An efficient route to diverse H-pyrazolo[5,1-a]isoquinolines via sequential multi-component/cross-coupling reactions

Article abstract of DOI:10.1016/j.tet.2010.12.005

Multi-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, electrophile (bromine or iodine), and ketone or aldehyde under mild conditions proceeds smoothly to afford the functionalized H-pyrazolo[5,1-a]isoquinolines in good yields. This one-pot process involves intermolecular condensation, electrophilic cyclization, nucleophilic addition, intramolecular condensation, and aromatization. The resulting halo-containing H-pyrazolo[5,1-a]isoquinolines could be further elaborated via palladium-catalyzed cross-coupling reactions.

Full text of DOI:10.1016/j.tet.2010.12.005

Tetrahedron 67 (2011) 1145e1149
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient route to diverse H-pyrazolo[5,1-a]isoquinolines via sequential
multi-component/cross-coupling reactions
,b,
Xingxin Yu a, Xiaolin Pan a, Jie Wu a
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 October 2010
Received in revised form 1 December 2010
Accepted 3 December 2010
Available online 9 December 2010
Multi-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, electrophile (bromine or
iodine), and ketone or aldehyde under mild conditions proceeds smoothly to afford the functionalized
H-pyrazolo[5,1-a]isoquinolines in good yields. This one-pot process involves intermolecular condensa-
tion, electrophilic cyclization, nucleophilic addition, intramolecular condensation, and aromatization.
The resulting halo-containing H-pyrazolo[5,1-a]isoquinolines could be further elaborated via palladium-
catalyzed cross-coupling reactions.
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
2-Alkynylbenzaldehyde
Cross-coupling reaction
Electrophile
Multi-component reaction
H-Pyrazolo[5,1-a]isoquinoline
1. Introduction
triflate, which then underwent nucleophilic addition of enolate for
further transformation. Prompted by this result, we envisioned that
1,2-Dihydroisoquinolines are of interest because of their frequent
occurrence in nature and their wide range of biological and physio-
logical effects.1,2 1,2-Dihydroisoquinoline derivatives currently in
pharmaceutical use or development include inhibitor of human
topoisomerase I (Lamellarin D)3 and selective inhibitor against HIV-1
integrase.4 Recently, we also discovered that 1,2-dihydroisoquinoline
compounds displayed promising activity as PTP1B (protein tyrosine
phosphatase) inhibitor. The search for better hits encouraged us to
construct structural novel 1,2-dihydroisoquinoline library for the
subsequent biological assays.
It is well recognized that a focused library can be generated via
parallel diversity-oriented synthesis.5 Recently, we have demon-
strated that H-pyrazolo[5,1-a]isoquinolines could be accessed via
AgOTf-catalyzed tandem reactions6 of N0-(2-alkynylbenzylidene)
hydrazides with silyl enolates.7a For generation of the diverse
H-pyrazolo[5,1-a]isoquinoline library (Fig.1), we decided to explore
efficient strategies that would allow us considerable flexibility to
introduce a diversity of functionalities in a high-throughput man-
ner. The strategy for library production is outlined in Scheme 1. In
our previous report for the reaction of N0-(2-alkynylbenzylidene)
hydrazide with enolate,7 the key isoquinolinium intermediate
would be formed during the reaction process via 6-endo cyclization
of N0-(2-alkynylbenzylidene)hydrazide8 in the presence of silver
the reaction could be traced back to 2-alkynylbenzaldehyde9 1 and
sulfonohydrazide (Scheme 1). After intermolecular condensation,
N0-(2-alkynylbenzylidene)hydrazide A would be obtained. Sub-
sequently, in the presence of electrophiles, such as iodine or bro-
mine, N0-(2-alkynylbenzylidene)hydrazide
A would undergo
electrophilic cyclization leading to halo-containing isoquinolinium-
2-yl amide B. Meanwhile, the in situ formed enolate (derived from
ketone or aldehyde 2 in the presence of base) would attack the
halo-containing isoquinolinium-2-yl amide
B to produce in-
termediate C. After intramolecular condensation and aromatiza-
tion, the halo-containing H-pyrazolo[5,1-a]isoquinoline 3 would be
generated. The further elaboration via palladium-catalyzed cross-
coupling reactions would afford the diverse H-pyrazolo[5,1-a]iso-
quinoline compounds 4. Thus, based on these considerations, we
embark on exploring the possibility of this multi-component re-
action10 of 2-alkynylbenzaldehyde, sulfonohydrazide, electrophile
(bromine or iodine), and ketone or aldehyde.
different
R3
N
R4
substitutions
different
N
substitutions
different
aromatics
R1
R2
R5
* Corresponding author. E-mail address: jie_wu@fudan.edu.cn (J. Wu).
Fig. 1. H-Pyrazolo[5,1-a]isoquinoline scaffold.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.005

1146
X. Yu et al. / Tetrahedron 67 (2011) 1145e1149
yield (Table 1, entry 3). A similar result was obtained when cyclo-
hexanone 2c was utilized in the reaction (Table 1, entry 4). When
iodine was used in the reaction of 2-alkynylbenzaldehyde 1a, sul-
fonohydrazide, and cyclohexanone 2c, the desired product 3e was
isolated with 62% yield (Table 1, entry 5). Pentan-3-one 2d was
found to be a good substrate as well and the expected 6-bromo-2-
ethyl-1-methyl-5-phenylH-pyrazolo[5,1-a]isoquinoline 3f was
generated in 54% yield (Table 1, entry 6). When 2-alkynyl-
benzaldehyde with cyclopropyl or n-butyl group attached to the
C^C triple bond was employed in the multi-component reactions
of sulfonohydrazide, bromine or iodine, and butyraldehyde 2a, the
corresponding products were furnished in good yields (Table 1,
entries 7e10). Meanwhile, chloro- or fluoro-substituted 2-alky-
nylbenzaldehydes 1deg were explored (Table 1, entries 11e16), and
all reactions proceeded efficiently to generate the desired products
in good yields.
Scheme 1. Proposed synthetic route for the one-pot reaction of 2-alkynylbenzalde-
hyde, sulfonohydrazide, electrophile, and ketone or aldehyde.
2. Results and discussion
Table 1
In order to simplify the reaction optimization process, initial
attempts were performed for the sequential reaction of 2-alky-
nylbenzaldehyde 1a (Scheme 2, Eq. 1). At the outset, 2-alky-
nylbenzaldehyde 1a reacted with sulfonohydrazide and bromine,
which afforded the isolated 4-bromo-isoquinolinium-2-yl amide.
Subsequently, butyraldehyde 2a was added in ethanol in the
presence of different bases (inorganic and organic bases). Gratify-
ingly, the expected H-pyrazolo[5,1-a]isoquinoline 3a was obtained
in 87% yield when K2CO3 was employed in the reaction. A similar
yield was observed when K3PO4 was utilized as a replacement.
Inferior results were displayed when other bases were used. With
this promising result in hands, we started to investigate the one-
pot multi-component reaction of 2-alkynylbenzaldehyde 1a, sul-
fonohydrazide, bromine, and butyraldehyde 2a (Scheme 2, Eq. 2).
After screening different solvents, bases, and temperatures, we fi-
nally identified that the reaction proceeded efficiently in ethanol at
70 ꢀC in the presence of 3.0 equiv of K3PO4 as base with a 45%
isolated yield.
Multi-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, electro-
phile, and ketone or aldehyde
R4
R3
CHO
TsNHNH2
O
R1
K3PO4 (3.0 equiv)
N
+
+
R3
EtOH, 70 ο
C
N
R4
R1
X2
R2
R2
2
1
X = Br or I
3
X
Entry
R1, R2
X2
R3, R4
Yielda (%)
1
2
3
4
5
6
7
8
H, Ph (1a)
H, Ph (1a)
H, Ph (1a)
H, Ph (1a)
H, Ph (1a)
H, Ph (1a)
H, cyclopropyl (1b)
H, cyclopropyl (1b)
H, n-Bu (1c)
H, n-Bu (1c)
5-Cl, Ph (1d)
4-F, Ph (1e)
4-F, cyclopropyl (1f)
4-F, cyclopropyl (1f)
4-F, n-Bu (1g)
Br2
I2
Br2
Br2
I2
Br2
Br2
I2
Br2
I2
Br2
Br2
Br2
I2
Br2
I2
Et, H (2a)
Et, H (2a)
H, Ph (2b)
45 (3a)
75 (3b)
50 (3c)
50 (3d)
62 (3e)
54 (3f)
71 (3g)
86 (3h)
46 (3i)
80 (3j)
50 (3k)
60 (3l)
60 (3m)
76 (3n)
55 (3o)
78 (3p)
e(CH2)4e (2c)
e(CH2)4e (2c)
Me, Et (2d)
Et, H (2a)
Et, H (2a)
Et, H (2a)
Et, H (2a)
Et, H (2a)
Et, H (2a)
Et, H (2a)
Et, H (2a)
Et, H (2a)
Et, H (2a)
9
10
11
12
13
14
15
16
Et
O
2a
CHO
N
N
TsNHNH2
N
Ts
H
N
(1)
(2)
4-F, n-Bu (1g)
Br2
base, EtOH
Ph
Ph
3a
a
EtOH
Isolated yield based on 2-alkynylbenzaldehyde 1.
Ph
Br
Br
1a
Et
CHO
N
O
TsNHNH2
Br2
After successful generation of 6-halo-H-pyrazolo[5,1-a]-iso-
quinoline 3, we considered to introduce more diversities in the
H-pyrazolo[5,1-a]isoquinoline scaffold via palladium-catalyzed
cross-coupling reaction. Thus, SuzukieMiyaura coupling re-
action11 using arylboronic acid derivatives was investigated. After
optimization of the reaction conditions, we found that the re-
actions worked efficiently in the presence of Pd/C (5 mol %), PPh3
(10 mol %), and Na2CO3 in DME at 80 ꢀC (Table 2). As expected, all
the reactions proceeded well to afford the desired product 4 in
good to excellent yields. For example, reaction of 6-bromo-1-
ethyl-5-phenyl H-pyrazolo[5,1-a]isoquinoline 3a with 4-methox-
yphenylboronic acid gave rise to the corresponding product 4a in
88% yield (Table 2, entry 1). When 4-acetylphenylboronic acid was
used as a partner, compound 4b was isolated with 76% yield
(Table 2, entry 2). Compound 3e was a suitable substrate as well in
the reaction of 4-methoxyphenylboronic acid, which furnished the
desired product 4c in 80% yield (Table 2, entry 3). Excellent yields
were obtained when fluoro-substituted H-pyrazolo[5,1-a]iso-
quinoline 3l or 3p was employed in the coupling reaction (Table 2,
entries 6 and 7).
N
base
solvent
+
+
H
Ph
Br 3a
Ph
1a
2a
Scheme 2. Initial studies for multi-component reaction of 2-alkynylbenzaldehyde 1a,
sulfonohydrazide, bromine, and butyraldehyde 2a.
Under the optimized conditions [K3PO4 (3.0 equiv), EtOH, 70 ꢀC],
we then examined the reaction scope of this multi-component
reaction (Table 1). We found that the condition was demonstrated
to be useful for various 2-alkynylbenzaldehydes. Both electron-rich
and electron-poor 2-alkynylbenzaldehydes are workable in this
process. Besides bromine, iodine was a suitable partner as well in
this multi-component reaction. For instance, 2-alkynylbenzalde-
hyde 1a reacted with sulfonohydrazide, iodine, and butyraldehyde
2a leading to the desired 1-ethyl-6-iodo-5-phenylH-pyrazolo[5,1-
a]isoquinoline 3b in 75% yield (Table 1, entry 2). We also tested
other ketones with
a hydrogen. Reaction of 2-alkynylbenzaldehyde
1a, sulfonohydrazide, bromine, and acetophenone 2b gave rise to
the 6-bromo-2,5-diphenylH-pyrazolo[5,1-a]isoquinoline 3c in 50%

X. Yu et al. / Tetrahedron 67 (2011) 1145e1149
1147
Table 2
silica gel (eluting with PE/EA¼50/1 to 20/1) to provide the desired
product 3.
Palladium-catalyzed cross-coupling reactions of 6-halo-H-pyrazolo[5,1-a]isoquino-
line 3 with arylboronic acids
R4
R4
R3
R3
4.1.1. 6-Bromo-1-ethyl-5-phenylH-pyrazolo[5,1-a]isoquinoline
(3a). Light yellow solid, mp: 141.1e141.7 ꢀC. 1H NMR (400 MHz,
CDCl3): 1.43 (t, J¼7.3 Hz, 3H), 3.04e3.10 (m, 2H), 7.49e7.64 (m, 7H),
N
N
N
N
R1
R1
Pd/C, PPh3, Na2CO3
DME, 80 o
R5 B(OH)2
+
7.78 (s, 1H), 8.23e8.25 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 14.0,
R2
R2
C
R5
4
X
3
19.6, 109.0, 117.4, 123.4, 125.5, 127.8, 128.3, 128.5, 128.8, 129.5, 130.1,
133.5, 134.6, 138.0, 141.1; HRMS calcd for C19H16BrN2 (MþþH):
351.0497, found: 351.0498.
Entry
Substrate 3
R5
Product 4
Yielda (%)
1
2
3
4
5
6
7
3a
3a
3e
3g
3j
4-MeOC6H4
4-AcC6H4
4-MeOC6H4
4-MeOC6H4
4-AcC6H4
4a
4b
4c
4d
4e
4f
88
76
80
91
77
99
93
4.1.2. 1-Ethyl-6-iodo-5-phenylH-pyrazolo[5,1-a]isoquinoline
(3b). Light yellow solid, mp: 144.5e145.2 ꢀC. 1H NMR (400 MHz,
CDCl3): 1.41 (t, J¼7.3 Hz, 3H), 3.02e3.08 (m, 2H), 7.41e7.43 (m, 2H),
7.51e7.61 (m, 7H), 7.74 (s, 1H), 8.16 (d, J¼7.3 Hz, 2H); 13C NMR
3l
3p
4-AcC6H4
4-MeOC6H4
(100 MHz, CDCl3)
d 14.1, 19.6, 87.2, 117.1, 123.4, 125.3, 128.1, 128.2,
4g
128.9, 129.5, 130.0, 130.3, 133.1, 133.9, 138.4, 141.2, 141.6; HRMS
a
calcd for C19H16IN2 (MþþH): 399.0358, found: 399.0366.
Isolated yield based on 6-halo-H-pyrazolo[5,1-a]isoquinoline 3.
4.1.3. 6-Bromo-2,5-diphenylH-pyrazolo[5,1-a]isoquinoline
(3c). Light yellow solid, mp: 147.6e148.2 ꢀC. 1H NMR (400 MHz,
CDCl3): 7.26e7.42 (m, 4H), 7.50e7.60 (m, 6H), 7.83e7.85 (m, 2H),
7.97e8.02 (m, 1H), 8.08e8.10 (m, 1H), 8.17e8.19 (m, 1H); 13C NMR
3. Conclusions
In summary, we have described a multi-component reaction of
2-alkynylbenzaldehyde, sulfonohydrazide, electrophile (bromine
or iodine), and ketone or aldehyde under mild conditions, which
generates the halo-containing H-pyrazolo[5,1-a]isoquinolines in
good yields. In the reaction process, intermolecular condensation,
electrophilic cyclization, nucleophilic addition, intramolecular
condensation, and aromatization may be involved. The resulting
halo-containing H-pyrazolo[5,1-a]isoquinolines could be further
decorated via palladium-catalyzed SuzukieMiyaura cross-coupling
reactions to afford the functionalized H-pyrazolo[5,1-a]isoquino-
line derivatives. We believe that this method provides an excellent
complement for the H-pyrazolo[5,1-a]isoquinoline synthesis. Fur-
ther efforts for the focused library construction and screening for
biological activity of these small molecules are ongoing in our
laboratory, and the result will be reported in due course.
(100 MHz, CDCl3)
d 95.1, 108.9, 123.7, 123.9, 126.5, 127.9, 128.3,
128.4, 128.5, 128.7, 128.8, 129.4, 129.7, 130.7, 133.0, 134.1, 137.9,
139.7, 152.6; HRMS calcd for C23H16BrN2 (MþþH): 399.0497, found:
399.0501.
4.1.4. 5-Bromo-6-phenyl-9,10,11,12-tetrahydroindazolo[3,2-a]iso-
quinoline (3d). Light yellow solid, mp: 225.4e226.8 ꢀC. 1H NMR
(400 MHz, CDCl3): 1.83e1.96 (m, 4H), 2.79e2.81 (m, 2H), 3.04e3.06
(m, 2H), 7.48e7.58 (m, 7H), 8.11e8.18 (m, 2H); 13C NMR (100 MHz,
CDCl3)
d 23.0, 23.1, 23.5, 24.4, 107.7, 110.2, 123.4, 125.4, 127.5, 127.6,
127.8, 128.5, 128.6, 129.3, 130.3, 133.8, 134.8, 137.9, 151.8; HRMS
calcd for C21H18BrN2 (MþþH): 377.0653, found: 377.0664.
4.1.5. 5-Iodo-6-phenyl-9,10,11,12-tetrahydroindazolo[3,2-a]isoquino-
line (3e). Light yellow solid, mp: 207.0e207.5 ꢀC. 1H NMR
(400 MHz, CDCl3): 1.83e1.91 (m, 4H), 2.77e2.80 (m, 2H), 3.03e3.06
(m, 2H), 7.40e7.42 (m, 2H), 7.49e7.56 (m, 5H), 8.04e8.12 (m, 2H);
4. Experimental section
4.1. General
13C NMR (100 MHz, CDCl3)
d 23.0, 23.1, 23.5, 24.3, 85.7, 110.0, 123.4,
125.2, 127.8, 127.9, 128.8, 129.4, 130.2, 130.3, 132.7, 134.1, 138.5,
141.5, 151.8; HRMS calcd for C21H18IN2 (MþþH): 425.0515, found:
425.0522.
All reactions were performed in test tubes under nitrogen
atmosphere. Flash column chromatography was performed using
ꢀ
silica gel (60-A pore size, 32e63
mm, standard grade). Analytical
thin layer chromatography was performed using glass plates pre-
coated with 0.25 mm 230e400 mesh silica gel impregnated with
a fluorescent indicator (254 nm). Thin layer chromatography plates
were visualized by exposure to ultraviolet light. Organic solutions
were concentrated on rotary evaporators at ∼20 Torr (house vac-
uum) at 25e35 ꢀC. Commercial reagents and solvents were used as
received.
4.1.6. 6-Bromo-2-ethyl-1-methyl-5-phenylH-pyrazolo[5,1-a]iso-
quinoline (3f). Light yellow solid, mp: 138.5e139.8 ꢀC. 1H NMR
(400 MHz, CDCl3): 1.19 (t, J¼7.3 Hz, 3H), 2.53 (s, 3H), 2.71e2.77 (m,
2H), 7.49e7.57 (m, 7H), 8.17e8.26 (m, 2H); 13C NMR (100 MHz,
CDCl3)
d 10.8, 14.2, 20.1, 107.5, 107.6, 123.1, 125.6, 127.5, 127.6, 127.8,
128.4, 128.7, 129.2, 130.5, 134.7, 137.9, 155.5; HRMS calcd for
C20H18BrN2 (MþþH): 365.0653, found: 365.0661.
General procedure for multi-component reactions of 2-alky-
nylbenzaldehyde, sulfonohydrazide, electrophile, and ketone or
aldehyde: A solution of 2-alkynylbenzaldehyde 1 (0.3 mmol), sul-
fonohydrazide (0.3 mmol, 1.0 equiv) in CH2Cl2 (1.0 mL) was stirred
at room temperature for 10 min in a tube. Then Br2 or I2 (0.33 mmol,
1.1 equiv) were added. The reaction mixture was stirred at room
temperature for 10 min with Br2 or 24 h with I2. After workup with
Na2S2O3, ketone or aldehyde 3 (0.6 mmol, 2.0 equiv) and K3PO4
(0.9 mmol, 3.0 equiv) were added to the solution. The reaction
mixture was stirred at 70 ꢀC vigorously until completion of the
reaction. Then 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 was purified by column chromatography on
4.1.7. 6-Bromo-5-cyclopropyl-1-ethylH-pyrazolo[5,1-a]isoquinoline
(3g). Light yellow solid, mp: 87.3e88.2 ꢀC. 1H NMR (400 MHz,
CDCl3): 1.24e1.28 (m, 2H), 1.31e1.35 (m, 2H), 1.40 (t, J¼7.8 Hz, 3H),
2.26e2.33 (m, 1H), 2.97e3.03 (m, 2H), 7.48e7.53 (m, 2H), 7.83 (s,
1H), 8.09e8.14 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 10.0, 14.0, 14.1,
19.6, 110.8, 116.9, 123.0, 124.8, 127.1, 127.4, 128.5, 133.2, 137.8, 140.1;
HRMS calcd for C16H16BrN2 (MþþH): 315.0497, found: 315.0486.
4.1.8. 5-Cyclopropyl-1-ethyl-6-iodoH-pyrazolo[5,1-a]isoquinoline
(3h). Light yellow solid, mp: 82.8e84.0 ꢀC. 1H NMR (400 MHz,
CDCl3): 1.14e1.18 (m, 2H), 1.40 (t, J¼7.3 Hz, 3H), 1.41e1.46 (m, 2H),
2.24e2.28 (m, 1H), 2.97e3.02 (m, 2H), 7.46e7.49 (m, 2H), 7.81 (s,
1H), 8.03e8.05 (m, 1H), 8.09e8.13 (m, 1H); 13C NMR (100 MHz,

1148
X. Yu et al. / Tetrahedron 67 (2011) 1145e1149
CDCl3)
d
12.4, 14.0, 18.3, 19.6, 89.2, 116.8, 123.0, 124.5, 127.5, 127.8,
2JCF¼24 Hz), 115.7 (d, 2JCF¼23 Hz), 116.7, 121.3, 125.5 (d, 3JCF¼9 Hz),
3
1
130.4, 132.3, 133.6, 140.0, 140.7; HRMS calcd for C16H16IN2 (MþþH):
130.6 (d, JCF¼9 Hz), 132.6, 140.5, 140.7, 161.9 (d, JCF¼246 Hz);
HRMS calcd for C17H19BrFN2 (MþþH): 349.0716, found: 349.0701.
363.0358, found: 363.0357.
4.1.9. 6-Bromo-5-butyl-1-ethylH-pyrazolo[5,1-a]isoquinoline
(3i). Light yellow solid, mp: 98.9e100.8 ꢀC. 1H NMR (400 MHz,
CDCl3): 0.99 (t, J¼7.3 Hz, 3H), 1.43 (t, J¼7.3 Hz, 3H), 1.52e1.58 (m,
2H), 1.75e1.81 (m, 2H), 3.03e3.09 (m, 2H), 3.49e3.53 (m, 2H),
7.56e7.58 (m, 2H), 7.85 (s, 1H), 8.15e8.19 (m, 2H); 13C NMR
4.1.16. 5-Butyl-1-ethyl-8-fluoro-6-iodoH-pyrazolo[5,1-a]isoquinoline
(3p). Light yellow solid, mp: 93.2e94.6 ꢀC. 1H NMR (400 MHz,
CDCl3): 1.00 (t, J¼7.3 Hz, 3H), 1.40 (t, J¼7.3 Hz, 3H), 1.51e1.59 (m,
2H), 1.70e1.75 (m, 2H), 2.93e2.98 (m, 2H), 3.50e3.56 (m, 2H),
7.16e7.20 (m, 1H), 7.74e7.78 (m, 2H), 8.00e8.03 (m, 1H); 13C NMR
(100 MHz, CDCl3)
d
14.0,14.1,19.6, 22.9, 28.9, 31.6,107.9,117.3,123.2,
(100 MHz, CDCl3) d 13.8, 14.0, 19.5, 23.0, 28.9, 36.6, 83.8, 115.5 (d,
3
124.8, 127.2, 127.3, 127.6, 128.4, 133.0, 139.5, 140.3; HRMS calcd for
2JCF¼24 Hz), 116.5, 117.9 (d, 2JCF¼24 Hz), 121.1, 125.5 (d, JCF¼9 Hz),
C17H20BrN2 (MþþH): 331.0810, found: 331.0789.
132.5 (d, JCF¼9 Hz), 132.8, 140.5, 143.5, 162.0 (d, JCF¼246 Hz);
HRMS calcd for C17H19FIN2 (MþþH): 397.0577, found: 397.0566.
3
1
4.1.10. 5-Butyl-1-ethyl-6-iodoH-pyrazolo[5,1-a]isoquinoline
(3j). Light yellow solid, mp: 95.7e96.5 ꢀC. 1H NMR (400 MHz,
CDCl3): 1.00 (t, J¼7.3 Hz, 3H), 1.41 (t, J¼7.3 Hz, 3H), 1.52e1.59 (m,
2H), 1.72e1.80 (m, 2H), 2.97e3.03 (m, 2H), 3.55e3.59 (m, 2H),
7.45e7.50 (m, 2H), 7.79 (s, 1H), 8.04e8.06 (m, 2H); 13C NMR
4.2. General procedure for palladium-catalyzed cross-
coupling reactions of 6-halo-H-pyrazolo[5,1-a]isoquinoline
3 with arylboronic acids
(100 MHz, CDCl3)
d
14.0, 14.1, 19.6, 23.0, 29.0, 36.5, 85.7, 117.0, 123.2,
To
a
solution of 6-halo-H-pyrazolo[5,1-a]isoquinoline
3
124.6, 127.3, 127.8, 130.1, 132.3, 133.3, 140.3, 142.4; HRMS calcd for
(0.2 mmol), boronic acid (0.3 mmol), and PPh3 (0.036 mmol) in
DME (2.0 mL) was added Na2CO3 (2.0 M, 1.0 mL) and 5% Pd/C (water
content 54%) (0.01 mmol). The reaction mixture was stirred at 80 ꢀC
for 9 h. After filtration, the water layer was extracted twice with
EtOAc (10 mL). The combined organic layers were washed with 10%
NaOH (aq) and brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel (PE/EA¼20/1 to 5/1) to give the product 4.
C17H20IN2 (MþþH): 379.0671, found: 379.0639.
4.1.11. 6-Bromo-9-chloro-1-ethyl-5-phenylH-pyrazolo[5,1-a]iso-
quinoline (3k). Light yellow solid, mp: 127.9e129.1 ꢀC. 1H NMR
(400 MHz, CDCl3): 1.44 (t, J¼7.3 Hz, 3H), 3.02e3.08 (m, 2H),
7.47e7.60 (m, 6H), 7.79 (s, 1H), 8.15e8.18 (m, 2H); 13C NMR
(100 MHz, CDCl3)
d 13.7, 19.4, 108.2, 117.9, 122.7, 126.3, 127.0, 128.1,
128.8, 129.4, 129.6, 130.0, 132.4, 134.2, 138.3, 141.2; HRMS calcd for
C19H15BrClN2 (MþþH): 385.0107, found: 385.0113.
4.2.1. 1-Ethyl-6-(4-methoxyphenyl)-5-phenylH-pyrazolo[5,1-a]iso-
quinoline (4a). Light yellow solid, mp: 219.7e220.2 ꢀC. 1H NMR
(400 MHz, CDCl3): 1.47 (t, J¼7.3 Hz, 3H), 3.11e3.16 (m, 2H), 3.76 (s,
3H), 6.79 (d, J¼8.7 Hz, 2H), 7.09 (d, J¼8.7 Hz, 2H), 7.23e7.30 (m, 5H),
7.38e7.45 (m, 2H), 7.57 (t, J¼7.3 Hz, 1H), 7.82 (s, 1H), 8.32 (d,
4.1.12. 6-Bromo-1-ethyl-8-fluoro-5-phenylH-pyrazolo[5,1-a]iso-
quinoline (3l). Light yellow solid, mp: 145.9e146.8 ꢀC. 1H NMR
(400 MHz, CDCl3): 1.41 (t, J¼7.3 Hz, 3H), 2.98e3.04 (m, 2H),
7.31e7.35 (m,1H), 7.46e7.59 (m, 5H), 7.77 (s,1H), 7.88e7.91 (m,1H),
J¼7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 14.3, 19.7, 55.2, 113.5,
8.17e8.21 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
13.9, 19.5, 107.7,
116.9, 123.3, 123.4, 125.6, 126.8, 126.9, 127.2, 128.1, 128.2, 128.6,
130.7, 130.8, 132.7, 133.7, 133.8, 136.8, 140.6, 158.5; HRMS calcd for
C26H23N2O (MþþH): 379.1810, found: 379.1819.
2
2
113.6 (d, JCF¼24 Hz), 116.6 (d, JCF¼23 Hz), 116.9, 122.1, 125.7 (d,
3
3JCF¼9 Hz), 128.8, 129.7, 130.0, 130.9 (d, JCF¼9 Hz), 133.2, 134.3,
1
139.1, 141.4, 162.0 (d, JCF¼247 Hz); HRMS calcd for C19H15BrFN2
(MþþH): 369.0403, found: 369.0411.
4.2.2. 1-(3-(1-Ethyl-5-phenylH-pyrazolo[5,1-a]isoquinolin-6-yl)phe-
nyl)ethanone (4b). Light yellow solid, mp: 203.5e204.1 ꢀC. 1H NMR
(400 MHz, CDCl3): 1.48 (t, J¼7.3 Hz, 3H), 2.47 (s, 3H), 3.12e3.17 (m,
2H), 7.24e7.29 (m, 5H), 7.35e7.44 (m, 4H), 7.60 (t, J¼7.3 Hz, 1H),
7.78 (s, 1H), 7.82e7.85 (m, 2H), 8.33e8.36 (d, J¼8.2 Hz, 1H); 13C
4.1.13. 6-Bromo-5-cyclopropyl-1-ethyl-8-fluoroH-pyrazolo[5,1-a]iso-
quinoline (3m). Light yellow solid, mp: 159.1e160.0 ꢀC. 1H NMR
(400 MHz, CDCl3): 1.28e1.34 (m, 4H), 1.40 (t, J¼7.3 Hz, 3H),
2.27e2.34 (m, 1H), 2.92e2.97 (m, 2H), 7.19e7.23 (m, 1H), 7.79e7.82
NMR (100 MHz, CDCl3)
d 14.2, 19.7, 26.7, 117.1, 122.6, 123.5, 125.7,
(m, 2H), 8.02e8.06 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
9.8, 13.8,
126.4, 127.1, 127.2, 127.5, 128.2, 128.5, 128.6, 129.9, 130.8, 131.8,
133.2, 133.9, 136.4, 136.9, 137.0, 140.9, 197.9; HRMS calcd for
C27H23N2O (MþþH): 391.1810, found: 391.1809.
2
2
14.2, 19.5, 109.4, 112.8 (d, JCF¼24 Hz), 115.8 (d, JCF¼23 Hz), 116.4,
3
121.3, 125.3 (d, JCF¼9 Hz), 130.8 (d, 3JCF¼9 Hz), 132.8, 139.0, 140.3,
1
161.7 (d, JCF¼246 Hz); HRMS calcd for C16H15BrFN2 (MþþH):
333.0403, found: 333.0392.
4.2.3. 5-(4-Methoxyphenyl)-6-phenyl-9,10,11,12-tetrahydroindazolo
[3,2-a]isoquinoline (4c). Light yellow solid, mp: 214.7e215.9 ꢀC. 1H
NMR (400 MHz, CDCl3): 1.88e1.98 (m, 4H), 2.83e2.86 (m, 2H),
3.14e3.17 (m, 2H), 3.77 (s, 3H), 6.78 (d, J¼8.7 Hz, 2H), 7.06 (d,
J¼8.2 Hz, 2H), 7.23e7.31 (m, 5H), 7.38e7.42 (m, 2H), 7.51e7.55 (m,
4.1.14. 5-Cyclopropyl-1-ethyl-8-fluoro-6-iodoH-pyrazolo[5,1-a]iso-
quinoline (3n). Light yellow solid, mp: 103.1e103.5 ꢀC. 1H NMR
(400 MHz, CDCl3): 1.17e1.22 (m, 2H), 1.41 (t, J¼7.3 Hz, 3H),
1.42e1.46 (m, 2H), 2.25e2.30 (m, 1H), 2.97e3.01 (m, 2H), 7.20e7.24
(m, 1H), 7.82 (s, 1H), 7.85e7.88 (m, 1H), 8.05e8.08 (m, 1H); 13C NMR
1H), 8.23 (d, J¼7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 23.1, 23.2,
23.6, 24.3, 55.2, 109.6, 113.4, 114.6, 116.1, 123.3, 125.4, 126.5, 126.7,
126.8, 127.9, 128.1, 128.8, 130.7, 131.0, 132.8, 133.7, 134.1, 151.2,
158.4; HRMS calcd for C28H25N2O (MþþH): 405.1967, found:
405.1961.
(100 MHz, CDCl3)
d
12.3, 13.9, 18.5, 19.6, 87.4, 115.8 (d, 2JCF¼24 Hz),
2
3
116.3, 118.0 (d, JCF¼25 Hz), 121.1, 125.4 (d, JCF¼9 Hz), 132.9 (d,
3JCF¼9 Hz), 133.3, 140.2, 141.9, 161.9 (d, 1JCF¼245 Hz); HRMS calcd
for C16H15FIN2 (MþþH): 381.0264, found: 381.0264.
4.2.4. 5-Cyclopropyl-1-ethyl-6-(4-methoxyphenyl)H-pyrazolo[5,1-a]
isoquinoline (4d). Light yellow solid, mp: 113.9e114.8 ꢀC. 1H NMR
(400 MHz, CDCl3): 0.62e0.66 (m, 2H), 0.84e0.89 (m, 2H), 1.46 (t,
J¼7.3 Hz, 3H), 2.14e2.19 (m, 1H), 3.09e3.14 (m, 2H), 3.90 (s, 3H),
7.03 (d, J¼8.2 Hz, 2H), 7.27 (d, J¼8.7 Hz, 2H), 7.35e7.41 (m, 2H),
7.48e7.52 (m, 1H), 7.91 (s, 1H), 8.26 (d, J¼7.8 Hz, 1H); 13C NMR
4.1.15. 6-Bromo-5-butyl-1-ethyl-8-fluoroH-pyrazolo[5,1-a]isoquino-
line (3o). Light yellow solid, mp: 87.6e88.1 ꢀC. 1H NMR (400 MHz,
CDCl3): 0.99 (t, J¼7.3 Hz, 3H), 1.41 (t, J¼7.3 Hz, 3H), 1.51e1.57 (m,
2H), 1.73e1.78 (m, 2H), 2.96e3.01 (m, 2H), 3.44e3.48 (m, 2H),
7.22e7.25 (m, 1H), 7.78e7.84 (m, 2H), 8.07e8.12 (m, 1H); 13C NMR
(100 MHz, CDCl3)
d
13.8, 14.0, 19.5, 22.9, 28.8, 31.7, 106.5, 112.8 (d,
(100 MHz, CDCl3) d 8.3, 12.1, 14.2, 19.7, 55.4, 113.8, 116.6, 123.1, 125.0,

X. Yu et al. / Tetrahedron 67 (2011) 1145e1149
1149
Hartman, G. D.; Dinsmore, C. J. J. Med. Chem. 2006, 49, 6954; (b) Ramesh, P.;
Reddy, N. S.; Venkateswarlu, Y. J. Nat. Prod. 1999, 62, 780; (c) Kaneda, T.;
Takeuchi, Y.; Matsui, H.; Shimizu, K.; Urakawa, N.; Nakajyo, S. J. Pharm. Sci.
2005, 98, 275; (d) Mikami, Y.; Yokoyama, K.; Tabeta, H.; Nakagaki, K.; Arai, T. J.
Pharm. Dyn. 1981, 4, 282; (e) Marchand, C.; Antony, S.; Kohn, K. W.; Cushman,
M.; Ioanoviciu, A.; Staker, B. L.; Burgin, A. B.; Stewart, L.; Pommier, Y. Mol.
Cancer Ther. 2006, 5, 287; (f) Pettit, G. R.; Gaddamidi, V.; Herald, D. L.; Singh, S.
B.; Cragg, G. M.; Schmidt, J. M.; Boettner, F. E.; Williams, M.; Sagawa, Y. J. Nat.
Prod. 1986, 49, 995.
3. (a) Bailly, C. Curr. Med. Chem.: Anti-Cancer Agents 2004, 4, 363; (b) Marco, E.;
Laine, W.; Tardy, C.; Lansiaux, A.; Iwao, M.; Ishibashi, F.; Bailly, C.; Gago, F. J.
Med. Chem. 2005, 48, 3796.
4. (a) Reddy, M. V. R.; Rao, M. R.; Rhodes, D.; Hansen, M. S. T.; Rubins, K.; Bush-
man, F. D.; Venkateswarlu, Y.; Faulkner, D. J. J. Med. Chem. 1999, 42, 1901;
(b) Aubry, A.; Pan, X.-S.; Fisher, L. M.; Jarlier, V.; Cambau, E. Antimicrob. Agents
Chemother. 2004, 48, 1281.
126.2, 126.5, 126.6, 129.2, 130.5, 132.5, 133.5, 136.5, 139.9, 158.9;
HRMS calcd for C23H23N2O (MþþH): 343.1810, found: 343.1799.
4.2.5. 1-(3-(5-Butyl-1-ethylH-pyrazolo[5,1-a]isoquinolin-6-yl)phe-
nyl)ethanone (4e). Light yellow oil. 1H NMR (400 MHz, CDCl3): 0.77
(t, J¼7.3 Hz, 3H), 1.26e1.31 (m, 2H), 1.48 (t, J¼7.3 Hz, 3H), 1.69e1.74
(m, 2H), 2.64 (s, 3H), 2.91e2.96 (m, 2H), 3.10e3.16 (m, 2H), 7.11 (d,
J¼7.8 Hz, 1H), 7.36 (t, J¼8.2 Hz, 1H), 7.50e7.56 (m, 2H), 7.64 (t,
J¼7.3 Hz, 1H), 7.91e7.95 (m, 2H), 8.08 (d, J¼7.8 Hz, 1H), 8.28 (d,
J¼8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 13.8, 14.2, 19.7, 22.8,
26.8, 29.2, 30.0, 117.0, 120.9, 123.3, 124.8, 126.0, 126.6, 126.9, 127.7,
129.1, 130.1, 131.0, 133.5, 135.8, 137.6, 137.8, 138.0, 140.2, 197.9;
HRMS calcd for C25H27N2O (MþþH): 371.2123, found: 371.2110.
5. (a) Walsh, D. P.; Chang, Y.-T. Chem. Rev. 2006, 106, 2476; (b) Arya, P.; Chou,
D. T. H.; Baek, M.-G. Angew. Chem., Int. Ed. 2001, 40, 339; (c) Schreiber, S. L.
Science 2000, 287, 1964; (d) Pinilla, C.; Appel, J. R.; Houghten, R. A. Nature
Med. 2003, 9, 118.
4.2.6. 1-(3-(1-Ethyl-8-fluoro-5-phenylH-pyrazolo[5,1-a]isoquinolin-
6-yl)phenyl)ethanone (4f). Light yellow solid, mp: 187.0e188.0 ꢀC.
1H NMR (400 MHz, CDCl3): 1.47 (t, J¼7.3 Hz, 3H), 2.49 (s, 3H),
3.08e3.14 (m, 2H), 6.99e7.02 (m, 1H), 7.25e7.41 (m, 8H), 7.76 (s,
1H), 7.83e7.86 (m, 2H), 8.30e8.33 (m, 1H); 13C NMR (100 MHz,
6. For reviews, see: (a) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890;
(b) Negishi, E.; Coperet, C.; Ma, S.; Liou, S. Y.; Liu, F. Chem. Rev. 1996, 96, 365;
(c) Tietze, L. F. Chem. Rev. 1996, 96, 115; (d) Grigg, R.; Sridharan, V. J. Organomet.
Chem. 1999, 576, 65; (e) Miura, T.; Murakami, M. Chem. Commun. 2007, 217;
(f) Malacria, M. Chem. Rev. 1996, 96, 289; (g) Nicolaou, K. C.; Montagnon, T.;
Snyder, S. A. Chem. Commun. 2003, 551; (h) Nicolaou, K. C.; Edmonds, D. J.;
Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134; (i) Enders, D.; Grondal, C.;
CDCl3)
d
14.1, 19.6, 26.7, 111.8 (d, 2JCF¼23 Hz), 115.8 (d, 2JCF¼24 Hz),
3
116.6, 122.0, 122.3, 125.7 (d, JCF¼9 Hz), 127.4, 128.2, 128.7, 128.8,
€
Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570; (j) Tietze, L. F.; Brasche, G.;
3
130.6, 131.6, 132.0 (d, JCF¼9 Hz), 132.9, 133.5, 136.2, 136.5, 137.1,
Gericke, K. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim,
Germany, 2006.
7. (a) Yu, X.; Chen, Z.; Yang, X.; Wu, J. J. Comb. Chem. 2010, 12, 374; (b) Yu, X.; Ye, S.;
Wu, J. Adv. Synth. Catal. 2010, 352, 2050.
1
138.0, 141.2, 161.4 (d, JCF¼245 Hz), 197.7; HRMS calcd for
C27H22FN2O (MþþH): 409.1716, found: 409.1718.
8. For selected examples, see: (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) Yu, X.; Yang, X.; Wu, J. Org. Biomol. Chem. 2009, 7, 4526; (d) Chen, Z.; Su, M.;
Yu, X.; Wu, J. Org. Biomol. Chem. 2009, 7, 4641; (e) Ding, Q.; Chen, Z.; Yu, X.;
Peng, Y.; Wu, J. Tetrahedron Lett. 2009, 50, 340; (f) Yu, X.; Ding, Q.; Chen, Z.; Wu,
J. Tetrahedron Lett. 2009, 50, 4279; (g) Chen, Z.; Wu, J. Org. Lett. 2010, 12, 4856;
(h) Ye, S.; Yang, X.; Wu, J. Chem. Commun. 2010, 46, 5238; (i) Chen, Z.; Yu, X.;
Wu, J. Chem. Commun. 2010, 46, 6356; (j) Ren, H.; Ye, S.; Liu, F.; Wu, J. Tetra-
hedron 2010, 66, 8242.
9. Selected examples for metal-catalyzed cyclization of 2-alkynylbenzaldehyde:
(a) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007,
129, 1413 and references cited therein; (b) Asao, N. Synlett 2006, 1645;
(c) Nakamura, I.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc.
2005, 127, 9844; (d) Kim, N.; Kim, Y.; Park, W.; Sung, D.; Gupta, A.-K.; Oh, C.-H.
Org. Lett. 2005, 7, 5289; (e) Sato, K.; Asao, N.; Yamamoto, Y. J. Org. Chem. 2005,
70, 8977; (f) Asao, N.; Sato, K.; Menggenbateer; Yamamoto, Y. J. Org. Chem.
2005, 70, 3682; (g) Kusama, H.; Funami, H.; Takaya, J.; Iwasawa, N. Org. Lett.
2004, 6, 605; (h) Asao, N.; Aikawa, H.; Yamamoto, Y. J. Am. Chem. Soc. 2004,
126, 7458; (i) Ding, Q.; Wu, J. Org. Lett. 2007, 9, 4959; (j) Gao, K.; Wu, J. J. Org.
Chem. 2007, 72, 8611; (k) Sun, W.; Ding, Q.; Sun, X.; Fan, R.; Wu, J. J. Comb.
Chem. 2007, 9, 690; (l) Ohta, Y.; Kubota, Y.; Watabe, T.; Chiba, H.; Oishi, S.;
Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 6299; (m) Yu, X.; Wu, J. J. Comb.
Chem. 2010, 12, 238; (n) Ding, Q.; Wang, B.; Wu, J. Tetrahedron 2007, 63, 12166;
(o) Ye, S.; Wu, J. Tetrahedron Lett. 2009, 50, 6273; (p) Zhou, H.; Jin, H.; Ye, S.;
He, X.; Wu, J. Tetrahedron Lett. 2009, 50, 4616; (q) Yu, X.; Ding, Q.; Wu, J. J.
Comb. Chem. 2010, 12, 743.
4.2.7. 5-Butyl-1-ethyl-8-fluoro-6-(4-methoxyphenyl)H-pyrazolo[5,1-
a]isoquinoline (4g). Light yellow oil. 1H NMR (400 MHz, CDCl3):
0.80 (t, J¼7.3 Hz, 3H), 1.27e1.33 (m, 2H), 1.45 (t, J¼7.3 Hz, 3H),
1.67e1.71 (m, 2H), 2.94e2.98 (m, 2H), 3.04e3.08 (m, 2H), 3.90 (s,
3H), 6.85e6.89 (m, 1H), 7.05 (d, J¼7.8 Hz, 2H), 7.20e7.23 (m, 3H),
7.89 (s, 1H), 8.19e8.22 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 13.9,
14.1, 19.6, 22.9, 29.2, 30.0, 55.4, 111.6 (d, 2JCF¼23 Hz), 114.2, 114.7 (d,
3
2JCF¼24 Hz), 116.3, 121.4, 125.2 (d, JCF¼9 Hz), 127.8, 128.7, 131.9,
133.0 (d, 3JCF¼9 Hz), 133.1, 139.2, 140.1, 159.2, 161.3 (d, 1JCF¼245 Hz);
HRMS calcd for C24H26FN2O (MþþH): 377.2029, found: 377.2021.
Acknowledgements
Financial support from National Natural Science Foundation of
China (No. 20972030) and the Science & Technology Comm-
ission of Shanghai Municipality (No. 09JC1404902) is gratefully
acknowledged.
Supplementary data
10. For selected examples of multi-component reactions, see: (a) Multicomponent
Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005;
(b) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602; (c) Nair, V.;
Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekenth, A. R.; Balagopal, L. Acc. Chem. Res.
2003, 36, 899; (d) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471; (e) Balme, G.;
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.12.005.
€
Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101; (f) Domling, A.; Ugi, I.
References and notes
ꢁ
Angew. Chem., Int. Ed. 2000, 39, 3168; (g) Bienayme, H.; Hulme, C.; Oddon, G.;
Schmitt, P. Chem.dEur. J. 2000, 6, 3321; (h) Weber, L.; Illgen, K.; Almstetter, M.
Synlett 1999, 366; (i) Ugi, I.; Domling, A.; Werner, B. J. Heterocycl. Chem. 2000,
37, 647; (j) Zhu, J. Eur. J. Org. Chem. 2003, 1133; (k) Hulme, C.; Gore, V. Curr. Med.
Chem. 2003, 10, 51; (l) Weber, L. Curr. Med. Chem. 2002, 9, 1241.
11. For recent reviews, see: (a) Miyaura, N. Top. Curr. Chem. 2002, 219, 11; (b)Suzuki,
A. J. Organomet. Chem. 1999, 576, 147; (c) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
2002, 41, 4176.
1. For selected examples, see: (a) Bentley, K. W. The Isoquinoline Alkaloids; Har-
wood Academic: Australia, 1998; Vol. 1; (b) Phillipson, J. D.; Roberts, M. F.; Zenk,
M. H. The Chemistry and Biology of Isoquinoline Alkaloids; Springer: New York,
NY, 1985.
2. For selected examples, see: (a) Trotter, B. W.; Nanda, K. K.; Kett, N. R.; Regan, C.
P.; Lynch, J. J.; Stump, G. L.; Kiss, L.; Wang, J.; Spencer, R. H.; Kane, S. A.; White,
R. B.; Zhang, R.; Anderson, K. D.; Liverton, N. J.; McIntyre, C. J.; Beshore, D. C.;