Electrochemical transformation of 4-cyanocinnolines into 4(1H)-cinnolones

Article abstract of DOI:10.1016/S0040-4039(00)01352-6

Electrochemical transformation of 4-cyanocinnolines into 4(1H)-cinnolones has been achieved, for the first time, in 70 ~ 100% yield. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01352-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7901–7904
Electrochemical transformation of 4-cyanocinnolines into
4(1H)-cinnolones
Yoshio Matsubara, Takuya Matsuda, Atsuhisa Kato, Yoshihiro Yamaguchi and
Zen-ichi Yoshida*
Faculty of Science and Engineering, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan
Received 17 April 2000; revised 31 July 2000; accepted 4 August 2000
Abstract
Electrochemical transformation of 4-cyanocinnolines into 4(1H)-cinnolones has been achieved, for the
first time, in 70ꢀ100% yield. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: cyano compounds; electrochemical reaction; nitrogen heterocycles.
Recent interest in the molecular functions of cinnolines has been focused on their biological
activity and functions.1,2 To clarify their structure–activity relationship, it should be necessary to
develop new methods for synthesis and functional group transformation which provide various
kinds of cinnolines. Very recently, we reported a versatile, single-step synthesis of cyanocinnoli-
nes from aromatic hydrazones and TCNE.3 Among the possible functional group transforma-
tion of cyanocinnolines, we were interested in the behavior of 4-cyanocinnolines (1) toward
electrochemical reduction.
Electrode reaction of cinnolines in acidic media is reported to give indole derivatives via the
1,4-dihydro derivatives.4 Electrochemical reduction of cyanopyridines having the same structural
moiety as 1 in alkaline media is known to afford pyridine and cyanide ion by CꢀCN bond
fission.5
In marked contrast to these examples, we report here that cyanocinnolines (1) can be
selectively converted into 4(1H)-cinnolones by electrochemical reduction (electrode: Pt). The
reaction of 1a–f (which were prepared according to our method3) was conducted at ambient
temperature for 2 h under constant voltage (−8 V) in benzonitrile in the presence of O2 and H2O.
Workup gave 2a–f in good to high yields.6 In the absence of O2 and H2O, formation of 2a–f was
not observed.
* Corresponding author. Tel: +81-6-6730-5880 (ext. 4368); fax: +81-6-6727-4301; e-mail: y-matsu@apch.kindai.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01352-6

7902
Benzonitrile as solvent and n-Bu4NBF4 as supporting electrolyte were the best choice for the
synthetic purpose.
When acetonitrile was used instead of benzonitrile, the yield of cinnolones decreased in
30ꢀ40%, and formation of cinnoline-4-carboxylic acid amides (CN“CONH2) was observed.
As exemplified below, the transformation is general for cyanocinnolines, and occurs efficiently
irrespective of kind of substituent (R).
Cyclic voltammograms of 1, O2, and O2+1 in PhCN are considered to be useful for disclosing
the initial step of the reaction. As shown in Fig. 1(A), the cyclic voltammogram of 1a
demonstrates only one reversible one electron reduction wave.7 The cyclic voltammogram of O2
shows also one reversible wave (Fig. 1(B)). On the contrary, the cyclic voltammogram of an
O2-saturated PhCN solution of 1a shows an irreversible wave of 1a, where the cathodic peak
corresponding to 1a“1a− is shifted to cathodic side by 0.13 V, presumably because of complex
’
−
’
formation with O2, and the anodic peak corresponding to 1a “1a disappears. No reduction
wave of O2 is observed. These data indicate the initial step of the reaction to be the formation
−
’
1a , followed by its reaction of O2.
Figure 1. Cyclic voltammograms of 1a (A), O2 (B), and 1a+O2 (C). Potentials were measured in benzonitrile at 25°C
with a scan rate 100 mV s−1 using Pt electrode. An Ag/AgCl electrode was used as a reference electrode, and ferrocene
was added as an internal reference. n-Bu4NBF4 was added as a supporting electrolyte

7903
HPLC and TLC monitoring of the reaction demonstrated 1,4-dihydro derivatives of 1 not to
be detected. In the presence of methanol the reaction provided methylcarbamate besides 2,
indicating the formation of isocyanic acid (HNCO).
Thus the transformation of 1 into 2 is considered to proceed according to the following
scheme.
It is certain that the reaction proceeds via an intermediate C, because we observe that the
reaction of 1a with Na2O2 in the presence of 18-crown-6 in PhCN gives 2a exclusively.
As for the final step leading to 2a, a concerted ring fission of the dioxetane type intermediate
E is more conceivable than a nonconcerted decomposition of the noncyclic intermediate F
(protonated C) judging from (1) nature of the both processes; (2) detection of isocyanic acid
during the reaction, and (3) large strain energy difference (E>F, 28 kcal/mol) between both
structural isomers, E and F, which have small heat of formation differences (E>F, 9 kcal/mol).12
Since the electrochemical transformation of 1 into 2 is a safety reaction compared with
chemical transformation using Na2O2, and proceeds efficiently under mild conditions, this
reaction could be useful as a new tool for 4(1H)-cinnolone synthesis.13
Acknowledgements
This work was supported in part by JSPS (JSPS-RFTF 96R 11601) and a grant-in-aid from
the Ministry of Education, Science, Sports and Culture, Japan (No. 10132263).
References
1. Lednicer, D.; Mitscher, L. A. In The Organic Chemistry of Drug Synthesis; John Wiley and Sons: New York,
1980; Vol. 2, p. 387–390.

7904
2. (a) Zeneca, Drug Data Report, 1990, 12 (11), 856; US 4886800; (b) Pharmacia & Upjohn, Drug Data Report,
1991, 13 (4), 332; US 48268837; (c) Mitsubisi Chem., Drug Data Report, 1994, 16 (2), 129; (d) Pierre Fabre, Drug
Data Report, 1993, 15 (10), 910; WO 93/09098.
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4. (a) Lund, H. Acta Chem. Scand. 1967, 21, 2525; (b) Maruyama, M.; Murakami, K. Nippon Kagaku Kaishi. 1977,
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5. Volke, J.; Kardos, A. M. Collect. Czech. Chem. Commun. 1968, 33, 2560.
6. Into a cathodic chamber of an electrolysis cell equipped with a platinum cathode (2×2 cm) was added a solution
of 1a (1 mmol) in benzonitrile (30 ml) containing n-Bu4NBF4 (0.5 g) as supporting electrolyte. The anodic
solution was 10 ml of benzonitrile containing n-Bu4NBF4 (0.5 g), and a platinum anode (2×2 cm) was used. The
electroreduction was carried out under constant voltage conditions (−8 V) at room temperature in the presence
of O2 and H2O. After 2 h, the reaction mixture was evaporated under reduced pressure. The residue was purified
by recrystallization from methanol to give 2a in quantitative yield, pale orange crystals, mp 268–270.5°C (lit.8
1
268–270°C); IR (KBr, cm−1) 2893, 1549; H NMR (DMSO-d6) l 13.64 (s, 1H), 8.15 (d, 1H), 8.08 (d, 2H), 7.78
(dd, 1H), 7.63 (d, 1H), 7.43 (d, 2H), 7.42 (dd, 1H), 7.41 (m, 1H); HRMS found: m/z 222.0758, calcd for
C14H10N2O 222.0793. Further reaction of 2a (known compound) with methyl iodide in the presence of potassium
hydroxide led to 1-methyl-3-phenyl-4(1H)-cinnolone (isolated yield 90%), pale orange crystals, mp 106.5–110.5°C
(lit.9 107–108°C); HRMS found: m/z 236.0931, calcd for C15H12N2O 236.0950. 2b (known compound): white
crystals, yield 82.0%; mp 328–330°C (lit.8 329–330°C); FT-IR (KBr pellet, cm−1) 2894, 1546; 1H NMR
(DMSO-d6) l 13.79 (s, 1H), 8.16 (d, 1H), 8.15 (d, 2H), 7.80 (dd, 1H), 7.64 (d, 1H), 7.50 (d, 2H), 7.45 (dd, 1H);
HRMS found: m/z 256.0396, calcd for Cl4H9ClN2O 256.0403. 2c (new compound): pale orange crystals, yield
1
71.5%; mp 266.5–268°C; FT-IR (KBr pellet, cm−1) 2834, 1542; H NMR (DMSO-d6) l 13.61 (s, 1H), 8.13 (d,
1H), 8.09 (d, 2H), 7.77 (dd, 1H), 7.61 (d, 1H), 7.41 (dd, 1H), 7.00 (d, 2H), 3.80 (s, 3H); 13C NMR (DMSO-d6)
l 169.25, 159.49, 145.08, 140.69, 133.51, 129.59, 127.38, 124.66, 123.19, 116.42, 113.27, 109.02, 55.16; HRMS
found: m/z 252.0877, calcd for C15H12N2O2 252.0899. 2d (new compound): pale orange crystals, yield 73.5%; mp
1
299–301°C; FT-IR (KBr pellet, cm−1) 2920, 1544; H NMR (DMSO-d6) l 13.86 (s, 1H), 8.87 (s, 1H), 8.20 (d,
1H), 8.17 (d, 1H), 7.99 (d, 1H), 7.97 (d, 1H), 7.93 (d, 1H), 7.82 (dd, 1H), 7.67 (d, 1H), 7.57–7.52 (m, 2H), 7.47
(dd, 1H); 13C NMR (DMSO-d6) l 169.42, 144.93, 140.71, 133.50, 132.76, 132.63, 132.42, 128.40, 127.71, 127.35,
127.07, 126.37, 126.08, 125.60, 124.82, 124.63, 123.59, 116.47; HRMS found: m/z 272.0921, calcd for C18H12N2O
272.0950. 2e (new compound): pale yellow crystals, yield 80.9%; mp 210.5–212.0°C; FT-IR (KBr pellet, cm−1
)
1
2882, 1542; H NMR (DMSO-d6) l 13.28 (s, 1H), 8.04 (d, 1H), 7.73 (dd, 1H), 7.53 (d, 1H), 7.37 (dd, 1H), 7.23
(s, 5H); 13C NMR (DMSO-d6) l 169.57, 149.63, 141.62, 141.11, 133.42, 128.30, 128.26, 125.79, 124.18, 124.09,
121.22, 116.17, 32.44, 31.53; HRMS found: m/z 250.1124, calcd for C18H12N2O 250.1106. 2f (known compound):
1
pale yellow crystals, yield 84.0%; mp 178.5–180°C (lit.10 178–180°C); FT-IR (KBr pellet, cm−1) 2868, 1548; H
NMR (DMSO-d6) l 13.20 (s, 1H), 8.01 (d, 1H), 7.72 (dd, 1H), 7.52 (d, 1H), 7.34 (dd, 1H), 2.68 (t, 2H), 1.59 (m,
2H), 1.33 (m, 2H), 0.89 (t, 3H); HRMS found: m/z 202.1109, calcd for C12H14N2O 202.1106.
7. From observed Ep value (0.029 V) and Ep=E1/2+0.0285/n (at 25°C) equation11, n becomes 1.
8. (a) Lowrie, H. S. J. Med. Chem. 1966, 9, 670; (b) Noland, W. E.; Jones, D. A. J. Org. Chem. 1962, 27, 341.
9. Lowrie, H. S. J. Med. Chem. 1966, 9, 784.
10. Ames, D. E.; Ansari, H. R.; France, A. D. G.; Lovesey, A. C.; Novitt, B.; Simpson, R. J. Chem. Soc. (C) 1971,
3088.
11. Matsuda, H.; Ayabe, Y. Z. Electrochemistry 1955, 59, 494.
12. AM1 calculation for both structural isomers, E and F, indicates that heat of formation (kcal/mol) is 112.8 for E
and 103.1 for F (DDHf 9 kcal/mol), but strain energy (kcal/mol) is 28.6 for E and zero for F (DSE 28 kcal/mol).
13. Chemical reduction of 1 afforded quite different products from electrochemical reduction. For example, reaction
of 1a with zinc dust in acetic acid at 25°C gave 3-cyano-2-phenylindole in quantitative yield. Reaction of 1 with
NaBH4 in ethanol under reflux provided 3-phenylcinnoline in almost quantitative yield.
.
.