Synthesis of pyrazolo[1,5-a]indoles via copper(I)-catalyzed intramolecular amination

Article abstract of DOI:10.1016/j.tetlet.2007.07.033

A variety of pyrazolo[1,5-a]indole derivatives were synthesized via Cu(I)-catalyzed intramolecular amination reactions. This novel method provides a general and efficient synthesis to indoles fused with pyrazole rings in high yields.

Full text of DOI:10.1016/j.tetlet.2007.07.033

Tetrahedron Letters 48 (2007) 6262–6266
Synthesis of pyrazolo[1,5-a]indoles via
copper(I)-catalyzed intramolecular amination
Yong-Ming Zhu,a,* Lie-Na Qin,a Rui Liu,a Shun-Jun Jia and Hajime Katayamab
aCollege of Pharmacy, Soochow University, Ren-ai Road, Suzhou Industrial Park, Suzhou 215123, People’s Republic of China
bCollege of Pharmacy, Kinjo Gakuin University, 2-1723 Ohmori, Moriyama-Ku, Nagoya City 463-8521, Japan
Received 9 May 2007; revised 4 July 2007; accepted 6 July 2007
Available online 30 July 2007
Abstract—A variety of pyrazolo[1,5-a]indole derivatives were synthesized via Cu(I)-catalyzed intramolecular amination reactions.
This novel method provides a general and efficient synthesis to indoles fused with pyrazole rings in high yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The construction of substituted pyrazolo[1,5-a]indole
skeleton has been our long-standing interest because it
was reported for the first time by Katayama that pyraz-
olo[1,5-a]indole derivatives (e.g., derivative A Fig. 1)
have fairly potent inhibitory activity against DNA
topoisomerases I and II, and have strong cytotoxic
activity against cancer cells.1 Further study on the struc-
ture activity relationship (SAR) clarified that the size
and polarity of the substituents were crucial for its activ-
ity.2 The initial results prompted us to figure out a vari-
ety of pyrazolo[1,5-a]indole derivatives in the hopes of
expanding the scope. Although, Alley3 and Padwa4
reported many years ago that 4-oxopyrazolo[1,5-a]indo-
line and 9,9a-dihydro-1H-pyrazolo[2,3-a]indole-2-car-
boxylate were synthesized during their experiments,
further exploration on this subject had not been found.
According to Katayama et al.,5–7 several methods have
been reported in preparing these kinds of compounds.
A summarization of the literature shows that these
methods can be basically generalized into two catego-
ries: (1) Pyrazole (C) and benzene (A) rings are con-
nected to each other at the last synthetic step.3,5,7 (2)
Construction of the pyrazole ring is realized at the last
step when either the carbonyl group is connected to
the carbon atom6 or the N-moiety is introduced to a car-
bonyl group.7 Common to these existing methods is a
nitrogen atom being connected to the benzene ring from
the starting material. This process requires harsh reac-
tion conditions and in most cases, gives poor yields.
Thus, in order to make diverse substituents to be
attached to ring A and ring C, we considered to search
for an efficient way to form the skeleton B (Fig. 1) by
connecting the N-moiety to the benzene ring directly.
Herein, we report a novel, expedient and general syn-
thetic method for preparation of pyrazolo[1,5-a]indole
framework (Scheme 1).
As shown in Scheme 1, compound 3 could be synthe-
sized by two main steps in which the intermediate
pyrazoles were directly prepared from substituted 2-
bromophenylacetic acid. The acid 1, prepared by a
modified literature procedure,8 was converted to acid
chloride, which immediately reacted with anion derived
from ketones to form 1,3-diketones. By addition of
hydrazine, 1,3-diketones were rapidly converted into
pyrazoles.9 The N-moiety was smoothly connected to
the benzene ring through Cu(I)-catalyzed intramolecuar
amination in a pressure tube at 110 ꢁC for 20 h.
N(CH3)2
H
N
N+
CH3
A
B
N
C
N
TfO-
A
B
Figure 1. The structure of active compound and the basic skeleton.
To our knowledge, copper catalysts have been shown to
be efficient for the intermolecular amination of aryl
halides with amides or pyrazoles.10–14 Inspired by this,
*
Corresponding author. Tel.: +86 512 6288 0109; fax: +86 512 6588
0031; e-mail: zhuyongming@suda.edu.cn
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.033

Y.-M. Zhu et al. / Tetrahedron Letters 48 (2007) 6262–6266
6263
O
2
R
2
R
3
R
CuI
ligand
3
R
2
3
COOH
1
1
R
R
1
R
R
R
HN
N
K2CO3, dioxane, 110oC
N
Br
Br
a (COCl)2
b LiHMDS
N
c NH2NH2.H2O
1
2
3
Scheme 1.
we hypothesized that it might undergo intramolecular
reactions if proper conditions were employed. This
prompted us to test whether the intramolecular reaction
could happen to produce the anticipated results. During
the course of our investigation, we first explored the
effects of solvents, ligands and bases on a typical reac-
tion of 3-[2-bromophenylacetyl]-cyclohexen[1,2-c]pyra-
zole 2a (Table 1). We were interested in the potential
effects of ligands, so several ligands including TCHDA,
PHAN and EDA were explored with CuI as the metal
source, and PHAN/EDA offered the best result. When
no ligands were utilized, the product was obtained in
low yield. In the instance that no catalysts were intro-
duced, no cyclized products were found. It was also
found that when CuBr was used as a catalyst, it pro-
duced slightly lower yield. Our investigation of alterna-
tive bases showed that K2CO3 was the optimal protocol,
and a stronger base, such as t-BuONa, offered a trace
amount of products. In light of this, it is clear that using
dioxane as a solvent, and CuI, PHAN or EDA and
K2CO3 as the base, is the most optimal condition to syn-
thesize pyrazolo[1,5-a]indoles.
than the one substituted with nucleophilic functional
groups (Table 2, entries e–g). The reaction yields did
not obviously change when a variety of groups are
substituted to ring C. The cyclization reaction proceeded
well with almost all of these substrate and gave good
satisfactory yields, except for some compounds with
substituents in the ortho position of bromine atom
(Table 2, entry h). Surprisingly, compounds 2i and 2n,
which have a phenyl group fused to ring A, gave a trace
amount of products under the given conditions and pro-
longed reaction time was helpful. Evidently, the increase
in steric hindrance at the ortho position of ring A was
influential to this intramolecular reaction while ligand
PHAN was acting effectively. Then EDA was also used
as a ligand and we found that it performed better than
PHAN when steric hindrance at ortho position of bro-
mine existed (Table 2, entry h). However, compounds
3i and 3n were obtained in low yields. During our inves-
tigation, we found that without the steric hindrance of
ring A, the reaction using EDA as a ligand gave slightly
lower yields than the one with PHAN in the case of a–g.
Especially, when phenyl or methyl substituents were
attached to 3-position of pyrazole ring, the reaction
yields dropped dramatically.
With the optimal reaction protocol in hand, we then
sought to study, and possibly expand, the scope of the
intramolecular amination. PHAN was chosen as a
ligand. A diversity-oriented synthesis of compounds
including alkyl, aryl, and halogen substituted indolo-
[1,5-a]pyrazoles was investigated and the result is listed
in Table 2. As shown in the table, ring A, substituted
with electrophilic functional groups, gave lower yields
In summary, we have developed a new method for the
synthesis of pyrazolo[1,5-a]indoles 3 from pyrazole
derivatives 2 via copper(I)-catalyzed intramolecular
cyclization. This method provides a general, simplified,
and easily operated route to pharmacologically attrac-
tive compounds and can afford products in good yields.
Table 1. Effects of solvents, ligands and bases on reaction of copper(I)-catalyzed intramolecular aminationa
Cu(I), ligand
N
base, solvent
HN
N
Br
N
3a
2a
Cu(I)
CuI
Entry
Solvent
Ligand
Base (mol %)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Dioxane
Dioxane
Dioxane
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
K2CO3 (250)
K2CO3 (250)
K2CO3 (250)
K2CO3 (250)
Cs2CO3 (140)
t-BuONa (250)
K2CO3 (250)
K2CO3 (250)
K2CO3 (250)
21
0
85
48
80
Trace
91
64
90
PHAN
PHAN
PHAN
PHAN
PHAN
PHANd
TCHDAc
EDAe
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
a Reaction conditions: 2a (1 mmol), Cu(I) (0.05 mmol), ligand (0.1 mmol), base (2.5 mmol) and solvent (3 mL) in a pressure tube, 110 ꢁC, 20 h.
b Isolated yields after silica gel chromatography.
c TCHDA: trans-1,2-cyclohexanediamine.
d PHAN: 1,10-phenanthroline.
e EDA: ethylenediamine, 0.3 mmol.

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Y.-M. Zhu et al. / Tetrahedron Letters 48 (2007) 6262–6266
Table 2. Synthesis of a variety of pyrazolo[1,5-a]indoles via copper(I)-catalyzed intramolecular aminationa
R2
R3
R2
R3
5 mol% CuI, ligand
R1
R1
K2CO3, dioxane, 110 oC
N
HN
N
N
Br
3
2
Entry
118
216
317
Yieldb (%)
91c/90d
N
HN
N
N
N
Br
3a
2a
N
2
3
89/87
78/74
HN
Br
N
2b
3b
N
HN
N
N
Br
3c
2c
COOC2H5
CH3
COOC2H5
CH3
415,18
82/69
N
HN
N
N
Br
3d
2d
H3CO
H3CO
5
6
7
8
9
92/86
N
N
3e
HN
N
Br
2e
Cl
Cl
81/76
N
HN
N
Br
2f
N
3f
F
F
77/70
N
HN
N
Br
2g
N
3g
61e/88
Trace/44
N
HN
N
N
Br
CH3
CH3
3h
2h
N
HN
N
Br
2i
N
3i
Ph
HN
10
N
98/45
96/46
N
Br
2j
N
Ph
N
3j
H3CO
H3CO
Ph
1118
HN
N
Br
N
Ph
3k
2k
Cl
Cl
Ph
HN
12
83/42
N
N
Br
N
Ph
2l
3l

Y.-M. Zhu et al. / Tetrahedron Letters 48 (2007) 6262–6266
6265
Table 2 (continued)
Entry
216
317
Yieldb (%)
95/50
F
F
Ph
13
14
15
16
17
18
HN
N
N
Br
N
Ph
Ph
2m
3m
Ph
HN
Br
N
Trace/45
89/37
N
N
2n
3n
CH3
HN
N
N
Br
N
CH3
2o
3o
C6H4OCH3-p
HN
N
86/51
N
Br
N
C6H4OCH3-p
C6H4NO2-p
2p
3p
C6H4NO2-p
N
HN
97/63
N
Br
N
2q
3q
2-Nap
HN
N
64/54
N
Br
N
2-Nap
2r
3r
a Reaction conditions: A mixture of 2 (1 mmol), Cu(I) (0.05 mmol), ligand, K2CO3 (2.5 mmol) and 1,4-dioxane (3 mL) was reacted in a pressure tube
at 110 ꢁC for 20 h.
b Yields are isolated yields after chromatography.
c 10 mol % PHAN was used as ligand.
d 30 mol % EDA was used as ligand.
e Time was prolonged to 40 h.
7. Zhu, Y.-M.; Kaneko, K.; Kato, O.; Kiryu, Y.; Takatsu,
N.; Shiono, K.; Katayama, H. Heterocycles 2003, 61, 147–
162.
8. Newman, M.; Kosak, A. J. Org. Chem. 1949, 14, 375–378.
9. Heller, S. T.; Natarajan, S. R. Org. Lett. 2006, 8, 2675–
2678.
Applications of this method to the synthesis of potential
biological active compounds are being undertaken and
will be reported in due course.
10. Klapars, A.; Antilla, J. C.; Huang, X. H.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7727–7729.
Acknowledgements
11. Hosseinzadeh, R.; Tajbakhsh, M.; Alikarami, M. Tetra-
hedron Lett. 2006, 47, 5203–5205.
12. Zhang, H.; Cai, Q.; Ma, D.-W. J. Org. Chem. 2005, 70,
5164–5173.
13. Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 11684–11688.
This work was partially supported by the National Nat-
ural Science Foundation of China (Grants 20472062 and
20672079), the Natural Science Foundation of Jiangsu
Province (No. BK2006048).
14. Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L.
J. Org. Chem. 2004, 69, 5578–5587.
15. Preparation of 2d: Ethyl acetoacetate (1.30 g, 10 mmol)
dissolved in dry THF (5 mL) was placed in an addition
funnel which was mounted on a three-necked flask
containing 60% sodium hydride (0.42 g, 10.5 mmol) sus-
pended in dry THF (10 mL). The flask was cooled to 0 ꢁC
in an ice-bath before the ethyl acetoacetate was added to it
in drops. The solution of ethyl acetoacetate anion was
added to the acid chloride solution by a syringe immedi-
ately after the addition was completed. The resulting
mixture was stirred overnight at room temperature. Water
(10 mL) was added and the resulting mixture was stirred
for 15 min. Then the aqueous layer was extracted with
ether (10 mL) twice. The combined organic layers were
washed with brine and dried over anhydrous Na2SO4.
References and notes
1. Katayama, H.; Kawada, Y.; Kaneko, K.; Oshiyama, T.;
Takatsu, N. Chem. Pharm. Bull. 1999, 47, 48–53.
2. Katayama, H.; Kiryu, Y.; Kaneko, K.; Ohshima, R.
Chem. Pharm. Bull. 2000, 48, 1628–1633.
3. Alley, P.; Shirley, D. J. Am. Chem. Soc. 1958, 80, 6271–
6274.
4. Padwa, A.; Nham, S. J. Org. Chem. 1981, 46, 1402–1409.
5. Katayama, H.; Sakurada, M.; Herath, W.; Takatsu, N.;
Shen, J.-K. Chem. Pharm. Bull. 1992, 40, 2267–2269.
6. Sheng, J.-K.; Katayama, H.; Takatsu, N. J. Chem. Soc.,
Perkin Trans. 1 1993, 2087–2097.

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Y.-M. Zhu et al. / Tetrahedron Letters 48 (2007) 6262–6266
After filtration and evaporation of solvents, EtOH
(50 mL) was added to the crude oil, and then 10 mL of
AcOH and hydrazine monohydrate were added. The
mixture was stirred for 10 min and the procedure of the
reaction was exothermic reaction. Then the product was
extracted with ethyl acetate and the extracts were washed
with saturated sodium bicarbonate. 2d was obtained after
silica gel chromatography.
7,8,9,10-Tetrahydro-11H-indolo[1,2-b]indazole 3a: 91%
yield, mp 104–106 ꢁC. H NMR (400 MHz, CDCl3) ppm
1
1.95–1.64 (m, 4H), 2.56 (t, J = 5.50, 5.50 Hz, 2H), 2.81 (t,
J = 6.03, 6.03 Hz, 2H), 3.68 (s, 2H), 7.09 (t, J = 7.43,
7.43 Hz, 1H), 7.42–7.28 (m, 2H), 7.53 (d, J = 7.73 Hz,
1H). 13C NMR (400 MHz, CDCl3) ppm 21.0, 23.7, 23.8,
24.6, 27.8, 110.1, 111.1, 123.8, 126.2, 128.3, 133.5, 141.1,
141.4, 165.6. HRMS: C14H14N2 calcd, 210.1157; found,
210.1151.
16. General procedure for synthesis of 2: Ketone (10 mmol) was
dissolved in 25 mL dry toluene, and then the solution was
cooled to 0 ꢁC under nitrogen. LiHMDS (10.5 mL, 1.0 M
in THF, 10.5 mmol) was added quickly via syringe with
stirring. As soon as the anion was formed in one minute,
the acid chloride (5 mmol) in 5 mL of dry toluene was
added rapidly via syringe and the reaction mixture was
allowed to stir at room temperature for 5 min, and then
10 mL of AcOH was added with stirring. EtOH (50 mL)
and THF (25 mL) were added to form a homogeneous
mixture, then hydrazine monohydrate (10 mL, 10.3 g,
205.8 mmol) was added. The mixture was stirred for
10 min. The resulting solution was extracted with 100 mL
of EtOAc, the organic fraction was then washed with
saturated sodium bicarbonate and brine, dried over
Na2SO4 (anhydrous) and evaporated under reduced
pressure. The resulting residue was isolated by chroma-
tography (Silica Gel H 120 g, solvents: petroleum ether/
ethyl acetate) to afford white solid 2.
17. General procedure for synthesis of 3: CuI (10 mg,
0.05 mmol), 1,10-phenanthroline (18 mg, 0.1 mmol) and
K2CO3 (345 mg, 2.5 mmol) were added to a solution of
compound 2 (1.0 mmol) dissolved in anhydrous 1,4-
dioxane (3 mL) in a pressure tube under the protection
of Argon. The reaction mixture was stirred at 110 ꢁC for
20 h and filtered through a pad of celite. After the removal
of solvent under reduced pressure, the residue was purified
by chromatography (Silica Gel H 10 g, solvents: petro-
leum ether/ethyl acetate) to give 3 as a solid.
Ethyl 3-[2-bromobenzyl]-5-methyl-pyrazole-4-formate 2d:
68% yield, mp 104–105 ꢁC. H NMR (400 MHz, CDCl3)
1
ppm 1.21 (t, J = 7.11, 7.11 Hz, 3H), 2.40 (s, 3H), 4.21 (q,
J = 7.10, 7.10, 7.10 Hz, 2H), 4.30 (s, 2H), 6.97 (d,
J = 7.29 Hz, 1H), 7.03 (t, J = 6.93, 6.93 Hz, 1H) 7.13 (t,
J = 6.97, 6.97 Hz, 1H), 7.52 (d, J = 7.87 Hz, 1H), 11.80–
10.14 (br, 1H). 13C NMR (400 MHz, CDCl3) ppm 13.2,
14.6, 34.4, 60.2, 109.6, 125.0, 128.0, 128.5, 130.6, 133.1,
138.5, 148.4, 150.3, 164.6. HRMS: C14H15N2O281Br calcd,
324.0296; found, 324.0344, C14H15N2O279Br calcd,
322.0317; found, 322.0320.
Ethyl 2-methyl-indolo[1,2-a]pyrazole-3-formate 3d: 82%
yield, mp 93–94 ꢁC. 1H NMR (400 MHz, CDCl3) ppm 1.40
(t, J = 6.88, 6.88 Hz, 3H), 2.61 (s, 3H), 4.01 (s, 2H), 4.33 (q,
J = 6.80 Hz, 6.8 Hz, 6.8 Hz, 2H), 7.31–7.15 (m, 1H), 7.52–
7.35 (m, 2H), 7.61 (d, J = 7.83 Hz, 1H). 13C NMR
(400 MHz, CDCl3) ppm 14.8, 14.9, 30.5, 60.4, 111.1,
125.3, 126.4, 128.6, 133.4, 136.0, 140.4, 149.8, 156.1, 164.1.
HRMS: C14H14N2O2 calcd, 242.10055; found, 242.1050.
3-[2-Bromo-5-methoxybenzyl]-5-phenyl-pyrazole 2k: 73%
1
yield, mp 100–101 ꢁC. H NMR (400 MHz, CDCl3) ppm
3.67 (s, 3H), 4.04 (s, 2H), 6.35 (s, 1H), 6.64 (d, J = 8.01 Hz,
1H), 6.76 (s, 1H), 7.37–7.18 (m, 3H), 7.41 (d, J = 8.52 Hz,
1H), 7.64 (d, J = 6.21 Hz, 2H), 10.86–9.43 (br, 1H). 13C
NMR (400 MHz, CDCl3) ppm 34.2, 55.8, 102.6, 114.4,
115.2, 116.7, 126.0(·2), 128.4, 129.1(·2), 131.9, 133.8,
139.7, 146.9, 148.9, 159.4. HRMS: C17H15N2O81Br calcd,
344.0347; found, 344.0364, C17H15N2O79Br calcd,
342.0368; found, 342.0384.
18. All new compounds have been characterized by 1H NMR,
13C NMR and HRMS. Data for selected compounds: 3-[2-
Bromobenzyl]-cyclohexen[1,2-c]pyrazole 2a: 78% yield,
mp 84–86 ꢁC. 1H NMR (400 MHz, CDCl3) ppm 1.89–
1.55 (m, 4H), 2.28 (s, 2H), 2.59 (d, J = 5.6 Hz, 2H), 4.02 (s,
2H), 7.13–6.97 (m, 2H), 7.23–7.13 (m, 1H), 7.61–7.45 (m,
1H), 10.92–10.17 (br, 1H). 13C NMR (400 MHz, CDCl3)
ppm 20.5, 22.6, 23.3, 23.7, 33.0, 114.1, 124.9, 127.9, 128.4,
130.9, 133.1, 138.8, 143.3, 144.0. HRMS: C14H15N281Br
calcd, 292.0398; found, 292.0381, C14H15N279Br calcd,
290.0419; found, 290.0421.
6-Methoxy-2-phenyl-pyrazolo[1,5-a]indole 3k: 96% yield,
mp 130–132 ꢁC. 1H NMR (400 MHz, CDCl3) ppm 3.81 (s,
3H), 3.82 (s, 2H), 6.54 (s, 1H), 6.90 (dd, J = 8.51, 2.16 Hz,
1H), 6.99 (s, 1H), 7.35–7.25 (m, 1H), 7.46–7.35 (m, 2H),
7.57 (d, J = 8.53 Hz, 1H), 7.87 (d, J = 7.91 Hz, 2H). 13C
NMR (400 MHz, CDCl3) ppm 29.0, 56.2, 98.5, 111.1,
112.9, 113.1, 126.1(·2), 128.1, 129.1(·2), 134.4, 134.9,
135.4, 145.6, 155.9, 157.6. HRMS: C17H14N2O calcd,
262.1106; found, 262.1111.