NMR (DMSO-d6, 600 MHz): δ = 14.6 (s, 1 H), 9.05 (s, 1 H), 8.52 (d,
J = 7.5 Hz, 1 H), 8.32 (d, J = 8.4 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 8.09
(d, J = 7.8 Hz, 1 H), 8.06 (d, J = 7.8 Hz, 1 H), 7.90 (d, J = 7.2 Hz, 1 H),
7.83–7.76 (m, 2 H), 7.71 (t, J = 7.5 Hz, 1 H), 7.60 (t, J = 7.2 Hz, 1 H),
7.55 (t, J = 7.5 Hz, 1 H).
HRMS (EI): m/z calcd for C16H11FN2 [M]+: 250.0906; found: 250.0901.
13C NMR (DMSO-d6, 150 MHz): δ = 146.1, 145.8, 144.9, 141.5, 134.1,
131.5, 129.9, 129.7, 129.6, 129.5, 129.0, 128.9, 127.5, 127.2, 126.7,
126.2, 126.1, 122.6, 116.1, 115.9.
Methyl 4-(2,8-Dihydroindeno[2,1-c]pyrazol-3-yl)benzoate (6f)
Yield: 54.4 mg (75%); pale yellow solid; mp 226–228 °C.
1H NMR (CDCl3, 300 MHz): δ = 8.21 (d, J = 8.1 Hz, 2 H), 7.84 (d, J = 8.1
Hz, 2 H), 7.70 (d, J = 7.5 Hz, 1 H), 7.51 (d, J = 7.2 Hz, 1 H), 7.35–7.30 (m,
1 H), 7.24–7.22 (m, 1 H), 3.97 (s, 3 H), 3.82 (s, 2 H).
13C NMR (CDCl3, 75 MHz): δ = 166.5, 160.3, 145.6, 135.9, 135.6, 134.9,
130.4, 129.8, 127.0, 126.5, 125.8, 125.5, 124.6, 120.3, 52.3, 30.2.
HRMS (EI): m/z calcd for C20H13N3 [M]+: 295.1109; found: 295.1109.
3-Phenyl-1H-pyrazolo[4,3-c]quinoline (12b)15
Yield: 33.0 mg (90%); white solid; mp >300 °C.
1H NMR (DMSO-d6, 600 MHz): δ = 14.48 (s, 1 H), 9.51 (s, 1 H), 8.45 (d,
J = 7.8 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 8.11 (d, J = 7.2 Hz, 2 H), 7.79 (t,
J = 7.5 Hz, 1 H), 7.74 (t, J = 7.5 Hz, 1 H), 7.57 (t, J = 7.2 Hz, 2 H), 7.49–
7.48 (m, 1 H).
13C NMR (DMSO-d6, 600 MHz): δ = 146.2, 146.0, 144.7, 142.0, 133.0,
129.9, 129.6, 129.5, 129.0, 127.8, 127.4, 122.5, 115.9, 114.3.
HRMS (EI): m/z calcd for
290.1055.
C
18H14N2O2 [M]+: 290.1055; found:
3-Butyl-2,8-dihydroindeno[2,1-c]pyrazole (6g)
Yield: 23.3 mg (44%); yellow solid; mp 96–98 °C.
1H NMR (CDCl3, 300 MHz): δ = 7.45 (d, J = 7.8 Hz, 2 H), 7.31 (d, J = 7.5
Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 3.73 (s, 2 H), 2.90 (t, J = 7.7 Hz, 2 H),
1.82–1.71 (m, 2 H), 1.49–1.37 (m, 2 H), 0.96 (t, J = 7.4 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 160.5, 145.0, 136.6, 126.9, 125.7, 124.5,
120.0, 31.2, 30.3, 25.7, 22.3, 13.8.
HRMS (EI): m/z calcd for C16H11N3 [M]+: 245.0953: found: 245.0957.
3-(4-Methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline(12c)
Yield: 39.2 mg (95%); white solid; mp >300 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

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M. Jash et al.
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1H NMR (DMSO-d6, 600 MHz): δ = 14.4 (s, 1 H), 9.46 (s, 1 H), 8.44 (d,
J = 7.8 Hz, 1 H), 8.13 (d, J = 7.8 Hz, 1 H), 8.03 (d, J = 9.0 Hz, 2 H), 7.78 (t,
J = 7.5 Hz, 1 H), 7.72 (t, J = 7.5 Hz, 1 H), 7.12 (d, J = 9.0 Hz, 2 H), 3.84 (s,
3 H).
13C NMR (DMSO-d6, 150 MHz): δ = 144.8, 129.9, 129.4, 129.1, 127.3,
122.5, 115.0, 55.7.
(5) (a) Skotnicki, J. S.; Gilman, C. S.; Steinbaugh, B. A.; Musser, J. H.
U.S. Patent 4,748,246, 1988; Chem. Abstr. 1988, 109, 110425u
(b) Probst, G.; Aubele, D. L.; Bowers, S.; Dressen, D.; Garofalo, A.
W.; Hom, R. K.; Konradi, A. W.; Marugg, J. L.; Mattson, M. N.;
Neitzel, M. L.; Semko, C. M.; Sham, H. L.; Smith, J.; Sun, M.;
Truong, A. P.; Ye, X. M.; Xu, Y.-Z.; Dappen, M. S.; Jagodzinski, J. J.;
Keim, P. S.; Peterson, B.; Latimer, L. H.; Quincy, D.; Wu, J.;
Goldbach, E.; Ness, D. K.; Quinn, K. P.; Sauer, J.-M.; Wong, K.;
Zhang, H.; Zmolek, W.; Brigham, E. F.; Kholodenko, D.; Hu, K.;
Kwong, G. T.; Lee, M.; Liao, A.; Motter, R. N.; Sacayon, P.;
Santiago, P.; Willits, C.; Bard, F.; Bova, M. P.; Hemphill, S. S.;
Nguyen, L.; Ruslim, L.; Tanaka, K.; Tanaka, P.; Wallace, W.;
Yednock, T. A.; Basi, G. S. J. Med. Chem. 2013, 56, 5261.
HRMS (EI): m/z calcd for C17H13N3O [M]+: 275.1059; found: 275.1030.
Funding Information
M.J. thanks UGC, New Delhi for a fellowship. Partial Financial support
from WB-DBT (GAP 340) is gratefully acknowledged.
W
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4
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(6) (a) Murineddu, G.; Asproni, B.; Ruiu, S.; Deligia, F.; Falzoi, M.;
Pau, A.; Thomas, B. F.; Zhang, Y.; Pinna, G. A.; Pani, L.; Lazzari, P.
Open Med. Chem. J. 2012, 6, 1. (b) Minegishi, H.; Fukashiro, S.;
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C.-M.; Guo, X.-L.; Liu, Z.-P. J. Med. Chem. 2016, 59, 5341.
(d) Schenone, S.; Bruno, O.; Ranise, A.; Brullo, C.; Bondavalli, F.;
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L.; Chen, X.; Long, S. A.; Mahoney, M. W.; Rico, J. R.; Garland, D.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591737. X-ray crystallographic data
of 5d, 5e, 6b, and 6d, experimental procedures, and spectral data of
compounds 8 and 9 and copies of 1H, 13C NMR spectra of compounds
5–8 and 12 are included.
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References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

J
M. Jash et al.
Paper
Synthesis
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graphic data for this paper. The data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J