Convenient synthesis of benzo[b]pyrazolo[5,1-f][1,6]naphthyridines by silver triflate catalyzed three-component reaction of 2-alkynyl-3- formylquinolines, tosylhydrazine and carbonyl compounds

Article abstract of DOI:10.1016/j.tet.2013.02.060

Benzo[b]pyrazolo[5,1-f][1,6]naphthyridines were prepared by silver triflate catalyzed one-pot cyclization of tosylhydrazine, carbonyl compounds and 2-alkynyl-3-formylquinolines, which are available by Sonogashira reaction of 2-chloro-3-formylquinoline.

Full text of DOI:10.1016/j.tet.2013.02.060

Tetrahedron 69 (2013) 3451e3458
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convenient synthesis of benzo[b]pyrazolo[5,1-f][1,6]naphthyridines
by silver triflate catalyzed three-component reaction of 2-alkynyl-3-
formylquinolines, tosylhydrazine and carbonyl compounds
,
,d,
Muhammad Zahid a, Viktor O. Iaroshenko a b, Ashot S. Saghyan c y, Christine Fischer e,
,e,
Peter Langer a
*
a
€
€
Institut fur Chemie, Universitat Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b National Taras Shevchenko University, 62 Volodymyrska Str., Kyiv-33, 01033, Ukraine
c Scientific and Production Center “Armbiotechnology” of NAS RA, 14 Gyurjyan Str., 0056 Yerevan, Armenia
d Department of Pharmaceutical Chemistry, Yerevan State University, Alex Manoogian Str. 1, 0025 Yerevan, Armenia
e
€
€
Leibniz-Institut fur Katalyse an der Universitat Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 January 2013
Received in revised form 13 February 2013
Accepted 18 February 2013
Available online 26 February 2013
Benzo[b]pyrazolo[5,1-f][1,6]naphthyridines were prepared by silver triflate catalyzed one-pot cyclization
of tosylhydrazine, carbonyl compounds and 2-alkynyl-3-formylquinolines, which are available by So-
nogashira reaction of 2-chloro-3-formylquinoline.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Catalysis
Cyclizations
N-Heterocycles
One-pot reactions
1. Introduction
widespread use of acyclovir and nucleoside analogues has led to the
increase of HSV strains, which are resistant to these drugs.
Quinolines, isoquinolines, naphthyridines and their polycyclic
derivatives are found in many naturalproducts and biologicallyactive
molecules (Fig. 1).1e6 1,6-Naphthyridines exhibit a broad range of
pharmacological activities, including antifungal, antimalarial, anti-
hypertensive, antitumour and antihistaminic activity.2e5 The lamel-
larin alkaloids, which constitute a family of novel marine natural
products, contain a highly substituted fused 1,2-dihydroisoquinoline
core.5 Lamellarin D has been discovered as a potent inhibitor of hu-
Kolodziejczyk and Orito reported a new synthesis of pyr-
azolonaphthyridines by multi-component reactions.9 Denny and
co-workers prepared 3-aryl-7-halo-1,6-naphthyridin-2-amines
and 3-aryl-7-halo-1,6-naphthyridin-2(1H)-ones by diazotization
of 3-aryl-1,6-naphthyridine-2,7-diamines.10 Recently, Wu and co-
workers reported the synthesis of pyrazolo[5,1-a]isoquinolines by
silver triflate catalyzed multi-component reaction of 2-
alkynylbenzaldehydes, tosylhydrazine and ketones or aldehydes.11
Herein, we report the first application of this methodology to
a heterocyclic substrate. The one-pot reaction of readily available 2-
alkynyl-3-formylquinolines with tosylhydrazine, and ketones or
aldehydes provides a new and convenient approach to benzo[b]
pyrazolo[5,1-f][1,6]naphthyridines, which are not readily available
by other methods.
man topoisomerase-1,5 and lamellarin
a-20-sulfate displays selective
inhibition against HIV-1 integrase in vitro.3,7 Wu and co-workers
found that pyrazolo[5,1-a]isoquinolines are inhibitors of PTP1B
(protein tyrosine phosphatase
1 B, IC50 1.75 m
g/mL).8 1,6-
Naphthyridines exhibit anti-HSV activity as well as inhibition of
HIV-1 integrase, HCMV, FGF receptor-1 tyrosine kinase and of ace-
tylcholinesterase (Fig.1).8 Herpes simplex virus type-1 (HSV-1) is the
primary cause of facial lesions (mouth, lips and eyes) in humans. The
2. Results and discussion
2-Chloroquinoline-3-carbaldehyde (2) was prepared, following
a known procedure,12 by Vilsmeier reaction of acetanilide (1). The-
Sonogashira coupling of 2 with various alkynes afforded the
* Corresponding author. Fax: þ49 381 49864112; e-mail addresses: peter.langer@
uni-rostock.de, iva108@googlemail.com (P. Langer).
y
Fax: þ374 10 654183, þ374 10 559355.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.060

3452
M. Zahid et al. / Tetrahedron 69 (2013) 3451e3458
Fig. 1. Polycyclic quinolines, isoquinolines and naphthyridines as clinically used drugs.
known13 2-alkynyl-3-formylquinolines 3aed (Scheme 1, Table 1).
The cyclization of 3aed with tosylhydrazine and various carbonyl
compounds (4), in the presence of silver triflate (AgOTf)14,15
(10 mol %) and a base, afforded the benzo[b]pyrazolo[5,1-f][1,6]
naphthyridines 5aey in 56e82% yields (Table 2). The best yields
were obtained when K3PO4 (3.0 equiv) and EtOH were used as base
and solvent, respectively, and when the reactions were carried out
under reflux. The reaction in the absence of AgOTf or the employ-
mentof other Lewis acids resulted in a decrease of the yield (Table 3).
Table 1
Synthesis of 2-alkynyl-3-formylquinolines 3aed
3
R1
3 (%)a
a
b
c
Ph
88
84
74
71
Pent
cPr
d
SiMe3
a
Yields of isolated products.
O
Table 2
Synthesis of benzo[b]pyrazolo[5,1-f][1,6]naphthyridines 5aey
POCl3,
DMF
O
H
3
4
5
R1
R2
R3
5 (%)a
N
H
N
Cl
10h, 80°C
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
b
b
b
b
b
b
c
a
b
c
d
e
f
g
h
i
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
cPr
H
H
H
H
H
CH3
C2H5
n-C3H7
n-C6H13
n-C8H17
n-C10H21
H2C]CH(CH2)6
H
82
75
68
70
60
91
84
64
87
75
63
60
84
64
62
72
72
66
75
76
89
75
74
76
72
2 (93%)
1
R1
Pd(PPh3)2Cl2
(4 mol %)
CH3CN, 80°C
CH3
e(CH2)3e
e(CH2)4e
CH(CH3)e(CH2)3e
e(CH2)5e
e(CH2)6e
CO2CH3
C2H5
4-(MeO)C6H4
H
O
j
k
l
R3
R2
N
R3
R2
4a-q
O
H
m
n
o
p
a
i
q
h
g
j
CH3
C6H5
H
CH3
H
N
N
H2N-NHTs
R1
N
R1
EtOH
n-C3H7
3a-d
AgOTf (10 mol %)
Reflux, 3h
5a-y
(71-88%)
e(CH2)4e
e(CH2)2eCH(CH3)eCH2e
e(CH2)3e
C2H5
CH(CH3)e(CH2)3e
n-C3H7
(56-82%)
s
t
Scheme 1. Synthesis of benzo[b]pyrazolo[5,1-f][1,6]naphthyridines 5aey.
u
v
w
x
y
C2H5
H
c
c
d
a
i
a
cPr
cPr
e(CH2)4e
n-C3H7
Both aryl and alkyl substituted alkynes could be successfully
employed to give products 5aeo and 5pex, respectively. The
unsubstituted product 5y (R1¼H) was prepared from TMS
substituted derivative 3d. The use of (aromatic and aliphatic)
Hb
H
a
Yields of isolated products.
b
Prepared from 3d (R1¼SiMe3).

M. Zahid et al. / Tetrahedron 69 (2013) 3451e3458
3453
Table 3
with the carbonyl compound provided intermediate C, which un-
derwent a cyclization by attack of the nitrogen atom to the carbonyl
group to give D. Base mediated cleavage of the tosyl group resulted
in aromatization and formation of 5aev.
In conclusion, we have reported an efficient synthesis of benzo
[b]pyrazolo[5,1-f][1,6]naphthyridines by AgOTf-catalyzed one-pot
cyclization of 2-alkynyl-3-formylquinolines, tosylhydrazine and
carbonyl compounds.
Optimization of the reaction conditions for 5a
Entry
Catalyst
Solvent
Base
T (ꢀC)
Time (h)
5a (%)a
1
2
3
4
5
6
7
8
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
d
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeCN
Toluene
Toluene
Toluene
K3PO4
K2CO3
DIPA
Proline
Piperidine
TEA
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
70
70
70
70
70
70
70
90
90
90
90
6
6
6
7
6
6
7
7
3
9
9
82
73
27
36
28
37
15
55
67
47
34
AgOTf
Pd(PPh3)2Cl2
Pd(PPh3)4
AgOTf
3. Experimental section
3.1. General
9
10
11
a
Yields of isolated products.
Reactions were carried out under inert atmosphere (Argon 4.6) in
ordertosimultaneouslyexclude oxygen and water whenappropriate.
Pressure tubes were used to avoid condenser. Solvents for reactions
were dried and distilled by standard methods or purchased from
MerckÒ, AldrichÒ, Acros OrganicsÒ and others whenever exclusion of
water wasdesired. Solvents forliquid chromatographyand extraction
were always distilled prior to use and partly reused after fractional
distillation (n-heptane, ethyl acetate). NMR Spectroscopy: Bruker AC
250, Bruker ARX 300, Bruker ARX 500. For NMR characterization the
one-dimensional 1H NMR, proton-decoupled 13C NMR and DEPT 135
spectra were collected. If necessary other techniques (NOESY, COSY,
HMQC and HMBC) were applied as well. All NMR spectra presented in
this work, were collected inDMSO-d6 and CDCl3solution. All chemical
shifts were given in parts per million. References (1H NMR): TMS
aldehydes and ketones was equally successful. The use of cyclic
ketones resulted in the formation of the corresponding pentacyclic
products 5hel, 5ret, 5v and 5x. Most of the ketones were either
symmetrical, such as acetone (4f), pentan-3-one (4g), cyclohexa-
none (4i) or 4-methylcyclohexanone (4q) or they contain only one
enolizable carbon atom adjacent to the carbonyl group, such as
propiophenone (5n). Therefore, no issue of regioselectivity had to
be considered in these reactions. The cyclization of 3a with (un-
symmetrical) methyl acetoacetate (4m), product 5m was formed
with very good regioselectivity. The selectivity can be explained by
the higher acidity of the central CH2 group as compared to the
terminal CH3 group of 4m. In case of (unsymmetrical) 2-
methylcyclohexanone (4j) the cyclizations proceeded regiose-
lectively via the sterically less hindered carbon atom C-6 to give
products 5j and 5v.
(d
¼0.00) or residual CHCl3 (
d
¼7.26) were taken as internal standard.
References (13C NMR): TMS (
d
¼0.0) or residual CHCl3 ( ¼77.0) were
d
taken as internal standard. Multiplicities are given as follows:
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad
signal. More complex coupling patterns are represented by combi-
nations of the respective symbols. For example, td indicates a triplet
of doublets with the larger coupling constant associated with the first
symbol (here: triplet). Infrared Spectroscopy (IR): Nicolet 205 FT-IR,
The formation of the products can be explained in analogy to the
mechanism suggested by Wu and co-workers:11 The reaction of
3aed with tosylhydrazine afforded hydrazone A (Scheme 2). The
Lewis acid catalyzed attack of the nitrogen atom to the triple bond
gave zwitterionic intermediate B. The reaction of the iminium ion
ꢀ
Nicolet Protege 460 FT-IR Peaks are given the following assign-
ments: w¼weak, m¼medium, s¼strong, br¼broad. Mass Spektr-
ometry (MS): AMD MS40, Varian MAT CH 7, MAT 731 (EI, 70 eV),
Intecta AMD 402 (EI, 70 eV and CI), FinniganMAT 95(CI, 200 eV). High
Resolution Mass Spectrometry (HRMS): Varian MAT 311, Intecta AMD
402. Elemental Analysis:LECO CHNS-932ThermoquestFlashEA1112.
O
H
N
H2N NHTs
H
N
Ts
Ts
N
N
R1
R1
€
Melting Points: Micro heating table HMK 67/1825 Kuestner (Buchi
3a-d
A
Apparatus). Leitz Labolux 12 Pol with heating table Mettler FP 90.
Melting points are uncorrected. X-ray crystal structure analysis:
BrukerX8Apex Diffractometerwith CCD-Kamera (Mo K
a
und Graphit
¼0.71073 A) or Bruker Apex Kappa-II CCD dif-
fractometer using graphite monochromated Mo radiation
¼0.71073). Thin Layer Chromatography (TLC): Merck Kiesel gel 60
AgOTf
R2
O
ꢁ
Monochromator,
l
R3
O
Ka
R2
R3
(l
N
4
N
N
F254 on aluminium foil from MachereyeNagel. Detection was carried
out under UV light at 254 nm and 365 nm. As colourizing reagent the
following mixtures were used: 1e2/100 p-anisaldehyde or vanillin,
10/100 glacial acetic acid, 5/100 sulfuric acid, 83e84/100 methanol.
Column chromatography: Column chromatography was performed
with Merck Silica Gel 60 or MachereyeNagel Silica Gel 60
(0.063e0.200 mm, 70e230 mesh). The finer Merck Silica Gel 60
(0.040e0.063 mm, 230e400 mesh) was chosen when appropriate.
N
Ts
N
R1
base
N
R1
C
B
-H2O
R2
N
R3
R2
N
R3
3.2. Synthesis of 2-alkynylquinoline-3-carbaldehydes 3aed
base
The known products 3aed were prepared by the following re-
ported procedure:13 the reaction of 2 (0.25 mmol) with alkynes
(0.26 mmol) were carried out in the presence of Pd(PPh3)2Cl2
(4 mol %), triphenylphosphine (8 mol %) and triethylamine (2 equiv)
in CH3CN as a solvent at 80 ꢀC under an inert atmosphere for 3e6 h
(TLC control). The reaction mixture was concentrated in vacuo and
Ts
N
N
N
R1
N
R1
5a-v
D
Scheme 2. Possible mechanism of the formation of 5aev.

3454
M. Zahid et al. / Tetrahedron 69 (2013) 3451e3458
the residue was purified by column chromatography on silica gel
29.5, 29.7, 31.9 (CH2), 118.3 (CH), 119.2, 119.7 (C), 126.3, 126.5, 128.1,
using EtOAc/hexane as eluent.
128.4, 28.4, 128.9, 129.5, 129.5, 129.7, 130.0, 130.3, 133.3 (CH), 133.4
~
(C), 141.6 (CH), 143.5, 147.7, 147.9 (C). IR (ATR):
n
¼1614, 1493 (w),
3.3. Synthesis of benzo[b]pyrazolo[5,1-f][1,6]naphthyridines
5aev
1459, 1338 (s), 1226, 989 (w), 911, 857, 694 (m) cmꢁ1. GCeMS (EI,
70 eV): m/z (%)¼407 (37, Mþ), 309 (27), 308 (100),154 (6). HRMS (EI):
calcd for C28H29N3 [M]þ: 407.2356. Found: 407.2357.
2-Alkynylquinoline-3-carbaldehyde 3 (0.3 mmol) was added to
a solution of tosylhydrazine (0.3 mmol) in EtOH (3 ml). The mixture
was stirred at room temperature for 10 min. Then AgOTf (7.7 mg,
10 mol %) was added and the reaction mixture was heated to 70 ꢀC.
Subsequently, 4 (0.6 mmol) and K3PO4 (0.9 mmol) were added to
the mixture. After completion of reaction as indicated by TLC, the
mixture was diluted with ethyl acetate (5.0 ml) and quenched with
H2O (5.0 ml). The organic layer was washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The residue
obtained was purified by flash chromatography column on silica gel
to provide the desired product 5.
3.3.4. 1-Decyl-5-phenylbenzo[b]pyrazolo[5,1-f][1,6]naphthyridine
(5d). Starting with 2-(phenylethynyl)quinoline-3-carbaldehyde (3a)
(150 mg, 0.58 mmol), sulfonohydrazide (186 mg, 1 mmol), dodecanal
(4d) (177 mg, 0.96mmol), AgOTf (10 mol %), K3PO4 (1.8 mmol) in EtOH
(3 ml), 5d was isolated after column chromatography (silica gel, n-
heptane/EtOAc¼9:1) as
a
yellowish solid (112 mg, 70%),
mp¼56e58 ꢀC. 1H NMR (300 MHz, CDCl3):
¼0.81 (t, J¼6.6 Hz, 3H,
d
CH3),1.20e1.21 (m,12H, CH2),1.47e1.49 (m, 2H, CH2),1.80 (p, J¼8.1 Hz,
2H, CH2), 3.03 (t, J¼7.6 Hz, 2H, CH2), 7.23 (s,1H, Ar), 7.46e7.47 (m, 4H,
Ar), 7.68e7.69 (m, 1H, Ar), 7.82e7.83 (m, 3H, Ar), 7.91 (d, J¼8.1 Hz,1H,
Ar), 8.11 (d, J¼8.5 Hz,1H, Ar), 8.79 (s,1H, Ar).13C NMR (75 MHz, CDCl3):
3.3.1. 5-Phenyl-1-propylbenzo[b]pyrazolo[5,1-f][1,6]naphthyridine
(5a). Starting with 2-(phenylethynyl)quinoline-3-carbaldehyde 3a
(150 mg, 0.58 mmol), sulfonohydrazide (186 mg, 1.0 mmol), pen-
tanal 4a (0.083 mg, 0.96 mmol), AgOTf (10 mol %), K3PO4 (1.8 mmol)
in EtOH (3 ml), 5a was isolated after column chromatography (silica
gel, n-heptane/EtOAc¼9:1) as a yellowish solid (107 mg, 82%),
d
¼14.1 (CH3), 22.7, 26.1, 28.9, 29.4, 29.5, 29.6, 29.7, 29.7, 31.9 (CH2),
113.4 (CH),119.3,119.7 (C),126.4,126.5,128.2,128.4,128.4,128.9,129.6,
129.6,129.8,130.1, 130.3 (CH), 133.3, 133.4 (C), 141.7 (CH), 143.5, 147.8,
~
n
147.9 (C). IR (ATR): ¼2915 (s),1614,1492 (w),1456 (s),1340 (m),1072
(w), 912, 852 (m), 743, 687 (s), 619 (m) cmꢁ1. GCeMS (EI, 70 eV): m/z
(%)¼379 (33, Mþ), 309 (24), 308 (100), 154 (6). HRMS (EI): calcd for
C30H33N3 [M]þ: 435.2669. Found: 435.2666.
mp¼150e152 ꢀC. 1H NMR (300 MHz, CDCl3):
¼1.09 (t, J¼7.3 Hz,
d
3H, CH3), 1.80e1.92 (m, 2H, CH2), 3.04 (t, J¼7.8 Hz, 2H, CH2), 7.25 (s,
1H, Ar), 7.44e7.55 (m, 4H, Ar), 7.67e7.74 (m, 1H, Ar), 7.82e7.87 (m,
3H, Ar), 7.93 (d, J¼8.6 Hz, 1H, Ar), 8.10 (d, J¼8.6 Hz, 1H, Ar), 8.81 (s,
3.3.5. 1-(Non-8-en-1-yl)-5-phenylbenzo[b]pyrazolo[5,1-f][1,6]naph-
thyridine (5e). Starting with 2-(phenylethynyl)quinoline-3-carbalde-
hyde (3a) (150 mg, 0.58 mmol), sulfonohydrazide (186 mg, 1 mmol),
undecylenic aldehyde (4e) (161 mg, 0.96 mmol), AgOTf (10 mol %),
K3PO4 (1.8 mmol) in EtOH (3 ml), 5e was isolated after column
chromatography (silica gel, n-heptane/EtOAc¼9:1) as a yellowish
solid (97 mg, 60%), mp¼77e79 ꢀC. 1H NMR (300 MHz, CDCl3):
1H, Ar). 13C NMR (75 MHz, CDCl3):
113.2 (CH), 119.0, 119.74 (C), 126.4 (CH), 126.5, 147.8 (C), 128.2, 128.4,
d
¼14.2 (CH3), 22.2, 28.2 (CH2),
128.4, 128.8, 129.5, 129.5, 129.8, 130.2, 130.4 (CH), 133.3, 133.4 (C),
~
141.7 (CH), 143.6, 147.7 (C). IR (ATR):
n
¼1614, 1492 (w), 1460, 1334
(m), 1049 (w), 912 (m), 744 (s), 617 (m) cmꢁ1. GCeMS (EI, 70 eV):
m/z (%)¼337 (39, Mþ), 309 (24), 308 (100), 154 (16). HRMS (EI):
calcd for C23H19N3 [M]þ: 337.1573. Found: 337.1573.
d
¼1.33e1.35 (m, 8H, CH2), 1.80e1.81 (m, 2H, CH2), 1.96e1.98 (m, 2H,
CH2), 3.02 (t, J¼7.7 Hz, 2H, CH2), 5.71e5.73 (m, 1H, Ar), 4.86e4.88 (m,
2H, C]C), 7.22 (s,1H, Ar), 7.47e7.49 (m, 4H, Ar), 7.67e7.68 (m,1H, Ar),
7.81 (s, 1H, Ar), 7.83e7.85 (m, 2H, Ar), 7.90 (d, J¼8.5 Hz, 1H, Ar), 8.07
3.3.2. 1-Hexyl-5-phenylbenzo[b]pyrazolo[5,1-f][1,6]naphthyridine
(5b). Starting with 2-(phenylethynyl)quinoline-3-carbaldehyde 3a
(150 mg, 0.58 mmol), sulfonohydrazide (186 mg, 1.0 mmol), octanal
4b (123 mg, 0.96 mmol), AgOTf (10 mol %), K3PO4 (1.8 mmol) in
EtOH (3 ml), 5b was isolated after column chromatography (silica
gel, n-heptane/EtOAc¼9:1) as a yellowish solid (110 mg, 75%),
(d, J¼8.5 Hz,1H, Ar), 8.77 (s,1H, Ar). 13C NMR (75 MHz, CDCl3):
¼26.1,
d
28.9, 28.9, 29.1, 29.4, 29.6, 33.8 (CH2), 113.4 (CH), 114.3 (CH2), 119.2,
119.7 (C), 126.4 (CH), 126.5 (C), 128.1, 128.4, 128.4, 128.9, 129.5, 129.8
(CH), 129.8,130.0, 130.3 (CH), 133.3, 133.4 (C), 139.1, 141.1 (CH), 143.49,
~
147.8, 147.9 (C). IR (ATR):
n
¼2920 (m), 1613, 1492 (w), 1457 (m), 1358
mp¼103e105 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼0.87 (t, J¼6.8 Hz,
(w), 1336 (m), 1138, 988 (w), 896, 745, 692 (s), 618 (m) cmꢁ1. GCeMS
(EI, 70 eV): m/z (%)¼420 (11, Mþþ1), 419 (34, Mþ), 309 (27), 308 (100).
HRMS (EI): calcd for C29H29N3 [M]þ: 419.2356. Found: 419.2354.
3H, CH3), 1.34e1.36 (m, 4H, CH2), 1.5 (p, J¼7.0 Hz, 2H, CH2), 1.82 (p,
J¼7.0 Hz, 2H, CH2), 3.04 (t, J¼7.3 Hz, 2H, CH2), 7.49e7.51 (m, 4H, Ar),
7.24 (s, 1H, Ar), 7.83e7.86 (m, 3H, Ar), 7.70e7.73 (m, 1H, Ar), 7.92 (d,
J¼8.1 Hz, 1H, Ar), 8.10 (d, J¼8.2 Hz, 1H, Ar), 8.79 (s, 1H, Ar). 13C NMR
3.3.6. 2-Methyl-5-phenylbenzo[b]pyrazolo[5,1-f][1,6]naphthyridine
(5f). Starting with 2-(phenylethynyl)quinoline-3-carbaldehyde
(3a) (150 mg, 0.58 mmol), sulfonohydrazide (186 mg, 1 mmol), ac-
etone (4f) (0.057 mg, 0.96 mmol), AgOTf (10 mol %), K3PO4
(1.8 mmol) in EtOH (3 ml), 5f was isolated after column chroma-
tography (silica gel, n-heptane/EtOAc¼9:1) as a yellowish solid
(75 MHz, CDCl3):
d¼14.1 (CH3), 22.7 (CH2), 26.1, 28.89, 29.4, 31.8
(CH2), 113.3 (CH), 119.3, 119.7 (C), 126.4 (CH), 126.5 (C), 128.1, 128.4,
128.4, 128.9, 129.5, 129.8, 129.8, 130.1, 130.3 (CH), 133.3, 133.4 (C),
~
141.6 (CH), 143.6, 147.7, 147.8 (C). IR (ATR):
n
¼1613, 1492 (w), 1456
(m), 1170, 1073 (w), 910 (m), 740, 694 (s), 618 (m) cmꢁ1. GCeMS (EI,
70 eV): m/z (%)¼379 (33, Mþ), 309 (24), 308 (100), 154 (6). HRMS
(EI): calcd for C26H25N3 [M]þ: 379.2043. Found: 379.2043.
(107 mg, 91%), mp¼150e152 ꢀC. 1H NMR (300 MHz, CDCl3):
¼2.41
d
(s, 3H, CH3), 6.88 (s, 1H, Ar), 7.16 (s, 1H, Ar), 7.43e7.45 (m, 4H, Ar),
7.63e7.66 (m,1H, Ar), 7.81 (d, J¼8.1 Hz,1H, Ar), 7.84e7.87 (m, 2H, Ar),
8.03 (d, J¼8.2 Hz, 1H, Ar), 8.59 (s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
3.3.3. 1-Octyl-5-phenylbenzo[b]pyrazolo[5,1-f][1,6]naphthyridine
(5c). Starting with 2-(phenylethynyl)quinoline-3-carbaldehyde (3a)
(150 mg, 0.58 mmol), sulfonohydrazide (186 mg, 1 mmol), decanal
(4c) (150 mg, 0.96 mmol), AgOTf (10 mol %), K3PO4 (1.8 mmol) in
EtOH (3 ml), 5c was isolated after column chromatography (silica gel,
d
¼14.3 (CH3), 100.7 (CH), 122.9 (C), 125.4 (CH), 125.5 (C), 126.3 (CH),
127.1 (C), 127.9, 128.4, 128.4, 128.6, 129.5, 129.8, 130.2, 130.3, 133.3
~
(CH),139.2,143.1,147.3,148.7,148.9,151.1 (C). IR (ATR):
n
¼1613,1555,
1494 (w), 1428, 1328 (m), 1180, 858 (w), 793 (m), 747, 693 (s), 622
(m) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼310 (18, Mþþ1), 309 (89, Mþ),
308 (100), HRMS (EI): calcd for C21H15N3 [M]þ: 309.1250. Found:
309.1250.
n-heptane/EtOAc¼9:1) as
a yellowish solid (100 mg, 68%),
mp¼70e72 ꢀC. 1H NMR (300 MHz, CDCl3):
¼0.78e0.81 (m, 3H,
d
CH3), 1.17e1.19 (m, 10H, CH2), 1.78 (p, J¼8.3 Hz, 2H, CH2), 3.01 (t,
J¼7.7 Hz, 2H, CH2), 7.2 (s,1H, Ar), 7.43e7.45 (m, 4H, Ar), 7.65e7.67 (m,
1H, Ar), 7.81e7.83 (m, 4H, Ar), 8.03 (d, J¼8.3 Hz, 1H, Ar), 8.73 (s, 1H,
3.3.7. 1-Ethyl-2-methyl-5-phenylbenzo[b]pyrazolo[5,1-f][1,6]naph-
thyridine (5g). Starting with 2-(phenylethynyl)quinoline-3-
Ar). 13C NMR (75 MHz, CDCl3):
d¼14.1 (CH3), 22.7, 26.1, 28.9, 29.4,

M. Zahid et al. / Tetrahedron 69 (2013) 3451e3458
3455
carbaldehyde (3a) (150 mg, 0.58 mmol), sulfonohydrazide (186 mg,
1 mmol), 2-pentanon (4g) (0.081 mg, 0.96 mmol), AgOTf (10 mol %),
K3PO4 (1.8 mmol) in EtOH (3 ml), 5g was isolated after column
chromatography (silica gel, n-heptane/EtOAc¼9:1) as a yellowish
solid (111 mg, 84%), mp¼189e191 ꢀC. 1H NMR (300 MHz, CDCl3):
(CH), 31.9 (CH2),112.1 (CH),118.2,118.6,119.6 (C),126.1 (CH),126.4 (C),
127.9,128.4,128.4,128.6,128.8,128.9,129.5 (CH),129.6 (C),129.7,130.0
~
(CH),133.4,143.4,147.9151.8(C). IR(ATR)
n
¼2846,1613,1567 (w),1486,
1349 (m), 1138, 895, 856, 765 (m), 742, 694 (s), 611 (m) cmꢁ1. GCeMS
(EI, 70 eV): m/z (%)¼364 (28, Mþþ1), 363 (100, Mþ), 362 (28), 334 (25).
HRMS (EI): calcd for C25H21N3 [M]þ: 363.1730. Found: 363.1727.
d¼1.24 (t, J¼7.1 Hz, 3H, CH3), 2.54 (s, 3H, CH3), 2.76 (q, J¼6.3 Hz, 2H,
CH2), 7.13 (s, 1H, Ar), 7.42e7.44 (m, 4H, Ar), 7.64 (t, J¼7.1 Hz, 1H, Ar),
7.84 (d, J¼8.7 Hz, 1H, Ar), 7.90e7.92 (m, 2H, Ar), 8.03 (d, J¼8.5 Hz,
3.3.11. 7-Phenyl-11,12,13,14-tetrahydro-10H-benzo[b]cyclopenta[3,4]
pyrazolo[5,1-f][1,6]-naphthyridine (5k). Starting with 2-(phenyl-
ethynyl)quinoline-3-carbaldehyde (3a) (150 mg, 0.58 mmol), sulfo-
nohydrazide (186 mg, 1 mmol), cycloheptanone (4k) (108 mg,
0.96 mmol), AgOTf (10 mol %), K3PO4 (1.8 mmol) in EtOH (3 ml), 5k was
isolated after column chromatography (silica gel, n-heptane/
EtOAc¼9:1) as a yellowish solid (89 mg, 63%), mp¼205e207 ꢀC. 1H
1H, Ar), 8.74 (s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
(CH3), 20.0 (CH2), 111.1 (C), 112.2 (CH), 119.8 (C), 126.1 (CH), 126.4
d
¼10.7, 13.9
(C), 128.1, 128.2, 128.6, 128.6, 128.8, 129.6, 129.6, 129.7, 130.1 (CH),
~
133.5, 134.5, 143.3, 147.8, 148.1, 155.5 (C). IR (ATR):
n
¼1613, 1555,
1494 (w), 1428, 1328 (m), 1180, 858 (w), 793 (m), 747, 693 (s), 622
(m) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼338 (24, Mþþ1), 337 (100,
Mþ), 336 (54), 281 (22). HRMS (EI): calcd for C23H19N3 [M]þ:
337.1573. Found: 337.1571.
NMR (300 MHz, CDCl3):
d
¼1.70e1.72 (m, 2H, CH2), 1.85e1.87 (m, 4H,
CH2), 2.89e2.92 (m, 2H, CH2), 3.22e3.24 (m, 2H, CH2), 7.11 (s, 1H, Ar),
7.42e7.44 (m, 4H, Ar), 7.67e7.69 (m, 1H, Ar), 7.86e7.88 (m, 3H, Ar), 8.06
3.3.8. 6-Phenyl-2,3-dihydro-1H-benzo[b]cyclopenta[3,4]pyrazolo
[5,1-f][1,6]naphthyridine (5h). Starting with 2-(phenylethynyl)
quinoline-3-carbaldehyde (3a) (150 mg, 0.58 mmol), sulfonohy-
drazide (186 mg, 1 mmol), cyclopentanone (4h) (0.081 mg,
0.96 mmol), AgOTf (10 mol %), K3PO4 (1.8 mmol) in EtOH (3 ml), 5h
was isolated after column chromatography (silica gel, n-heptane/
EtOAc¼9:1) as a yellowish solid (83 mg, 64%), mp¼223e225 ꢀC. 1H
(d, J¼8.1 Hz,1H, Ar), 8.96 (s,1H, Ar). 13C NMR (75 MHz, CDCl3):
¼26.2,
d
27.1, 28.4, 29.3, 31.5 (CH2), 112.2 (CH), 118.9, 119.9 (C), 126.2 (CH), 126.3
(C),128.1,128.3,128.3,128.7,129.6,129.7,129.7,129.8,130.2 (CH),133.5,
~
133.6, 143.4, 147.8, 148.2, 156.8 (C). IR (ATR):
n
¼2922 (m), 1632, 1614
(w), 1477, 1320 (m), 1125 (w), 849, 769 (m), 744, 692 (s) cmꢁ1. GCeMS
(EI, 70 eV): m/z (%)¼364 (26, Mþþ1), 363 (100, Mþ), 362 (46), 334 (23).
HRMS (EI): calcd for C25H21N3 [M]þ: 363.1730. Found: 363.1732.
NMR (250 MHz, CDCl3):
d
¼2.56 (q, J¼7.6 Hz, 2H, CH2), 2.87 (t,
J¼6.7 Hz, 2H, CH2), 3.01 (t, J¼6.7 Hz, 2H, CH2), 7.09 (s, 1H, Ar), 7.41
(m, 4H, Ar), 7.62 (m, 1H, Ar), 7.76 (d, J¼6.9 Hz, 1H, Ar), 7.80e7.82 (m,
2H, Ar), 8.01 (d, J¼6.9 Hz, 1H, Ar), 8.53 (s, 1H, Ar). 13C NMR (75 MHz,
3.3.12. 7-Phenyl-10,11,12,13,14,15-hexahydrobenzo[b]cyclopenta[3,4]
pyrazolo[5,1-f ][1,6]naphthyridine (5l). Starting with 2-(phenyl-
ethynyl)quinoline-3-carbaldehyde (3a) (150 mg, 0.58 mmol), sul-
fonohydrazide (186 mg, 1 mmol), cycloctanone (4l) (121 mg,
0.96 mmol), AgOTf (10 mol %), K3PO4 (1.8 mmol) in EtOH (3 ml), 5l
was isolated after column chromatography (silica gel, n-heptane/
EtOAc¼9:1) as a yellowish solid (89 mg, 60%), mp¼165e167 ꢀC. 1H
CDCl3):
d
¼24.3, 25.1, 30.2 (CH2), 111.6 (CH), 118.8, 121.7 (C), 126.1
(CH), 126.5 (C), 127.7, 127.7, 128.4, 128.9, 129.4, 129.4, 129.7, 130.1,
130.4 (CH), 132.1, 133.6, 144.3, 147.6, 148.3, 164.1 (C). IR (ATR):
~
n
¼2917, 1633, 1595, 1494 (w), 1438 (m), 1288, 1126 (w), 894, 771
(m), 747, 697 (s) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼336 (24, Mþþ1),
335 (100, Mþ), 334 (74), 167 (15). HRMS (EI): calcd for C23H17N3
[M]þ: 335.1414; Found: 335.1412.
NMR (300 MHz, CDCl3):
d
¼1.37e1.39 (m, 2H, CH2),1.52 (p, J¼6.8 Hz,
2H, CH2), 1.69 (p, J¼6.1 Hz, 2H, CH2), 1.89 (p, J¼6.1 Hz, 2H, CH2), 2.88
(t, J¼6.1 Hz, 2H, CH2), 3.15 (t, J¼6.1 Hz, 2H, CH2), 7.11e7.14 (m, 1H,
Ar), 7.43e7.45 (m, 4H, Ar), 7.65e7.68 (m, 1H, Ar), 7.88e7.90 (m, 3H,
Ar), 8.04 (d, J¼8.1 Hz, 1H, Ar), 8.79 (s, 1H, Ar). 13C NMR (75 MHz,
3.3.9. 7-Phenyl-1,2,3,4-tetrahydrobenzo[b]indazolo[3,2-f][1,6]naph-
thyridine (5i). Starting with 2-(phenylethynyl)quinoline-3-carbal-
dehyde (3a) (150 mg, 0.58 mmol), sulfonohydrazide (186 mg,
1 mmol), cyclohexanone (4i) (0.094mg, 0.96mmol), AgOTf (10 mol %),
K3PO4 (1.8 mmol) in EtOH (3 ml), 5i was isolated after column chro-
matography (silica gel, n-heptane/EtOAc¼12:1) as a yellowish solid
(117 mg, 87%), mp¼235e237 ꢀC. 1H NMR (300 MHz, CDCl3):
CDCl3):
d
¼21.7, 24.6, 25.1, 25.8, 26.7, 30.0 (CH2), 111.1 (CH), 115.0,
118.6 (C), 125.1 (CH), 125.4 (C), 127.0, 127.3, 127.3, 127.8, 128.4, 128.6,
128.7, 128.7, 129.1 (CH), 132.5, 132.6, 142.4, 146.8, 146.9, 154.4 (C). IR
~
(ATR):
n
¼3054, 2845, 1633, 1568 (w), 1483, 1438, 1353 (m), 1255,
899 (w), 840 (m), 748, 693 (s), 610 (m) cmꢁ1. GCeMS (EI, 70 eV): m/
z (%)¼378 (29, Mþþ1), 377 (100, Mþ), 376 (21), 349 (33), 334 (38).
HRMS (EI): calcd for C26H23N3 [M]þ: 337.1886. Found: 337.1889.
d
¼1.84e1.86 (m, 4H, CH2), 2.81 (t, J¼6.9 Hz, 2H, CH2), 3.01 (t, J¼5.9 Hz,
2H, CH2), 7.11 (s, 1H, Ar), 7.42e7.44 (m, 4H, Ar), 7.60e7.63 (m, 1H, Ar),
7.76 (d, J¼8.3 Hz, 1H, Ar), 7.80e7.83 (m, 2H, Ar), 8.01 (d, J¼8.1 Hz, 1H,
3.3.13. Methyl-2-methyl-5-phenylbenzo[b]pyrazolo[5,1-f][1,6]naph-
thyridine-1-carboxylate (5m). Starting with 2-(phenylethynyl)
quinoline-3-carbaldehyde (3a) (150 mg, 0.58 mmol), sulfonohy-
drazide (186 mg, 1.0 mmol), methyl acetoacetate (4m) (111 mg,
0.96 mmol), AgOTf (10 mol %), K3PO4 (1.8 mmol) in EtOH (3 ml), 5m
was isolated after column chromatography (silica gel, n-heptane/
EtOAc¼9:1) as a yellowish solid (120 mg, 84%), mp¼87e89 ꢀC. 1H
Ar), 8.52 (s,1H, Ar). 13C NMR (75 MHz, CDCl3):
d¼22.9, 22.9, 23.3, 24.2
(CH2), 112.2 (CH), 118.2, 118.6, 119.6 (C), 126.1 (CH), 126.4 (C), 127.9,
128.4,128.4 (CH),128.6 (C),128.8,129.6,129.6,129.7,129.8,130.0 (CH),
~
133.5, 143.4, 147.8, 151.8 (C). IR (ATR):
n
¼2936, 1614, 1571 (w), 1449,
1351 (m), 1197 (w), 895, 766 (m), 742 (s), 611 (m) cmꢁ1. GCeMS (EI,
70 eV): m/z (%)¼350 (25, Mþþ1), 349 (100, Mþ), 348 (47), 321 (30).
HRMS (EI): calcd for C24H19N3 [M]þ: 349.1573. Found: 349.1570.
NMR (300 MHz, CDCl3):
d
¼2.58 (s, 3H, CH3), 3.98 (s, 3H, OCH3),
7.50e753 (m, 5H, Ar), 7.76e7.78 (m, 1H, Ar), 7.84e7.87 (m, 2H, Ar),
8.10 (q, J¼7.7 Hz, 2H, Ar),10.59 (s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
3.3.10. 4-Methyl-7-phenyl-1,2,3,4-tetrahydrobenzo[b]indazolo[3,2-f]
[1,6]naphthyridine (5j). Starting with 2-(phenylethynyl)quinoline-3-
carbaldehyde (3a) (150 mg, 0.58 mmol), sulfonohydrazide (186 mg,
1 mmol), 2-methylcyclohexanone (4j) (108 mg, 0.96 mmol), AgOTf
(10 mol %), K3PO4 (1.8 mmol) in EtOH (3 ml), 5j was isolated after
column chromatography (silica gel, n-heptane/EtOAc¼9:1) as a yel-
lowish solid (106 mg, 75%), mp¼157e159 ꢀC. 1H NMR (300 MHz,
d
¼14.9, 50.7 (CH3), 107.9 (C), 114.4 (CH), 116.8, 125.4 (C), 125.5,
125.5, 127.3, 127.3, 128.4, 128.4, 128.9, 128.9, 130.5 (CH), 131.9 (C),
35.4 (CH), 139.2, 141.6, 146.3, 147.8, 152.8, 164.4 (C). IR (ATR):
~
n
¼2924 (w), 1704 (m), 1616 (w), 1533 (m), 1493 (w), 1448, 1257,
1190 (m), 1081 (s), 855 (m), 744, 688 (s), 628 (m) cmꢁ1. GCeMS (EI,
70 eV): m/z (%)¼368 (24, Mþþ1), 367 (100, Mþ), 366 (62), 336 (33):
HRMS (EI): calcd for C23H17N3 O2 [M]þ: 367.1315. Found: 367.1314.
CDCl3):
d
¼1.35 (d, J¼5.9 Hz, 3H, CH3),1.49e1.52 (m,1H, CH),1.80e1.81
(m, 1H, CH2), 2.05e2.07 (m, 2H, CH2), 3.03e3.05 (m, 3H, CH2), 7.18 (s,
1H, Ar), 7.44e7.46 (m, 4H, Ar), 7.66e7.68 (m, 1H, Ar), 7.86 (d, J¼9.5 Hz,
1H, Ar), 7.94e7.96 (m, 2H, Ar), 8.07 (d, J¼8.34 Hz, 1H, Ar), 8.67 (s, 1H,
3.3.14. 1-Methyl-2,5-diphenylbenzo[b]pyrazolo[5,1-f][1,6]naphthyr-
idine (5n). Starting with 2-(phenylethynyl)quinoline-3-carbaldehyde
(3a) (150 mg, 0.58 mmol), sulfonohydrazide (186 mg, 1.0 mmol),
Ar). 13C NMR (75 MHz, CDCl3):
d¼20.4 (CH3), 22.1, 23.3 (CH2), 29.8

3456
M. Zahid et al. / Tetrahedron 69 (2013) 3451e3458
propiophenone (4n) (129 mg, 0.96 mmol), AgOTf (10 mol %), K3PO4
(1.8 mmol) in EtOH (3 ml), 5n was isolated after column chroma-
tography (silica gel, n-heptane/EtOAc¼9:1) as a yellowish solid
d
¼14.0, 14.2 (CH3), 22.2, 22.5, 26.5, 28.1, 30.9, 31.5 (CH2), 110.3 (CH),
118.8, 119.3 (C), 126.0 (CH), 126.2 (C), 128.1, 128.7, 130.1, 130.2 (CH),
132.8 (C), 141.1 (CH), 145.1, 147.6, 147.7 (C). IR (ATR):
2927 (m), 1614, 1494 (w), 1462, 1333 (m), 1192, 986 (w), 899, 853,
752, 647 (s) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼332 (20, Mþþ1),
331 (86, Mþ), 330 (48), 303 (24), 302 (100), 288 (17). HRMS (EI):
calcd for C22H25N3 [M]þ: 331.2039. Found: 331.2039.
~
n
¼3099 (w),
(96 mg, 64%), mp¼208e210 ꢀC. 1H NMR (300 MHz, CDCl3):
d¼2.69 (s,
3H, CH3), 7.21 (s, 1H, Ar), 7.36e7.38 (m, 7H, Ar), 7.62e7.66 (m, 3H, Ar),
7.85 (d, J¼8.1 Hz, 1H, Ar), 7.96e7.99 (m, 2H, Ar), 8.04 (d, J¼8.7 Hz, 1H,
Ar), 8.81 (s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
(CH), 118.3, 119.8, 126.3 (C), 126.3, 128.1, 128.3, 128.3, 128.5, 128.5,
d
¼11.9 (CH3), 111.3
128.9, 128.9, 129.2, 129.2, 129.7, 129.7, 129.8, 129.8, 130.3 (CH), 133.2,
3.3.18. 7-Pentyl-1,2,3,4-tetrahydrobenzo[b]indazolo[3,2-f][1,6]naph-
thyridine (5r). Starting with 2-(hept-1-yn-1-yl)quinoline-3-
carbaldehyde (3b) (98 mg, 0.39 mmol), sulfonohydrazide (75 mg,
0.40 mmol), cyclohexanone (4i) (0.078 mg, 0.8 mmol), AgOTf
(10 mol %), K3PO4 (255 mg, 1.17 mmol) EtOH (3 ml), 5r was isolated
after column chromatography (silica gel, n-heptane/EtOAc¼9:1) as
a yellowish solid (105 mg, 66%), mp¼194e196 ꢀC. 1H NMR
~
135.2,143.2,147.8,147.9,152.9,171.2 (C). IR (ATR):
n
¼3053, 1613, 1555,
1493 (w), 1467, 1327 (m), 1173 (w), 1020, 913, 783 (m), 744, 696
(s) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼386 (26, Mþþ1), 385 (100, Mþ),
384 (76), 281 (21). HRMS (EI): calcd for C27H19N3 [M]þ: 385.1574.
Found: 385.1576.
3.3.15. 2-(4-Methoxyphenyl)-5-phenylbenzo[b]pyrazolo[5,1-f][1,6]
naphthyridine (5o). Starting with 2-(phenylethynyl)quinoline-3-
carbaldehyde (3a) (150 mg, 0.58 mmol), sulfonohydrazide (186 mg,
1 mmol), p-methoxyacetophenone (4o) (144 mg, 0.96 mmol), AgOTf
(10 mol %), K3PO4 (1.8 mmol) in EtOH (3 ml), 5o was isolated after
column chromatography (silica gel, n-heptane/EtOAc¼9:1) as a yel-
lowish solid (97 mg, 62%), mp¼195e197 ꢀC. 1H NMR (300 MHz,
(300 MHz, CDCl3):
d
¼0.81 (t, J¼7.1 Hz, 3H, CH3), 1.39e1.42 (m, 4H,
CH2), 1.88e1.90 (m, 6H, CH2), 2.89 (t, J¼5.1 Hz, 2H, CH2), 3.01e3.06
(m, 4H, CH2), 6.97e7.01 (m,1H, Ar), 7.35e7.43 (m,1H, Ar), 7.67e7.71
(m, 1H, Ar), 7.81 (d, J¼8.1 Hz, 1H, Ar), 8.1 (d, J¼8.1 Hz, 1H, Ar), 8.6 (s,
1H, Ar). 13C NMR (75 MHz, CDCl3):
23.0, 23.3, 24.0, 26.4, 30.8, 31.5 (CH2), 77.4, 108.9 (CH), 113.4, 119.2
d
¼14.0 (CH3), 22.6 (CH2), 22.9,
(C), 125.8 (CH), 126.2 (C), 127.9, 128.7, 130.0 (CH), 132.8, 145.2, 147.5,
~
CDCl3):
d
¼3.91 (s, 3H, OCH3), 7.01 (d, J¼8.2 Hz, 2H, Ar), 7.21 (s,1H, Ar),
147.7, 151.4 (C). IR (ATR):
n
¼3054 (w), 2921, 1635, 1573 (m), 1538
7.41 (s, 1H, Ar), 7.52 (s, 1H, Ar), 7.59e7.61 (m, 4H, Ar), 7.81e7.82 (m,
1H, Ar), 7.98e8.1 (m, 2H, Ar), 8.04 (d, J¼8.1 Hz, 1H, Ar), 8.10e8.13 (m,
2H, Ar), 8.23 (d, J¼8.1 Hz, 1H, Ar), 8.92 (s, 1H, Ar). 13C NMR (75 MHz,
(w), 1485 (s), 1391 (w), 1348 (s), 1129 (m), 977 (w), 855 (s), 787 (m),
759, 696 (s) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼344 (14, Mþþ1),
343 (56, Mþ), 342 (39), 288 (24), 287 (100), 259 (30). HRMS (EI):
calcd for C23H25N3 [M]þ: 343.2043. Found: 343.2041.
CDCl3):
d
¼55.3 (OCH3), 97.3, 113.1, 114.1, 114.1 (CH), 118.1, 125.6 (C),
126.4 (CH), 126.6 (C), 127.6, 127.6, 127.9, 128.2, 128.2, 129.1, 129.8,
129.8, 129.8, 130.5, 130.5 (CH), 133.1, 139.7, 143.2, 147.3, 148.8, 152.7,
3.3.19. 3-Methyl-7-pentyl-1,2,3,4-tetrahydrobenzo[b]indazolo[3,2-f]
[1,6]naphthyridine (5s). Starting with 2-(hept-1-yn-1-yl)quino-
lone-3-carbaldehyde (3b) (98 mg, 0.39 mmol), sulfonohydrazide
(75 mg, 0.40 mmol), 3-methylcyclohexanone (4p) (0.096 mg,
0.8 mmol), AgOTf (10 mol %), K3PO4 (0.09 mg, 1.17 mmol) in EtOH
(3 ml), 5s was isolated after column chromatography (silica gel, n-
~
159.9 (C). IR (ATR):
n
¼2924 (w), 1704 (m), 1616 (w), 1533 (m), 1493
(w), 1448, 1257, 1190 (m), 1081 (s), 855 (m), 744, 688 (s), 628
(m) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼402 (29, Mþþ1), 401 (100,
Mþ), 400 (39). HRMS (EI): calcd for C27H19N3O [M]þ: 401.1516. Found:
401.1516.
heptane/EtOAc¼9:1) as
a yellowish solid (105 mg, 75%),
3.3.16. 2-Methyl-5-pentylbenzo[b]pyrazolo[5,1-f][1,6]naphthyridine
(5p). Starting with 2-(hept-1-yn-1-yl)quinoline-3-carbaldehyde,
(3b) (98 mg, 0.39 mmol), sulfonohydrazide (75 mg, 0.40 mmol),
acetone (4f) (0.046 mg, 0.8 mmol), AgOTf (10 mol %), K3PO4
(255 mg, 1.17 mmol) in EtOH (3 ml), 5p was isolated after column
chromatography (silica gel, n-heptane/EtOAc¼9:1) as a yellowish
solid (84 mg, 72%), mp¼95e97 ꢀC. 1H NMR (300 MHz, CDCl3):
mp¼162e164 ꢀC. 1H NMR (300 MHz, CDCl3):
¼1.03 (t, J¼6.8 Hz,
d
3H, CH3), 1.21 (d, J¼6.8 Hz, 3H, CH3), 1.48e1.51 (m, 5H, CH2),
1.97e2.01 (m, 4H, CH2), 2.53 (q, J¼9.7 Hz, CH), 2.96e3.24 (m, 5H,
CH2), 7.01 (s, 1H, Ar), 7.48e7.53 (m, 1H, Ar), 7.71e7.75 (m, 1H, Ar),
7.88 (d, J¼7.8 Hz, 1H, Ar), 8.11 (d, J¼8.1 Hz, 1H, Ar), 8.6 (s, 1H, Ar). 13C
NMR (75 MHz, CDCl3):
d
¼14.0, 21.6 (CH3), 22.2, 22.6, 26.3 (CH2),
29.3 (CH), 30.8, 31.4, 31.5, 32.2 (CH2), 108.9 (CH), 112.9, 119.0 (C),
125.7, 127.8, 128.6, 129.9, 129.9 (CH), 132.6, 145.1, 147.6, 147.7, 151.5
d
¼0.89 (t, J¼7.1 Hz, 3H, CH3), 1.39e142 (m, 4H, CH2), 1.88 (dd, J¼8.1,
~
7.1 Hz, 2H, CH2), 2.49 (s, 3H, CH3), 3.12 (t, J¼8.1 Hz, 2H, CH2), 6.89 (s,
1H, Ar), 6.99 (s, 1H, Ar), 7.47 (t, J¼7.1 Hz,1H, Ar), 7.71 (t, J¼7.1 Hz,1H,
Ar), 7.86 (d, J¼8.1 Hz, 1H, Ar), 8.11 (d, J¼8.1 Hz, 1H, Ar), 8.65 (s, 1H,
(C). IR (ATR):
n
¼3051 (w), 2922, 2851 (m), 1574 (w), 1486 (s), 1369
(m), 1319 (s), 1129 (m), 977 (w), 900 (m), 826 (w), 757 (s), 653
(m) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼358 (13, Mþþ1), 357 (57,
Mþ), 356 (39), 302 (25), 301 (100), 259 (25). HRMS (EI): calcd for
C24H27N3 [M]þ: 357.2200. Found: 357.2201.
Ar). 13C NMR (75 MHz, CDCl3):
31.5 (CH2), 100.4, 109.3 (CH), 125.4 (C), 126.0 (CH), 126.2 (C), 127.9,
d
¼14.0, 14.2 (CH3), 22.6, 26.3, 30.8,
128.9, 130.3, 130.5 (CH), 138.5, 144.9, 147.3, 148.5, 150.8 (C). IR (ATR)
~
n
¼3051, 1808 (w), 1639 (s), 1615, 1497 (m), 1326 (s), 1180, 1077 (w),
3.3.20. 6-Pentyl-2,3-dihydro-1H-benzo[b]cyclopenta[3,4]pyrazolo
[5,1-f][1,6]naphthyridine (5t). Starting with 2-(hept-1-yn-1-yl)qui-
nolone-3-carbaldehyde 3b (98 mg, 0.39 mmol), sulfonohydrazide
(75 mg, 0.40 mmol), cyclopentanone (4h) (0.067 mg, 0.8 mmol),
AgOTf (10 mol %), K3PO4 (255 mg, 1.17 mmol) in EtOH (3 ml), 5t was
isolated after column chromatography (silica gel, n-heptane/
EtOAc¼9:1) as a yellowish solid (97 mg, 76%), mp¼152e154 ꢀC. 1H
973, 903 (m), 754, 732 (s), 587 (m) cmꢁ1. GCeMS (EI, 70 eV): m/z
(%)¼304 (10, Mþþ1), 303 (45, Mþ), 302 (17), 248 (22), 247 (100).
HRMS (EI): calcd for C20H21N3 [M]þ: 303.1730. Found: 303.1727.
3.3.17. 5-Pentyl-1-propylbenzo[b]pyrazolo[5,1-f][1,6]naphthyridine
(5q). Starting with 2-(hept-1-yn-1-yl)quinoline-3-carbaldehyde
(3b) (98 mg, 0.39 mmol), sulfonohydrazide (75 mg, 0.40 mmol),
pentanal (4a) (0.069 mg, 0.8 mmol), AgOTf (10 mol %), K3PO4
(255 mg, 1.17 mmol) in EtOH (3 ml), 5q was isolated after column
chromatography (silica gel, n-heptane/EtOAc¼9:1) as a yellowish
solid (93 mg, 72%), mp¼88e90 ꢀC. 1H NMR (300 MHz, CDCl3):
NMR (300 MHz, CDCl3):
d
¼0.81 (t, J¼7.1 Hz, 3H, CH3), 1.42 (t,
J¼7.1 Hz, 6H, CH2), 1.78e1.82 (m, 2H, CH2), 2.58e2.62 (m, 2H, CH2),
2.89e2.93 (m, 2H, CH2), 2.97e3.03 (m, 2H, CH2), 6.93 (s, 1H, Ar),
7.38e7.42 (m, 1H, Ar), 7.70e7.73 (m, 1H, Ar), 7.92 (d, J¼8.1 Hz, 1H,
Ar), 8.11 (d, J¼8.1 Hz, 1H, Ar), 8.53 (s, 1H, Ar). 13C NMR (75 MHz,
d
¼0.81 (t, J¼7.1 Hz, 3H, CH3), 1.11 (t, J¼7.1 Hz, 3H, CH3), 1.38e1.40
CDCl3):
d
¼11.2 (CH3), 22.5, 24.2, 24.9, 26.5, 30.2, 30.3, 31.5 (CH2),
(m, 4H, CH2),1.78e1.81 (m, 4H, CH2), 2.89 (t, J¼7.1 Hz, 2H, CH2), 3.08
(t, J¼7.1 Hz, 2H, CH2), 7.01 (s, 1H, Ar), 7.43e7.46 (m, 1H, Ar),
7.64e7.67 (m, 1H, Ar), 7.78 (s, 1H, Ar), 7.81 (d, J¼8.1 Hz, 1H, Ar), 8.01
(d, J¼8.1 Hz, 1H, Ar), 8.72 (s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
77.4, 108.9 (CH), 113.4, 119.2 (C), 125.8 (CH), 126.2 (C), 127.9 (CH),
128.7 (CH), 130.0 (CH), 132.8, 145.2, 147.5, 147.7, 151.4 (C). IR (ATR):
~
n
¼3050 (w), 2924, 1481 (m), 1349 (s), 1127, 971 (w), 902, 757 (s),
603 (m) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼330 (11, Mþþ1), 329 (55,

M. Zahid et al. / Tetrahedron 69 (2013) 3451e3458
3457
Mþ), 328 (83), 273 (100), 272 (40). HRMS (EI): calcd for C22H23N3
[M]þ: 329.1892. Found: 329.1895.
AgOTf (10 mol %), K3PO4 (255 mg, 1.17 mmol) in EtOH (3 ml), 5x was
isolated after column chromatography (silica gel, n-heptane/
EtOAc¼9:1) as a yellowish solid (93 mg, 76%), mp¼183e185 ꢀC. 1H
3.3.21. 2-Ethyl-1-methyl-5-pentylbenzo[b]pyrazolo[5, 1-f][1,6]naph-
thyridine (5u). Starting with 2-(hept-1-yn-1-yl)quinolone-3-
carbaldehyde (3b) (98 mg, 0.39 mmol), sulfonohydrazide (75 mg,
0.40 mmol), 3-pentanone (4g) (0.069 mg, 0.8 mmol), AgOTf
(10 mol %), K3PO4 (255 mg, 1.17 mmol) in EtOH (3 ml), 5u was
isolated after column chromatography (silica gel, n-heptane/
EtOAc¼9:1) as a yellowish solid (115 mg, 89%), mp¼137e139 ꢀC. 1H
NMR (300 MHz, CDCl3):
d
¼0.93e0.97 (m, 2H, CH2), 1.12e1.17 (m,
2H, CH2), 1.87e1.93 (m, 4H, CH2), 2.67e2.71 (m, 1H, CH), 2.89e2.92
(m, 2H, CH2), 2.67e2.71 (m, 2H, CH2), 6.59e6.62 (s, 1H, Ar), 7.41 (t,
J¼7.3 Hz, 1H, Ar), 7.62 (t, J¼7.3 Hz, 1H, Ar), 7.72 (d, J¼8.1 Hz, 1H, Ar),
7.91 (d, J¼8.1 Hz, 1H, Ar), 8.53 (s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
d
¼8.5, 8.6 (CH2), 11.2 (CH), 22.8, 22.9, 23.2, 24.1 (CH2), 104.9 (CH),
113.5, 118.8, 125.7 (C), 125.9, 127.9 (CH), 128.4 (C), 129.9, 130.0 (CH),
~
NMR (300 MHz, CDCl3):
d
¼0.87 (t, J¼6.1 Hz, 3H, CH3), 1.31 (t,
132.7, 147.0, 147.4, 147.7 (C), 151.5 (CH). IR (ATR):
n
¼2930, 1614, 1557
J¼7.1 Hz, 3H, CH3), 1.42 (t, J¼7.1 Hz, 8H, CH2), 1.89e1.93 (m, 2H,
CH2), 2.62 (s, 3H, CH3), 7.01 (s, 1H, Ar), 7.53 (t, J¼8.1 Hz, 1H, Ar), 7.71
(t, J¼8.1 Hz, 1H, Ar), 7.92 (d, J¼8.1 Hz, 1H, Ar), 8.21 (d, J¼8.1 Hz, 1H,
(w), 1486 (m), 1200, 1048 (w), 970, 894 (m), 740 (s), 657, 624
(w) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼314 (22, Mþþ1), 313 (100,
Mþ), 312 (84), 298 (82). HRMS (EI): calcd for C21H19N3 [M]þ:
313.1573. Found: 313.1571.
Ar), 8.82 (s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
d
¼10.6, 11.2, 13.9
(CH3), 20.0, 22.5, 26.4, 30.8, 31.5 (CH2), 77.4, 109.9 (CH), 116.4, 120.2
(C), 125.3 (CH), 126.7 (C), 127.5, 128.3, 131.2 (CH), 133.8, 146.2, 147.1,
3.3.25. 1-Propylbenzo[b]pyrazolo[5,1-f][1,6]naphthyridine
(5y). Starting with 2-((trimethylsilyl)ethynyl)quinoline-3-carbal-
dehyde (3d) (99 mg, 0.39 mmol), sulfonohydrazide (75 mg,
0.40 mmol), pentanal (4a) (0.067 mg, 0.8 mmol), AgOTf (10 mol %),
K3PO4 (255 mg, 1.17 mmol) in EtOH (3 ml), 5y was isolated after
column chromatography (silica gel, n-heptane/EtOAc¼9:1) as
~
147.9, 152.1 (C). IR (ATR):
n
¼3053, 1613, 1555, 1493 (w), 1467, 1327
(m), 1173 (w), 1020, 913, 783 (m), 744, 696 (s) cmꢁ1. GCeMS (EI,
70 eV): m/z (%)¼332 (12, Mþþ1), 331 (50, Mþ), 330 (18), 276 (22),
274 (100). HRMS (EI): calcd for C22H25N3 [M]þ: 331.2043. Found:
331.2041.
a
yellowish solid (83 mg, 81%), mp¼127e128 ꢀC. 1H NMR
3.3.22. 7-Cyclopropyl-4-methyl-1,2,3,4-tetrahydrobenzo[b]indazolo
[3,2-f][1,6]naphthyridine (5v). Starting with 2-(cyclopropylethynyl)
quinoline-3-carbaldehyde (3c) (86 mg, 0.39 mmol), sulfonohy-
drazide (75 mg, 0.40 mmol), 3-methylcyclohexanone (4j)
(0.096 mg, 0.8 mmol), AgOTf (10 mol %), K3PO4 (255 mg, 1.17 mmol)
in EtOH (3 ml) of ethanol, 5v was isolated after column chroma-
tography (silica gel, n-heptane/EtOAc¼9:1) as a yellowish solid
(300 MHz, CDCl3):
d
¼1.11 (t, J¼7.1 Hz, 3H, CH3), 1.81 (dt, J¼8.1,
7.1 Hz, 2H, CH2), 3.02 (t, J¼7.1 Hz, 2H, CH2), 7.13 (d, J¼8.1 Hz, 1H,
Ar), 7.48e7.53 (m, 1H, Ar), 7.67e7.72 (m, 1H, Ar), 7.77 (s, 1H, Ar),
7.91 (d, J¼8.1 Hz, 1H, Ar), 8.13 (d, J¼7.4 Hz, 1H, Ar), 8.22 (d,
J¼6.9 Hz, 1H, Ar), 8.71 (s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
¼14.2
d
(CH3), 22.2, 28.0 (CH2), 112.9 (CH), 118.8, 120.1, 126.5 (C), 126.6 (CH)
128.1 (CH), 129.0, 130.3, 130.5, 131.5 (CH), 132.5 (C), 142.0 (CH),
(105 mg, 75%), mp¼92e94 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼0.87 (t,
147.5, 147.6 (C). IR (ATR):
n
¼3053, 1613, 1555, 1493 (w), 1467, 1327
~
J¼7.1 Hz, 3H, CH3), 1.18e1.23 (m, 2H, CH2), 1.37e1.42 (m, 6H),
1.85e1.94 (m, 2H, CH2), 3.17 (t, J¼7.6 Hz, 2H, CH2), 7.11 (s, 1H, Ar),
7.47e7.53 (m, 1H, Ar), 7.67e7.72 (m, 1H, Ar), 7.91 (d, J¼8.1 Hz, 1H,
Ar), 8.11 (d, J¼8.1 Hz, 1H, Ar), 8.81 (s, 1H, Ar). 13C NMR (75 MHz,
(m), 1173 (w), 1020, 913, 783 (m), 744, 696 (s) cmꢁ1. GCeMS (EI,
70 eV): m/z (%)¼262 (6, Mþþ1), 261 (31, Mþ), 233 (19), 232 (100),
205 (11). HRMS (EI): calcd for C26H17N3 [M]þ: 261.1266. Found:
261.1266.
CDCl3):
d¼14.3 (CH3), 22.8, 26.5, 30.0, 31.5, 31.8 (CH2), 77.2, 100.6,
110.6 (CH), 117.5, 118.2, 126.3 (C), 126.7 (CH), 128.2, 128.3 (C), 129.2
Acknowledgements
(CH), 129.3 (C), 130.5, 130.8 (CH), 131.1, 138.1 (C), 141.4 (CH). IR
~
(ATR):
n
¼3050 (w), 2951 (m), 2926 (s), 1639, 1443 (m), 1332 (s),
Financial support by the State of Mecklenburg-Vorpommern, by
Deutsche Krebshilfe and by the BMBF (REMEDIS Verbundprojekt) is
gratefully acknowledged.
1247 (w), 921, 740, 614, 528 (m) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼
327 (4, Mþ), 312 (24), 299 (42), 286 (100). HRMS (EI): calcd for
C26H17N3 [M]þ:327.1735. Found: 327.1730.
References and notes
3.3.23. 5-Cyclopropyl-1-propylbenzo[b]pyrazolo[5,1-f][1,6]naphthyr-
idine (5w). Starting with 2-(cyclopropylethynyl)quinoline-3-
carbaldehyde (3c) (86 mg, 0.39 mmol), sulfonohydrazide (75 mg,
0.40 mmol), pentanal (4a) (0.069 mg, 0.8 mmol), AgOTf (10 mol %),
K3PO4 (255 mg, 1.17 mmol) in EtOH (3 ml), 5w was isolated after
column chromatography (silica gel, n-heptane/EtOAc¼9:1) as a yel-
lowish solid (87 mg, 74%), mp¼227e229 ꢀC. 1H NMR (300 MHz,
1. Bentley, K. W. The Isoquinoline Alkaloids; Hardwood Academic: Amsterdam, The
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2. (a) Fish, P. V.; Barber, C. G.; Brown, D. G. J. Med. Chem. 2007, 50, 2341; (b) Ukita, T.;
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N.; Kurono, N.; Ohkuma, T.; Orito, K. Eur. J. Org. Chem. 2007, 4320.
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CDCl3):
d
¼0.94e0.98 (m, 2H, CH2), 1.11 (t, J¼6.7 Hz, 3H, CH3),
1.15e1.18 (m, 2H, CH2), 1.78e1.83 (m, 2H, CH2), 2.67e2.72 (m, 1H,
CH), 3.01 (t, J¼7.6 Hz, 2H, CH2), 6.72 (s, 1H, Ar), 7.43 (t, J¼7.6 Hz, 1H,
Ar), 7.71 (t, J¼8.1 Hz, 1H, Ar), 7.78e7.81 (m, 2H, Ar), 8.2 (d, J¼7.9 Hz,
1H, Ar), 8.6 (s,1H, Ar).13C NMR (75 MHz, CDCl3):
(CH), 14.2 (CH3), 22.2, 28.1 (CH2), 106.8 (CH), 118.9, 119.0 (C), 126.0
d
¼8.1, 8.2 (CH2),11.3
(CH), 126.1 (C), 128.1, 128.6, 130.1, 130.2 (CH), 132.8 (C), 141.3 (CH),
~
146.8, 147.6, 147.8 (C). IR (ATR):
n
¼2865 (m), 2819 (s), 2479 (m), 2387
(w), 1390 (s), 1158, 805 (m) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼302
(16, Mþþ1), 301 (74, Mþ), 300 (25), 286 (32), 273 (22), 272 (100).
HRMS (EI): calcd for C20H19N3 [M]þ: 301.1570. Found: 301.1573.
3.3.24. 7-Cyclopropyl-1,2,3,4-tetrahydrobenzo[b]indazolo[3,2-f][1,6]
naphthyridine (5x). Starting with 2-(cyclopropylethynyl)quino-
lone-3-carbaldehyde (3c) (86 mg, 0.39 mmol), sulfonohydrazide
(75 mg, 0.40 mmol), cyclohexanone (4i) (0.078 mg, 0.8 mmol),

3458
M. Zahid et al. / Tetrahedron 69 (2013) 3451e3458
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Yamamoto, Y. J. Org. Chem. 2005, 70, 3682; (g) Kusama, H.; Funami, H.; Takaya, J.;
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