Silver triflate-palladium chloride cooperative catalysis in a tandem reaction for the synthesis of H-pyrazolo [5,1-α]isoquinolines

Article abstract of DOI:10.1002/adsc.201300327

A tandem reaction of N'-(2-alkynylbenzylidene) hydrazone with alcohol in the presence of oxygen co-catalyzed by silver triflate and palladium chloride under mild conditions is reported, providing H-pyrazolo [5,1-α] isoquinolines in good yields. During the transformation, isoquinolinium-2-yl amide was the key intermediate via a silver(I)-catalyzed 6-endo cyclization of N'-(2-alkynylbenzyli- dene)hydrazone. The presence of a palladium catalyst and molecular oxygen promoted the oxidation of the alcohol to the aldehyde or ketone. Subsequent nucleophilic attack of the in situ generated enolate to isoquinolinium-2-yl amide, intramolecular condensation, and aromatization afforded the H-pyrazolo- [5,1-α]isoquinolines. The easily available starting materials, good substrate generality, mild reaction conditions, and experimental ease should make this method attractive for further library construction.

Full text of DOI:10.1002/adsc.201300327

FULL PAPERS
DOI: 10.1002/adsc.201300327
Silver Triflate-Palladium Chloride Cooperative Catalysis
in a Tandem Reaction for the Synthesis of
H-Pyrazolo[5,1-a]isoquinolines
AHCTUNGTRENNUNG
Qing Xiao,a Jie Sheng,b Qiuping Ding,a,* and Jie Wub,c,*
a
Key Laboratory of Functional Small Organic Molecules, Ministry of Education and College of Chemistry & Chemical
Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, Peopleꢀs Republic of China
E-mail: dqpjxnu@gmail.com
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Peopleꢀs Republic of China
b
Fax : (+86)-216-564-1740; e-mail: jie_wu@fudan.edu.cn
Key Laboratory of Organic Synthesis of Jiangsu Province,College of Chemistry, Chemical Engineering and Materials
c
Science, Soochow University, Suzhou, 215123, Peopleꢀs Republic of China
Received: April 18, 2013; Revised: June 6, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300327.
Abstract: A tandem reaction of N’-(2-alkynylbenzyli- nucleophilic attack of the in situ generated enolate
dene)hydrazone with alcohol in the presence of to isoquinolinium-2-yl amide, intramolecular conden-
oxygen co-catalyzed by silver triflate and palladium sation, and aromatization afforded the H-pyrazolo-
chloride under mild conditions is reported, providing
ACHTUNGTREN[NUGN 5,1-a]isoquinolines. The easily available starting ma-
H-pyrazolo[5,1-a]isoquinolines in good yields. terials, good substrate generality, mild reaction con-
ACHTUNGTRENNUNG
During the transformation, isoquinolinium-2-yl ditions, and experimental ease should make this
amide was the key intermediate via a silver(I)-cata- method attractive for further library construction.
lyzed 6-endo cyclization of N’-(2-alkynylbenzyli-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Introduction
For example, H-pyrazolo
tives have been reported for inhibitory activity against
ACHTUNGTNER[NUNG 5,1-a]isoquinoline deriva-
The power of cooperative catalysis has been demon- PTP1B (protein tyrosine phosphatase 1 B) and
strated in organic synthesis.[1] Usually, two or more CDC25B.[4] It would be attractive if this architectural
catalysts are combined in a one pot process, which complexity could be constructed from easily available
would enable activation of both reactants. The trans- starting materials via a cascade process. Recently, the
formation could not be fulfilled by one activation N’-(2-alkynylbenzylidene)hydrazone moiety has been
mechanism alone. For instance, Hu and co-workers employed as a useful building block for the synthesis
described several sequential reaction cascades under of N-heterocycles.[5] During the transformation, an
cooperative catalysis that provided stereo-controlled isoquinolinium-2-yl amide was demonstrated as the
access to useful structural motifs.[2] In connection with key intermediate formed via a silver(I)-catalyzed 6-
our interest in the generation of natural product-like endo cyclization of N’-(2-alkynylbenzylidene)hydra-
compounds for the studies of chemical genetics,[3] we zone. For example, H-pyrazolo
ACTHNUTRGNEUNG[5,1-a]isoquinolines
were attracted by the power of cooperative catalysis could be generated via a silver triflate-catalyzed
and the efficiency of tandem reactions. These process- three-component reaction of 2-alkynylbenzaldehyde,
es would lead to a rapid build-up of molecular com- sulfonohydrazide, and ketone or aldehyde.[5c] Amine
plexity and diversity with the formation of multi- could also be utilized as a partner in the reaction of
bonds.
N’-(2-alkynylbenzylidene)hydrazone under palladium-
[5,1- catalyzed oxidative conditions via C H bond activa-
À
Among the N-heterocycles, the H-pyrazolo
G
a]isoquinoline structure has been recognized as a priv- tion.[5g] The enamine was believed to be the key inter-
ileged scaffold with remarkable biological activities. mediate during the process. Since the aldehyde or
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Scheme 1. A proposed synthetic route to H-pyrazoloACTHNUTRGNE[NUG 5,1-a]isoquinolines
ketone could be afforded in situ from alcohol, we con- ladium acetate (5 mol%) were used as the co-cata-
ceived that the scaffold of H-pyrazolo[5,1-a]isoquino- lysts. To our delight, the desired H-pyrazolo[5,1-a]iso-
A
ACHTUNGTRENNUNG
line would be constructed as well via a cascade reac- quinoline 3a was isolated and obtained in 47% yield
tion of N’-(2-alkynylbenzylidene)hydrazone with alco- when the reaction was run in the presence of potassi-
hol in the presence of oxygen under cooperative cat- um carbonate as a base in toluene under air (Table 1,
alysis.
entry 1). As expected, the reaction failed when the
The proposed synthetic route is shown in Scheme 1. transformation was performed under a nitrogen at-
We envisaged that the presence of silver and palladi- mosphere. (Table 1, entry 2). The yield was improved
um catalysts would enable the activation of both sub- to 61% when the reaction proceeded using a balloon
strates, which would promote the transformation of oxygen (Table 1, entry 3). Subsequently, a range of
smoothly. As mentioned above, a silver(I)-catalyzed solvents was surveyed (Table 1, entries 4–8). Howev-
6-endo cyclization of N’-(2-alkynylbenzylidene)hydra- er, no better results were observed when other sol-
zone 1 would occur to form isoquinolinium-2-yl vents were employed in the reaction, and toluene was
amide A. Meanwhile, the alcohol 2 would be oxidized demonstrated as the best choice. We further screened
to aldehyde or ketone B in the presence of a palladi- the reaction with different bases (Table 1, entries 9–
um catalyst and molecular oxygen.[6] Subsequently, an 14). Again, the results were inferior. We next shifted
enolate C would be formed if there was a base in the our focus to other palladium catalysts (Table 1, en-
reaction system. Therefore, a nucleophilic attack of tries 15–18). A similar outcome was obtained when
enolate C to the isoquinolinium-2-yl amide A would Pd
be expected, leading to the intermediate D. An intra- Interestingly, the yield was increased to 75% when
molecular condensation with a loss of a molecule of Pd(PPh3)3Cl2 or PdCl2 was utilized as a replacement
ACHTUNGRTENUN(NG TFA)2 was used in the reaction (Table 1, entry 15).
AHCTUNGTRENNUNG
water would produce compound E, which would then (Table 1, entries 16 and 17). A control experiment
undergo aromatization to generate compound 3. This without the addition of palladium catalyst failed to
one-step tandem transformation[7] reveals a complex give the corresponding product (Table 1, entry 19).
structure formed with exquisite control of three new The yield was lower when the reaction occurred in
bonds and an array of exploitable functionality. the presence of 2 mol% of palladium chloride
During the process, the presence of cooperative catal- (Table 1, entry 20). No improvement was observed
ysis would play an important role if the cascade pro- when the catalytic amount of palladium chloride was
cess were feasible. Otherwise, the efficiency and suc- increased to 10 mol% (Table 1, entry 21).
cess would be hampered.
Using the optimized reaction conditions as shown
in Table 1, a range of N’-(2-alkynylbenzylidene)hydra-
zones 1 reacted with selected alcohols leading to di-
Results and Discussion
verse H-pyrazolo
(Table 2). This silver(I) and palladium(II) co-cata-
[5,1-a]isoquinoline formation was
triflate-palladium chloride cooperative catalysis in found to be workable with various alcohols. The alco-
a tandem reaction for the synthesis of H-pyrazolo[5,1- hols bearing pyridinyl and indolyl functionality were
ACHTUNGTRENN[UNG 5,1-a]isoquinolines 3 in good yields
To identify suitable conditions for the proposed silver lyzed H-pyrazoloACHTGNUTRENNUNG
AHCTUNGTRENNUNG
a]isoquinolines, we started to explore the possibility all compatible under the standard conditions. The
of this protocol as presented in Scheme 1. The model substrate N’-(2-alkynylbenzylidene)hydrazones 1 with
reaction of N’-(2-alkynylbenzylidene)hydrazone 1a electron-withdrawing and electron-donating substitu-
and n-butanol 2a was selected for reaction develop- ents on the aromatic backbone were also investigated
ment. At the outset, silver triflate (10 mol%) and pal- to provide the H-pyrazoloACTHNUTRGNEU[GN 5,1-a]isoquinoline core
2
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Silver Triflate-Palladium Chloride Cooperative Catalysis in a Tandem Reaction
Table 1. Initial studies on the reaction of N’-(2-alkynylbenzy-
lidene)hydrazone 1a with n-butanol 2a.
Table 2. Synthesis of H-pyrazoloACTHNGUETRNNU[G 5,1-a]isoquinolines through
reaction of N’-(2-alkynylbenzylidene)hydrazones with alco-
hols in the presence of a cooperative catalysis.[a]
Entry
[Pd]
Solvent
Base
Yield [%][a]
1[b]
2[c]
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20[d]
21[e]
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
toluene
toluene
toluene
DMF
dioxane
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO4
Cs2CO3
KOAc
KHCO3
tBuOk
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
47
trace
61
39
37
30
52
51
23
52
24
19
15
17
61
75
75
MeCN
DCE
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
PdCl
G
PdCl2
PdBr2
–
PdCl2
PdCl2
68
trace
40
73
[a]
Isolated yield based on N’-(2-alkynylbenzylidene)hydra-
zone 1a.
The reaction was carried out under air.
The reaction was performed under a nitrogen atmos-
phere.
[b]
[c]
[d]
[e]
[a]
In the presence of 2 mol% of PdCl2.
In the presence of 10 mol% of PdCl2.
Isolated yield based on N’-(2-alkynylbenzylidene)hydra-
zone 1.
structure. Additionally, it seemed that the substituents
Reactions of N’-(2-alkynylbenzylidene)hydrazones
on the triple bond of N’-(2-alkynylbenzylidene)hydra- 1 with secondary alcohols were explored as well
zone 1 did not affect the final outcome. (Scheme 2). For instance, N’-(2-alkynylbenzylidene)-
Scheme 2. Reactions of N’-(2-alkynylbenzylidene)hydrazone 1a with secondary alcohols.
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7.92 (d, J=7.2 Hz, 2H), 7.73 (d, J=8.0 Hz, 1H), 7.62 (d, J=
7.2 Hz, 2H), 7.58–7.52 (m, 5H), 7.50–7.45 (m, 2H), 7.34 (t,
J=7.2 Hz, 1H), 7.07 (s, 1H). 13C NMR (100 MHz, CDCl3):
d=144.7, 138.6, 134.6, 134.1, 134.0, 130.1, 129.8, 129.5, 129.4,
128.8, 128.5, 127.9, 127.5, 127.3, 127.0, 124.7, 123.3, 117.1,
hydrazone 1a reacted with cyclohexanol leading to
the desired product 3s in 72% yield. When 1-methyl-
1-propanol was employed in the reaction of N’-(2-al-
kynylbenzylidene)hydrazone 1a under the cooperative
catalysis conditions, a mixed product was isolated al-
though the regioselectivity is reasonable.
+
113.0; HR-MS (ACPI); m/z=321.1392, calcd. for C23H17N2
[M+H+]: 321.1386.
1-Benzyl-5-phenylpyrazolo
G
(3e):
1H NMR (400 MHz, CDCl3): d=8.12 (d, J=7.6 Hz, 1H),
7.90 (d, J=6.8 Hz, 2H), 7.82 (s, 1H), 7.74 (d, J=7.2 Hz,
1H), 7.58–7.47 (m, 5H), 7.33–7.32 (m, 4H), 7.26–7.23 (m,
1H), 7.04 (s, 1H), 4.50 (s, 2H); 13C NMR (100 MHz,
CDCl3): d=142.5, 139.6, 138.7, 135.4, 134.0, 129.7, 129.5,
129.3, 128.7, 128.5, 127.4, 127.3, 127.2, 126.4, 125.0, 123.5,
113.2, 112.8, 32.0; HR-MS (ACPI): m/z=335.1551, calcd. for
Conclusions
In conclusion, we have reported a tandem reaction of
N’-(2-alkynylbenzylidene)hydrazones with alcohols in
the presence of oxygen co-catalyzed by silver triflate
and palladium chloride under mild conditions. Di-
+
C24H19N2 [M+H+]: 335.1543.
verse H-pyrazoloACTHNUTRGNEUNG[5,1-a]isoquinolines were generated
1-Decyl-5-phenylpyrazolo
G
(3f):
under the cooperative catalysis conditions. Applica-
tion of the cooperative catalysis system for the forma-
tion of other N-heterocycles is currently under inves-
tigation in our laboratory.
1H NMR (400 MHz, CDCl3): d=7.26 (d, J=8.0 Hz, 1H),
7.78–7.85 (m, 3H), 7.74 (d, J=7.6 Hz, 1H), 7.59 (t, J=
7.2 Hz, 1H), 7.56–7.49 (m, 4H), 6.97 (s, 1H), 3.08 (d, J=
7.6 Hz, 2H), 1.88–1.81 (m, 2H), 1.67–1.48 (m, 4H), 1.45–
1.28 (m, 10H), 0.90 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=141.1, 138.7, 134.6, 134.1, 129.6, 129.4, 129.2,
128.4, 127.3, 127.1, 123.2, 115.7, 112.4, 31.9, 29.7, 29.6, 29.4,
26.2, 22.7, 14.2; HR-MS (ACPI): m/z=385.2664, calcd. for
Experimental Section
+
C27H33N2 [M+H+]: 385.2638.
General Experimental Procedure for the Synthesis of
H-PyrazoloACHTUNGTRENNUNG[5,1-a]isoquinolines through Reaction of
N’-(2-Alkynylbenzylidene)hydrazones with Alcohol in
the Presence of a Cooperative Catalysis
5-Phenyl-1-(pyridin-2-yl)pyrazoloACHTUNTRGNEUNG[5,1-a]isoquinoline (3g):
1H NMR (400 MHz, CDCl3): d=8.81 (d, J=4.0 Hz, 1H),
8.59 (d, J=8.4 Hz, 1H), 8.13 (s, 1H), 7.91–7.71 (d, J=
6.8 Hz, 2H), 7.82 (t, J=8.0 Hz, 1H), 7.74 (d, J=8.4 Hz,
1H), 7.65 (d, J=6.80 Hz, 1H), 7.58–7.49 (m, 4H), 7.45–7.41
(m, 1H), 7.32 (t, J=7.2 Hz, 1H), 7.11 (s, 1H); 13C NMR
(100 MHz, CDCl3): d=153.9, 149.7, 142.1, 136.8, 134.0,
130.1, 129.6, 129.3, 128.4, 127.2, 127.0, 124.6, 124.5, 124.3,
121.9, 117.0, 113.7; HR-MS (ACPI): m/z=322.1372, calcd.
N’-(2-Alkynylbenzylidene)hydrazone
1
(0.3 mmol) was
added to a solution of AgOTf (10 mol%) in toluene
(2.0 mL) under air. After stirring of the mixture at 658C for
one hour, PdCl2 (2 or 10 mol%), alcohol 2 (1.5 mmol), and
K2CO3 (0.9 mmol) were added. The mixture was stirred at
808C. After completion of the reaction as indicated by TLC
(~16 h), the mixture was purified directly by flash column
chromatograph (EtOAc/n-hexane, 1:50) to give the desired
product 3.
+
for C22H16N3 [M+H+]: 322.1339.
1-(Indol-3-yl)-5-phenylpyrazolo
G
(3h):
1H NMR (400 MHz, CDCl3): d=8.02 (d, J=8.0 Hz, 2H),
7.95 (d, J=6.8 Hz, 2H), 7.72 (d, J=8.0 Hz, 1H), 7.58 (t, J=
6.8 Hz, 2H), 7.54–7.49 (m, 2H), 7.45 (t, J=7.6 Hz, 2H), 7.36
(d, J=2.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.24–7.21 (m,
1H), 7.12 (t, J=8.0 Hz, 1H), 7.09 (s, 1H); 13C NMR
(100 MHz, CDCl3): d=142.9, 138.7, 136.3, 135.8, 134.1,
129.7, 129.6, 129.3, 128.5, 127.7, 127.6, 127.0, 126.9, 125.0,
123.8, 123.6, 122.5, 120.4, 120.2, 112.9, 111.1, 109.2, 108.5;
1-Ethyl-5-phenylpyrazolo
[5,1-a]isoquinoline
(3a):[8]
1H NMR (400 MHz, CDCl3): d=7.29 (d, J=8.0 Hz, 1H),
7.90–7.88 (m, 3H), 7.76 (d, J=8.4 Hz, 1H), 7.63–7.52 (m,
5H), 7.01 (s, 1H), 3.19–3.13 (m, 2H), 1.50 (t, J=7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=140.4, 138.7, 134.5,
134.1, 129.4, 129.2, 128.4, 127.2, 127.17, 127.11, 117.1, 112.4,
19.5, 14.1.
+
HR-MS (ACPI): m/z=360.1498, calcd. for C25H18N3 [M+
1-Methyl-5-phenylpyrazolo
[5,1-a]isoquinoline
(3b):[8]
H+]: 360.1495.
5-(p-Tolyl)pyrazolo
1H NMR (400 MHz, CDCl3): d=8.30 (d, J=8.0 Hz, 1H),
7.88 (d, J=7.2 Hz, 2H), 7.84 (s, 1H), 7.27 (d, J=8.0 Hz,
1H), 7.57–7.51 (m, 5H), 6.32 (d, J=8.0 Hz, 1H), 6.98 (s,
1H), 2.68 (s, 3H); 13C NMR (100 MHz, CDCl3): d=142.1,
138.6, 135.2, 134.1, 129.4, 129.2, 128.4, 127.1, 125.7, 123.2,
112.4, 110.1, 11.9.
[5,1-a]isoquinoline
(3i):
1H NMR
(400 MHz, CDCl3): d=8.14–8.12 (m, 1H), 8.00 (d, J=
2.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.75–7.73 (m, 1H),
7.59–7.52 (m, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.09 (d, J=
2.0 Hz, 1H), 7.04 (s, 1H), 2.46 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=140.3, 139.3, 131.0, 129.3, 129.1, 127.9, 127.2,
127.1, 123.6, 112.2, 97.8, 21.5; HR-MS (ACPI): m/z=
5-Phenylpyrazolo
[5,1-a]isoquinoline
(3c):[8]
1H NMR
(400 MHz, CDCl3): d=8.14–8.12 (m 1H), 8.03 (d, J=2.0 Hz,
1H), 7.92–7.90 (m, 2H), 7.76–73.7 (m, 1H), 7.60–7.49 (m,
5H), 7.10 (d, J=2.0 Hz, 1H), 7.06 (s, 1H); 13C NMR
(100 MHz, CDCl3): d=140.9, 139.4, 138.6, 133.9, 129.5,
129.3, 129.2, 128.4, 128.0, 127.4, 127.2, 124.1, 123.6, 112.6,
97.9.
+
259.1230, calcd. for C18H15N2 [M+H+]: 259.1235.
5-(4-Methoxyphenyl)pyrazolo[5,1-a]isoquinoline
(3j):
1,5-Diphenylpyrazolo
(400 MHz, CDCl3): d=8.08 (d, J=8.0 Hz, 1H), 7.97 (s, 1H),
[5,1-a]isoquinoline (3d): 1H NMR
ACHTUNGTRENNUNG
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Silver Triflate-Palladium Chloride Cooperative Catalysis in a Tandem Reaction
113.7, 111.7, 97.8, 55.4; HR-MS (ACPI): m/z=275.1185,
calcd. for C18H15N2O+ [M+H+]: 275.1179.
CDCl3): d=161.9 (d, JC,F =245.7 Hz), 140.7, 138.4, 130.8 (d,
C,F =9.1 Hz), 125.6 (d, JC,F =8.9 Hz), 120.2, 115.2 (d, JC,F
J
=
23.8 Hz), 111.2 (d, JC,F =21.6 Hz), 108.7, 97.4, 30.7, 28.9,
22.6, 14.0; HR-MS (ACPI): m/z=243.1296, calcd. for
5-(4-Chlorophenyl)pyrazolo
G
(3k):
1H NMR (400 MHz, CDCl3): d=8.12 (d, J=6.8 Hz, 1H),
8.00 (d, J=2.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 2H), 7.75–7.73
(m, 1H), 7.60–7.55 (m, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.09
(d, J=2.0 Hz, 1H), 7.03 (s, 1H); 13C NMR (100 MHz,
CDCl3): d=140.9, 139.4, 137.3, 135.3, 132.2, 130.8, 129.0,
128.7, 128.1, 127.6, 127.2, 124.2, 123.6, 112.7, 98.0; HR-MS
(ACPI): m/z=279.0679, calcd. for C17H12N2Cl+ [M+H+]:
279.0684.
+
C15H16FN2 [M+H+]: 243.1292.
5-Cyclopropyl-8-methoxypyrazoloACTHUNTGRNEUNG[5,1-a]isoquinoline (3r):
1H NMR (400 MHz, CDCl3): d=8.01 (d, J=2.0 Hz, 1H),
7.96 (d, J=8.8 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.02 (d, J=
1.6 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.58 (s, 1H), 3.89 (s,
3H), 2.73–2.66 (m, 1H), 1.22–1.17 (m, 2H), 0.94–0.90 (m,
2H); 13C NMR (100 MHz, CDCl3): d=159.2, 141.3, 140.8,
138.9, 130.8, 125.0, 117.6, 116.4, 107.5, 106.5, 96.6, 55.4, 11.4,
7.1; HR-MS (ACPI): m/z=239.1206, calcd. for C15H15N2O+
[M+H+]: 239.1179.
5-CyclopropylpyrazoloACHTNUTGRNEUNG
[5,1-a]isoquinoline (3l): 1H NMR
(400 MHz, CDCl3): d=8.06 (d, J=2.0 Hz, 2H), 7.62 (d, J=
2.8 Hz, 1H), 7.50–7.47 (m, 2H), 7.05 (d, J=1.6 Hz, 1H),
6.65 (m, 1H), 2.73–2.66 (m, 1H), 1.23 À1.18 (m, 2H), 0.95–
0.91 (m, 2H); 13C NMR (100 MHz, CDCl3): d=140.7, 138.8,
129.1, 127.7, 126.6, 126.5, 123.4, 106.9, 97.8, 11.5, 7.0; HR-
6-Phenyl-9,10,11,12-tetrahydroindazoloACTHNUTRGNEUGN[3,2-a]isoquinoline
(3s):[5c] 1H NMR (400 MHz, CDCl3): d=8.18 (d, J=7.6 Hz,
1H), 7.91 (d, J=6.8 Hz, 2H), 7.71 (d, J=7.6 Hz, 1H), 7.54–
7.48 (m, 5H), 6.92 (s, 1H), 3.15 (t, J=6.0 Hz, 2H), 2.94 (d,
J=6.0 Hz, 2H), 1.98–1.94 (m, 4H); 13C NMR (100 MHz,
CDCl3): d=151.1, 138.5, 134.8, 134.3, 129.6, 129.4, 129.2,
128.3, 126.9, 126.8, 125.4, 123.3, 111.5, 109.9, 24.3, 23.6, 23.1,
23.0.
MS (ACPI): m/z=209.1080, calcd. for C14H13N2 [M+H+]:
+
209.1073.
5-Cyclopropyl-9-methylpyrazoloACTHUNTGRNEUNG[5,1-a]isoquinoline (3m):
1H NMR (400 MHz, CDCl3): d=8.04 (d, J=2.0 Hz, 1H),
7.85 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.31–7.29 (m, 1H),
7.02 (d, J=2.0 Hz, 1H), 6.62 (s, 1H), 2.71–2.64 (m, 1H),
2.51 (s, 3H), 1.21–1.16 (m, 2H), 0.93–0.89 (m, 2H);
13C NMR (100 MHz, CDCl3): d=140.5, 139.9, 138.7, 136.6,
129.3, 126.9, 126.4, 123.4, 123.2, 106.8, 97.6, 21.7, 11.4, 6.9;
1,2-Dimethyl-5-phenylpyrazolo
[5,1-a]isoquinoline
(3t):
+
HR-MS (ACPI): m/z=223.1255, calcd. for C15H15N2 [M+
H+]: 223.1230.
+
10.8; HR-MS (ACPI): m/z=273.1394, calcd. for C19H17N2
5-Cyclopropyl-9-fluoropyrazolo
(3n):
[M+H+]: 273.1386.
1H NMR (400 MHz, CDCl3): d=8.04 (d, J=2.4 Hz, 1H),
7.66 (dd, J=9.2 Hz, 1H), 7.58 (dd, J=8.8 Hz, 1H), 7.20 (t,
J=8.8 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.60 (s, 1H), 2.69–
2.62 (m, 1H), 121–1.16 (m, 2H), 0.92–0.87 (m, 2H);
13C NMR (100 MHz, CDCl3): d=161.1(d, JC,F=245.4 Hz),
140.7, 140.1, 138.1, 128.7 (d, JC,F =8.6 Hz), 125.7, 124.5 (d,
2-Ethyl-5-phenylpyrazolo
N
(3t’):
J
C,F =9.3 Hz), 116.4 (d, JC,F =23.5 Hz), 108.6 (d, JC,F =
22.7 Hz), 106.3, 98.3, 11.3, 6.9; HR-MS (ACPI); m/z=
273.1375, calcd. for C19H17N2 [M+H+]: 273.1386.
+
227.0997, calcd. for C14H12FN2 [M+H+]: 227.0979.
5-Phenylbenzo[h]pyrazolo
G
(3o):
1H NMR (400 MHz, CDCl3): d=8.99 (d, J=8.4 Hz, 1H),
8.20 (d, J=2.0 Hz, 1H), 8.00 (d, J=8.00 Hz, 1H), 7.97–7.92
(m, 3H), 7.80 (t, J=8.0 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H),
7.67 (t, J=7.6 Hz, 1H), 7.63 (d, J=2.2 Hz, 1H), 7.60–7.52
(m, 3H), 7.23 (s, 1H); 13C NMR (100 MHz, CDCl3): d=
141.7, 140.5, 139.9, 139.2, 138.7, 138.3, 136.6, 134.1, 132.9,
129.5, 129.4, 129.3, 129.2, 129.1, 129.0, 128.5, 127.5, 126.9,
126.4, 126.3, 125.7, 124.9, 123.4, 123.2, 120.3, 113.5, 106.8,
101.2, 97.6; HR-MS (ACPI): m/z=295.1242, calcd. for
Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (Nos. 21032007, 21172038) is gratefully ac-
knowledged. We thank Dr. Jason Wong for English review.
+
C21H15N2 [M+H+]: 295.1230.
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These are not the final page numbers!

FULL PAPERS
Silver Triflate-Palladium Chloride Cooperative Catalysis in
7
a Tandem Reaction for the Synthesis of H-Pyrazolo
a]isoquinolines
ACHTUNGTNER[NUNG 5,1-
Adv. Synth. Catal. 2013, 355, 1 – 7
Qing Xiao, Jie Sheng, Qiuping Ding,* Jie Wu*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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ÞÞ
These are not the final page numbers!