A convenient and efficient protocol for the synthesis of 4(1H)-cinnolones, 1,4-dihydrocinnolines, and cinnolines in aqueous medium: Application for detection of nitrite ions

Article abstract of DOI:10.1016/j.tet.2011.09.016

3-Aryl/alkyl-4(1H)-cinnolones are obtained in one step from 2-aryl/alkylethynyl aniline by reaction with sodium nitrite and dilute hydrochloric acid via Richter cyclization. The alkyl cinnolones on reduction with Sn/HCl furnish 1,4-dihydro-3-alkylcinnolin

Full text of DOI:10.1016/j.tet.2011.09.016

Tetrahedron 67 (2011) 8918e8924
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A convenient and efficient protocol for the synthesis of 4(1H)-cinnolones,
1,4-dihydrocinnolines, and cinnolines in aqueous medium: application for
detection of nitrite ions
*
Raju Dey, Brindaban C. Ranu
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 April 2011
Received in revised form 5 September 2011
Accepted 7 September 2011
Available online 17 September 2011
3-Aryl/alkyl-4(1H)-cinnolones are obtained in one step from 2-aryl/alkylethynyl aniline by reaction with
sodium nitrite and dilute hydrochloric acid via Richter cyclization. The alkyl cinnolones on reduction
with Sn/HCl furnish 1,4-dihydro-3-alkylcinnolines, which are converted to 3-alkylcinnolines by treat-
ment with NaNO2/HCl/KI. The whole process is carried out in aqueous medium at ambient temperature
within a short reaction period. The reaction of 2-phenylethynyl aniline exhibits yellow color with UV
absorbance at 391 nm and has been successfully tested for the detection of nitrite ions in water at parts
per million concentration.
Keywords:
Cinnolone
Dihydrocinnoline
Cinnoline
Ó 2011 Elsevier Ltd. All rights reserved.
Richter cyclization
Detection of nitrite ion
O
R
1. Introduction
The cinnolines, dihydrocinnolines, and cinnolones have received
considerable attention in recent times because of their promising
biological activities against several diseases as shown below.1
Several methods have been developed for their synthesis2 and
most of them are based on Richter cyclization of ortho-ethy-
nyldiazonium salts.3e8 However, cyclization of ortho-ethynyldia-
zonium salts led to five-membered pyrazole ring or a six-
membered pyridazine system (cinnoline) or a mixture with little
variation of the reaction conditions and nature of substituents
present in the alkynyl moiety6,9e12 (Scheme 1). Thus, an efficient,
reliable, and general method for the synthesis of cinnolines is
highly desirable. The synthesis of 4(1H)-cinnolones, which are also
pharmaceutically very important1 is not addressed adequately. We
found only two reports for their synthesis in the literature.6,13 These
are also not very convenient and efficient. Thus, a direct and con-
venient route to cinnolones is also appreciated.
N
R
N
H
O
+
N2
N
N
H
Scheme 1. Richter cyclization of 2-arylethynyl diazonium compound.
cinnolines by the same protocol. We chose commercially available
2-iodo aniline as the starting material. Sonogashira coupling with
substituted acetylenes14 followed by treatment with NaNO2/HCl
provided 3-aryl/alkyl-4(H)-cinnolones via Richter cyclization
(Scheme 2).
A further two-step transformation of 3-alkyl-cinnolones led to
3-alkylcinnolines (Scheme 3).
In the context of diverse applications and importance of these
compounds we considered it worthwhile to investigate this
synthetic problem. Our primary interest is to develop a general
and efficient method for the synthesis of both cinnolones and
2. Results and discussion
The experimental procedures are very simple. The Sonogashira
coupling of 2-iodoanilines and alkyl/aryl acetylenes was carried out
in water by standard procedure14 using Pd(PPh3)4 as catalyst. The
2-amino phenyl acetylenes were then treated with NaNO2/HCl
* Corresponding author. Fax: þ91 33 24732805; e-mail address: ocbcr@iacs.res.in
(B.C. Ranu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.016

R. Dey, B.C. Ranu / Tetrahedron 67 (2011) 8918e8924
8919
O
O
R2
N
COOR2
O
O
COOH
R1
N
N
N
N
Et
N
R3
R1
R1, R2, R3 = CH3, C2H5, C3H7
Used for urinary
R1 = 2-pyridyl, methyl
R2 = phenyl, pyridyl
tract infections
Highly active in antiallergic bioassays
O
O
Bacteriostatic activity against
COOR2
COOH
O
F
gram-positive bacteria
N
N
R2
N
R
O
N
OCOCH3
H
R1
R1
N
N
R1 = alkyl, aryl, alkoxyl
R = alkyl, R1 = H, F, Cl
R2 = H, C2H5
R2 = morpholinyl, piperazinyl
HO
OCOCH3
Antibacterial profile against
gram-negative bacteria
Higher antibacterial activity
Estrogen-like activity
compared to cinoxacin
nitrite ion also does not interfere in the detection process. For an on-
the-spot survey when a paper strip (1 cm2) soaked with ethanolic
solution of 2-phenylethynyl aniline (0.05 mg) and aqueous HCl (2 N,
1 drop) was quenched with a drop of sample containing nitrite ion,
the presence of nitrite was immediately reflected by a change of
color to yellow. The presence of other ions has absolutely no effect.
Thus, 2-phenylethynyl aniline serves as a chemodosimeter.
This part dealing with the preliminary results of reactions of
2-arylethynyl anilines has been recently reported by us in a com-
munication.15 We include here the results of further investigations
with detailed experimental procedure and characterization data of
all products.
The aryl-substituted alkynyl anilines provided the correspond-
ing cinnolones as sole products, whereas the products formed from
alkyl-substituted alkynyl anilines remain in tautomeric mixture of
3-alkyl-cinnolones and 4-hydroxy-3-alkylcinnolines. Thus after the
reaction was over, the reaction mixture was further stirred for an-
other 4 h to provide cinnolone as exclusive product. To carry out
further derivatization of cinnolones, these compounds are then
reduced with Sn/HCl to give 3-alkyl-1,4-dihydrocinnolines. The
dihydrocinnolines are aromatized by NaNO2/HCl/KI to furnish 3-
alkylcinnolines (Table 3). Interestingly, the aryl-substituted cinno-
lones remain inert during this derivatization process as outlined in
Table 3.
The entire process from iodoanilines to 3-alkylcinnolines was
carried out in aqueous medium at ambient temperatures and
minimum amount of ethyl acetate was used for extraction in cer-
tain steps to maintain a low environmental impact for the process.
All the products were characterized adequately by spectroscopic
data (IR, 1H NMR, 13C NMR, and HRMS).
A few of these cinnolones are known compounds and were
identified by comparison of their spectroscopic data with those
reported earlier.13 The structure of 3-hexyl-1,4-dihydrocinnoline
was also established by X-ray crystal data16 (Fig. 4).
O
R
R
NaNO2 / HCl
N
N
H
NH2
R = alkyl, aryl
Scheme 2. Cyclization to 3-substituted cinnolones.
O
R
R
R
Sn
Conc.HCl
NaNO2
HCl / KI
N
N
N
N
H
N
N
H
R1
R1
R1
2
1
Scheme 3. Synthesis of 3-substituted 1,2-dihydrocinnoline and cinnolines.
(2 N) at 0e5 ꢀC to produce 3-substituted 4(1H)-cinnolones. The
results are summarized in Table 1 for aryl-substituted cinnolones
and Table 2 reports alkyl-substituted ones. A variety of substituted
phenyl and naphthyl-ethynyl anilines participate in this reaction to
produce the corresponding cinnolones and several functional
groups, such as Cl, CN, OMe are compatible with the reaction
conditions. The formation of 3-phenyl-4(1H)-cinnolones shows an
immediate change of color to yellow from colorless. The change of
color is clearly visible up to as less as 10 ppm concentration of ni-
trite ions.
One of the products, 3-phenyl-4(1H)-cinnolone shows a char-
acteristic UV absorption at 391 nm (Fig. 1). On fluorescence studies
it was found that starting compound, 2-phenylethynyl aniline as
well as the product, 3-phenyl-4(1H) cinnolone are not fluorescence
active. However, we discovered that 6-methoxy-2-naphthylethynyl
aniline shows strong fluorescence emission at 401 nm (excitation at
lmax 315 nm), whereas the corresponding cinnolone obtained by
reaction with nitrite, was completely fluorescence inactive (Fig. 2).
This property was successfully utilized for the detection of nitrite
ions at a very low concentration (<1 ppm). The effect of a wide va-
riety of other ions including Fꢁ, Clꢁ, Brꢁ, Iꢁ, N3ꢁ, PO34ꢁ, OAcꢁ, SCNꢁ,
SO24ꢁ, NOꢁ3 , have also been investigated in the sensing process of
nitrite by this reaction. Remarkably, in an experiment in absence of
nitrite ion none of these ions even at a higher concentration
(1000 ppm) shows any change of color (Fig. 3) or UV absorption at
391 nm (Fig. 1) or quenching of fluorescence emission at 401 nm
(Fig. 2). The presence of these ions in the test sample containing
Regarding the reaction pathway, the O-ethynyl aniline un-
dergoes diazotization followed by hydration of ethynyl moiety and
cyclization to give the cinnolone, which is further transformed to
dihydrocinnolone by Sn/HCl reduction. The oxidationearomatiza-
tion was accomplished by NaNO2/HCl/KI as outlined in Scheme 4
although we do not have a clear understanding of this step, par-
ticularly the role of KI. Nevertheless, the reaction did not proceed in
absence of KI.
In general, the reactions are very fast, clean, and high yielding.
The 4(1H)-cinnolones (Tables 1 and 2) are obtained pure by simple
crystallization of the crude products from ethyl acetate. The 4(1H)-

8920
R. Dey, B.C. Ranu / Tetrahedron 67 (2011) 8918e8924
Table 1
Synthesis of 3-aryl-cinnolones
O
NaNO2/ HCl
H2O, 0-5 oC, 5 min
N
N
H
NH2
Entry
Substrate
Product
Yield
92
O
1
N
N
H
NH2
Me
Cl
Me
Cl
O
2
90
N
N
H
NH2
NH2
NH2
NH2
O
3
4
5
95
92
95
N
N
H
Me
Me
O
N
Cl
N
H
Cl
Cl
Cl
O
NC
NC
N
N
H
6
7
91
90
8
92

R. Dey, B.C. Ranu / Tetrahedron 67 (2011) 8918e8924
8921
Table 2
Synthesis of 3-alkyl-cinnolones
Entry
Substrate
Product
Yielda
O
OH
OH
1
80
N
N
NH2
H
O
OH
OH
2
3
4
5
6
80
N
N
NH2
NH2
NH2
H
O
n
Bu
n
Bu
85
N
N
H
Fig. 1. UV spectroscopic studies for nitrite sensing (L¼6-methoxy-2-naphthylethynyl
aniline, 10ꢁ6 M in H2O).
O
Hexn
Hexn
83
86
83
N
N
H
O
n
Bu
n
Bu
N
Cl
N
H
Cl
NH2
O
n
Pr
n
Pr
N
Cl
N
H
Cl
NH2
Hexn
O
Hexn
NC
Fig. 2. Fluorescence studies for nitrite sensing (L¼2-phenylethynyl aniline, 10ꢁ4 M in
NC
7
80
H2O).
N
N
H
NH2
a
substituted 4(1H)-cinnolones, 1,4-dihydrocinnolines, and cinno-
lines. In addition, the reaction of 2-phenylethynyl aniline and ni-
trite in acidic aqueous medium provides a simple tool for sensing
nitrite ions selectively in presence of other ion contaminants by
visual color change, UV absorption, and fluorescence emission.
Yields refer to those of pure isolated products characterized by spectroscopic
data (IR, 1H NMR, 13C NMR, and HRMS).
cinnolones are easily converted to 1,4-dihydrocinnolines and cin-
nolines by simple operations.
4. Experimental section
3. Conclusion
4.1. General
We have developed a general and green protocol for the syn-
thesis of 4(1H)-cinnolones, 1,4-dihydrocinnolines, and cinnolines
starting from commercially available 2-iodoanilines through simple
operations. To the best of our knowledge, we are not aware of any
efficient, direct, and general method for the synthesis of 4(1H)-
cinnolones and 1,4-dihydrocinnolines, which have demonstrated
a variety of biological activities.1 The reaction in aqueous medium
at ambient temperature in open air, easy separation of product with
minimum use of organic solvent (ethyl acetate), chromatographic
purification only in one step of the reactions and high yield of
products make this approach very attractive for an access to
1H NMR and 13C NMR spectra were recorded on a Bruker in-
strument at 300 and 75 MHz, respectively. The chemical shifts (d)
are reported in parts per million, using TMS as an internal standard
and CDCl3 as the solvent. HRMS were recorded on a Microtek Qtof
Micro YA263 spectrometer. IR spectra were recorded on a Shi-
madzu 8300 FTIR spectrometer. UV studies were carried out in
a Carry Bio 100 spectrometer. Luminescence spectra were carried
out in a PerkineElmer LS-55 instrument. Melting points of the
products cannot be determined as these compounds have very high
melting and prone to decompose beyond 200 ꢀC.

8922
R. Dey, B.C. Ranu / Tetrahedron 67 (2011) 8918e8924
Fig. 3. Colorimetric studies for nitrite sensing (L¼2-phenylethynyl aniline, 10ꢁ4 M in H2O).
4.2. General experimental procedure for the synthesis of
4(1H)-cinnolones. Representative procedure for 3-phenyl-1H-
cinnolin-4-one (entry 1, Table 1)
Table 3
Synthesis of 1,4-dihydrocinnolines and cinnolines
O
R
R
R
Sn
NaNO2
HCl / KI
To 2 N-acidic suspension (2 mL) of 2-phenylethynyl-phenyl-
amine (193 mg, 1 mmol), NaNO2 (103 mg, 1.5 mmol) was added in
portions at 0e5 ꢀC. The reaction mixture was stirred at 0e5 ꢀC for
5 min followed by further 5 min at room temperature. The re-
action mixture was extracted with EtOAc (2ꢂ5 mL), dried, con-
centrated and was left at room temperature to give 3-phenyl-1H-
cinnolin-4-one as a pale yellow solid (204 mg, 92%), IR (KBr): 756,
N
N
N
Conc.HCl
N
H
N
N
H
R1
R1
R1
2
1
Entry
R
R1
Yielda of
1
2
1305, 1477, 1546, 2860, 2929 cmꢁ1
7.36e7.46 (m, 4H), 7.63 (d, J¼8.4 Hz, 1H), 7.77 (t, J¼7 Hz, 1H),
8.09e8.17 (m, 3H), 13.70 (s, 1H); 13C NMR (DMSO-d6, 75 MHz)
;
1H NMR (DMSO-d6, 300 MHz)
1
2
3
Hexyl
Butyl
Butyl
H
4-Cl
H
70
75
72
75
70
76
d
a
Yields refer to those of pure isolated products characterized by spectroscopic
data (IR, 1H NMR, 13C NMR, and HRMS).
d
117.0, 124.0, 125.2, 125.3, 128.4 (2C), 128.8 (2C), 134.1, 135.5, 141.3,
146.0, 169.8; HRMS calcd for C14H10N2O (MþþH): 223.0871, Found:
223.0868.
The reactions of alkyl-substituted alkynes, the crude products
were further stirred in water for another 4 h to allow the tautomeric
mixture of cinnolones and hydroxy cinnolines to furnish only 3-
alkyl-4(1H)-cinnolones.
These procedures were followed for all the reactions listed in
Tables 1 and 2. A few of these products are known compounds and
were identified by comparison of their spectra with those reported
earlier.13 The products, which were not reported earlier were
characterized by their spectroscopic data (IR, 1H NMR, 13C NMR, and
HRMS). These data are provided below in order of their entries in
Tables 1 and 2.
Fig. 4. ORTEP diagram of 3-hexyl-1,4-dihydrocinnoline.
4.2.1. 3-p-Tolyl-1H-cinnolin-4-one (entry 2, Table 1). Yield 90%, pale
R
R
R
yellow solid, IR (KBr): 667, 754, 821, 1301, 1477, 1545, 2841,
2887 cmꢁ1 1H NMR (DMSO-d6, 500 MHz)
; d 2.33 (S, 3H), 7.23 ( d,
NaNO2 + HCl
Diazotisation
J¼8 Hz, 2H), 7.41 (t, J¼7.5 Hz, 1H), 7.61 (d, J¼8 Hz, 1H), 7.77 ( t,
N
NH2
J¼7.5 Hz, 1H), 7.99 (d, J¼8 Hz, 2H), 8.13 (d, J¼8 Hz, 1H), 13.62 (s, 1H);
N
13C NMR (DMSO-d6, 125 MHz)
d 21.4, 116.9, 123.8, 125.1, 125.2, 128.6
H2O
OH
(2C), 128.9 (2C), 132.6, 134.0, 138.3, 141.2, 145.9, 169.7; HRMS calcd
for C15H13N2O (MþþH): 237.101, Found: 237.101.
R
N
N
4.2.2. 7-Chloro-3-p-tolyl-1H-cinnolin-4-one (entry 4, Table 1). Yield
N
N
92%; pale yellow solid; IR (KBr): 819, 1051, 1454, 1537, 1560, 2825,
2885, 2982, 3051 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz)
d 2.32 (s, 3H),
O
7.22 (d, J¼8 Hz, 2H), 7.40 (d, J¼8.5 Hz, 1H), 7.65 (s, 1H), 7.96 (d,
R
R
J¼8 Hz, 2H), 8.11 (d, J¼8.5 Hz, 1H), 13.74 (s, 1H); 13C NMR (DMSO-d6,
Sn/HCl
Reduction
125 MHz)
d 21.4, 116.0, 122.3, 125.6, 127.8, 128.7 (2C), 129.0 (3C),
N
N
N
N
H
132.2, 138.6, 141.8, 146.5, 169.3; HRMS calcd for C15H12ClN2O
H
R
(MþþH): 271.0638, Found: 271.0633.
NaNO2/HCl/KI
Oxidation
N
N
4.2.3. 3-(4-Chloro-phenyl)-4-oxo-1,4-dihydro-cinnoline-6-
carbonitrile (entry 5, Table 1). Yield 95%; pale yellow solid; IR (KBr):
Scheme 4. Possible reaction pathway.
823, 1091, 1300, 1487, 1585, 2231, 3027, 3277 cmꢁ1 1H NMR
;

R. Dey, B.C. Ranu / Tetrahedron 67 (2011) 8918e8924
8923
(DMSO-d6, 500 MHz)
d
7.37 (d, J¼8.5 Hz, 2H), 7.68 (d, J¼8.5 Hz, 1H),
157.9, 174.1; HRMS calcd for C15H17N3ONa (MþþNa): 278.1269,
7.94 (d, J¼8.5 Hz, 1H), 8.0 (d, J¼8 Hz, 2H), 8.3 (s, 1H), 14.1 (s, 1H), 13C
Found: 278.1269.
NMR (DMSO-d6, 125 MHz)
d 107.4, 118.8, 123.1, 128.5 (3C), 130.4
(2C), 131.5, 133.4, 134.2, 135.3, 142.6, 145.9, 168.8; HRMS calcd for
4.3. General experimental procedure for the synthesis of 1,4-
dihydrocinnolines. Representative procedure for 3-butyl-1,4-
dihydrocinnoline (entry 3 [1], Table 3)
C15H9ClN3O (MþþH): 282.0434, Found: 282.0429.
4.2.4. 7-Chloro-3-(4-methoxy-phenyl)-1H-cinnolin-4-one (entry 7,
Table 1). Yield 92%; pale yellow solid; IR (KBr): 827, 1055, 1300,
To concd HCl suspension (2 mL) of 3-butyl-1H-cinnolin-4-one
(202 mg, 1 mmol), tin powder (298 mg, 2.5 mmol) was added in
portions at 25 ꢀC. The reaction mixture was stirred for 15 min with
occasional warming at 50 ꢀC for 2e3 times. The reaction mixture
was extracted with EtOAc (2ꢂ5 mL) under basic condition (pH 12)
to give 3-butyl-1,4-dihydro-cinnoline as a yellow solid (135 mg,
72%), IR (KBr): 709, 746, 1078, 1303, 1462, 1494, 1597, 2866, 2949,
1556, 2885, 3054 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz)
d 3.7 (s, 3H),
7.0 (d, J¼8.5 Hz, 2H), 7.23 (d, J¼7.5 Hz, 1H), 7.48 (s, 1H), 7.98 (d,
J¼8 Hz,1H), 8.18 (d, J¼8.5 Hz, 2H),13.90 (s, 1H); 13C NMR (DMSO-d6,
125 MHz)
d 55.56, 112.3, 113.9 (2C), 120.7, 121.2, 121.7, 124.1, 128.8,
131.7 (3C), 134.0, 142.8, 161.0; HRMS calcd for C15H12ClN2O2
(MþþH): 287.0587, Found: 287.0583.
3311 cmꢁ1
;
1H NMR (CDCl3, 500 MHz)
d
0.92 (t, J¼7 Hz, 3H),
4.2.5. 3-Hydroxymethyl-1H-cinnolin-4-one (entry 1, Table 2). Yield
1.34e1.39 (m, 2H), 1.53e1.62 (m, 2H), 2.31 (t, J¼7.5 Hz, 2H), 3.25 (s,
2H), 6.69 (d, J¼7.5 Hz, 1H), 6.92 (t, J¼7 Hz, 1H), 7.02 (d, J¼7.5 Hz,
1H), 7.11 (t, J¼9.5 Hz, 1H), 7.20 (s, 1H); 13C NMR (CDCl3, 125 MHz)
80%; pale yellow solid; IR (KBr): 763, 1008, 1039, 1357, 1386, 1473,
2870, 2920, 3371 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz)
d 2.5 (s, 1H),
4.52 (s, 2H), 7.39e7.42 (m, 1H), 7.62 (d, J¼8.4 Hz, 1H), 7.74e7.77 (m,
d
14.0, 22.6, 28.6, 29.7, 36.5, 111.9, 116.6, 122.2, 127.1, 127.6, 140.7,
1H), 8.05 (d, J¼8.1 Hz, 1H), 13.45 (s, 1H); 13C NMR (DMSO-d6,
147.7; HRMS calcd for C12H17N2 (MþþH): 189.1392, Found:
125 MHz) d 59.2, 116.9, 122.6, 124.4, 124.9, 134.0, 141.7, 149.6, 169.9;
189.1386.
HRMS calcd for C9H8N2O2Na (MþþNa): 199.0483, Found: 199.0483.
This procedure was followed for all the reactions listed in Table 3.
The products were all new compounds and were characterized by
their spectroscopic data (IR, 1H NMR, 13C NMR, and HRMS). These
data are provided below in order of their entries in Table 3.
4.2.6. 3-(2-Hydroxy-ethyl)-1H-cinnolin-4-one (entry 2, Table 2).
Yield 80%; pale yellow solid; IR (KBr): 750, 1012, 1182, 1367, 1548,
1570, 2833, 2879 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz)
d 2.5 (s, 1H),
2.88 (t, J¼7 Hz, 2H), 3.72 (t, J¼6.5 Hz, 2H), 7.37 (t, J¼7 Hz, 1H), 7.55
4.3.1. 3-Hexyl-1,4-dihydro-cinnoline (entry 1[1], Table 3). Yield 70%;
(d, J¼8.5 Hz, 1H), 7.75 (t, J¼7.5 Hz, 1H), 8.04 (d, J¼8 Hz, 1H), 13.25 (s,
pale yellow solid; IR (KBr): 640, 746, 1303, 1465, 1491, 1597, 2926,
1H); 13C NMR (DMSO-d6, 125 MHz)
d 34.3, 59.4, 116.6, 121.7, 124.5,
3306 cmꢁ1
;
1H NMR (CDCl3, 500 MHz)
d
0.87 (t, J¼6 Hz, 3H),
124.6, 133.8, 141.6, 148.9, 170.3; HRMS calcd for C10H10N2O2Na
1.25e1.35 (m, 6H), 1.56e1.62 (m, 2H), 2.36 (t, J¼8 Hz, 2H), 3.29 (s,
(MþþNa): 213.0640, Found: 213.064.
2H), 6.72 (d, J¼8 Hz, 1H), 6.93e6.96 (m, 2H), 7.03 (d, J¼7.5 Hz, 1H),
7.12e7.15 (m, 1H); 13C NMR (CDCl3, 125 MHz)
d 14.1, 22.5, 26.2, 29.1,
4.2.7. 3-Hexyl-1H-cinnolin-4-one (entry 4, Table 2). Yield 83%; pale
29.6, 31.7, 36.7, 112.0, 116.4, 122.9, 126.4, 127.1, 140.6, 147.8; HRMS
yellow solid; IR (KBr): 758, 1373, 1546, 2868, 2929 cmꢁ1 1H NMR
;
calcd for C14H21N2 (MþþH): 217.1705, Found: 217.1699.
(DMSO-d6, 500 MHz)
d
0.90 (t, J¼7.2 Hz, 3H), 1.16e1.23 (m, 6H),
1.48e1.54 (m, 2H), 2.58 (t, J¼7.5 Hz, 2H), 7.25 (t, J¼7.5 Hz, 1H), 7.43
(d, J¼8.5 Hz, 1H), 7.62 (t, J¼8 Hz, 1H), 7.93 (d, J¼8 Hz, 1H), 13.09 (s,
4.3.2. 3-Butyl-7-chloro-1,4-dihydro-cinnoline (entry 2[1], Table 3).
Yield 75%; pale yellow solid; IR (KBr): 669, 1066, 1591, 1741, 2856,
1H); 13C NMR (DMSO-d6, 125 MHz)
d 14.4, 22.5, 27.1, 29.0, 30.0, 31.6,
2926, 3421 cmꢁ1; 1H NMR (CDCl3, 500 MHz)
d
0.92 (t, J¼7.5 Hz, 3H),
116.6, 121.6, 124.5, 124.6, 133.7, 141.6, 151.1, 170.0; HRMS calcd for
1.35e1.39 (m, 2H), 1.53e1.59 (m, 2H), 2.31 (t, J¼7 Hz, 2H), 3.21 (s,
2H), 6.7 (s,1H), 6.88 (d, J¼8 Hz,1H), 6.92 (d, J¼8 Hz,1H), 7.29 (s,1H);
C14H18N2ONa (MþþNa): 253.1317, Found: 253.1315.
13C NMR (CDCl3, 125 MHz)
d 14.0, 22.5, 28.4, 29.1, 36.4, 111.9, 114.9,
4.2.8. 3-Butyl-7-chloro-1H-cinnolin-4-one (entry 5, Table 2). Yield
122.1, 128.7, 132.7, 141.4, 148.0; HRMS calcd for C12H15N2ClNa
86%; pale yellow solid; IR (KBr): 876, 1074, 1180, 1373, 1508, 1543,
(MþþNa): 245.0821, Found: 245.0828.
2835, 2960 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz)
d
0.87 (t, J¼7.5 Hz,
3H), 1.29e1.33 (m, 2H), 1.54e1.60 (m, 2H), 2.64 (t, J¼7 Hz, 2H), 7.32
(d, J¼9 Hz, 1H), 7.54 (s, 1H), 7.99 (d, J¼10 Hz, 1H), 13.24 (s, 1H); 13C
4.4. General experimental procedure for the synthesis of
cinnolines. Representative procedure for 3-butyl cinnoline
(entry 3[2], Table 3)
NMR (DMSO-d6, 125 MHz) d 14.3, 22.5, 29.3, 29.6, 115.6, 120.1, 125.0,
127.3, 138.5, 142.2, 151.9, 169.7; HRMS calcd for C12H13ClN2O
(MþþNa): 259.0614, Found: 259.0610.
To 2(M) HCl suspension (2 mL) of 3-butyl-1,4-dihydro-cinnoline
(188 mg,1 mmol), NaNO2 was added (103 mg,1.5 mmol) in portions
at 5e10 ꢀC. The reaction mixture was stirred for 15 min at this
temperature and extracted with EtOAc (2ꢂ5 mL) and dried. Evap-
oration of solvent followed by column chromatography (Rf value:
0.7, hexane/EtOAc: 9:1) of the crude product gave 3-butyl-cinnoline
as a yellow liquid (139 mg, 76%), IR (neat): 752, 1066, 1109, 1456,
4.2.9. 7-Chloro-3-propyl-1H-cinnolin-4-one (entry 6, Table 2). Yield
83%; pale yellow solid; IR (KBr): 860, 1094, 1210, 1380, 1502, 1552,
2833, 3010 cmꢁ1
;
1H NMR (DMSO-d6, 500 MHz)
d
0.91 (t, J¼7 Hz,
3H), 1.60e1.65 (m, 2H), 2.63 (t, J¼7.5 Hz, 2H), 7.34 (d, J¼9 Hz, 1H),
7.53 (s, 1H), 8.0 (d, J¼8.5 Hz, 1H), 13.2 (s, 1H); 13C NMR (DMSO-d6,
125 MHz)
d 14.4, 20.5, 32.1, 115.7, 120.2, 125.1, 127.4, 138.6, 142.3,
151.9, 169.8; HRMS calcd for C11H11ClN2ONa (MþþNa): 245.0458;
1587, 1622, 2858, 2929, 2956, 3412 cmꢁ1
;
1H NMR (CDCl3,
Found: 245.0453.
500 MHz)
d
0.94 (t, J¼7.5 Hz, 3H), 1.38e1.42 (m, 2H), 1.81e1.87 (m,
2H), 3.19 (t, J¼8 Hz, 2H), 7.60 (s, 1H), 7.63e7.66 (m, 1H), 7.70e7.73
4.2.10. 3-Hexyl-4-oxo-1,4-dihydro-cinnoline-6-carbonitrile (entry 7,
(m, 2H), 8.45 (d, J¼9 Hz,1H); 13C NMR (CDCl3, 125 MHz)
d 13.9, 22.4,
Table 2). Yield 80%; pale yellow solid; IR (KBr): 551, 837, 1180, 1381,
32.3, 35.8, 120.8, 126.3, 126.6, 129.6, 129.7, 131.0, 149.6, 158.0; HRMS
1475, 1572, 1629, 2229, 2928, 3130 cmꢁ1 1H NMR (DMSO-d6,
;
calcd for C12H15N2 (MþþH): 187.1235, Found: 187.1239.
500 MHz)
2H), 2.65 (t, J¼7.5 Hz, 2H), 7.65 (d, J¼9 Hz, 1H), 7.99 (d, J¼9 Hz, 1H),
8.37 (s, 1H), 13.56 (s, 1H); 13C NMR (DMSO-d6, 125 MHz)
19.1, 27.2,
31.6, 33.7, 34.7, 36.3, 111.2, 123.1, 123.6, 125.4, 136.0, 139.8, 147.8,
d
0.82 (t, J¼7.5 Hz, 3H), 1.23e1.32 (m, 6H), 1.56e1.60 (m,
This procedure was followed for all the reactions listed in Table 3.
All of these products are new compounds and were characterized
by their spectroscopic data (IR, 1H NMR, 13C NMR, and HRMS). These
data are provided below in order of their entries in Table 3.
d

8924
R. Dey, B.C. Ranu / Tetrahedron 67 (2011) 8918e8924
4.4.1. 3-Hexyl-cinnoline (entry 1[2], Table 3). Yield 75%; pale yellow
liquid (Rf value: 0.7, hexane/EtOAc: 9:1); IR (neat): 731, 752, 1458,
Supplementary data
1587, 2856, 2926, 3419 cmꢁ1
;
1H NMR (CDCl3, 500 MHz)
d
0.83 (t,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.09.016.
J¼7 Hz, 3H),1.20e1.28 (m, 4H),1.35e1.40 (m, 2H),1.80e1.86 (m, 2H),
3.16 (t, J¼8 Hz, 2H), 7.58 (s,1H), 7.61e7.64 (m,1H), 7.68e7.71 (m, 2H),
8.44 (d, J¼8.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
d 15.3, 22.6, 29.0,
30.2, 31.7, 36.2, 120.8, 126.4, 126.6, 129.6, 129.8, 131.0, 149.6, 158.0;
References and notes
HRMS calcd for C14H19N2 (MþþH): 215.1548, Found: 215.1635.
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2. Haider, N.; Holzer, W. Sci. Synth. 2004, 16, 251e313 Product Class 9:
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3. von Richter, V. Ber. Dtsch. Chem. Ges. 1883, 16, 677e683.
4. Schofield, K.; Swain, T. J. Chem. Soc. 1949, 2393e2399.
5. Schofield, K.; Simpson, J. C. E. J. Chem. Soc. 1945, 512e520.
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4.4.2. 3-Butyl-7-chloro-cinnoline (entry 2[2], Table 3). Yield 70%;
pale yellow liquid (Rf value: 0.6, hexane/EtOAc: 9:1); IR (neat): 756,
1245, 1458, 2850, 3450 cmꢁ1 1H NMR (CDCl3, 500 MHz)
; d 0.98 (t,
J¼7.5 Hz, 3H), 1.42e1.50 (m, 2H), 1.84e1.91 (m, 2H), 3.24 (t,
J¼7.5 Hz, 2H), 7.68 (d, J¼7 Hz, 1H), 7.72 (s, 1H), 7.76 (d, J¼9 Hz, 1H),
8.51 (s, 1H); 13C NMR (CDCl3, 125 MHz)
d 14.0, 22.5, 32.3, 35.5, 121.7,
125.5, 127.9, 128.3, 132.9, 136.0, 149.4, 158.4; HRMS calcd for
C12H14N2Cl (MþþH): 221.0845, Found: 221.0849.
Acknowledgements
We are pleased to acknowledge the financial support from DST,
New Delhi through the award of J.C. Bose National Fellowship to
B.C.R. (Grant no. SR/S2/JCB-11/2008). R.D. thanks CSIR, New Delhi
for his fellowship. We sincerely thank to M. Arunachalam and B.
Nisar Ahamed of IACS for their help in solving crystal structure of
one of the compounds.
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