One-pot to fused pyrazoles by a double cyclization of o-alkynylaldehydes with ketones and hydrazine under metal-free condition

Article abstract of DOI:10.1016/j.tet.2014.04.032

An efficient one-pot synthesis of fused pyrazoles has been developed. The procedure involved three components reaction of o-alkynylaldehydes 1a-s with ketones 2a-m and hydrazine under mild, metal-free reaction conditions. The desired products were obtained in one-step up to 85% yield. The molecular structure was confirmed by the X-ray crystallographic analysis.

Full text of DOI:10.1016/j.tet.2014.04.032

Tetrahedron 70 (2014) 3782e3787
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One-pot to fused pyrazoles by a double cyclization of o-
alkynylaldehydes with ketones and hydrazine under metal-free
condition
,
,
Jinxia Qiao a y, Bin Liu a y, Zongquan Liao a, Ying Li a, Lei Ma b, Chune Dong a,
Hai-Bing Zhou a
,
*
a State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Ministry of Education, Wuhan
University School of Pharmaceutical Sciences, Donghu Road 185#, Wuhan 430071, China
b Center for Drug Evaluation, State Food and Drug Administration, Beijing 100038, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot synthesis of fused pyrazoles has been developed. The procedure involved three
components reaction of o-alkynylaldehydes 1aes with ketones 2aem and hydrazine under mild, metal-
free reaction conditions. The desired products were obtained in one-step up to 85% yield. The molecular
structure was confirmed by the X-ray crystallographic analysis.
Received 7 January 2014
Received in revised form 1 April 2014
Accepted 10 April 2014
Available online 18 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
One-pot synthesis
Pyrazoles
o-Alkynylaldehydes
Ketones
Hydrazine
1. Introduction
The pyrazoles and their derivatives are found as essential sub-
units in a number of natural products and synthetic compounds
that display important biological and pharmaceutical properties,
including anti-cancer agent,1 antipsychotic,2 auxin transport
inhibitor,3e5 and insecticidal activities.6e8 For example, the pyr-
azole based natural product withasomnine, isolated from the root
of indian medicinal plant Withania somnifera, was particularly at-
tractive due to its wide spectrum of pharmacological utility for
treatment of enlarged spleen, migraines, many infections, and as an
aphrodisiac as well (Fig. 1).9e11 In view of its biological properties,
extensive researches have been focused on the synthesis of fused
pyrazoles and withasomnine analogues over the past decades.
Traditional synthesis of these compounds usually adopt sydnone
cycloaddition,12e14 hydrazine 1,3-dicarbonyl cyclization,15,16 mul-
ticomponent coupling,17,18 and Claisen rearrangement19 as the key
steps. Among these, the Rh(III)-catalyzed oxidative coupling of 5-
aryl-functionalized NH pyrazoles with acrylates using Cu(OAc)2 as
Fig. 1. Selected example of biologically active fused pyrazoles and withasomnine.
an oxidant represents a useful contribution to fused pyrazole syn-
thesis.20 Very recently, Namboothiri and co-workers reported the
synthesis of withasomnine alkaloids in three steps from aldehydes
and 4-nitro-1-butanol.21 Although these methods have been
shown to be highly efficient in the construction of substituted an-
alogues of withsomnines, many of these processes still required the
use of expensive transition metal complex as catalyst or extra
synthetic steps to access the proper precursors. Also these reactions
exhibited limited substrate scopes. Therefore, the development of
new, more efficient route for rapid access to such functionalized
pyrazole architectures from readily available starting materials
under mild condition is highly desirable. As a part of our ongoing
efforts to develop novel and efficient methodologies for the
* Corresponding author. Tel.: þ86 27 68759586; fax: þ86 27 68759850; e-mail
address: zhouhb@whu.edu.cn (H.-B. Zhou).
y
These two authors contributed equally to this work.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.032

J. Qiao et al. / Tetrahedron 70 (2014) 3782e3787
3783
synthesis of functionalized N-heterocycles,22 we recently reported
the new pathway for synthesis of phthalazine derivatives via cy-
clization of ortho-alkynylphenyl ketones.23 On the base of our
previous work, we hypothesized that it may be possible to realize
the three components cyclization of ketone, hydrazine and ortho-
alkynylaldehydes.
Herein, we present a metal-free, one-step formation of the
skeleton of withasomnines by using commercially available ke-
tones, hydrazine and ortho-alkynylaldehydes under very mild
metal-free reaction condition. To the best of our knowledge, syn-
thesis of nonnatural analogues of withasomnine from straightfor-
ward cyclization of ortho-alkynylaldehydes, ketone, and hydrazine
has not been explored so far.
strategy is still effective for series of aliphatic ketones to give the
desired products in good yields. The reactions of 1a with 2-
pentanone and 3-pentanone afforded the products 3b and 3c in
71% and 62% yields, respectively. When methyl cyclopropyl ketone
2f was used, 3f was isolated in 43% yield. In order to reveal the
generality of the protocol, the reaction of 1a with substituted aro-
matic ketones were also studied. Initially, we investigated the re-
action of 1a with acetophenone 2g under various reaction
conditions. A screening of reaction condition showed those 2 equiv
of aromatic ketone, 5 equiv of hydrazine hydrogen chloride, and
10 equiv of NaOMe as the base in refluxing methanol led to 3g in
75% yield. Furthermore, the reaction worked efficiently for both
ketones bearing electron-withdrawing group or electron-donating
group on the phenyl ring, and the products 3gel were obtained in
good yields (Table 2). Heteroaromatic ketones, such as methyl 2-
thienyl ketone 2l also reacted with 1a smoothly to give 3l in 68%
yield.
2. Results and discussion
Initially, we chose 2-phenylethynyl benzaldehyde (1a), 2-
butanone, and hydrazine for our model study to optimize the re-
action conditions. However, the use of N2H4$HCl (1 equiv), Et3N
(1 equiv), 2a (2 equiv), and 1a (1 equiv) failed to afford desired
product 3a. After a survey of reaction conditions, we found that the
reaction was highly sensitive to the amount of triethyl amine and
hydrazine as well as the oxygen (see Table S1 in the Supplementary
data). It is notable that excess hydrazine and Et3N were required to
promote the reaction, indicating the pivotal role of Et3N in the re-
action. Solvents survey revealed that MeOH was found to be the
optimum reaction medium. We also found that the oxygen played
an important role in this cyclization reaction, usually the reaction
needed to be conducted under the dry air or oxygen, inert atmo-
sphere like argon led to a dramatic decrease of the product. Further
optimization indicated that the optimal isolated yield (74%) of the
corresponding pyrazoloisoindole 3a was achieved by the use of
1 equiv benzaldehyde 1a, 2 equiv of 2a, and 5 equiv of hydrazine
with 10 equiv triethyl amine in MeOH. Since the unsymmetrical
ketone 2a was used, a 1.7:1 mixture of two isomers of 3a (3aa and
3ab) were isolated due to the similarity between the methyl and
the ethyl fragments.
Table 2
Cyclization of 1a, aromatic acetone, and hydrazinea,b
Encouraged by the above results, the scope of the reaction was
expanded to other dialkyl ketones 2aef. As seen from Table 1, this
Table 1
Cyclization of 1a, aliphatic ketones, and hydrazinea,b
In addition to the demonstrated the scope of this method,
simple acetone was tested (Table 3). After optimizing the reaction
condition (see Supplementary data Table S2), we examined the
scope and generality of the reaction by employing a variety of or-
tho-alkynylaldehydes 1aes with acetone and hydrazine and mod-
erate to good yields were provided. As shown in Table 3, the
substituents R4 and R5 had almost no influence on the yield of the
products. Irrespective of whether electron-rich or electron-
deficient substituents on the benzene ring were used, the yields
of the cyclized products 4aer were general good in a range of
70e85% (entries 1e16). For instance, the reaction of acetone and 1b
having meta-chlorophenyl group at R5 proceeded well and gave the
product 4b in yield of 78% (entry 2). It seems that all substituents at
R4 are equally tolerated. When methyl group was used as R4, and
electron-rich aromatic or heteroaromatic substitutes were used as
R5, reactions proceeded well and 4mer were obtained in 66e72%
yields (entries 13e18). In the case of n-hexyl substituent at R5 po-
sition, the product 4s was obtained in 47% (entry 19).
The regioselective formation of 4a, 4d, 4i, 4m, and 4q was
confirmed by X-ray crystallography (Fig. 2).24

3784
J. Qiao et al. / Tetrahedron 70 (2014) 3782e3787
Table 3
obtained under the similar reaction conditions from reaction using
I as starting material, which demonstrated the proposed mecha-
nism is plausible.
One-step synthesis of pyrazoloisoindolesa
Entry
R4
R5
Product
Yieldb (%)
1
2
3
4
5
6
7
8
H
H
4-F
H
H
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
40
4p
4q
4r
4s
85
78
82
78
79
78
75
78
74
70
72
70
72
72
70
72
66
68
47
m-CleC6H4
3,5-Di-CF3eC6H3
p-MeeC6H4
p-FeC6H4
2-Thienyl
2-Thienyl
p-FeC6H4
p-EteC6H4
p-MeOeC6H4
p-PreC6H4
p-PentyleC6H4
Ph
p-MeeC6H4
p-EteC6H4
o-BreC6H5
2-Thienyl
p-MeOeC6H4
n-Hexyl
H
4-F
5-MeO
H
H
H
9
10
11
12
13
14
15
16
17
18
19
H
4-Me
4-Me
4-Me
H
4-Me
4-Me
H
Scheme 1. Alternative mechanisms for formation of pyrazoloisoindoline.
a
The reaction was performed in the using ortho-alkynylaldehydes 1 (0.4 mmol),
acetone (2.8 mmol), hydrazine (4 mol), Et3N (8 mol), in 5 mL of MeOH reflux for
12 hr under dry air.
3. Conclusions
b
In conclusion, for the first time, we have achieved the facile
synthesis of nonnatural analogues of withasomnine alkaloids, by
a simple three-component double cyclization of easily accessed o-
alkynylaldehydes, ketones, and hydrazine under mild condition.
This approach to withasomnine analogues represents a potential
platform for practically construction of pyrazole based nitrogen-
containing heterocyclic compounds with potential biological
activities.
Isolated yield.
4. Experimental section
4.1. General
Analytical-grade solvents were purchased, and used as received.
NMR spectra were measured at 400 MHz for 1H spectra and
100 MHz for 13C spectra and calibrated from residual solvent signal.
Analytical thin-layer chromatography (TLC) was performed on sil-
ica gel aluminum sheets with F-254 indicator. Visualization was
accomplished by UV light. Purification by chromatography was
performed using 230e400 mesh SiO2 with compressed air as
a source of positive pressure. Mass spectra were recorded under
electron impact conditions at 70 eV. The starting materials o-Phe-
nylethynyl benzaldehyde was prepared according to the
literature.26
4.2. Representative procedure for the synthesis of pyrazoles
To
a
solution of 2-phenylethynyl benzaldehyde 1a
(0.4 mmol), acetone (2.8 mmol), and hydrazine hydrochloride
(4 mmol) in methanol (5 mL), TEA (8 mmol) was added under
dry air. Then the mixture was refluxed for 12 h, after that, 5 mL
of water was added, extracted with ethyl acetate (3ꢀ20 mL).
Then the organic layer was dried with anhydrous sodium sul-
fate. Evaporation of ethyl acetate gave a yellow residue, which
was further purified by gel column chromatography to afford the
pure product.
Fig. 2. X-ray crystallographic structures of 4a, 4d, 4i, 4m, and 4q.
Based on the above results, a possible mechanism is proposed in
Scheme 1. Presumably the acetone and 2-alkynyl aldehyde would
generate the ketone intermediate I. Then the subsequent hydrazine
addition to carbonyl carbon affords the key intermediate II. The
intramolecular cyclization leads to the pyrazole III. Finally, the
intramolecular attack of nitrogen on alkyne, followed by isomeri-
zation give the formation of the product 4.25 Same product was
4.2.1. 8-Benzyl-2-ethyl-8H-pyrazole[5,1-
(400 MHz, CDCl3)
7.41 (d, J¼8.0 Hz, 1H), 7.26e7.31 (m, 3H), 7.01 (d,
J¼4.0 Hz, 2H), 7.01 (d, J¼4.0 Hz, 2H), 6.90 (d, J¼8.0 Hz, 1H), 6.11 (s,
a
]isoindole (3a). 1H NMR
d

J. Qiao et al. / Tetrahedron 70 (2014) 3782e3787
3785
1H), 5.34 (q, J¼4.0 Hz, 1H), 3.73 (dd, J¼8.0, 4.0 Hz, 1H), 3.10 (d,
J¼8.0 Hz, 1H), 2.78 (d, J¼8.0 Hz, 2H), 1.34 (t, J¼8.0 Hz, 3H). 13C NMR
J¼8.0 Hz, 1H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
156.0, 146.3,
143.8, 137.4, 135.4, 131.6, 131.4, 130.5, 129.8, 129.3, 128.4, 128.2,
128.1, 126.9, 126.8, 125.5, 123.8, 120.3, 93.2, 63.6, 40.0, 21.3. HRMS
calcd for C24H20N2 (M)þ: 336.1626, found: 336.1623.
(100 MHz, CDCl3)
d 159.4, 145.6, 143.9, 135.5, 129.7, 128.1, 126.7,
126.5, 123.8, 120.1, 94.3, 63.2, 40.0, 22.3, 14.3. HRMS calcd for
C
19H18N2 (M)þ: 274.1470, found: 274.1468.
4.2.9. 8-Benzyl-2-(4-fluorophenyl)-8H-pyrazole[5,1-
(3i). 1H NMR (400 MHz, CDCl3)
a]isoindole
7.86 (dd, J¼8.0, 4.0 Hz, 2H), 7.48
4.2.2. 8-Benzyl-2-propyl-8H-pyrazole[5,1-
NMR (400 MHz, CDCl3)
a
]isoindole
(3b). 1H
d
d
7.33 (d, J¼8.0 Hz, 1H), 7.20 (t, J¼8.0 Hz,
(d, J¼8.0 Hz, 1H), 6.96e7.26 (m, 10H), 6.54 (s, 1H), 5.44 (q, J¼4.0 Hz,
1H), 6.92e7.18 (m, 4H), 6.90 (d, J¼4.0 Hz, 2H), 6.86 (d, J¼8.0 Hz,
1H), 6.01 (s, 1H), 5.27 (q, J¼4.0 Hz, 1H), 3.63 (dd, J¼8.0, 4.0 Hz, 1H),
3.05 (d, J¼8.0 Hz, 1H), 2.65 (t, J¼8.0 Hz, 2H), 1.68 (m, 2H), 0.94 (t,
1H), 3.75 (dd, J¼8.0, 4.0 Hz, 1H), 3.21 (dd, J¼8.0, 4.0 Hz, 1H). 13C
NMR (100 MHz, CDCl3)
d 155.0, 146.5, 143.8, 135.3, 133.0, 131.5,
130.4, 129.7, 129.0, 128.9, 128.5, 128.3, 128.2, 127.3, 127.2, 126.9,
126.8, 123.8, 120.4, 115.6, 115.4, 93.2, 63.7, 40.0. HRMS calcd for
J¼8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 157.9, 145.6, 143.9,
135.4, 130.8, 129.7, 128.1, 126.7, 126.5, 123.8, 120.1, 94.9, 63.2, 39.9,
31.2, 23.3, 13.9. HRMS calcd for C20H20N2 (M)þ: 288.1626, found:
288.1620.
C
23H17FN2 (M)þ: 340.1376, found: 340.1375.
4.2.10. 8-Benzyl-2-(4-bromophenyl)-8H-pyrazole[5,1-
a
]isoindole
(3j). 1H NMR (400 MHz, CDCl3)
d
7.74 (d, J¼8.0 Hz, 2H), 7.53 (d,
4.2.3. 8-Benzyl-2-ethyl-3-methyl-8H-pyrazole[5,1-
a
]isoindole
J¼8.0 Hz, 2H), 7.46 (d, J¼4.0 Hz, 1H), 7.32 (t, J¼8.0 Hz, 1H),
7.25e7.12 (m, 4H), 7.08e6.90 (m, 3H), 6.55 (s, 1H), 5.43 (q,
J¼4.0 Hz, 1H), 3.74 (dd, J¼8.0, 4.0 Hz, 1H), 3.20 (dd, J¼8.0, 4.0 Hz,
(3c). 1H NMR (400 MHz, CDCl3)
d
7.38 (d, J¼8.0 Hz, 1H), 7.21 (t,
J¼8.0 Hz, 1H), 7.01e7.19 (m, 4H), 6.98 (d, J¼8.0 Hz, 2H), 6.74 (d,
J¼8.0 Hz, 1H), 6.03 (s, 1H), 5.21 (q, J¼4.0 Hz, 1H), 3.62 (dd, J¼8.0,
4.0 Hz,1H), 2.64 (dd, J¼8.0, 4.0 Hz, 2H), 2.01 (s, 3H),1.23 (t, J¼8.0 Hz,
1H). 13C NMR (100 MHz, CDCl3)
d 154.7, 146.5, 143.7, 135.2, 133.1,
131.7, 130.2, 129.7, 128.3, 128.2, 127.1, 127.0, 126.8, 123.9, 121.5,
120.4, 93.4, 63.7, 40.0. HRMS calcd for C23H17BrN2 (M)þ: 400.0575,
found: 400.0576.
3H). 13C NMR (100 MHz, CDCl3)
d 157.3, 143.8, 142.9, 135.7, 128.1,
126.7, 123.8, 119.4, 104.9, 63.0, 40.2, 20.4, 14.1, 8.1. HRMS calcd for
C
20H20N2 (M)þ: 288.1626, found: 288.1622.
4.2.11. 8-Benzyl-2-(furan-2-yl)-8H-pyrazole[5,1-
NMR (400 MHz, CDCl3)
a
]isoindole (3k). 1H
7.40 (d, J¼8.0 Hz, 2H), 7.25 (t, J¼8.0 Hz,
4.2.4. 8-Benzyl-2-butyl-8H-pyrazole[5,1-
NMR (400 MHz, CDCl3)
a
]isoindole
(3d). 1H
d
d
7.40 (d, J¼8.0 Hz, 1H), 7.28 (t, J¼8.0 Hz,
1H), 7.20e7.08 (m, 4H), 7.01e6.81 (m, 3H), 6.51e6.66 (m, 3H), 5.36
(q, J¼4.0 Hz, 1H), 3.73 (q, J¼4.0 Hz, 1H), 3.11 (dd, J¼8.0, 4.0 Hz, 1H).
1H), 7.00e7.16 (m, 4H), 6.91e6.99 (m, 3H), 6.09 (s, 1H), 5.35 (q,
J¼4.0 Hz, 1H), 3.70 (dd, J¼8.0, 4.0 Hz, 1H), 3.16 (d, J¼8.0 Hz, 1H),
2.75 (d, J¼8.0 Hz, 2H), 1.71 (m, 2H), 1.44 (m, 2H), 0.97 (t, J¼8.0 Hz,
13C NMR (100 MHz, CDCl3)
d 149.3, 148.0, 146.1, 143.9, 141.7, 135.3,
130.1, 129.7, 128.3, 128.2, 127.0, 126.8, 123.9, 120.5, 111.3, 105.5, 93.2,
63.7, 39.9. HRMS calcd for C21H16ON2 (M)þ: 312.1263, found:
312.1264.
3H). 13C NMR (100 MHz, CDCl3)
d 158.1, 145.6, 143.9, 135.4, 130.8,
129.7, 128.0, 126.7, 126.5, 123.8, 120.1, 94.9, 63.2, 39.9, 32.2, 28.8,
22.4, 14.0. HRMS calcd for C21H22N2 (M)þ: 302.1783, found:
302.1788.
4.2.12. 8-Benzyl-2-(thiophen-2-yl)-8H-pyrazole[5,1-
a
]isoindole
(3l). 1H NMR (400 MHz, CDCl3)
d
7.39 (d, J¼8.0 Hz, 1H), 7.31 (d,
4.2.5. 8-Benzyl-2-isopropyl-8H-pyrazole[5,1-
a
]isoindole
(3e). 1H
J¼4.0 Hz, 1H), 7.23 (t, J¼8.0 Hz,1H), 7.20e7.15 (m,1H), 7.15e7.06 (m,
4H), 7.04e6.98 (m, 1H), 6.98e6.91 (m, 2H), 6.86 (d, J¼8.0 Hz, 1H),
6.42 (s, 1H), 5.35 (q, J¼4.0 Hz, 1H), 3.68 (dd, J¼8.0, 4.0 Hz, 1H), 3.11
NMR (400 MHz, CDCl3)
d
7.32 (d, J¼8.0 Hz, 1H), 7.21 (d, J¼8.0 Hz,
1H), 7.07e7.18 (m, 4H), 6.86e6.91 (m, 3H), 6.03 (s, 1H), 5.28 (q,
J¼4.0 Hz, 1H), 3.62 (dd, J¼8.0, 4.0 Hz, 1H), 3.21e2.93 (m, 2H), 1.28
(dd, J¼8.0, 4.0 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 150.9, 146.4,
(d, J¼8.0 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d
164.1, 145.4, 143.9,
143.8, 137.5, 135.3, 130.2, 129.8, 128.3, 128.2, 127.5, 127.0, 126.8,
124.3, 123.9, 123.4, 120.4, 93.5, 63.7, 39.9. HRMS calcd for C21H16SN2
(M)þ: 328.1034, found: 328.1036.
135.4, 130.9, 129.7, 128.0, 126.7, 126.4, 123.7, 120.1, 92.8, 63.2, 39.9,
28.7, 23.1. HRMS calcd for C20H20N2 (M)þ: 288.1626, found:
288.1630.
4.2.13. 8-Benzyl-2-methyl-8H-pyrazole[5,1-a]isoindole
(4a). 1H
4.2.6. 8-Benzyl-2-cyclopropyl-8H-pyrazole[5,1-
a
]isoindole (3f). 1H
NMR (400 MHz, CDCl3)
d
7.31 (d, J¼8.0 Hz, 1H), 7.17 (d, J¼8.0 Hz,
NMR (400 MHz, CDCl3) 7.23e7.34 (m, 2H), 7.11e7.19 (m, 2H),
d
1H), 6.94e7.08 (m, 4H), 6.92 (d, J¼8.0 Hz, 2H), 6.78 (d, J¼8.0 Hz,1H),
5.98 (s,1H), 5.21 (dd, J¼4.0 Hz,1H), 3.63 (dd, J¼4.0 Hz,1H), 2.97 (dd,
7.05e7.09 (m, 2H), 6.95 (br, 2H), 6.82 (d, J¼8.0 Hz, 1H), 5.89 (s, 1H),
5.26 (q, J¼4.0 Hz, 1H), 3.66 (dd, J¼8.0, 4.0 Hz, 1H), 3.02 (dd, J¼8.0,
4.0 Hz, 1H), 1.99 (m, 1H), 0.96 (m, 2H), 0.76 (m, 2H). 13C NMR
J¼8.0 Hz, 1H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 151.9, 144.7,
142.8, 134.5, 129.6, 128.6, 127.1, 127.0, 125.7, 125.4, 122.7, 119.1, 94.8,
62.2, 38.9, 13.4. HRMS calcd for C18H16N2 (M)þ: 260.1313, found:
260.1316.
(100 MHz, CDCl3)
126.7, 126.6, 123.8, 120.2, 92.5, 63.4, 40.0, 9.9, 8.2. HRMS calcd for
20H18N2 (M)þ: 286.1470, found: 286.1476.
d 159.7, 143.9, 135.5, 131.7, 130.5, 129.7, 128.1,
C
4.2.14. 8-(3-Chlorobenzyl)-2-methyl-8H-pyrazole[5,1-
a
]isoindole
4.2.7. 8-Benzyl-2-phenyl-8H-pyrazole[5,1-
a
]isoindole (3g). 1H NMR
(4b). 1H NMR (400 MHz, CDCl3)
d
7.27 (d, J¼4.0 Hz, 1H), 7.07 (d,
(400 MHz, CDCl3)
d
7.84 (d, J¼8.0 Hz, 2H), 7.18e7.34 (m, 3H),
J¼8.0 Hz, 1H), 6.99 (d, J¼8.0 Hz, 1H), 6.82e6.92 (m, 4H), 6.68 (d,
J¼8.0 Hz, 1H), 5.93 (s, 1H), 5.17 (dd, J¼4.0 Hz, 1H), 3.45 (d,
J¼12.0 Hz, 1H), 3.07 (d, J¼12.0 Hz, 1H), 2.29 (s, 3H). 13C NMR
7.10e7.16 (m, 2H), 6.93e7.08 (m, 4H), 6.93 (br, 2H), 6.89 (d,
J¼8.0 Hz, 1H), 6.52 (s, 1H), 5.38 (q, J¼4.0 Hz, 1H), 3.68 (dd, J¼8.0,
4.0 Hz, 1H), 3.16 (dd, J¼8.0, 4.0 Hz, 1H). 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3)
d 153.2, 146.0, 143.5, 137.3, 133.8, 130.7, 129.8,
d
155.9, 146.3, 143.8, 135.3, 134.2, 130.5, 129.8, 128.7, 128.3, 128.2,
129.2, 128.3, 127.8, 126.9, 126.7, 123.5, 120.3, 96.0, 62.9, 39.4, 29.7,
14.3. HRMS calcd for C18H15N2Cl (MþH)þ: 295.1002, found:
295.0994.
127.6, 126.89, 126.82, 125.66, 123.88, 120.42, 93.49, 63.71, 40.03.
HRMS calcd for C23H18N2 (M)þ: 322.1470, found: 322.1471.
4.2.8. 8-Benzyl-2-(p-tolyl)-8H-pyrazole[5,1-
a
]isoindole
(3h). 1H
4.2.15. 8-(3,5-Bis(trifluoromethyl)benzyl)-2-methyl-8H-pyrazole
NMR (400 MHz, CDCl3)
d
7.79 (d, J¼8.0 Hz, 2H), 7.48 (d, J¼8.0 Hz,
[5,1-a d 7.52 (s, 1H),
]isoindole (4c). 1H NMR (400 MHz, CDCl3)
1H), 7.36e7.29 (m, 3H), 7.10e7.18 (m, 4H), 6.97e7.03 (m, 3H), 6.57
(s, 1H), 5.45 (q, J¼4.0 Hz, 1H), 3.76 (d, J¼8.0 Hz, 1H), 3.23 (d,
7.41e7.29 (m, 4H), 7.10 (s, 1H), 5.95 (s, 1H), 5.48 (t, J¼4.0 Hz, 1H),
3.79 (d, J¼8.0 Hz, 1H), 3.50 (d, J¼4.0 Hz, 1H), 2.39 (s, 3H). 13C NMR

3786
J. Qiao et al. / Tetrahedron 70 (2014) 3782e3787
(100 MHz, CDCl3)
d
153.8, 146.3, 142.4, 136.7, 130.8, 130.4, 129.9,
127.6, 126.5, 123.8, 120.2, 113.5, 95.8, 63.5, 55.1, 39.1, 14.4. HRMS
calcd for C19H18N2O (M)þ: 290.1419, found: 290.1423.
128.6, 127.0, 124.4, 123.1, 121.7, 120.4, 96.1, 62.3, 38.9, 29.7, 15.3.
HRMS calcd for C20H13N2F7 (M)þ: 414.0967, found: 414.0968.
4.2.23. 8-(4-Propylbenzyl)-2-methyl-8H-pyrazole[5,1-
a
]isoindole
4.2.16. 8-(4-Methylbenzyl)-2-methyl-8H-pyrazole[5,1-
a
]isoindole
(4k). 1H NMR (400 MHz, CDCl3)
d
7.32 (d, J¼8.0 Hz, 1H), 7.18 (t,
(4d). 1H NMR (400 MHz, CDCl3)
d
7.32 (d, J¼8.0 Hz, 1H), 7.18 (dd,
J¼4.0 Hz, 1H), 6.88e7.05 (m, 5H), 6.74 (d, J¼8.0 Hz, 1H), 6.00 (s, 1H),
5.18 (dd, J¼8.0, 4.0 Hz, 1H), 3.64 (dd, J¼8.0, 4 Hz, 1H), 2.87 (dd,
J¼8.0, 4.0 Hz, 1H), 2.32 (s, 3H), 1.51 (d, J¼8.0 Hz, 2H), 1.12 (m, 2H),
J¼8.0, 4.0 Hz, 1H), 7.04 (d, J¼4.0 Hz, 1H), 6.78e7.02 (m, 5H), 5.99 (s,
1H), 5.18 (d, J¼4.0 Hz, 1H), 3.61 (dd, J¼8.0, 4.0 Hz, 1H), 2.91 (dd,
J¼8.0, 4.0 Hz, 1H), 2.32 (s, 3H), 2.18 (s, 3H). 13C NMR (100 MHz,
0.82 (t, J¼8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 153.0, 145.7,
CDCl3)
d
152.9, 145.7, 144.1, 136.2, 132.5, 130.7, 129.6, 128.9, 128.0,
144.2, 141.1, 132.9, 130.7, 129.7, 129.6, 128.3, 128.0, 127.7, 126.5,
123.9, 120.1, 95.8, 63.4, 39.8, 37.6, 24.4, 14.4, 13.7. HRMS calcd for
126.5, 123.9, 120.1, 95.8, 63.4, 39.6, 31.6, 21.0, 14.4. HRMS calcd for
C
19H18N2 (M)þ: 274.1470, found: 274.1472.
C
21H22N2 (M)þ: 302.1783, found: 302.1776.
4.2.17. 8-(4-Fluorobenzyl)-2-methyl-8H-pyrazole[5,1-
(4e). 1H NMR (400 MHz, CDCl3)
a
]isoindole
4.2.24. 8-(4-Pentylbenzyl)-2-methyl-8H-pyrazole[5,1-
a
]isoindole
d
7.28 (d, J¼8.0 Hz,1H), 7.17 (br,1H),
(4l). 1H NMR (400 MHz, CDCl3)
d
7.34 (d, J¼8.0 Hz, 1H), 7.17 (d,
7.07 (br, 1H), 6.91 (d, J¼4.0 Hz, 1H), 6.85e6.59 (m, 4H), 5.95 (s, 1H),
J¼4.0 Hz, 1H), 7.05 (d, J¼8.0 Hz, 1H), 6.89e6.96 (m, 4H), 6.76 (d,
J¼8.0 Hz, 1H), 6.01 (s, 1H), 5.19 (dd, J¼8.0, 4.0 Hz, 1H), 3.64 (dd,
J¼8.0, 4.0 Hz, 1H), 2.86 (d, J¼8.0 Hz, 1H), 2.57e2.42 (m, 2H), 2.33 (s,
3H), 1.50 (m, 2H), 1.29e1.19 (m, 4H), 0.80 (t, J¼8.0 Hz, 3H). 13C NMR
5.18 (d, J¼4.0 Hz, 1H), 3.49 (d, J¼8.0 Hz, 1H), 3.12 (d, J¼8.0 Hz, 1H),
2.30 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 162.9, 160.5, 153.0, 145.9,
143.6, 131.2, 131.1, 128.2, 126.6, 123.5, 120.2, 114.9, 114.7, 95.9, 63.1,
38.8, 29.8, 14.4. HRMS calcd for C18H15N2F (M)þ: 278.1219, found:
278.1220.
(100 MHz, CDCl3)
d 153.0, 145.7, 144.2, 141.4, 132.9, 130.7, 129.6,
128.3,128.0,126.5,123.9,120.1, 95.8, 63.4, 39.8, 35.5, 31.4, 31.0, 22.5,
14.4, 14.0. HRMS calcd for C23H26N2 (M)þ: 330.2096, found:
330.2098.
4.2.18. 2-Methyl-8-(thiophen-2ylmethyl)-8H-pyrazole[5,1-
a
]iso-
indole (4f). 1H NMR (400 MHz, CDCl3)
d
7.33 (d, J¼8.0 Hz, 1H),
7.21 (t, J¼8.0 Hz, 1H), 7.11 (t, J¼8.0 Hz, 1H), 7.01 (d, J¼8.0 Hz, 1H),
6.92 (d, J¼8.0 Hz, 1H), 6.69 (d, J¼4.0 Hz, 1H), 6.47 (s, 1H), 5.99 (s,
1H), 5.22 (br, 1H), 3.72 (dd, J¼4.0 Hz, 1H), 3.43 (d, J¼4.0 Hz, 1H),
4.2.25. 8-Benzyl-2,6-di-methyl-8H-pyrazole[5,1-
(4m). 1H NMR (400 MHz, CDCl3)
a]isoindole
7.18 (d, J¼8.0 Hz, 1H), 7.09 (br,
d
3H), 6.93e6.99 (m, 3H), 6.58 (s, 1H), 5.92 (s, 1H), 5.15 (q, J¼4.0 Hz,
2.31 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 152.1, 145.0, 142.5, 135.8,
1H), 3.61 (d, J¼8.0 Hz,1H), 2.97 (d, J¼8.0 Hz,1H), 2.30 (s, 3H), 2.18 (s,
129.9, 127.3, 125.7, 125.6, 125.5, 123.4, 122.5, 119.1, 95.0, 61.9,
32.8, 13.3. HRMS calcd for C16H14N2S (M)þ: 266.0978, found:
266.0976.
3H). 13C NMR (100 MHz, CDCl3)
d 152.8, 145.9, 144.3, 136.5, 135.7,
129.8, 128.7, 128.1, 128.1, 126.7, 124.6, 119.9, 95.4, 63.2, 40.1, 21.6,
14.4. HRMS calcd for C19H18N2 (M)þ: 274.1470, found: 274.1472.
4.2.19. 6-Fluoro-2-methyl-8-(thiophen-2ylmethyl)-8H-pyrazole [5,1-
4.2.26. 8-(4-Methylbenzyl)-2,6-di-methyl-8H-pyrazole[5,1-
a
]iso-
a
]isoindole (4g). 1H NMR (400 MHz, CDCl3)
d
7.37 (br, 1H),
indole (4n). 1H NMR (400 MHz, CDCl3)
d
7.20 (d, J¼8.0 Hz, 1H), 6.98
7.00e7.08 (m, 2H), 6.81 (t, J¼4.0 Hz, 2H), 6.59 (d, J¼4.0 Hz, 1H), 6.06
(d, J¼8.0 Hz, 1H), 6.90 (d, J¼8.0 Hz, 2H), 6.83 (t, J¼4.0 Hz, 2H), 6.62
(s, 1H), 5.93 (s, 1H), 5.13 (q, J¼4.0 Hz, 1H), 3.56 (dd, J¼8.0, 4.0 Hz,
1H), 2.92 (d, J¼8.0 Hz, 1H), 2.30 (s, 3H), 2.18 (s, 6H). 13C NMR
(s, 1H), 5.31 (d, J¼4.0 Hz, 1H), 3.80 (d, J¼8.0 Hz, 1H), 3.51 (dd, J¼8.0,
4.0 Hz, 1H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 153.8, 146.3,
142.4, 136.7, 130.8, 130.4, 129.9, 128.6, 127.0, 123.1, 121.7, 120.4, 96.1,
62.3, 38.9, 14.1. HRMS calcd for C16H14N2FS (M)þ: 285.0862, found:
285.0851.
(100 MHz, CDCl3) d 152.8, 145.9, 144.4, 136.4, 136.2, 132.7, 129.6,
128.8, 128.7, 128.1, 124.6, 119.9, 95.4, 63.3, 39.6, 21.6, 21.0, 14.4.
HRMS calcd for C20H20N2 (M)þ: 288.1626, found: 288.1630.
4.2.20. 8-(4-Fluorobenzyl)-5-methoxyl-2-methyl-8H-pyrazole[5,1-
a
]
4.2.27. 8-(4-Ethylbenzyl)-2,6-di-methyl-8H-pyrazole[5,1-
a]isoindole
isoindole (4h). 1H NMR (400 MHz, CDCl3)
d
6.90e6.71 (m, 6H), 6.64
(4o). 1H NMR (400 MHz, CDCl3)
d
7.21e7.23 (m, 1H), 6.89e6.98 (m,
(d, J¼8.0 Hz, 1H), 5.97 (s, 1H), 5.18 (dd, J¼4.0 Hz, 1H), 3.74 (s, 3H),
3.51 (dd, J¼8.0, 4.0 Hz, 1H), 3.09 (dd, J¼8.0, 4.0 Hz, 1H), 2.32 (s, 3H).
5H), 6.57 (s, 1H), 5.95 (s, 1H), 5.14 (q, J¼4.0 Hz, 1H), 3.61 (dd, J¼8.0,
4.0 Hz, 1H), 2.89 (d, J¼8.0 Hz, 1H), 2.48 (m, 2H), 2.28 (s, 3H), 2.19 (s,
13C NMR (100 MHz, CDCl3)
d
161.9, 158.8, 151.9, 144.8, 134.6, 131.0,
3H), 1.12 (t, J¼8 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 152.8, 145.8,
130.1, 130.0, 123.3, 113.9, 113.7, 111.4, 104.8, 94.8, 61.8, 54.4, 38.0,
13.3. HRMS calcd for C19H17N2FO (MþH)þ: 309.1403, found:
309.1400.
144.5, 142.7, 136.4, 133.0, 129.7, 128.7, 128.0, 127.7, 124.7, 119.9, 95.4,
63.3, 39.8, 28.4, 21.6, 15.5, 14.4. HRMS calcd for C21H22N2 (M)þ:
302.1783, found: 302.1788.
4.2.21. 8-(4-Ethylbenzyl)-2-methyl-8H-pyrazole[5,1-
a
]isoindole
4.2.28. 8-(2-Bromobenzyl)-2-methyl-8H-pyrazole[5,1-
a
]isoindole
(4i). 1H NMR (400 MHz, CDCl3)
d
7.33 (d, J¼8.0 Hz, 1H), 7.18 (t,
(4p). 1H NMR (400 MHz, CDCl3)
d
7.43 (d, J¼8.0 Hz, 1H), 7.33 (d,
J¼8.0 Hz, 1H), 7.03 (t, J¼8.0 Hz, 1H), 6.95 (d, J¼8.0 Hz, 2H), 6.89 (d,
J¼8.0 Hz, 2H), 6.76 (d, J¼8.0 Hz, 1H), 5.99 (s, 1H), 5.17 (dd, J¼4.0 Hz,
1H), 3.63 (dd, J¼8.0, 4.0 Hz, 1H), 2.88 (br, 1H), 2.49 (q, J¼8.0 Hz, 2H),
J¼8.0 Hz, 1H), 7.17 (t, J¼8.0 Hz, 1H), 7.01e7.11 (m, 1H), 6.94e7.03 (m,
2H), 6.92 (dd, J¼4.0 Hz, 1H), 6.66 (d, J¼8.0 Hz, 1H), 6.02 (s, 1H), 5.32
(q, J¼4.0 Hz, 1H), 3.78 (d, J¼8.0 Hz, 1H), 2.91 (dd, J¼8.0 Hz, 1H), 2.30
2.32 (s, 3H),1.10 (t, J¼8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d
153.0,
(s, 3H). 13C NMR (100 MHz, CDCl3)
d 152.1, 144.6, 142.6, 134.7, 131.9,
145.7, 144.2, 142.7, 132.9, 130.7, 129.7, 128.1, 127.7, 126.5, 123.9, 120.1,
95.8, 63.4, 39.7, 28.4, 15.5, 14.4. HRMS calcd for C20H20N2 (M)þ:
288.1626, found: 288.1624.
131.2, 129.5, 127.7, 127.1, 126.2, 125.4, 124.0, 123.0, 119.1, 94.9, 60.5,
39.4, 13.4. HRMS calcd for C18H15N2Br (M)þ: 338.0419, found:
338.0420.
4.2.22. 8-(4-Methoxylbenzyl)-2-methyl-8H-pyrazole[5,1-
a
]isoindole
4.2.29. 2,6-Di-methyl-8-(thiophen-2ylmethyl)-8H-pyrazole [5,1-
a]
(4j). 1H NMR (400 MHz, CDCl3)
d
7.33 (d, J¼4.0 Hz, 1H), 7.19 (d,
isoindole (4q). 1H NMR (400 MHz, CDCl3)
d
7.23 (d, J¼4.0 Hz, 1H),
J¼8.0 Hz, 1H), 7.07 (t, J¼8.0 Hz, 1H), 6.83e6.88 (m, 3H), 6.62 (d,
J¼8.0 Hz, 2H), 5.99 (s, 1H), 5.20 (q, J¼4.0 Hz, 1H), 3.65 (s, 3H), 3.57
(d, J¼4.0 Hz, 1H), 2.96 (d, J¼8.0 Hz, 1H), 2.33 (s, 3H). 13C NMR
7.05 (d, J¼8.0 Hz, 1H), 6.98e6.93 (m, 1H), 6.85 (s, 1H), 6.71 (dd,
J¼4.0 Hz, 1H), 6.49 (d, J¼4.0 Hz, 1H), 5.96 (s, 1H), 5.21 (br, 1H), 3.71
(dd, J¼8.0, 4.0 Hz, 1H), 3.46 (dd, J¼8.0 Hz, 1H), 2.31 (s, 3H), 2.27 (s,
(100 MHz, CDCl3)
d
158.3, 152.9, 145.8, 144.0, 133.0, 130.7, 128.0,
3H). 13C NMR (100 MHz, CDCl3)
d 153.1, 146.2, 143.9, 137.0, 136.8,

J. Qiao et al. / Tetrahedron 70 (2014) 3782e3787
3787
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4934e4947.
128.9, 128.3, 126.7, 126.5, 124.4, 124.3, 119.9, 95.6, 62.8, 33.8, 21.6,
14.4. HRMS calcd for C17H16N2S (M)þ: 280.1034, found: 280.1039.
5. Pfefferkorn, J. A.; Choi, C.; Larsen, S. D.; Auerbach, B.; Hutchings, R.; Park, W.;
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4.2.30. 8-(4-Methoxylbenzyl)-2,6-di-methyl-8H-pyrazole[5,1-
a]iso-
indole (4r). 1H NMR (400 MHz, CDCl3)
d
7.01e7.22 (m, 2H),
6.89e6.83 (m, 2H), 6.64e6.68 (m, 3H), 5.95 (s,1H), 5.15 (q, J¼4.0 Hz,
1H), 3.68 (s, 3H), 3.53 (d, J¼4.0 Hz, 1H), 2.98 (d, J¼4.0 Hz, 1H), 2.32
(s, 3H), 2.24 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 158.3, 152.8, 144.4,
136.5, 132.9, 130.7, 128.7, 128.1, 127.7, 124.5, 119.9, 113.5, 95.3, 63.4,
55.1, 39.1, 29.8, 21.6, 14.4. HRMS calcd for C20H20N2O (M)þ:
304.1576, found: 304.1580.
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4.2.31. 8-Hexyl-2-methyl-8H-pyrazole[5,1-
(400 MHz, CDCl3)
a
]isoindole (4s). 1H NMR
7.43 (d, J¼8.0 Hz, 1H), 7.19e7.32 (m, 3H), 6.05 (s,
d
1H), 5.03 (t, J¼4.0 Hz,1H), 2.31 (s, 3H), 2.21e2.09 (m, 1H), 2.06e1.98
(m,1H),1.15e1.27 (m, 6H), 0.73 (t, J¼4.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3) d 147.6, 140.7, 139.6,125.6,122.7,121.6, 117.6,114.9, 90.3, 57.6,
28.2, 26.3, 17.9, 17.1, 9.2, 8.7. HRMS calcd for C17H22N2 (M)þ:
254.1783, found: 254.1780.
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Acknowledgements
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We thank Professors John A. Katzenellenbogen and Scott E.
Denmark for helpful discussions. This work was supported by the
National Natural Science Foundation of China (91017005, 81172935,
81373255), Key Project of Ministry of Education (313040),
and Hubei Province’s Outstanding Medical Academic Leader
Program.
ꢀ
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Supplementary data
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NMR spectra of products and X-ray data of compounds 4a, 4d,
4m, 4i, and 4q are available. Supplementary data related to this
article can be found at http://dx.doi.org/10.1016/j.tet.2014.04.032.
23. Dong, C.; Liao, Z.; Xu, X.; Zhou, H.-B. J. Heterocycl. Chem. 2013, http://dx.doi.org/
10.1002/jhet.1682 ASAP paper.
24. CCDC 937935 (4a), CCDC 937936 (4d), CCDC 937938 (4m), CCDC 937937 (4q),
CCDC 937939 (4i) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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References and notes
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Fantasies. In Targets in Heterocyclic Systems; Attanasi, O. A., Spinelli, D., Eds.;
Italian Society of Chemistry: Roma, 2002; pp 52e98.
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Bioorg. Med. Chem. Lett. 2000, 10, 1351e1355.
3. Abunada, N. M.; Hassaneen, H. M.; Kandile, N. G.; Miqdad, O. A. Molecules 2008,
13, 1501e1517.