Facile cyclization of 2-arylethynyl aniline to 4(1H)-cinnolones: A new chemodosimeter for nitrite ions

Article abstract of DOI:10.1016/j.tetlet.2010.11.098

2-Arylethynyl anilines undergo very fast reaction (5 min) with nitrite ions in aqueous acidic media to produce 4(1H)-cinnolones which exhibit yellow color and UV absorbance at 391 nm. This reaction is irreversible and has been successfully tested for the

Full text of DOI:10.1016/j.tetlet.2010.11.098

Tetrahedron Letters 52 (2011) 461–464
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile cyclization of 2-arylethynyl aniline to 4(1H)-cinnolones: a new
chemodosimeter for nitrite ions
⇑
Raju Dey, Tanmay Chatterjee, 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:
2-Arylethynyl anilines undergo very fast reaction (5 min) with nitrite ions in aqueous acidic media to
produce 4(1H)-cinnolones which exhibit yellow color and UV absorbance at 391 nm. This reaction is irre-
versible and has been successfully tested for the detection of nitrite ions in water at ppm concentration.
Thus, 2-phenylethynyl aniline serves as a chemodosimeter. An efficient and general method for the syn-
thesis of 4(1H)-cinnolones has been developed based on this reaction.
Received 27 October 2010
Revised 18 November 2010
Accepted 18 November 2010
Available online 24 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cinnolone
Chemodosimeter
Detection of nitrite ion
Arylethynyl aniline
The nitrite contamination in food, beverages, and drinking
water is of growing concern1 as nitrite reacts with dietary compo-
nents in the stomach to generate toxic and carcinogenic nitroso-
amines.2 Another potential danger of entry of nitrite ions in the
blood stream is its capability to convert oxyhemoglobin into met-
hemoglobin and thereby interfering with oxygen transport in the
blood.3 As defined by US Environmental Protection Agency (EPA)
the maximum content of nitrite ions in drinking water should
not exceed 1 ppm.4 Thus, even a trace amount of nitrite is harmful
to human health.
The change of color is clearly visible up to 10 ppm concentration
of nitrite ions.
O
Ar
Ar
NaNO2
N
HCl (2N)
0-5 oC, 5 min
N
H
NH2
Scheme 1. Reaction of nitrite with 2-arylethynyl aniline.
Various methods have been developed to detect the presence of
nitrite ions, based on organic chromophores,5 florophores,6 and ion
chromatography7 among others.8 However, these methods usually
require sophisticated and expensive instruments and thus restrict
their use in rural areas. Thus an easy-to-use colorimetric sensor is
more helpful for an on-the-spot survey. Recently, a noncross-link-
ing colorimetric nitrite sensor using 4-aminothiophenol modified
gold nanorods9a and gold nanoparticle probes9b have been re-
ported. We report herein a new chemodosimeter, 2-arylethynyl
aniline which undergoes fast reaction with nitrite ions to form
4(1H)-cinnolones displaying a yellow color (Scheme 1). Although
application of chemodosimeter in sensing other ions such as CNÀ
and FÀ is common10 similar use for the nitrite ions is rare.
In a typical experiment,11 2-phenylethynyl aniline was treated
with NaNO2/HCl(2 N) at 0–5 °C to produce 3-phenyl-4(1H)-cinnol-
ones with an immediate change of color to yellow from colorless.
⇑
Corresponding author. Tel.: +91 3324734971; fax: +91 3324732805.
E-mail address: ocbcr@iacs.res.in (B.C. Ranu).
Figure 1. UV spectroscopic studies for nitrite sensing (L = 2-phenylethynyl aniline,
10À4 M in H2O).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.098

462
R. Dey et al. / Tetrahedron Letters 52 (2011) 461–464
Figure 3. Colorimetric studies for nitrite sensing (L = 2-phenylethynyl aniline,
10À4 M in H2O).
6-methoxy-2-naphthylethynyl aniline shows strong fluorescence
emission at 401 nm (excitation at kmax 315 nm), whereas the corre-
sponding cinnolone obtained by reaction with nitrite was com-
pletely fluorescence inactive (Fig. 2).
This property was successfully utilized for the detection of ni-
trite ions at a very low concentration (<1 ppm). The effect of a wide
variety of other ions including FÀ, ClÀ, BrÀ, IÀ, N3À, PO43À, OAcÀ,
Figure 2. Fluorescence studies for nitrite sensing (L = 6-methoxy-2-naphthylethy-
nyl aniline, 10À6 M in H2O).
SCNÀ, SO42À, and NO3 has also been investigated in the sensing
À
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 pres-
ence of these ions in the test sample containing nitrite ion also
The end products, 3-phenyl-4(1H)-cinnolones show a charac-
teristic UV absorption at 391 nm (Fig. 1). We next turned our atten-
tion on fluorescence studies. It was found that starting compound,
2-phenylethynyl aniline as well as the product, 3-phenyl-4(1H)
cinnolone is not fluorescence active. However, we discovered that
Table 1
Synthesis of 3-aryl-cinnolones
O
NaNO2/ HCl
H2O, 0-5 oC, 5 min
N
N
H
NH2
Entry
1
Substrate
Product
Yielda
92
O
N
N
H
NH2
Me
Me
O
2
3
4
5
90
95
92
95
N
N
N
H
NH2
Cl
Cl
O
N
H
NH2
Me
Me
Cl
O
N
Cl
N
H
Cl
NH2
Cl
O
NC
NC
N
N
H
NH2

R. Dey et al. / Tetrahedron Letters 52 (2011) 461–464
463
Table 1 (continued)
Entry
Substrate
Product
Yielda
O
6
7
91
90
92
N
N
N
H
NH2
O
O
O
N
H
NH2
OMe
OMe
O
8
N
Cl
N
H
Cl
NH2
a
Yields refer to those of pure isolated products characterized by spectroscopic data (IR, 1H NMR, 13C NMR and HRMS).
does not interfere in the detection process. For an on-the-spot sur-
vey when a paper strip soaked with 2-phenylethynyl aniline and
aqueous HCl was quenched with a drop of sample, the presence
of nitrite was immediately reflected by a change of color to yellow.
The presence of other ions has absolutely no effect.
In general, the reactions are very fast, clean and high yielding.
The possible reaction pathway involves diazotization of the ethy-
nyl anilines followed by hydration of ethynyl moiety and subse-
quent cyclization to provide the 4(1H)-cinnolones, as outlined in
Scheme 2.
The 4(1H)-cinnolines, have received considerable attention in
recent times because of their promising biological activities.12 Sur-
prisingly, a few methods have been available for the synthesis of
cinnolines.13
In conclusion, we have developed a simple tool for sensing ni-
trite ions selectively in presence of other ion contaminants by vi-
sual color change, UV absorption, and fluorescence emission,
based on a key reaction of 2-arylethynyl aniline and nitrite in
acidic aqueous medium. This kit is also effective on a paper strip
for an on-the-spot survey without any instrument at low concen-
tration of nitrite ions (10 ppm). This reaction has been utilized to
develop a general procedure for the synthesis of 4(1H)-cinnolones
which are pharmaceutically very important. To the best of our
knowledge, this is the first direct method for the synthesis of
4(1H)-cinnolones. In addition, the significant advantages of high
yield, fast reaction, reaction in aqueous media, and ambient tem-
perature make this procedure very attractive.
The direct method for the synthesis of cinnolones is rare. We
have found only one report of their synthesis by electrochemical
reduction of cinnolines.14 Considering the importance of cinnol-
ones, we standardized the basic reaction of 2-phenylethynyl ani-
line and nitrite toward a general procedure15 for the synthesis of
4(1H)-cinnolones. Several 2-arylethynyl anilines which are ob-
tained by the Sonogashira coupling of 2-iodoanilines and aryl acet-
ylenes in water by a standard procedure,16 were converted into the
corresponding 3-aryl-4(1H)-cinnolones by this procedure.15 The
results are summarized in Table 1. A variety of substituted phenyl
and naphthyl-ethynyl anilines participate in this reaction and sev-
eral functional groups such as Cl, CN, and OMe are compatible with
the reaction conditions. The reactions in this two-step procedure
starting from 2-iodoanilines to 3-aryl-4(1H)-cinnolones were car-
ried out in aqueous medium and a minimum amount of relatively
safe17 ethyl acetate was used for extraction and crystallization. The
compounds are obtained in high purity on recrystallization and
were characterized by spectroscopic data (IR, 1H NMR, 13C NMR
and HRMS).
Acknowledgments
We are pleased to acknowledge the financial support from J. C.
Bose National Fellowship, awarded to B.C.R. (Grant no. SR/S2/JCB-
11/2008) by DST, Govt. of India. R.D. and T.C. thank CSIR, New Delhi
for their fellowship.
Supplementary data
Supplementary data (copies of 1H NMR and 13C NMR spectra of
all products listed in Table 1) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.11.098.
H2O
R
R
NaNO2 + HCl
References and notes
N
NH2
N
1. Johnson, C. J.; Burton, C. K. Am. J. Ind. Med. 1990, 18, 449–456.
2. Wolff, I. A.; Wasserman, A. E. Science 1972, 172, 15–19.
3. Burden, E. H. W. J. Analyst 1961, 86, 429–433.
OH
4. Nollet, I. M. I. Handbook of Water Analysis; CRC Press: New York, 2000.
5. (a) Green, L. C.; Wagner, D. A.; Glogowski, J.; Skipper, P. L.; Wishnok, J. S.;
Tannenbaum, S. R. Anal Biochem. 1982, 126, 131–138; (b) Mohr, G. J.; Wolfbeis,
O. S. Analyst 1996, 121, 1489–1494.
6. (a) Buldt, A.; Karst, U. Anal. Chem. 1999, 71, 3003–3007; (b) Barker, S. L. R.;
Thorsrud, B. A.; Kopelman, R. Annal. Chem. 1998, 70, 100–104.
7. Doyel, J. M.; Miller, M. I.; McCord, B. R.; McCollam, D. A.; Mushrush, G. W. Annal.
Chem. 2000, 72, 2302–2307.
O
R
R
N
N
N
N
H
Scheme 2. Possible reaction pathway.

464
R. Dey et al. / Tetrahedron Letters 52 (2011) 461–464
8. (a) Azad, U. P.; Ganesan, V. Chem. Commun. 2010, 6156–6158; (b) Wang, P.;
3-p-Tolyl-1H-cinnolin-4-one (Table 1, entry 2): Yield 90%, pale yellow solid, IR
(KBr) 667, 754, 821, 1301, 1477, 1545, 2841, 2887 cmÀ1 1H NMR (DMSO-d6,
Wang, X.; Bi, L.; Zhu, G. Analyst 2000, 125, 1291–1294; (c) Qui, Y.; Deng, H.;
Mou, J.; Yang, S.; Zeller, M.; Batten, S. R.; Wu, H.; Li, J. Chem. Commun. 2009,
5415–5417.
;
500 MHz) d 2.33 (S, 3H), 7.23 (d, J = 8 Hz, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.61 (d,
J = 8 Hz, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.99 (d, J = 8 Hz, 2H), 8.13 (d, J = 8 Hz, 1H),
13.62 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) d 21.4, 116.9, 123.8, 125.2, 128.6
(2C), 128.9 (2C), 132.6, 134.0, 138.3, 141.2, 145.9, 169.7; HRMS Calcd for
9. (a) Xiao, N.; Yu, C. Anal. Chem. 2010, 82, 3659–3663; (b) Daniel, W. L.; Han, M.
S.; Lee, J.-S.; Mirkin, C. A. J. Am. Chem. Soc. 2009, 131, 6362–6363.
10. (a) Lee, K.-S.; Kim, H.-J.; Kim, G.-H.; Shin, I.; Hong, J.-I. Org. Lett. 2008, 10, 49–
51; (b) Bhalla, V.; Singh, H.; Kumar, M. Org. Lett. 2010, 12, 628–631.
11. General procedure for the detection of nitrite ions: An aqueous nitrite solution
(10À4 M, 2 mL) was added to an aqueous HCl (4 N) solution of 2-phenylethynyl
aniline (2 mL, 0.5 Â 10À4 M) in a cubet and shaken well. UV study was carried
out with this solution. For fluorescence studies a similar experiment was
performed using a 10À6 M solution (2 mL) of 6-methoxynaphthyl-2-ethynyl
aniline.
C
15H13N2O (M++H): 237.101. Found: 237.101.
7-Chloro-3-p-tolyl-1H-cinnolin-4-one (Table 1, entry 4): Yield 92%; pale yellow
solid; IR (KBr) 819, 1051, 1454, 1537, 1560, 2825, 2885, 2982, 3051 cmÀ1 1H
NMR (DMSO-d6, 500 MHz) 2.32 (s, 3H), 7.22 (d, J = 8 Hz, 2H), 7.40 (d,
;
d
J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.96 (d, J = 8 Hz, 2H), 8.11 (d, J = 8.5 Hz, 1H), 13.74
(s, 1H); 13C NMR (DMSO-d6, 125 MHz) d 116.0, 122.3, 125.6, 127.8, 128.7 (2C),
129.0 (3C), 132.2, 138.6, 141.8, 146.5, 169.3; HRMS Calcd for C15H12ClN2O
(M++H): 271.0638. Found: 271.0633.
12. Lewgowd, W.; Stanczak, A. Arch. Pharm. Chem. Life Sci. 2007, 340, 65–80.
13. (a) Schofield, K.; Swain, T. J. Chem. Soc. 1949, 2393–2399; (b) Schofield, K.;
Simpson, J. C. E. J. Chem. Soc. 1945, 512–520; (c) Kiselyov, A.-S.; Dominguez, C.
Tetrahedron Lett. 1999, 40, 5111–5114; (d) Brase, S.; Dahmen, S.; Heuts, J.
Tetrahedron Lett. 1999, 40, 6201–6203; (e) Vinogradova, O. V.; Sorokoumov, V.
N.; Vasileusky, S. F.; Balova, I. A. Tetrahedron Lett. 2007, 48, 4907–4909.
14. Matsubara, Y.; Matsuda, T.; Kato, A.; Yamaguchi, Y.; Yoshida, Z. I. Tetrahedron
Lett. 2000, 41, 7901–7904.
3-(4-Chloro-phenyl)-4-oxo-1,4-dihydro-cinnoline-6-carbonitrile (Table 1, entry
5): Yield 95%; pale yellow solid; IR (KBr) 823, 1091, 1300, 1487, 1585, 2231,
3027, 3277 cmÀ1 1H NMR (DMSO-d6, 500 MHz) d 7.37 (d, J = 8.5 Hz, 2H), 7.68
;
(d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 8.0 (d, J = 8 Hz, 2H), 8.3 (s, 1H), 14.1 (s,
1H), 13C 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 C15H9ClN3O
(M++H): 282.0434. Found: 282.0429.
3-(2-Methoxynaphthalen-6-yl)cinnolin-4(1H)-one (Table 1, entry 7): Yield 90%;
15. General experimental procedure: representative procedure for the synthesis of 3-
phenyl-1H-cinnolin-4-one: To 2 N acidic suspension (2 mL) of 2-phenylethynyl-
phenylamine (193 mg, 1 mmol), NaNO2 (103 mg, 1.5 mmol) was added in
portions at 0–5 °C. The reaction mixture was stirred at 0–5 °C for 5 min
followed by further 5 min at room temperature. The reaction mixture was
extracted with EtOAc (2 Â 5 mL), dried, concentrated and was left at room
pale yellow solid; IR (KBr) 727, 871, 1201, 1481, 1612, 1629, 3198, 3223 cmÀ1
;
1H NMR (DMSO-d6, 500 MHz) d 3.93 (S, 3H), 7.26 (d, J = 9 Hz, 1H), 7.36 (t,
J = 7.5 Hz, 1H), 7.43 (S, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.96
(d, J = 8.5 Hz, 1H), 8.04 (d, J = 9 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.33 (d, J = 8 Hz,
1H), 8.94 (S, 1H), 14.00 (S, 1H), 13C NMR (DMSO-d6, 125 MHz) d 55.3, 106.0,
110.9, 119.3, 121.9, 123.0, 123.3, 126.3, 126.6, 127.0, 127.2, 131.2, 132.0, 132.7,
temperature to give 3-phenyl-1H-cinnolin-4-one as
a
pale yellow solid
1H NMR
136.6, 140.7, 142.4, 159.2, 187.5; HRMS Calcd for
325.0953. Found: 325.0954.
C
19H14N2O2 (M++Na):
(204 mg, 92%), IR (KBr) 756, 1305, 1477, 1546, 2860, 2929 cmÀ1
;
(DMSO-d6, 300 MHz) d 7.36–7.46 (m, 4H), 7.63 (d, J = 8.4 Hz, 1H), 7.77 (t,
J = 7 Hz, 1H), 8.09–8.17 (m, 3H), 13.70 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) 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 (M++H): 223.0871. Found: 223.0868.
This procedure was followed for all the reactions listed in Table 1. The products
in entries 3 and 6 of Table 1 are known14 and were identified by comparison of
their spectra with those reported. The products in entries 2, 4, 5, 7 and 8 in
7-Chloro-3-(4-methoxy-phenyl)-1H-cinnolin-4-one (Table 1, entry 8): Yield 92%;
pale yellow solid; IR (KBr) 827, 1055, 1300, 1556, 2885, 3054 cmÀ1 1H NMR
;
(DMSO-d6, 500 MHz) d 3.7 (s, 3H), 7.0 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 7.5 Hz, 1H),
7.48 (s, 1H), 7.98 (d, J = 8 Hz, 1H), 8.18 (d, J = 8.5 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 (M++H):
287.0587. Found: 287.0583.
Table
1
were not reported earlier and were characterized by their
16. Bhattacharya, S.; Sengupta, S. Tetrahedron Lett. 2004, 45, 8733–8736.
17. Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson, T. A.; Kleine,
H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green Chem. 2008, 10,
31–36.
spectroscopic data (IR, 1H NMR, 13C NMR and HRMS) which are provided
below in order of their entries.
In general, these cinnolones are very high melting (300 °C) and attempts to
determine the melting points on an electrical bath leads to decomposition.