Copper-catalyzed mild and efficient entry to 1-substituted indazolones

Article abstract of DOI:10.1055/S-2008-1077973

A variety of 1-alkyl- and aryl-substituted indazolones were synthesized easily starting from commercially available 2-halobenzoic acids and hydrazines via the copper-catalyzed intramolecular C-N bond formation of 2-halobenzohydrazides under mild conditions.

Full text of DOI:10.1055/S-2008-1077973

LETTER
1973
Copper-Catalyzed Mild and Efficient Entry to 1-Substituted Indazolones
Synthesis of
1h
in
Department of Bioscience and Informatics, Graduate School of Life and Environmental Sciences, Osaka Prefecture University,
1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan
Fax +81(72)2549918; E-mail: tanimori@bioinfo.osakafu-u.ac.jp
Received 17 April 2008
C3H5)Cl]2, dppf, and K2CO3 in THF at reflux gave a com-
plex mixture. On the other hand, the reaction of 1 with the
use of copper(I) iodide, L-proline,14 and K2CO3 in DMSO
at 70 °C for three hours produced cyclized product 215 in
91% yield. To delight of the result, we next examined the
some reaction conditions using tert-butyl hydrazide 1
(X = I, Y = H, R = t-Bu), and the results are summarized
in Table 1. The coupling reaction proceeded even at room
temperature16 in the presence of 10 mol% of CuI, 20
mol% of L-proline, and two equivalents of potassium car-
bonate in absolute DMSO (entry 2) for three hours to give
indazolone 2 in 82% isolated yield. In the absence of L-
proline, the reaction also proceeded to give product 2 in
82% yield, but the purity of product was somewhat low
(entry 3). Unpurified DMSO gave a slightly better result
than dry DMSO, probably due to the accelerating effect of
the reaction rate by small amount of water present (entry
4).17 When the catalytic amount was reduced to 5 mol%
and 1 mol%, the yields were declined to 79% and 63%, re-
spectively (entries 5 and 6), but still good to nice yield.
Abstract: A variety of 1-alkyl- and aryl-substituted indazolones
were synthesized easily starting from commercially available 2-ha-
lobenzoic acids and hydrazines via the copper-catalyzed intramo-
lecular C–N bond formation of 2-halobenzohydrazides under mild
conditions.
Key words: indazolone, copper, proline, coupling, hydrazide
Indazolones and derivatives are an important structural
motif for pharmaceutical development.1 For instance,
there are a lot of drugs and candidates possessing such
structure including pathway-selective estrogen receptor
ligands,2 inhibitors against sodium nitroprusside-induced
apoptosis,3 antiplatelet agents,4 selective rhokinase inhib-
itors.5 For the reason, there are huge amount of letters
dealing with the synthetic methods for indazolones and
derivatives, which include palladium-catalyzed intramo-
lecular amination reaction,6 N–N bond formation through
a PIFA-mediated oxidative cyclization,7 copper-catalyzed
cyclization of 2-haloarylcarbonylic compounds,8 cycliza-
tion of O-aminobenzoxime by selective activation of the
oxime,9 the [3+2] cycloaddition of diazo compounds with
arynes and subsequent acyl migration,10 and N–N bond-
forming heterocyclization.11 But some examples require
harsh reaction conditions, long reaction steps, stoichio-
metric amount of reagents, and low efficiency, so that the
development of mild, flexible, and efficient method for
the access to indazolones and derivatives is still highly de-
sirable. In this paper we report a simple and mild method
for the preparation of 1-substituted indazolones 2 from 2-
halobenzoic acid via copper-mediated intramolecular C–
We next focused on the examination of the scope of this
reaction. A variety of 1-substituted indazolones were syn-
thesized from the corresponding 2-halobenzohydrazides
including 2-bromo and 2-chloro series using the opti-
mized conditions (Table 1, entry 4), and the results are
summarized in Table 2.18 2-Bromo- and 2-chlorobenzhy-
drazides also gave acceptable yield of products, although
the latter needed heating (70 °C) and prolonged reaction
time (entries 1 and 2). The acceptance of 2-bromo and 2-
chloro derivatives in this reaction would be of great ad-
vantage for synthesizing a variety of indazolone deriva-
tives, because the commercial source of the substituted 2-
iodobenzoic acids is limited. Overall, moderate to excel-
lent yields were observed except for entries 6 and 9.19 In
the case of entry 6, the steric influence of the methoxy
group would inhibit the cyclization to afford a low yield
of the product. The electron-withdrawing groups would
decrease the yield for some reason (entries 9 and 5).
N
bond formation12 of 2-halobenzohydrazide
(Scheme 1).
1
The starting hydrazides 1 were synthesized easily from 2-
halobenzoic acid and hydrazine by a standard method.13
Treatment of 1 (X = I, Y = H, R = Ph) with [Pd(h3-
R
X
N
metal catalyst
In conclusion, a mild and simple method for synthesizing
1-substituted indazolone derivatives has been developed
by the use of copper-catalyzed cyclization reaction. Fur-
ther studies directed toward the mechanistic investigation
of coupling process, derivation of the products,21 synthe-
ses of other derivatives such as 2-substituted indazolone,
and the biological study of the compounds obtained in this
study are now under investigation.
Y
H
N
R
Y
NH
N
H
O
O
1
2
Scheme 1 Proposed route to 1-substituted indazolone
SYNLETT 2008, No. 13, pp 1973–1976
x
x
.x
x
.2
0
0
8
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1077973; Art ID: U03708ST
© Georg Thieme Verlag Stuttgart · New York

1974
S. Tanimori et al.
LETTER
Table 1 Reaction Conditions of Copper-Catalyzed Intramolecular Coupling Reaction
R
X
N
H
N
NH
R
N
H
O
O
Entry
X
I
R
Cu salt (mol%) Additive (mol%)
Base
Solvent
Conditions
70 °C, 3 h
r.t., 3 h
Yield (%)a
1
2
3
4
5
6
Ph
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (5)
L-proline (20)
L-proline (20)
none
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
dry DMSO
dry DMSO
dry DMSO
wet DMSO
wet DMSO
wet DMSO
91
82
82
97
79
63
I
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
I
r.t., 3 h
I
L-proline (20)
L-proline (10)
L-proline (2)
r.t., 3 h
I
r.t., 3 h
I
CuI (1)
r.t., 3 h
a Isolated yield.
Table 2 Synthesis of 1-Substituted Indazolones
Entry
1
Acid hydrazide
Indazole
Yield (%)a
91 (X = I)
Ph
X
N
H
N
65 (X = Br)
Ph
NH
66 (X = Cl)b
N
H
O
O
t-Bu
X
N
97 (X = I)
62 (X = Br)
H
N
2
3
t-Bu
NH
N
H
O
O
I
96
60
H
N
N
O
O
O
N
H
N
H
O
I
H
N
4
5
N
N
N
H
N
H
O
X
NO2
50 (X = I)
51 (X = Br)
H
N
N
H
N
H
O
I
NO2
MeO
OMe
H
N
N
H
6
23
70
N
O
N
H
O
I
Bn
N
720
H
N
N
H
NH
Bn
O
O
Synlett 2008, No. 13, 1973–1976 © Thieme Stuttgart · New York

LETTER
Synthesis of 1-Substituted Indazolones
1975
Table 2 Synthesis of 1-Substituted Indazolones (continued)
Entry
Acid hydrazide
Indazole
Yield (%)a
63
Ph
Me
Br
Me
N
H
8
N
Ph
NH
N
H
O
O
Ph
Br
O
N
H
9
25
N
Ph
NH
F
N
H
F
O
Ph
Br
O
N
H
N
10
56
Ph
NH
MeO
N
H
MeO
O
a Isolated yield.
b At 70 °C for 12 h.
amination reaction of N′-aryl-N′-(o-bromobenzyl) acetyl-
hydrazines, but the reaction need higher reaction tempera-
ture (100–105 °C) and long reaction time (20 h) in a pressure
tube. See: Liu, R.; Zhu, Y.; Qin, L.; Ji, S.; Katayama, S.
Heterocycles 2007, 71, 1755.
References and Notes
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Solvibile, W. R.; Trybulski, E.; Chadwick, C. C.; Chippari,
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Teng, C.-M.; Kuo, S. C. J. Med. Chem. 2002, 45, 4947.
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D. J.; Bentley, R.; Doe, C. P.; Hu, E.; Lee, D. J. Med. Chem.
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(13) The acid hydrazides were synthesized from corresponding
acid chloride with hydrazine or the condensation of
2-halobenzoic acid with hydrazine using EDC.
(14) (a) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70,
5164. (b) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5,
2453.
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Wheeler, K. A.; Wishart, G.; Woo, C.-K. J. Med. Chem.
2001, 44, 78.
(16) For a recent example for copper-catalyzed C–N coupling
reactions at room temperature, see: Shafir, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2006, 128, 8742.
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(17) Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128,
16050.
(18) Typical Experimental Procedure – Synthesis of 1-tert-
butyl-1,2-dihydroindazol-3-one
(8) Viña, D.; Del Olmo, E.; López-Pérez, J. L.; San Feliciano,
A. Org. Lett. 2007, 9, 525.
The mixture of 2-iodobenzoic acid N¢-tert-butylhydrazide
(0.32 g, 1.0 mmol), CuI (19 mg, 0.10 mmol, 10 mol%), L-
proline (23 mg, 0.20 mmol, 20 mol%), and K2CO3 (0.28 g,
2.0 mmol) in DMSO (10 mL) was stirred at r.t. for 3 h under
nitrogen atmosphere. The mixture was treated with H2O and
the mixture was extracted three times with EtOAc. The
combined organic layer was washed with H2O and brine, and
dried over MgSO4. After filtration, solvent was evaporated
in vacuo to ca. 1 mL and crystallization afforded 1-tert-
butyl-1,2-dihydroindazole-3-one (0.19 g, 97%) as white
crystals. Rf = 0.36 (hexane–EtOAc, 1:1); mp 115–117 °C. IR
(KBr): 2979 (NH), 1648 (C=O), 1538, 1209, 748 cm–1. 1H
NMR (400 MHz, DMSO): d = 10.47 (br s, 1 H, NH), 7.61 (d,
1 H, J = 8.5 Hz, C-4), 7.59 (d, 1 H, J = 7.8 Hz, C-7), 7.26
(dd, 1 H, J = 6.8, 8.5, Hz, C-5), 6.96 (dd, 1 H, J = 6.8, 7.8
Hz, C-6), 1.60 (s, 9 H, t-Bu). 13C NMR (136 MHz, DMSO):
d = 152.8, 139.5, 126.4, 120.1, 118.2, 113.9, 111.9, 58.3,
(9) Counceller, C. M.; Eichman, C. C.; Wray, B. C.; Stambuli,
J. P. Org. Lett. 2008, 10, 1021.
(10) Liu, Z.; Shi, F.; Martinez, P. D. G.; Raminelli, C.; Larock, R.
C. J. Org. Chem. 2008, 73, 219.
(11) (a) Mills, A. D.; Nazer, M. Z.; Haddadin, M. J.; Kurth, M. J.
J. Org. Chem. 2006, 71, 2687. Forsomeother referencesfor
the synthesis of indazolone analogues, see: (b) Baiocchi, L.;
Corsi, G.; Palazzo, G. Synthesis 1978, 633. (c) Barton, D.
H. R.; Lukacs, G.; Wagle, D. J. Chem. Soc., Chem. Commun.
1982, 450. (d) Wyrick, S. D.; Voorstad, J.; Cocolas, G.;
Hall, I. H. J. Med. Chem. 1984, 27, 768. (e) Bruneau, P.;
Delvare, C. J. Med. Chem. 1991, 34, 1028.
(12) (a) For a recent example for copper-catalyzed intramolecular
C–N coupling reaction, see: Lu, H.; Li, C. Org. Lett. 2006,
8, 5365. (b) During the preparation of this manuscript, Zhu
and co-workers disclosed their studies on the synthesis of 2-
aryl-2H-indazoles via copper(I)-catalyzed intramolecular
Synlett 2008, No. 13, 1973–1976 © Thieme Stuttgart · New York

1976
S. Tanimori et al.
LETTER
29.3 (3 × C). ESI-HRMS: m/z calcd for C11H14N2O
191.1179; found: 191.1182.
indazolone to recover the starting material even at heating
conditions (>100 °C).
(19) Acid hydrazide derived from 2,4,6-trichlorophenyl-
hydrazine, tert-butylcarbazide, benzoylhydrazine, and
p-toluenesulfonylhydrazine did not afford the corresponding
(20) Gordon, D. W. Synlett 1998, 1065.
(21) A variety of compounds possessing pharmaceutical profile
have been prepared from indazolone derivatives, see ref. 15.
Synlett 2008, No. 13, 1973–1976 © Thieme Stuttgart · New York