LETTER
Efficient Synthesis of 7-Substituted or 3,7-Disubstituted 1H-Indazoles
1205
Finally, a double functionalization of 5 could be achieved
by reaction with zinc cyanide (1.2 equiv) under protracted
reaction time: 3,7-dicyano-1H-indazole (14) could be ob-
tained in a pure form in 86% yield.
(4) Lukin, K.; Hsu, M. C.; Fernando, D.; Leanna, M. R. J. Org.
Chem. 2006, 71, 8166.
(
(
5) (a) Collot, V.; Bovy, R. B.; Rault, S. Tetrahedron Lett. 2001,
41, 9053. (b) Collot, V.; Dallemagne, P.; Bovy, R. B.; Rault,
S. Tetrahedron 1999, 55, 6917.
6) (a) El Kazzouli, S.; Bouissane, L.; Khouili, M.; Guillaumet,
G. Tetrahedron Lett. 2005, 46, 6163. (b) Bouissane, L.; El
Kazzouli, S.; Léger, J. M.; Jarry, C.; Rakib, E. M.; Khouili,
M.; Guillaumet, G. Tetrahedron 2005, 61, 8218.
Br
N
Br
N
CN
N
(
i)
(ii)
5
3%
86%
N
N
N
(c) Bouissane, L.; El Kazzouli, S.; Léonce, S.; Pfeiffer, B.;
H
H
H
CN
I
CN
Rakib, E. M.; Khouili, M.; Guillaumet, G. Bioorg. Med.
Chem. 2006, 14, 1078.
13
5
14
(
7) Raman, C. S.; Li, H.; Martasek, P.; Southan, G.; Masters, B.
S.; Poulos, T. L. Biochemistry 2001, 40, 13448.
8) Schumann, P.; Collot, V.; Hommet, Y.; Gsell, W.; Dauphin,
F.; Sopkova, J.; MacKenzie, E. T.; Duval, D.; Boulouard,
Scheme 5 Selective coupling of 3-bromo-7-iodo-1H-indazole.
Reagents and conditions: (i) Zn(CN)2 (0.6 equiv), Pd (dba) (4
2
3
(
mol%), dppf (8 mol%), Zn (25 mol%), DMA, reflux, 5 h; (ii) Zn(CN)2
1.2 equiv), Pd (dba) (4 mol%), dppf (8 mol%), Zn (25 mol%),
(
2
3
M.; Rault, S. Bioorg. Med. Chem. Lett. 2001, 11, 1153.
DMA, reflux, 48 h
+
(
9) For 3: mp 94 °C. MS (CI–CH ): m/z = 267 [M + H ]. HRMS:
4
+
m/z [M + NH ] calcd for C H N F O S: 326.0422; found:
4
8
5
2
3
3
1
In conclusion we have devised straightforward syntheses
of 7-OTf-1H-indazole and 7-iodo-1H-indazole, com-
pounds that should be useful reagents to prepare new
indazole-based building blocks of interest in medicinal
chemistry or in the synthesis of new ligands via palladi-
um-mediated coupling reactions. Two examples have
been described with the preparation of the 7-cyano- and 7-
ethynyl-1H-indazole. Additionally, 3-bromo-7-iodo-1H-
indazole has been synthesized and regioselectively
functionalized by cyanation at the C-7 or C-3 and C-7 po-
sitions.
326.0424. H NMR (200 MHz, acetone-d ): d = 8.27 (s, 1 H),
6
7.93 (2 × d, J = 9.2 Hz, 2 H), 7.50 (s, 1 H), 7.27 (t, J = 9.2
1
9
Hz, 1 H). F NMR (188 MHz, acetone-d ): d = –68.92 (s).
6
1
3
C NMR (75 MHz, acetone-d ): d = 128.4, 122.9, 122.5,
6
121.8, 119.4, 119.0, 115.8, 116.5.
(
(
10) Ritter, K. Synthesis 1993, 735.
11) (a) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33,
6299. (b) Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph,
S. P. Org. Synth. 1998, Coll. Vol. IX, 165.
(12) (a) Porter, H. D.; Peterson, W. D. Org. Synth. 1955, Coll.
Vol. III, 660. (b) Doyle, M. P.; Bryker, W. J. J. Org. Chem.
1979, 44, 1572. (c) Boulton, B. E.; Coller, B. A. W. Aust. J.
Chem. 1974, 27, 2343. (d) Suzuki, N.; Kaneko, Y.; Nomoto,
T.; Isawa, Y. Chem. Commun. 1984, 1523. (e) Doyle, M.
P.; Siegfried, B.; Elliot, R. C.; Dellaria, J. F. J. Org. Chem.
Acknowledgment
1977, 42, 2431.
+
+
We thank Dr. Luke J. Alvey and Dr. Gwilherm Evano for many
helpful discussions. B.C. acknowledges the Ministère de la Recher-
che (France) for a fellowship. C.S.R. is a Pew Scholar and is funded
by the Robert A. Welch Foundation to conduct work on NOS inhi-
bitors (AU-1524).
(13) For 4: mp 114.2 °C. MS (EI): m/z = 117 [M – I] ·, 127 [I ·],
+
244 [M ·]. Anal. Calcd for C H N I: C, 34.43; H, 2.05; N,
7
5
2
1
11.47. Found: C, 34.46; H, 1.93; N, 11.38. H NMR (200
MHz, CDCl ): d = 8.25 (s, 1 H), 7.77, 7.73 (2 × dd, J = 7.5
Hz, J = 0.9 Hz, 2 H), 7.55 (br s, 1 H), 6.97 (dd, J = 7.5, 7.5
Hz, 1 H). C NMR (75 MHz, CDCl ): d = 142.4, 136.3,
35.6, 123.2, 122.7, 121.0, 115.7.
3
3
4
1
3
3
1
References and Notes
(
14) To a solution of 2-methyl-6-nitroaniline (5.00 g, 32.9 mmol)
in glacial AcOH (235 mL) was added all at once a solution
(
1) (a) For reviews, see: Elguero, J. Pyrazoles and their Benzo
Derivatives, In Comprehensive Heterocyclic Chemistry,
Vol. 5; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press:
Oxford, 1984, 167–303. (b) Behr, L. C.; Fusco, R.; Jacobe,
C. H. In Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles
and Condensed Rings; Wiley, R. H., Ed.; Wiley Int.: New
York, 1969. (c) Minkin, V. I.; Glukhovtsev, M. N.; Simkin,
B. Y. Aromaticity and Antiaromaticity, Electronic and
Structural Aspects; Wiley: New York, 1994.
of sodium nitrite (2.27 g, 32.9 mmol) in H O (5.5 mL).
2
During this addition the temperature was not allowed to rise
above 25 °C. After the nitrite solution had been added,
stirring was maintained for 20 min. Any yellow precipitate
formed during this time was filtered and discarded. Then, the
solution was evaporated in vacuo. Cold H O was added to
2
the residue and the contents of the flask were washed into a
beaker where they were stirred. The product was filtered,
rinsed with cold H O and dried to afford 7-nitro-1H-indazole
2
(
2) As recent examples, see: (a) Hartinger, C. G.; Zorbas-
Seifired, S.; Jakupec, M. A.; Kynast, B.; Zorbas, H.;
Keppler, B. K. J. Inorg. Biochem. 2006, 100, 891.
(
5.29 g, 98% yield); mp 180 °C.
(
(
15) Noelting, E. Ber. Dtsch. Chem. Ges. 1904, 37, 2584.
16) Tsuji, J. In Palladium Reagents and Catalysts, New
(
b) Carella, A.; Vives, G.; Cox, T.; Jaud, J.; Rapenne, G.;
st
Perspectives for the 21 Century; Wiley, R. H., Ed.; Wiley
Launay, J. Eur. J. Inorg. Chem. 2006, 980.
Int.: New York, 2004.
(
3) As examples, see: (a) Tanitame, A.; Oyamada, Y.; Ofuji, K.;
Kyoya, Y.; Suzuki, K.; Ito, H.; Kawasaki, M.; Nagai, K.;
Wachi, M.; Yamagishi, J. I. Bioorg. Med. Chem. 2004, 14,
(
17) (a) Anderson, B. A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.;
Pagh, L. M.; Wepsiec, J. P. J. Org. Chem. 1998, 63, 8224.
(
b) Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.;
Sans, J.; Weiss, S.; Beller, M. Chem. Eur. J. 2003, 9, 1828.
c) Ma, D.; Tian, H. J. Chem. Soc., Perkin Trans. 1 1997,
493.
2857. (b) Iwakubo, M.; Takami, A.; Okada, Y.; Kawata, T.;
Tagami, Y.; Ohashi, H.; Sato, M.; Sugiyama, T.; Fukushima,
K.; Iijima, H. Bioorg. Med. Chem. 2007, in press. (c) De
Angelis, M.; Stossi, F.; Carlson, K. A.; Katzenellenbogen,
B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2005, 48,
(
3
(
18) Kumar, K.; Zapf, A.; Michalik, D.; Tillac, A.; Heinrich, T.;
Böttcher, H.; Arlt, M.; Beller, M. Org. Lett. 2004, 6, 7.
1132.
Synlett 2007, No. 8, 1203–1206 © Thieme Stuttgart · New York