rearrangements have been reported,10 but they require either
the presence of an activated methyl carbon ortho to the
nitrogen functionality or a good leaving group to generate
the N-aryl bond. Still other groups have used alkyne
precursors11 for indazole synthesis, although the more
reactive azide is necessary for cyclization.
Table 1. Effect of R Group on the Yield of Cinnoline (2) and
Isoindazole (3)
To determine the generality of the cyclization of triazenes
under neutral conditions, we synthesized a series of (4-
substituted-2-ethynylphenyl)triazenes which were heated in
o-dichlorobenzene to generate the cinnoline and isoindazole
products. Reactions were performed in a sealed glass pressure
tube previously open to air.12 A temperature of 170 °C was
necessary for each reaction to go to completion in 24 h. The
results are summarized in Table 1. In most cases the cinnoline
product dominated or was produced in amounts almost equal
to the isoindazole. It is noteworthy that the highest yields of
isoindazole occurred in the case of electron-withdrawing
substituents para to the triazene. A unique feature of this
synthetic route is the preparation of cinnolines and isoinda-
zoles that might not withstand typical acid-catalyzed cy-
clization conditions (entries h, i).
entry
R
cinnoline (2)a,b
isoindazole (3)a
a
b
c
d
e
f
H
35% (99%)
51% (97%)
61% (98%)
39% (83%)
70% (98%)
58% (97%)
35% (90%)
28% (96%)
45% (98%)
25% (93%)
55%
20%
22%
36%
15%
14%
25%
63%
50%
60%
Me
t-Bu
CtCH
Br
Cl
F
g
h
i
CO2Me
CN
NO2
jc
We have found little correlation between the amount of
water present or solvent effects and the product yield/
distribution. Neither heterocycle arises from the other.
Heating pure samples of each results in recovery of
unchanged material. The addition of water has no effect,
whereas a strict oxygen environment inhibits the reaction.
Heating the triazene precursors in nitrobenzene produces
similar yields, while other common organic solvents (ben-
zene, toluene, acetonitrile, etc.) do not produce appreciable
amounts of products. We have had some success in changing
the ratio of cinnoline to isoindazole produced. Specifically,
the cyclization reaction is temperature sensitive and will
generate the cinnoline compounds in high yield (90%) at
elevated temperatures (ca. 200 °C). Since the triazene
precursors are easily synthesized in four steps from readily
available starting materials, the excellent efficiency of this
high-temperature cinnoline synthesis corresponds to an
overall yield of ca. 65% for each substituent.
a Yield at 170 °C. b Yield at 200 °C in parentheses. c Yields using the
N,N-pentamethylene triazene derivative.
pseudo-Michael type fashion. Although other routes to
cinnolines have been reported,7 the Richter cyclization is by
far the most prevalent. Recently, this type of cyclization has
been modified to include triazenes in a solid-phase synthesis
of cinnolines;8 however, acidic media were necessary to
regenerate a diazonium which could cyclize in typical Richter
fashion. A significant limitation to the Richter method is that
synthesis of the cinnoline backbone necessitates substitution
at the 4- and often 3-position.6 For cinnolines having R
groups exclusively on the benzene portion, extensive trans-
formations and often harsh conditions are required to remove
substituents on the pyridazine ring. This restricts both the R
groups that can be used as well as the overall yield.
At lower temperatures, cinnoline formation occurs pref-
erentially to the isoindazole, but considerable starting material
is present even after 4 d at 145 °C. Although addition of a
radical trap (1,4-cyclohexadiene) has no effect on the yield
nor are trapped products observed, it is interesting to note
that for the fluoro compound (entry g) a third heterocycle,
6-diethylaminocinnoline, is produced in modest yield (ca.
35%). As activated aryl fluorides are excellent candidates
for nucleophilic aromatic substitution, this result suggests
that diethylamine is generated during cinnoline formation.
The synthesis of indazoles and isoindazoles is typically
carried out in acidic media using either an aryl azide or a
diazonium as the N-N source as well as an activated alkyl
or vinyl group ortho to the nitrogen group.9 Some thermal
(6) (a) Simpson, J. C. E. In The Chemistry of Heterocyclic Compounds.
Condensed Pyridazine and Pyrazine Rings (Cinnolines, Phthalazines, and
Quinoxalines); Weisberger, A., Ed.; Interscience Publishers: New York,
1953; p 3. (b) Tretyakov, E. V.; Knight, D. W.; Vasilevsky, S. F. J. Chem.
Soc., Perkin Trans. 1 1999, 24, 3721. (c) Vasilevsky, S. F.; Tretyakov, E.
V. Liebigs Ann. 1995, 775. (d) van der Plas, H. C.; Bourman, D. J.; Vos,
C. M. Recl. TraV. Chim. Pays-Bas 1978, 97, 50.
(7) Somei, M.; Kurizuka, Y. Chem. Lett. 1979, 127.
(8) Bra¨se, S.; Dahmen, S.; Heuts, J. Tetrahedron Lett. 1999, 40, 6201.
(9) (a) Elderfield, R. C. In Heterocyclic Compounds; Elderfield, R. C.,
Ed.; John Wiley & Sons: New York, 1957; Vol. 5, p 162. (b) Behr, L. C.;
Fusco, R.; Jarobe, C. H. In Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles
and Condensed Rings; Wiley, R. H., Ed.; International Wiley Science: New
York, 1969; p 289. For more recent examples, see: (c) Sun, J. H.; Teleha,
C. A.; Yan, J. S.; Rodgers, J. D.; Nugiel, D. A. J. Org. Chem. 1997, 62,
5627. (d) Baraldi, P. G.; Cacciari, B.; Spalluto, G.; Romagnoli, R.; Zaid,
A. N.; de las Infantes, M. J. P. Synthesis 1997, 1140. (e) Molina, P.; Arques,
A.; Vinader, M. V. J. Org. Chem. 1990, 55, 4724. (f) Dell’Erba, C.; Novi,
M.; Petrillo, G.; Tavani, C. Tetrahedron 1994, 50, 3529. (g) Kim, J. I.;
Kim, B. C.; Moon, S. W.; Jahng, Y. Heterocycles 1995, 41, 1471.
(10) (a) Halley, F.; Sava, X. Synth. Commun. 1997, 27, 1199. (b) Canlet,
C.; Khan, M. A.; Fung, B. M.; Roussel, F.; Judeinstein, P.; Bayle, J. P.
New. J. Chem. 1999, 23, 1223.
(11) (a) Prikhod’ko, T. A.; Vasilevsky, S. F. MendeleeV Commun. 1998,
149. (b) Prikhod’ko, T. A.; Vasilevsky, S. F. MendeleeV Commun. 1996,
98.
(12) General cyclization conditions: A solution of N,N-diethyl-N′-(4-
substituted-2-ethynylphenyl)triazene in o-dichlorobenzene (4 mL, 0.035 M)
was heated in a sealed glass pressure tube to 170 °C. After 24 h of stirring,
the tube was cooled and the solvent was evaporated. Preparative TLC (1:
1:4 CH2Cl2:EtOAc:hexanes) provided the isoindazole (Rf ) 0.50-0.65) and
cinnoline (Rf ) 0.10-0.20) products, respectively.
3826
Org. Lett., Vol. 2, No. 24, 2000