Tandem reactions of N′-(2-Alkynylbenzylidene)hydrazides with Silyl Enolates: A facile route to H -pyrazolo[5,1- a ]isoquinolines

Article abstract of DOI:10.1021/cc1000314

A silver triflate-catalyzed tandem reaction of N′-(2- alkynylbenzylidene)hydrazide with silyl enolate is described, which generates the unexpected H-pyrazolo[5,1-a]isoquinolines in good to excellent yields. Intramolecular cyclization, nucleophilic addition, condensation, and aromatization may be involved in the reaction process.

Full text of DOI:10.1021/cc1000314

374
J. Comb. Chem. 2010, 12, 374–378
Tandem Reactions of N′-(2-Alkynylbenzylidene)hydrazides with Silyl
Enolates: A Facile Route to H-Pyrazolo[5,1-a]isoquinolines
Xingxin Yu,† Zhiyuan Chen,† Xiaodi Yang,§ and Jie Wu*,†,‡
Department of Chemistry, Fudan UniVersity, 220 Handan Road, Shanghai 200433, China, State Key
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, China, and Laboratory of AdVanced Materials, Fudan
UniVersity, 220 Handan Road, Shanghai 200433, China
ReceiVed March 1, 2010
A silver triflate-catalyzed tandem reaction of N′-(2-alkynylbenzylidene)hydrazide with silyl enolate is
described, which generates the unexpected H-pyrazolo[5,1-a]isoquinolines in good to excellent yields.
Intramolecular cyclization, nucleophilic addition, condensation, and aromatization may be involved in the
reaction process.
Introduction
under mild conditions giving rise to the unexpected H-pyra-
zolo[5,1-a]isoquinoline in good to excellent yields.
High-throughput screening has created a critical demand
to develop practical routes for rapid chemical synthesis of
natural-product-like molecules.1 Among the approaches
utilized, tandem reactions have been recognized as a powerful
method for combinatorial synthesis of small molecule
libraries.2 1,2-Dihydroisoquinoline and related compounds
are found abundantly in nature and many alkaloids exist this
kind of scaffold.3 For instance, the lamellarin alkaloids, a
family of novel marine natural products, contain a highly
substituted fused 1,2-dihydroisoquinoline core.4 Among this
family, lamellarin D is a potent inhibitor of human topoi-
somerase I5 and lamellarin R-20-sulfate shows selective
inhibition against HIV-1 integrase in vitro.6,7 We are
interested in development of a methodology for the construc-
tion of 1,2-dihydroisoquinoline library.8–10 Subsequent bio-
logical assay revealed that this kind of compound displayed
promising activity as PTP1B inhibitor. This result prompted
us to undertake preparation of structural novel 1,2-dihy-
droisoquinolines, with an expectation for finding better hits
in the assays.
Result and Discussion
N′-(2-Alkynylbenzylidene)hydrazide could be easily ac-
cessed via condensation of 2-alkynylbenzaldehyde with
hydrazine. Since the treatment of N′-(2-alkynylbenzylidene-
)hydrazide in the presence of suitable Lewis acid would lead
to isoquinolinium intermediate,9 we anticipated that the
presence of a nucleophile, such as silyl enolate, could provide
access to functionalized 1,2-dihydroisoquinolines after sub-
sequent reaction processes. To identify suitable conditions
for this proposed transformation, we first evaluated the
tandem cyclization-nucleophilic addition of N′-(2-alkynyl-
benzylidene)hydrazide 1a with silyl enoalte 2a (Scheme 1).
As described previously, silver triflate was the most effective
catalyst for the isoquinolinium intermediate generation.9
Thus, the AgOTf-catalyzed reaction was carried out in the
presence of Na2CO3 as base in dichloroethane. However, only
isoquinolinium intermediate was isolated, and no further
transformation was observed. Similar results were obtained
when the solvent was changed to THF, CH3CN, toluene, or
1,4-dioxane. Further screening of solvents led to the iden-
tification of CH3CN/DMF (v/v 1:3) as the most effective
condition for the transformation, with an isolated unexpected
product in high yield (97%). Structural identification revealed
that the compound obtained was the H-pyrazolo[5,1-a]iso-
quinoline 3a. Subsequent reaction optimization recognized
that 3.0 equiv of Na2CO3 was the best choice after base
screening.
Although several efficient methods have been appeared
for the formation of 1,2-dihydroisoquinoline derivatives
recently,8–13 development of novel and efficient routes for
the generation of functionalized 1,2-dihydroisoquinolines
under mild conditions is still of high interest. Recently, we
identified that N′-(2-alkynylbenzylidene)hydrazide was a
versatile building block leading to biologically active iso-
quinoline-related compounds.9 Herein, we would like to
disclose another application, which reacts with silyl enolate
Using AgOTf-catalzyed conditions (3.0 equiv of Na2CO3,
CH3CN/DMF), silyl enolates 2 reacted with various N′-(2-
Scheme 1. Initial Studies for the Reaction of
N′-(2-Alkynylbenzylidene)hydrazide 1a and Silyl Enolate 2a
* To whom correspondence should be addressed. E-mail: jie_wu@
fudan.edu.cn.
† Department of Chemistry, Fudan University.
‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry.
§ Laboratory of Advanced Materials, Fudan University.
10.1021/cc1000314  2010 American Chemical Society
Published on Web 03/25/2010

Route to H-Pyrazolo[5,1-a]isoquinolines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3 375
Table 1. Silver Triflate-Catalyzed Reactions of N′-(2-Alkynylbenzylidene)hydrazides 1 with Silyl Enolate 2
a Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide 1.
alkynylbenzylidene)hydrazides 1 to generate a number of
H-pyrazolo[5,1-a]isoquinolines 3 (Table 1). This silver-
catalyzed H-pyrazolo[5,1-a]isoquinoline formation was found
to be workable with N′-(2-alkynylbenzylidene)hydrazides
1a-1k with electron-withdrawing and -donating substituents
on the aromatic backbone (Table 1, entries 1-11). In addition
to the aromatic groups attached to the Ct C triple bond,
cyclopropyl and n-butyl groups were found suitable as well
to cleanly generate the desired products in good yields.
Furthermore, reactions of N′-(2- alkynylbenzylidene)hy-
drazides 1 with silyl enolates 2b or 2c provided the
corresponding H-pyrazolo[5,1-a]isoquinolines with good
yields (Table 1, entries 12-19). The structure of 3i was
verified by X-ray diffraction analysis meanwhile (Figure 1).
For the reaction process, we reasoned that N′-(2-alkynylben-
zylidene)hydrazide 1 would be cyclized to isoquinolinium
intermediate A in the presence of silver triflate. The subsequent
nucleophilic addition of silyl enolate 2 to isoquinolinium
intermediate A would afford intermediate B, which then
underwent intramolecular condensation and subsequent aroma-
tization to generate the H-pyrazolo[5,1-a]isoquinoline 3 (Scheme
2).

376 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3
Yu et al.
was purified by flash chromatography column on silica gel
(eluting with PE/EA ) 60/1 to 20/1) to provide the desired
product 3.
1-Ethyl-5-phenyl-H-pyrazolo[5,1-a]isoquinoline 3a.
Yield: 97%. 1H NMR (400 MHz, CDCl3): δ 1.45 (t, J ) 7.3
Hz, 3H), 3.07-3.13 (m, 2H), 6.95 (s, 1H), 7.46-7.57 (m,
5H), 7.70 (d, J ) 7.3 Hz, 1H), 7.83-7.85 (m, 3H), 8.24 (d,
J ) 7.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 14.2, 19.6,
112.5, 117.2, 123.3, 125.5, 127.2, 127.3, 127.4, 128.4, 129.3,
129.5, 129.6, 134.2, 134.6, 138.7, 140.4. HRMS calcd for
C19H17N2 (M+ + H): 273.1392, found 273.1380.
5-Cyclopropyl-1-ethyl-H-pyrazolo[5,1-a]isoquinoline 3b.
Yield: 91%. 1H NMR (400 MHz, CDCl3): δ 0.87-0.91 (m,
2H), 1.16-1.18 (m, 2H), 1.43 (t, J ) 7.8 Hz, 3H), 2.63-2.67
(m, 1H), 3.07-3.09 (m, 2H), 6.60 (s, 1H), 7.45-7.50 (m,
2H), 7.61 (d, J ) 7.4 Hz, 1H), 7.90 (s, 1H), 8.19 (d, J ) 7.8
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 6.9, 11.5, 14.2,
19.5, 106.8, 117.2, 123.2, 124.8, 126.5, 126.6, 129.5, 134.1,
140.1, 140.9. HRMS calcd for C16H17N2 (M+ + H):
237.1392, found 237.1372.
Figure 1. ORTEP illustration of compound 3i (30% probability
ellipsoids).
Scheme 2. Possible Mechanism for Reaction of
N′-(2-Alkynylbenzylidene)hydrazide 1 with Silyl Enolate 2
5-Butyl-1-ethyl-H-pyrazolo[5,1-a]isoquinoline 3c. Yield:
1
84%. H NMR (400 MHz, CDCl3): δ 0.99 (t, J ) 7.3 Hz,
3H), 1.43 (t, J ) 7.3 Hz, 3H), 1.48-1.55 (m, 2H), 1.82-1.88
(m, 2H), 3.05-3.09 (m, 2H), 3.10-3.16 (m, 2H), 6.76 (s,
1H), 7.46-7.52 (m, 2H), 7.65 (d, J ) 7.3 Hz, 1H), 7.86 (s,
1H), 8.20 (d, J ) 7.3 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ 14.0, 14.2, 19.5, 22.7, 29.0, 30.8, 109.3, 117.0, 123.2,
124.9, 126.4, 126.6, 126.9, 129.5, 134.1, 139.6, 139.9. HRMS
calcd for C17H21N2 (M+ + H): 253.1705, found 253.1694.
1-Ethyl-7,8,9-trimethoxy-5-phenyl-H-pyrazolo[5,1-a]i-
1
soquinoline 3d. Yield: 80%. H NMR (400 MHz, CDCl3):
δ 1.46 (t, J ) 7.3 Hz, 3H), 3.07-3.12 (m, 2H), 3.99 (s,
3H), 4.03 (s, 3H), 4.04 (s, 3H), 7.26 (s, 1H), 7.46-7.53 (m,
4H), 7.81 (s, 1H), 7.84-7.87 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 14.4, 19.6, 56.1, 61.2, 61.7, 100.6, 106.5, 116.1,
119.0, 122.1, 128.4, 129.0, 129.5, 134.3, 134.5, 136.9, 140.2,
Conclusion
In conclusion, we have described silver triflate catalyzed
tandem reactions of N′-(2-alkynylbenzylidene)hydrazides
with silyl enolates. A number of H-pyrazolo[5,1-a]isoquino-
lines are generated in good to excellent yields using this
approach. In the reaction process, intramolecular cyclization,
nucleophilic addition, condensation, and aromatization may
be involved. Small library construction and further studies
by adaptation of the method described herein for the synthesis
of 1,2-dihydroisoquinoline alkaloids are currently in progress
and the results will be reported in due course.
141.5, 148.8, 153.6. HRMS calcd for C22H23N2O3 (M+
H): 363.1709, found 363.1704.
+
1-Ethyl-9-fluoro-5-phenyl-H-pyrazolo[5,1-a]isoquino-
line 3e. Yield: 96%. 1H NMR (400 MHz, CDCl3): δ 1.45 (t,
J ) 7.4 Hz, 3H), 3.03-3.09 (m, 2H), 6.93 (s, 1H), 7.21-7.25
(m, 1H), 7.47-7.52 (m, 3H), 7.65-7.69 (m, 1H), 7.79-7.88
(m, 4H). 13C NMR (100 MHz, CDCl3): δ 14.0, 19.3, 108.8
2
2
(d, J ) 24 Hz), 111.8, 115.6 (d, J ) 24 Hz), 117.7,
CF
CF
3
Experimental Section
126.1, 126.6 (d, J ) 9 Hz), 128.4, 129.2, 129.3, 129.4,
CF
133.9, 138.0, 140.3, 161.7 (d, 1J CF ) 245 Hz). HRMS calcd
for C19H16FN2 (M+ + H): 291.1298, found 291.1284.
General Experimental Procedure for Silver Triflate-
Catalyzed Reactions of N′-(2-Alkynylbenzylidene)hy-
drazides 1 with Silyl Enolate 2. A mixture of N′-(2-
Alkynylbenzylidene)hydrazides 1 (0.2 mmol) and AgOTf
(5.2 mg, 10 mol %) in CH3CN (1.0 mL) was stirred at 70
°C for 1 h. Then, silyl enolate 2 (0.6 mmol, 3.0 equiv) and
Na2CO3 (0.6 mmol, 3.0 equiv) in DMF (3.0 mL) were added
subsequently. The reaction mixture was stirred at room
temperature vigorously. After completion of the reaction as
indicated by TLC, the mixture was diluted with ethyl acetate
(5.0 mL) and quenched with water (5.0 mL). The organic
layer was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue obtained
1-Ethyl-9-fluoro-5-(4-methoxyphenyl)-H-pyrazolo[5,1-
a]isoquinoline 3f. Yield: 97%. 1H NMR (400 MHz, CDCl3):
δ 1.43 (t, J ) 7.3 Hz, 3H), 3.02-3.07 (m, 2H), 3.86 (s,
3H), 6.84 (s, 1H), 7.03 (d, J ) 8.7 Hz, 2H), 7.23-7.34 (m,
2H), 7.78 (d, J ) 8.2 Hz, 2H), 7.84 (s, 1H), 8.16-8.19 (m,
1H). 13C NMR (100 MHz, CDCl3): δ 14.0, 19.5, 55.4, 110.9,
111.0, 111.9 (d, 2J CF ) 22 Hz), 113.9, 115.3 (d, 2J CF ) 23
3
Hz), 116.6, 121.9, 125.4 (d, J
) 9 Hz), 126.1, 130.8,
CF
3
1
131.5 (d, J ) 10 Hz), 134.3, 139.5, 140.5, 161.6 (d, J
CF
) 218 Hz). HRMS calcd for C20H18FN2O (M+ + H):
CF
321.1403, found 321.1389.

Route to H-Pyrazolo[5,1-a]isoquinolines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3 377
5-Cyclopropyl-1-ethyl-9-fluoro-H-pyrazolo[5,1-a]iso-
quinoline 3g. Yield: 94%. H NMR (400 MHz, CDCl3): δ
Hz, 3H), 1.48-1.55 (m, 2H), 1.83-1.91 (m, 2H), 2.60-2.65
(m, 2H), 3.00-3.02 (m, 2H), 3.09-3.15 (m, 4H), 6.68 (s,
1H), 7.43-7.46 (m, 2H), 7.60-7.63 (m, 1H), 7.94-7.96 (m,
1H). 13C NMR (100 MHz, CDCl3): δ 14.1, 22.6, 24.4, 25.1,
29.0, 30.3, 31.0, 107.5, 118.0, 123.8, 123.9, 126.0, 126.1,
127.1, 129.5, 133.0, 140.4, 162.8. HRMS calcd for C18H21N2
(M+ + H): 265.1705, found 265.1691.
1
0.85-0.89 (m, 2H), 1.15-1.20 (m, 2H), 1.44 (t, J ) 7.3
Hz, 3H), 2.59-2.66 (m, 1H), 3.02-3.08 (m, 2H), 6.57 (s,
1H), 7.17-7.21 (m, 1H), 7.56-7.60 (m, 1H), 7.79-7.83 (m,
1H), 7.91 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 6.8, 11.4,
2
2
14.0, 19.3, 106.3, 108.6 (d, J ) 24 Hz), 115.4 (d, J
CF
CF
3
) 24 Hz), 117.6, 125.8 (d, J ) 9 Hz), 126.0, 128.6 (d,
CF
9-Fluoro-5-phenyl-H-cyclopenta[c]pyrazolo[5,1-a]iso-
1
3J
) 9 Hz), 133.4, 140.0, 140.1, 161.2 (d, J
) 243
1
CF
CF
quinoline 3n. Yield: 81%. H NMR (400 MHz, CDCl3): δ
Hz). HRMS calcd for C16H16FN2 (M+ + H): 255.1298, found
255.1294.
2.62-2.69 (m, 2H), 2.99-3.02 (m, 2H), 3.14-3.17 (m, 2H),
6.87 (s, 1H), 7.22-7.27 (m, 1H), 7.50-7.57 (m, 3H),
7.62-7.68 (m, 2H), 7.89-7.91 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 24.3, 25.3, 30.3, 109.0 (d, 2J CF ) 22 Hz),
5-Butyl-1-ethyl-9-fluoro-H-pyrazolo[5,1-a]isoquino-
1
line 3h. Yield: 82%. H NMR (400 MHz, CDCl3): δ 0.99
110.1, 115.9 (d, 2J CF ) 24 Hz), 118.8, 125.7 (d, 3J CF ) 10
(t, J ) 7.3 Hz, 3H), 1.44 (t, J ) 7.3 Hz, 3H), 1.48-1.53 (m,
2H), 1.81-1.89 (m, 2H), 3.01-3.06 (m, 2H), 3.12 (t, J )
7.3 Hz, 2H), 6.73 (s, 1H), 7.19-7.23 (m, 1H), 7.59-7.65
(m, 1H), 7.81-7.83 (m, 1H), 7.86 (s, 1H). 13C NMR (100
MHz, CDCl3): δ 14.0, 14.1, 19.3, 22.6, 29.0, 30.6, 108.6 (d,
2J CF ) 24 Hz), 108.7, 115.4 (d, 2J CF ) 23 Hz), 117.5, 125.9
3
Hz), 126.0, 128.4, 128.9 (d, J
) 9 Hz), 129.2, 129.3,
CF
132.8, 134.2, 138.8, 161.5 (d, 1J CF ) 245 Hz), 163.3. HRMS
calcd for C20H16FN2 (M+ + H): 303.1298, found 303.1296.
9-Fluoro-5-methoxyphenyl-H-cyclopenta[c]pyrazolo[5,1-
a]isoquinoline 3o. Yield: 60%. 1H NMR (400 MHz, CDCl3):
δ 2.57-2.64 (m, 2H), 2.93-2.97 (m, 2H), 3.09-3.12 (m,
2H), 3.87 (s, 3H), 6.76 (s, 1H), 7.02-7.04 (m, 2H),
7.20-7.25 (m, 1H), 7.30-7.32 (m, 1H), 7.79-7.82 (m, 2H),
3
3
(d, J ) 10 Hz), 126.0, 128.5 (d, J ) 10 Hz), 133.4,
CF
CF
1
138.9, 139.8, 161.2 (d, J
) 244 Hz). HRMS calcd for
CF
C17H20FN2 (M+ + H): 271.1611, found 271.1607.
1-Ethyl-8-fluoro-5-phenyl-H-pyrazolo[5,1-a]isoquino-
line 3i. Yield: 92%. 1H NMR (400 MHz, CDCl3): δ 1.44 (t,
J ) 7.3 Hz, 3H), 3.03-3.09 (m, 2H), 6.89 (s, 1H), 7.26-7.37
(m, 2H), 7.46-7.53 (m, 3H), 7.81-7.85 (m, 3H), 8.18-8.22
(m, 1H). 13C NMR (100 MHz, CDCl3): δ 14.0, 19.5, 111.6,
7.93-7.96 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 24.4,
2
25.3, 30.2, 55.4, 109.4, 111.3 (d, J
) 22 Hz), 113.9,
CF
2
3
115.2 (d, J ) 24 Hz), 117.8, 121.0, 126.0 (d, J ) 8
Hz), 126.4, 130.7, 131.3 (d, J ) 10 Hz), 133.1, 140.3,
CF
CF
3
CF
1
160.4, 161.8 (d, J
) 245 Hz), 163.6. HRMS calcd for
CF
2
2
112.1 (d, J ) 22 Hz), 115.6 (d, J ) 23 Hz), 116.7,
CF
CF
C21H18FN2O (M+ + H): 333.1403, found 333.1386.
3
122.1, 125.5 (d, J ) 9 Hz), 128.4, 129.4, 129.5, 131.5
CF
3
1
9-Fluoro-5-cyclopropyl-H-cyclopenta[c]pyrazolo[5,1-
a]isoquinoline 3p. Yield: 61%. 1H NMR (400 MHz, CDCl3):
δ 0.86-0.90 (m, 2H), 1.16-1.19 (m, 2H), 2.60-2.66 (m,
3H), 3.01-3.05 (m, 2H), 3.09-3.12 (m, 2H), 6.48 (s, 1H),
7.15-7.21 (m, 1H), 7.55-7.58 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 7.00, 11.6, 24.3, 25.2, 30.3, 104.3, 108.9
(d, J ) 10 Hz), 133.8, 134.3, 139.7, 140.7, 161.5 (d, J
CF
) 246 Hz). HRMS calcd for C19H16FN2 (M+ + H):
CF
291.1298, found 291.1298.
1-Ethyl-5-(4-methoxyphenyl)-H-pyrazolo[5,1-a]isoquin-
1
oline 3j. Yield: 98%. H NMR (400 MHz, CDCl3): δ 1.43
(t, J ) 7.8 Hz, 3H), 3.05-3.10 (m, 2H), 3.84 (s, 3H), 6.90
(s, 1H), 7.00-7.03 (m, 2H), 7.44-7.53 (m, 2H), 7.66 (d, J
) 7.8 Hz, 1H), 7.76-7.79 (m, 2H), 7.84 (s, 1H), 8.21 (d, J
) 7.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 14.2, 19.6,
55.4, 111.9, 113.9, 117.1, 123.2, 125.3, 126.5, 127.0, 127.1,
129.7, 130.9, 134.6, 138.5, 140.3, 160.3. HRMS calcd for
C20H19N2O (M+ + H): 303.1497, found 303.1490.
2
2
(d, J ) 23 Hz), 115.8 (d, J ) 24 Hz), 118.7, 124.9
CF
CF
3
1
(d, J ) 10 Hz), 125.9, 128.3 (d, J ) 9 Hz), 132.4,
CF
CF
1
140.9, 161.0 (d, J
) 244 Hz), 163.1. HRMS calcd for
CF
C17H16FN2 (M+ + H): 267.1298, found 267.1290.
9-Fluoro-5-butyl-H-cyclopenta[c]pyrazolo[5,1-a]isoquin-
1
oline 3q. Yield: 67%. H NMR (400 MHz, CDCl3): δ 0.99
(t, J ) 7.3 Hz, 3H), 1.46-1.55 (m, 2H), 1.82-1.90 (m, 2H),
2.59-2.66 (m, 2H), 2.95-3.01 (m, 2H), 3.04-3.13 (m, 4H),
6.65 (s, 1H), 7.16-7.21 (m, 1H), 7.55-7.61 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 14.0, 22.6, 24.3, 25.4, 28.9, 30.3,
1-Ethyl-5-phenyl-H-pyrazolo[5,1-a][1,3]dioxolo[8,9-g]iso-
quinoline 3k. Yield: 93%. H NMR (400 MHz, CDCl3): δ
1
1.42 (t, J ) 7.3 Hz, 3H), 2.98-3.04 (m, 2H), 6.03 (s, 2H),
6.81 (s, 1H), 7.03 (s, 1H), 7.44-7.50 (m, 3H), 7.59 (s, 1H),
7.79-7.82 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 14.2,
19.5, 101.6, 101.9, 105.3, 112.3, 115.4, 120.9, 125.5, 128.4,
129.0, 129.4, 134.2, 134.7, 137.1, 140.2, 147.5, 148.0. HRMS
calcd for C20H17N2O2 (M+ + H): 317.1290, found 317.1279.
5-Phenyl-H-cyclopenta[c]pyrazolo[5,1-a]isoquinoline 3l.
Yield: 95%. 1H NMR (400 MHz, CDCl3): δ 2.56-2.63 (m,
2H), 2.92-2.97 (m, 2H), 3.11-3.14 (m, 2H), 6.85 (s, 1H),
7.43-7.52 (m, 5H), 7.65-7.67 (m, 1H), 7.85-7.87 (m, 2H),
7.97-7.99 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 24.5,
25.4, 30.3, 110.8, 118.3, 123.9, 124.5, 126.7, 126.9, 127.3,
128.4, 129.2, 129.4, 129.5, 133.5, 134.5, 139.5, 163.3. HRMS
calcd for C20H17N2 (M+ + H): 285.1392, found 285.1382.
5-Butyl-H-cyclopenta[c]pyrazolo[5,1-a]isoquinoline 3m.
Yield: 60%. 1H NMR (400 MHz, CDCl3): δ 0.99 (t, J ) 7.3
2
2
30.9, 106.9, 108.8 (d, J ) 23 Hz), 115.8 (d, J ) 23
CF
CF
Hz), 125.0 (d, 3J CF ) 9 Hz), 126.0, 128.2 (d, 3J CF ) 9 Hz),
132.3, 132.4, 139.7, 161.0 (d, 1J CF ) 244 Hz), 162.8. HRMS
calcd for C18H20FN2 (M+ + H): 283.1611, found 283.1610.
8-Fluoro-5-phenyl-H-cyclopenta[c]pyrazolo[5,1-a]iso-
1
quinoline 3r. Yield: 78%. H NMR (400 MHz, CDCl3): δ
2.56-2.63 (m, 2H), 2.93-2.96 (m, 2H), 3.07-3.11 (m, 2H),
6.77 (s, 1H), 7.22-7.25 (m, 1H), 7.28-7.31 (m, 1H),
7.45-7.53 (m, 3H), 7.83-8.00 (m, 3H). 13C NMR (100
2
MHz, CDCl3): δ 24.4, 25.3, 30.2, 110.0, 111.5 (d, J
)
CF
22 Hz), 115.5 (d, 2J CF ) 24 Hz), 117.9, 121.1, 126.0 (d, 3J
3
) 9 Hz), 128.4, 129.3, 129.4, 131.2 (d, J
) 9 Hz),
CF
CF
133.1, 134.1, 140.5, 161.8 (d, 1J CF ) 246 Hz), 163.7. HRMS
calcd for C20H16FN2 (M+ + H): 303.1298, found 303.1286.

378 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3
Yu et al.
Ding, Q.; Ye, Y.; Fan, R.; Wu, J. J. Org. Chem. 2007, 72,
5439. (e) Ding, Q.; Wang, B.; Wu, J. Tetrahedron 2007, 63,
12166. (f) Ding, Q.; Yu, X.; Wu, J. Tetrahedron Lett. 2008,
49, 2752. (g) Ding, Q.; Wu, J. AdV. Synth. Catal. 2008, 350,
1850. (h) Yu, X.; Ding, Q.; Wang, W.; Wu, J. Tetrahedron
Lett. 2008, 49, 4390. (i) Ye, Y.; Ding, Q.; Wu, J. Tetrahedron
2008, 64, 1378.
9-Fluoro-5-methoxyphenyl-H-cyclohexa[c]pyrazolo[5,1-
a]isoquinoline 3s. Yield: 87%. 1H NMR (400 MHz, CDCl3):
δ 1.88-1.97 (m, 4H), 2.88-2.91 (m, 2H), 3.07-3.09 (m,
2H), 3.87 (s, 3H), 6.79 (s, 1H), 7.01-7.04 (m, 2H),
7.20-7.25 (m, 1H), 7.30-7.33 (m, 1H), 7.81-7.85 (m, 2H),
8.09-8.12 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 22.9,
23.0, 23.5, 24.2, 55.4, 109.4, 111.5 (d, 2J CF ) 21 Hz), 113.8,
(9) (a) Chen, Z.; Yang, X.; Wu, J. Chem. Commun. 2009, 3469.
(b) Chen, Z.; Ding, Q.; Yu, X.; Wu, J. AdV. Synth. Catal.
2009, 351, 1692. (c) Chen, Z.; Yu, X.; Su, M.; Yang, X.;
Wu, J. AdV. Synth. Catal. 2009, 351, 2702. (d) Yu, X.; Yang,
X.; Wu, J. Org. Biomol. Chem. 2009, 7, 4526. (e) Yu, X.;
Ding, Q.; Chen, Z.; Wu, J. Tetrahedron Lett. 2009, 50, 4279.
(10) (a) Ding, Q.; Wang, Z.; Wu, J. J. Org. Chem. 2009, 74, 921.
(b) Yu, X.; Wu, J. J. Comb. Chem. 2009, 11, 895. (c) Ye, S.;
Wu, J. Tetrahedron Lett. 2009, 50, 6273. (d) Chen, Z.; Su,
M.; Yu, X.; Wu, J. Org. Biomol. Chem. 2009, 7, 4641. (e)
Zhou, H.; Jin, H.; Ye, S.; He, X.; Wu, J. Tetrahedron Lett.
2009, 50, 4616. (f) Ding, Q.; Chen, Z.; Yu, X.; Peng, Y.;
Wu, J. Tetrahedron Lett. 2009, 50, 340. (g) Ye, S.; Zhou, H.;
Wu, J. Tetrahedron 2009, 65, 1294.
2
3
115.0 (d, J
) 23 Hz), 121.8, 125.4 (d, J
) 9 Hz),
CF
CF
126.3, 130.7, 130.8, 131.5 (d, 3J CF ) 10 Hz), 134.5, 139.3,
1
151.3, 160.4, 161.4 (d, J
) 247 Hz). HRMS calcd for
CF
C22H20FN2O (M+ + H): 347.1560, found 347.1540.
Acknowledgment. Financial support from National Natu-
ral Science Foundation of China (20972030), the Science
and Technology Commission of Shanghai Municipality
(09JC1404902), and Program for New Century Excellent
TalentsinUniversity(NCET-07-0208)isgratefullyacknowledged.
Supporting Information Available. Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
of compound 3. This material is available free of charge via
the Internet at http://pubs.acs.org.
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