Synthesis of 1-aryl-1H-indazoles via a ligand-free copper-catalyzed intramolecular amination reaction

Article abstract of DOI:10.1002/cjoc.201190223

A general synthesis of 1-aryl-1-H-indazoles from o-halogenated aryl aldehydes or ketones and aryl hydrazines was described. This protocol included an intermolecular condensation and a ligand-free copper-catalyzed intramolecular Ullmann-type coupling react

Full text of DOI:10.1002/cjoc.201190223

FULL PAPER
Synthesis of 1-Aryl-1H-indazoles via a Ligand-Free Copper-
Catalyzed Intramolecular Amination Reaction
Gao, Mingshana(高明山)
Liu, Xiujiea(刘秀洁)
Wang, Xianyangb(汪仙阳)
Cai, Qian*,a(蔡倩)
Ding, Ke*,a(丁克)
a Key Laboratory of Regenerative Biology and Institue of Chemical Biology, Guangzhou Institutes of Biomedicine
and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
b Jiangsu Provincial Institute of Materia Medica, Nanjing University of Technology, Nanjing, Jiangsu 210009，
China
A general synthesis of 1-aryl-1-H-indazoles from o-halogenated aryl aldehydes or ketones and aryl hydrazines
was described. This protocol included an intermolecular condensation and a ligand-free copper-catalyzed in-
tramolecular Ullmann-type coupling reaction. This method was applied to a wide range of substrates to produce the
indazole products in good yields.
Keywords copper, amination, ligand free
Introduction
Herein we reported a simple and efficient two-step syn-
thesis of 1-aryl-1H indazoles from o-halo arylaldehydes
or ketones with aryl hydrazines under the catalysis of
0.1 mol% of CuI without a supporting ligand (Scheme
1).
The 1-aryl-1H-indazole fragment is well recognized
in many biologically active and pharmaceutically im-
portant compounds which exhibit potent antitumor,1
antidepressant,2 anti-HIV,3 anti-inflammatory4 or con-
traceptive activity.5 Great efforts have been devoted to
the development of method for synthesizing this kind of
compounds.6 Classical methods included intramolecular
reduction of o-nitrobenzylamin,7 Pd-catalyzed cycliza-
tion of arylhydrazones or arylhadrzines with o-haloaryl
aldehyde,8 and condensation-nucleophilic substitution
cascade process of 2-haloarylcarbonylic compounds
with hydrazines etc.9
Scheme 1 Two-step synthesis of 1-aryl-1H indazoles
In the past years, Ullmann-type C-N coupling reac-
tions have been extensively studied and applied for the
preparation of highly diversified heterocycles.10 Cop-
per-catalyzed N-arylation has been successfully adapted
to the synthesis of 1H-indazole derivatives.11 For in-
stance, Olmo et al.11b have reported a CuO-promoted
synthesis of 1-aryl or 1-alkyl-1H-indazoles through an
amination-dehydration cascade process of 2-chloro or
2-fluoroarylcarbonylic compounds with hydrazines at
110 ℃ . Liu and colleagues11c also reported that
1-aryl-1H-indazoles could be efficiently synthesized
from a CuI (5 mol%) catalyzed intramolecular amina-
tion reaction of arylhydrazones with the assistance of 10
mol% of 1,10-phenanthroline. Furthermore, copper-
catalyzed construction of heterocycles under ligand-free
conditions has recently attracted much attention due to
its environmental benignity and atom economy.12
Results and discussion
The investigation was initiated by the preparation of
1-phenyl-1H-indazole (5) using o-bromobenzaldehyde
and phenyl hydrazine as starting materials (Table 1).
Firstly, the condensation of o-bromobenzaldehyde and
phenyl hydrazine in the presence of HOAc almost quan-
titatively yielded arylhydrazone intermediate 4. After
removing the solvent, the intermediate was successfully
transformed to 1-phenyl-1H-indazole (5) in about 68%
yield, under the catalysis of 1.0 mol% CuI at 80 ℃
(Table 1, Etnry 2). The results also indicated that CuI
was essential for the cyclizaton, and no desired product
*
E-mail: cai_qian@gibh.ac.cn or ding_ke@gibh.ac.cn; Tel.: 0086-020-32015226 or 0086-020-32015276; Fax: 020-32015298 or 0086-020-32015298
Received October 11, 2010; revised January 14, 2011; accepted February 21, 2011.
Project supported by the National Natural Science Foundation of China (No. 21002102), and State Key Laboratory of Bioorganic and Natural Prod-
ucts Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences (No. 10184).
Chin. J. Chem. 2011, 29, 1199— 1204
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Gao et al.
FULL PAPER
Table 1 Optimization of reaction conditions of o-bromoben-
zaldehyde with benzene hydrazinea
with 1.0 mol% CuI as catalyst. However, a moderate
yield was obtained when elevating the reacting tem-
perature to 120 ℃ with an increasing catalyst loading
(Table 2, Entry 12). The reacting efficiency of
1-(2-chlorophenyl)ethanone was also evaluated, and no
desired product was detected even if the reaction was
performed under much more harsh conditions.
Heterocyclic fused pyrazoles are especially attractive
compounds because of their unique structures and
pharmaceutical importance. Therefore we further inves-
tigated the potential application of this new method for
the synthesis of the heterocyclic fused pyrazoles. As
shown in Table 3, the protocol worked well for o-bromo
or o-chloro heteroaryl aldehydes and ketones. For in-
stance, 2-bromo-3-pyridine aldehyde easily yielded the
desired products with satisfactory yields by reacting
with different aryl hydrazines under the catalysis of 0.1
mol% CuI at 100 ℃ (Table 3, Entries 1 and 2).
3-Bromofuran-2-carbaldehyde gave a similar result (Ta-
ble 3, Entry 3). More importantly, the method was
highly efficient for the o-chloro ketone substrates when
the reactions were performed at 120 ℃ with 10 mol%
CuI as catalyst (Table 3, Entry 4).
Entry
CuI/mol%
—
Solvent
DMF
Base
Cs2CO3
Cs2CO3
K2CO3
NaOH
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Yieldb/%
n.d.c
68
1
2
3
4
5
6
7
8
9
1.0
DMF
1.0
DMF
45
1.0
DMF
24
1.0
DMF
63
1.0
DMSO
Dioxane
Toluene
DMSO
67
1.0
n.d.c
n.d.c
84d
1.0
0.1
a
Reaction conditions: o-bromobenzaldehyde (1.0 mmol), ben-
zene hydrazine (1.0 mmol), CuI, base (2.0 mmol), solvent (1.0
mL), 80 ℃. b Isolated yields. c No desired products. d 100 ℃.
was detected in the absence of copper catalysts (Table 1,
Entry 1). Other copper salts such as CuBr and CuCl
gave significantly worse results. The reaction condition
screen suggested that K3PO4 and DMSO were the opti-
mal base and solvent respectively (Table 1, Entries
3—6). More significantly, further investigation revealed
that 0.1 mol% of CuI was sufficient to catalyze the cy-
clization with an excellent yield at a slightly elevated
temperature (Table 1, Entry 9). Thus, the combination
of 0.1 mol% of CuI, K3PO4 in DMSO was chosen as the
optimal conditions for further exploration at 100 ℃.
The scope of this new protocol was further explored
by using a variety of combinations of o-halophenyl al-
dehydes or ketones with hydrazines under the optimized
conditions. As showed in Table 2, the electronic proper-
ties of o-halophenyl aldehydes or ketones seemed to
have little influence on the reacting efficiency. Both the
electron-rich and electron-deficient o-bromobenzald-
edydes could deliver the corresponding products with
excellent yields (Table 2, Entries 1—4), except that
1-bromo-2-naph-aldehyde gave a much lower yield
(Table 2, Entry 5), which might be due to a steric hin-
drance of 8-H in the 1-bromo-2-naph-aldehyde substrate.
The protocol also worked well for the other aryl
hydrazines with o-bromophenyl aldehydes or ketones
(Table 2, Entries 6—9). It was noteworthy that
3-substituted indazoles were also produced with excel-
lent yields when using 2-bromophenyl ketones as the
starting materials (Table 2, Entries 10 and 11).
Conclusion
In summary, a simple and efficient protocol for the
synthesis of 1-aryl-1H-indazoles was developed. This
method involved an intermolecular condensation fol-
lowed by a ligand-free copper-catalyzed intramolecular
Ullmann-type coupling reaction, and could be applied to
a wide range of substrates to produce the indazole
products in good yields. Most importantly, only 0.1
mol% CuI catalyst was needed for the reaction systems
of aryl bromide substrates. Our effort may become an
attractive addition to the synthesis of biological impor-
tant 1-aryl-1H-indazole analogues.
Experimental
All reagents and solvents were purchased from
commercial sources and were used without further puri-
fication. 1H and 13C NMR spectra were measured at 400
MHz.
Typical experiment procedure for the two-step syn-
thesis of indazoles
The mixture of aryl halide (1 mmol), aryl hydrazine
(1 mmol) and acetic acid (trace) was refluxed in EtOH
until the transformation to aryl hydrazone was com-
pleted (monitored by TLC, about 2 h). The solvent was
evacuated. CuI, K3PO4 (2.0 mmol) and DMSO (1.0 mL)
were added, and the mixture was heated under the indi-
cated temperature for about 12 h in Ar atmosphere. Af-
ter cooling to room temperature, the mixture was par-
tioned between water and ethyl acetate. The organic
phase was separated and washed with brine, then dried
over Na2SO4 and concentrated under vacuum. The resi-
due was loaded on the silic gel column to give the
It is well known that aryl chlorides are highly chal-
lenging substrates for most of Ullmann-type coupling
reactions.10 We also wished to investigate if our new
protocol worked well for o-chlorobenzaldehyde sub-
strates. Only a trace amount of the desired product was
detected when the reaction was carried out at 100 ℃
1200
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Chin. J. Chem. 2011, 29, 1199— 1204

Synthesis of 1-Aryl-1H-indazoles via Intramolecular Amination Reaction
Table 2 Synthesis of indazoles from o-halogenated aryl aldehydes or ketones with aryl hydrazinesa
Entry
1
Aryl halide
Hydrazine
PhNHNH2
Product
Yieldb/%
85
2
3
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
81
93
96
36
52
75
64
70
81
4
5
6
7
8
9
10
PhNHNH2
PhNHNH2
PhNHNH2
11
12
82
50c
a CuI (0.1 mol%), K3PO4 2.0 mmol, DMSO 1 mL, 100 ℃. b Isolated yield. c 10 mol% CuI, 120 ℃, only trace amount of product was
found at 100 ℃ with 1 mol% CuI.
Chin. J. Chem. 2011, 29, 1199— 1204
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Gao et al.
FULL PAPER
Table 3 Reactions of o-halogenated heteroaryl aldehydes or
100 MHz) δ: 139.71, 137.19, 135.64, 130.22, 128.15,
127.46, 126.46, 122.75, 121.09, 112.71; ESI＋-MS m/z
(%): 229.1 ([M＋H]＋, 100), 231.1 ([M＋3] , 32.0);
HRMS (ESI) calcd for C13H9ClN2 [M＋H]＋ 229.0537,
found 229.0532.
ketones with aryl hydrazinesa
Entry Aryl halide
1
Hydrazine
PhNHNH2
Product
Yieldb/%
85
1-Phenyl-5-(trifluoromethyl)-1H-indazole
(8d)
1
White solid, m.p. 102—104 ℃; H NMR (CDCl3, 400
MHz) δ: 8.30 (s, 1H), 8.13 (s, 1H), 7.83 (d, J＝7.2 Hz,
1H), 7.73 (d, J＝8.8 Hz, 2H), 7.66 (d, J＝7.2 Hz, 1H),
7.57 (t, J＝8.8 Hz, 2H), 7.42 (t, J＝8.8 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ: 139.73, 139.55, 136.14,
129.66, 127.43, 124.48, 123.75, 123.72, 123.0＋5, 119.55,
119.50, 111.06; ESI-MS m/z: 263.1＋[M＋H] ; HRMS
(ESI) calcd for C14H9F3N2 [M＋H] 263.0791, found
263.0787.
2
4-Cl-PhNHNH2
57
1-Phenyl-1H-benzo[g]indazole (8e) White solid,
m.p. 107— 109 ℃; 1H NMR (DMSO, 400 MHz) δ: 8.37
(s, 1H), 8.07 (d, J＝8.0 Hz, 1H), 7.87 (d, J＝8.8 Hz,
1H), 7.86— 7.62 (m, 6H), 7.55 (t, J＝8.0 Hz, 1H), 7.46
(d, J＝8.4 Hz, 1H), 7.38 (t, J＝7.2 Hz, 1H); 13C NMR
(DMSO, 100 MHz) δ: 141.87, 136.00, 135.85, 133.35,
130.23, 129.86, 129.59, 127.69, 126.86, 126.48, 123.50,
121.77, ＋121.74, 120.51, 119.79; ESI-MS m/z: 245.＋1
[M＋H] ; HRMS (ESI) calcd for C17H12N2 [M＋H]
245.1073, found 245.1075.
3
4
5
PhNHNH2
PhNHNH2
PhNHNH2
50
86
90
1-(4-Methoxyphenyl)-1H-indazole (8f)
White
solid, m.p. 34— 36 ℃ (lit.8a 35—38 ℃); H NMR
(DMSO, 400 MHz) δ: 8.32 (d, J＝0.8 Hz, 1H), 7.88 (d,
J＝8.1 Hz, 1H), 7.77 (d, J＝8.1 Hz, 1H), 7.66 (d, J＝
2.0 Hz, 1H), 7.46 (t, J＝7.2 Hz, 1H), 7.24 (d, J＝7.2 Hz,
1H), 7.16 (d, J＋＝2.0 Hz, 1H), 3.85 (s, 3H); ESI-MS m/z:
225.1 [M＋H] .
1
a Reaction conditions: for aryl bromides, CuI (0.1 mol%), K3PO4
(2.0 mmol), DMSO (1 mL), 100 ℃; for aryl chlorides CuI (10
mol%), 120 ℃. b Isolated yields.
1-(4-Chlorophenyl)-1H-indazole (8g) Yellow oil;
1H NMR (DMSO, 400 MHz) δ: 8.41 (s, 1H), 7.92 (d,
J＝8.0 Hz, 1H), 7.87 (d, J＝8.0 Hz, 1H), 7.83 (d, J＝
8.8 Hz, 2H), 7.66 (d, J＝8.8 Hz, 2H), 7.52 (t, J＝7.6 Hz,
1H), 7.29 (t, J＝7.6 Hz, 1H); ESI-MS m/z: 229.0 [M＋
H]＋ (100), 231.0 [M＋3]＋ (32.0).
product.
1-Phenyl-1H-indazole
(5)
White
solid,
m.p.78—80 ℃ (lit.8a 76—78 ℃); 1H NMR (CDCl3, 400
MHz) δ: 8.21 (s, 1H), 7.82 (d, J＝8.0 Hz, 1H), 7.75 (t,
J＝8.0 Hz, 3H), 7.54 (t, J＝8.0 Hz, 2H), 7.44 (t, J＝7.2
Hz, 1H), 7.37 (t, J＝7.2 Hz, 1H), 7.23—7.21 (m, 1H);
ESI-MS m/z: 195.0 [M＋H]＋.
1-(4-Fluorophenyl)-6-methyl-1H-indazole
(8h)
White solid, m.p. 56— 58 ℃ (lit.8a 52—54 ℃); 1H NMR
(CDCl3, 400 MHz) δ: 8.13 (d, J ＝ 0.8 Hz, 1H),
7.69— 7.66 (m, 3H), 7.45 (s, 1H), 7.25— 7.21 (m, 2H),
7.06 (dd, J＝8＋.4, 0.8 Hz, 1H), 2.51 (s, 3H); ESI-MS m/z:
227.1 [M＋H] .
1-Phenyl-6-methyl-1H-indazole (8a) White solid,
m.p. 86—87 ℃ (lit.8a 84—86 ℃); H NMR (DMSO,
1
400 MHz) δ: 8.29 (d, J＝0.4 Hz, 1H), 7.77—7.74 (m,
3H), 7.64 (s, 1H), 7.57 (t, J＝7.4 Hz, 2H), 7.41 (t, J＝
7.4 Hz, 1H), 7.11 (dd, J＝8.＋0, 0.4 Hz, 1H), 2.47 (s, 3H);
ESI-MS m/z: 255.1 [M＋H] .
1-(4-Methoxyphenyl)-5-(trifluoromethyl)-1H-
indazole (8i) White solid, m.p. 115— 117 ℃; 1H
NMR (CDCl3, 400 MHz) δ: 8.27 (s, 1H), 8.11 (s, 1H),
7.71 (d, J＝0.4 Hz , 1H), 7.62— 7.57 (m, 3H), 7.09 (dd,
J＝6.8, 2.0 Hz , 2H), 3.89 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ: 158.94, 139.95, 135.59. 132.60, 124.83,
124.05, 124.00, 123.52, 123.49, 119.47, 119.4＋2, 114.78,
110.88, 55.64; ESI-MS m/z: 293.1 [M＋H] ; HRMS
(ESI) calcd for C15H11F3N2O [M ＋ H] ＋ 292.0896,
found 293.0899.
5,6-Dimethoxy-1-phenyl-1H-indazole (8b) White
1
solid, m.p. 91—92 ℃; H NMR (DMSO, 400 MHz) δ:
8.14 (d, J＝0.8 Hz, 1H), 7.79 (d, J＝8.0 Hz, 2H), 7.58 (t,
J＝8.0 Hz, 2H), 7.38 (t, J＝8.0 Hz, 1H), 7.28 (s, 1H),
7.21 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H); ESI-MS m/z:
209.1 [M＋H]＋.
5-Chloro-1-phenyl-1H-indazole (8c) White solid,
m.p. 116—117 ℃; 1H NMR (DMSO, 400 MHz) δ: 8.37
(s, 1H), 8.00 (s, 1H), 7.87 (d, J＝8.8 Hz, 1H), 7.77 (d,
J＝7.2 Hz, 2H), 7.61 (t, J＝7.2 Hz, 2H), 7.51 (d, J＝8.8
Hz, 1H), 7.46 (t, J＝7.2 Hz, 1H); 13C NMR (DMSO,
1-Phenyl-3-methyl-1H-indazole (8j) White solid,
1
m.p. 73— 74 ℃ (lit.13 73—74 ℃); H NMR (CDCl3,
400 MHz) δ: 7.74 (dd, J＝8.8, 1.2 Hz, 4H), 7.52 (t, J＝
7.6 Hz, 2H), 7.43 (m, 1H), 7.33 (t, J＝7.6 Hz, 1H), 7.21
1202
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1199— 1204

Synthesis of 1-Aryl-1H-indazoles via Intramolecular Amination Reaction
(t, J＝7.6 Hz, 1H), 2.67 (s, 3H); ESI-MS m/z: 208.7 [M
＋H]＋.
Iwasaki, T. Arzneim. Forsch. 1979, 29, 511.
3
(a) Sun, J.-H.; Teleha, C. A.; Yan, J.-S.; Rodgers, J. D.;
Nugiel, D. A. J. Org. Chem. 1997, 62, 5627.
3-Phenethyl-1-phenyl-1H-indazole (8k)
Pale
1
yellow oil; H NMR (CDCl3, 400 MHz) δ: 7.74 (d, J＝
8.4 Hz, 3H), 7.70 (d, J＝8.0 Hz, 1H), 7.54 (t, J＝7.6 Hz,
2H), 7.44— 7.30 (m, 6H), 7.26— 7.18 (m, 2H),
3.39— 3.35 (m, 2H), 3.24— 3.20 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ: 147.23, 141.77, 140.31, 139.50,
129.40, 128.49, 128.43, 127.06, 126.19, 126.05, 124.31,
122.54, 120.84, 120＋.52, 110.40,35.39, 29.18; ESI-MS
m/z: 299.1 [M＋H] ; HRMS (ESI) calcd for C21H18N2
[M＋H]＋ 298.1453, found 299.1542.
(b) Rodgers, J. D.; Johnson, B. L.; Wang, H.; Greenberg, R.
A.; Erickson-Viitanen, S.; Klabe, R. M.; Cordova, B. C.;
Rayner, M. M.; Lam, G. N.; Chang, C.-H. Bioorg. Med.
Chem. Lett. 1996, 6, 2919.
4
(a) Bistochi, G. A.; De Meo, G.; Pedini, M.; Ricci, A.;
Brouilhet, H.; Bucherie, S.; Rabaud, M.; Jacquignon, P.
Farmaco Ed. Sci. 1981, 36, 315.
(b) Picciola, G.; Ravenna, F.; Carenini, G.; Gentili, P.; Riva,
M. Farmaco Ed. Sci. 1981, 36, 1037.
1-Phenyl-1H-pyrazolo[3,4-b]pyridine (9a) White
5
6
Corsi, G.; Palazzo, G.; Germani, C.; Barcellona, P. S.;
Silvestrini, B. J. Med. Chem. 1976, 19, 778.
1
solid, m.p. 53— 55 ℃ (lit.14 53 ℃); H NMR (CDCl3,
400 MHz) δ: 8.63 (dd, J＝4.8, 1.6 Hz, 1H), 8.29 (d, J＝
7.2 Hz, 2H), 8.12 (s, 1H), 8.10 (dd, J＝7.2, 1.6 Hz, 1H),
7.56 (t, J＝7.2 Hz, 2H), 7.32 (t, J＝6.4 Hz, 1H), 7.＋21
(dd, J＝8.4, 4.8 Hz, 1H); ESI-MS m/z: 196.1 [M＋H] .
1-(4-Chlorphenyl)-1H-pyrazolo[3,4-b]pyridine (9b)
For reviews, see: (a) Elguero, J. In Comprehensive
Heterocyclic Chemistry, Vol 5, Eds.: Karizky, A. R.; Rees,
C. W., Pergamon Press, New York, 1984, p. 167.
(b) Behr, L. C.; Fusco, R.; Jarobe, C. H. In Pyrazoles,
Pyrazonlines, Pyrazolidines, Indazoles and Condensed
Rings, R. H. Wiley Int, New York, 1969, p. 28.
(a) Paal, C. Chem. Ber. 1891, 24, 959.
1
White solid, m.p. 100—101 ℃; H NMR (CDCl3, 400
MHz) δ: 8.63 (dd, J＝4.4, 1.6 Hz, 1H), 8.31 (dt, J＝8.8,
2.8 Hz, 2H), 8.20 (s, 1H), 8.15 (dd, J＝8.0, 1.6 Hz, 1H),
7.51 (dt, J＝8.8, 2.8 Hz, 2H), 7.25 (dd, J＝8.0, 4.4 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ: 150.13, 149.23,
138.12, 134.12, 131.34, 130.30, 129.15, 122.18, 117.81,
117.32; ESI-MS m/z (%): 230.0 ([M＋H]＋, 100), 232.0
([M＋3]＋, 32.1); HRMS (ESI) calcd for C12H8ClN3
[M＋H]＋ 230.0480, found 230.0484.
7
8
(b) Campi, E. M.; Habsuda, J.; Jackson, W. R.; Jonasson, C.
A. M.; McCubbin, Q. Aust. J. Chem. 1995, 48, 2023.
(c) Frontana-Uribe, B. A.; Moinet, C. Tetrahedron 1998, 54,
3197.
(a) Lebedev, A. Y.; Khartulyari, A. S.; Voskoboynikov, A.
Z. J. Org. Chem. 2005, 70, 596.
(b) Song, J. J.; Yee, N. K. Tetrahedron Lett. 2001, 42, 2937.
(c) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805.
1-Phenyl-1-H-furo[3,2-c]pyrazole (9c)
White
1
solid, m.p. 39— 40 ℃; H NMR (CDCl3, 400 MHz) δ:
7.65 (d, J＝2.0 Hz, 2H), 7.52 (s, 1H), 7.48 (d, J＝2.4
Hz, 1H), 7.38 (t, J＝2.4 Hz, 2H), 7.15 (t, J＝2.4 Hz,
1H), 6.67 (d, J＝2.0 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ: 150.28, 148.83, 140.36, 135.02, 129.45, 125.42,
121.05, 117.74, 99.36; ESI-MS m/z: 185.0 [M＋H]＋;
HRMS (ESI) calcd for C11H8N2O [M＋H]＋ 185.0797,
found 185.0713.
(d) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(a) Caron, S.; Vazquez, E. Synthesis 1999, 4, 588.
(b) Cui, J. J.; Araldi, G.-L.; Reiner, J. E.; Reddy, K. M.;
Kemp, S. J.; Ho, J. Z.; Siev, D. V.; Mamedova, L.; Gibson,
T. S.; Gaudette, J. A.; Minami, N. K.; Anderson, S.;
Bradbury, A. E.; Nolan, T. G.; Semple, J. E. Bioorg. Med.
Chem. Lett. 2002, 12, 2925.
9
3-Methyl-1-phenyl-1H-thieno[3, 2-c]pyrazole (9d)
Black soild, m.p. 45— 47 ℃ (lit.15 46—47 ℃); 1H NMR
(CDCl3, 400 MHz) δ: 7.77 (d, J ＝ 2.0 Hz, 2H),
7.54— 7.48 (m, 3H), 7.31— 7.25 (m, 2H), 2.57 (s, 3H);
ESI-MS m/z: 215.1 [M＋H]＋.
(c) Dehmlow, H.; Aebi, J. D.; Jolidon, S.; Ji, Y.-H.; Mark, E.
M.; Himer, J.; Morand, O. H. J. Med. Chem. 2003, 46,
3354.
10 For recent reviews about copper-catalysed Ullmann-type
coupling reactions, see: (a) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400.
5-Chloro-3-methyl-1-phenyl-1H-thieno[2,3-c]pyra-
zole (9e) White solid, m.p. 53—54 ℃; 1H NMR
(CDCl3, 400 MHz) δ: 7.67 (d, J＝8.8 Hz, 2H), 7.48 (t,
J＝8.8 Hz, 2H), 7.27— 7.23 (m, 1H), 6.93 (s, 1H), 2.50
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 142.27, 139.33,
137.98, 129.61, 127.68, 125.47, 117.45, 115.05, 13.02;
ESI-MS m/z (%): 249.9 ( [M＋H]＋, 100), 251.9 ([M＋
3]＋, 36.5); HRMS (ESI) calcd for C12H9ClN2S [M＋
H]＋ 249.0248, found 249.0248.
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11 (a) Pabba, C.; Wang, H.; Mulligan, S. R.; Chen, Z.; Stark, T.
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(b) Vina, D.; Olmo, E.; Lopez-Perez, J. L.; Feliciano, A. S.
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1204
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1199— 1204