Synthesis of 2,3,4,11b-tetrahydro-1 H-pyridazino[6,1-a]isoquinolines via the three-component reaction of 2-alkynylbenzaldehydes, a sulfonohydrazide and dimethyl cyclopropane-1,1-dicarboxylate

Article abstract of DOI:10.1055/s-0030-1260063

A three-component reaction of 2-alkynylbenzaldehydes, a sulfonohydrazide and dimethyl cyclopropane-1,1-dicarboxylate, co-catalyzed by silver(I) triflate and nickel(II) perchlorate hexahydrate, is described, which affords 2,3,4,11b-tetrahydro-1H-pyridazino[6,1-a]isoquinolines in moderate to good yields. A possible reaction pathway that proceeds via a tandem 6-endo-cyclization and [3+3] cycloaddition sequence is proposed. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260063

2268
SPECIAL TOPIC
Synthesis of 2,3,4,11b-Tetrahydro-1H-pyridazino[6,1-a]isoquinolines via the
Three-Component Reaction of 2-Alkynylbenzaldehydes, a Sulfonohydrazide
and Dimethyl Cyclopropane-1,1-dicarboxylate
T
hree-Component
i
Synthe
n
sis of Tetrah
g
ydroisoquino
x
lines in Yu,a Guanyinsheng Qiu,a Jianping Liu,*b Jie Wu*a
a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China
Fax +86(21)65641740; E-mail: jie_wu@fudan.edu.cn
EENT Hospital, Fudan University, 83 Fenyang Road, Shanghai 200031, P. R. of China
b
Received 10 March 2011
has had a long-standing interest in this field and recently
disclosed a tandem ring-opening/Conia–ene sequence,
which involved a zinc(II) bis-triflimide [Zn(NTf2)2] cata-
lyzed nucleophilic ring-opening of 1,1-cyclopropanedi-
Abstract: A three-component reaction of 2-alkynylbenzaldehydes,
a sulfonohydrazide and dimethyl cyclopropane-1,1-dicarboxylate,
co-catalyzed by silver(I) triflate and nickel(II) perchlorate hexahy-
drate, is described, which affords 2,3,4,11b-tetrahydro-1H-py-
ridazino[6,1-a]isoquinolines in moderate to good yields. A possible esters by 2-alkynylindoles followed by a Conia–ene ring-
reaction pathway that proceeds via a tandem 6-endo-cyclization and
[3+3] cycloaddition sequence is proposed.
closure. We have previously described a tandem cycliza-
tion–[3+3] cycloaddition of 2-alkynylbenzaldoximes with
cyclopropane-1,1-dicarboxylate.20 This reaction proceed-
Key words: 2-alkynylbenzaldehydes, dimethyl cyclopropane-1,1-
dicarboxylate, nickel perchlorate hexahydrate, silver(I) triflate, sul-
fonohydrazide
ed smoothly in the presence of catalytic amounts of sil-
ver(I) triflate (AgOTf) and ytterbium(III) triflate
[Yb(OTf)3], providing a useful method for the synthesis
of functionalized fused 1,2-dihydroisoquinolines. En-
The importance of di- and tetrahydroisoquinolines in both
natural products and pharmaceuticals cannot be overstat-
ed; their ubiquity in both natural and unnatural bioactive
compounds1 is testament to this, and some examples are
presented in Figure 1. A highly substituted fused 1,2-di-
hydroisoquinoline core is found in the lamellarin alka-
loids (a family of novel marine natural products).2 Among
these compounds, lamellarin D inhibits human topo-
isomerase I.3 Additionally, lamellarin a-20-sulfate serves
as a selective inhibitor against HIV-1 integrase in vitro.4
Saframycin,5 which is produced by Streptomyces laven-
dulae, belongs to the tetrahydroisoquinoline family of an-
tibiotics, and is a highly potent antibiotic which binds to
DNA inhibiting both DNA and RNA syntheses. The anti-
cancer isocarbostyril, narciclasine, a component of vari-
ous Narcissus species, could represent a powerful weapon
for targeting the Achilles’ heel of glioblastoma.6 Conse-
quently, numerous efforts have been directed toward the
construction of 1,2-dihydroisoquinolines and related
compounds.7
Annulation reactions of donor–acceptor cyclopropanes8
as dipolarophiles have received considerable attention
due to their ability to allow rapid access to a variety of het-
erocycles via cycloaddition reactions. Substrates includ-
ing aldehydes,8j,9 imines or azomethine imines,10
nitrones,11 allenes or acetylenes,12 nitriles,13 isocyanates,14
isothiocyanates,15 isocyanides,16 a,b-unsaturated ke-
tones,17 and diazenes1,8 have been employed in reactions
of activated cyclopropanes. Notably, Kerr’s group11d,e,f,19
couraged by this result, we envisioned that N¢-(2-alkynyl-
benzylidene)hydrazides might also be suitable substrates
in reactions with cyclopropane-1,1-dicarboxylate due to
their structural similarity with 2-alkynylbenzaldoxime.
Since N¢-(2-alkynylbenzylidene)hydrazides can be ob-
tained from 2-alkynylbenzaldehydes and a sulfonohy-
drazide,21 we reasoned that a three-component reaction of
a 2-alkynylbenzaldehyde, a sulfonohydrazide and a cyclo-
propane-1,1-dicarboxylate might be a good method for
the synthesis of tetrahydroisoquinolines (Scheme 1). Af-
ter condensation and intramolecular cyclization, the inter-
mediate isoquinolinium-2-yl amide B would react with
HO
OH
O
N
OH
MeO
H
O
O
O
OH
MeO
NH
HO
OH
narciclasine
OMe
O
OH
MeO
lamellarin D
HO
O
O
OH
OMe
N
N
MeO
NH
NH2
O
saframycin
SYNTHESIS 2011, No. 14, pp 2268–2274
x
x.
x
x
.
2
0
1
1
Advanced online publication: 09.06.2011
DOI: 10.1055/s-0030-1260063; Art ID: C26411SS
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Selected di- and tetrahydroisoquinoline-related natural
products

SPECIAL TOPIC
Three-Component Synthesis of Tetrahydroisoquinolines
2269
the cyclopropane-1,1-dicarboxylate leading to 2,3,4,11b- perchlorate hexahydrate (10 mol%) showed high efficien-
tetrahydro-1H-pyridazino[6,1-a]isoquinolines. Herein, cy as the catalyst system in tetrahydrofuran as the solvent.
we report our preliminary results on this transformation.
The expected product 4a was obtained in 50% yield in one
pot. Further screening of solvents indicated that 1,4-diox-
ane was the best choice affording 4a in an increased yield
of 68%. The reaction was retarded at lower temperatures.
H
CHO
N
N
Ts
R1
R1
TsNHNH2
+
A
2
TsNHNH2
MeO2C
R2
R2
1
2
CHO
[Ag]
Lewis acid
(cat.)
MeO2C
+
MeO2C
6-endo
AgOTf
(cat.)
CO2Me
CO2Me
CO2Me
CO2Me
N
R3
solvent
additive
cyclization
N
Ts
MeO2C
–
N
Ph
1a
N
+
N
R3
Ph
3
3a
Ts
N
Ts
R1
4a
R1
[3+3]
B
4
R2
R2
cycloaddition
Scheme 2 Optimization of the conditions for the three-component
reaction of 2-alkynylbenzaldehyde 1a, sulfonohydrazide 2, and di-
methyl cyclopropane-1,1-dicarboxylate (3a)
Scheme 1 Proposed route for the three-component reaction of 2-al-
kynylbenzaldehyde 1, sulfonohydrazide 2 and cyclopropane-1,1-di-
carboxylate 3
Using the optimized conditions [silver(I) triflate (10
mol%), nickel(II) perchlorate hexahydrate (10 mol%), 4
Å molecular sieves, 1,4-dioxane, 50 °C], the scope of this
three-component reaction was investigated, and the re-
sults are shown in Table 1. All the reactions proceeded
smoothly leading to the desired 2,3,4,11b-tetrahydro-1H-
pyridazino[6,1-a]isoquinolines 4 in moderate to good
yields. For example, reaction of 2-alkynylbenzaldehyde
1b, sulfonohydrazide 2 with dimethyl cyclopropane-1,1-
dicarboxylate (3a) gave rise to the desired product 4b in
75% yield (Table 1, entry 2). In addition to the aryl group
attached to the C∫C triple bond, 2-alkynylbenzaldehydes
with a cyclopropyl or n-butyl group were found to be suit-
able substrates yielding the expected products (Table 1,
entries 3, 7, 10, 12 and 15). These reaction conditions also
proved to be useful for 2-alkynylbenzaldehydes 1d–p
with electron-withdrawing and electron-donating substit-
uents on the aromatic ring. Interestingly, 2-alkynylbenzal-
dehyde 1m possessing a nitro group on the aromatic ring
was well-tolerated and gave the corresponding product
Our experiments began with the identification of an opti-
mum Lewis acid system for the three-component reaction
of 2-(phenylethynyl)benzaldehyde (1a), sulfonohy-
drazide 2, and dimethyl cyclopropane-1,1-dicarboxylate
(3a) (Scheme 2). Since the condensation of 2-alkynyl-
benzaldehyde 1a with sulfonohydrazide 2 had proceeded
efficiently in tetrahydrofuran, and silver(I) triflate had
proved to be the most effective catalyst for the subsequent
6-endo-cyclization,21 we initially attempted the three-
component reaction of 1a, 2 and dimethyl cyclopropane-
1,1-dicarboxylate (3a) using silver(I) triflate (10 mol%) as
the catalyst in tetrahydrofuran. Unfortunately, only the in-
termediate isoquinolinium-2-yl amide B was generated
(99% yield, two hours, 60 °C) and no further transforma-
tion was observed. Based on this result, we envisaged that
an additional Lewis acid might be necessary to facilitate
the subsequent [3+3] cycloaddition. Hence, the reaction
of isoquinolinium-2-yl amide B with dimethyl cyclopro-
pane-1,1-dicarboxylate (3a) in tetrahydrofuran was inves-
tigated. A control experiment established that a Lewis
acid was needed to activate the dicarboxylate 3a, since no
conversion was observed in a blank experiment. No reac-
tion occurred when copper(II) triflate [Cu(OTf)2] or bis-
muth(III) triflate [Bi(OTf)3] was employed as the catalyst.
A trace amount of product was obtained when ytterbi-
um(III) chloride [YbCl3] was used in the reaction. Grati-
fyingly, the formation of product 4a was detected (38%
yield) when dysprosium(III) triflate [Dy(OTf)3] was uti-
lized as the catalyst (10 mol%) at 50 °C. Further screening
of Lewis acids revealed that magnesium perchlorate
[Mg(ClO4)2], scandium(III) triflate [Sc(OTf)3] and nick-
el(II) perchlorate hexahydrate [Ni(ClO4)2·6H2O] were all
good catalysts, with the latter being the most efficient for
the transformation into 4a (58% yield). Further extensive
studies showed that the yield could be improved when 4
Å molecular sieves were included as an additive. We next
reinvestigated the three-component reaction of 1a, sul-
fonohydrazide 2, and dimethyl cyclopropane-1,1-dicar-
boxylate (3a), and to our delight, found that the
combination of silver(I) triflate (10 mol%) and nickel(II)
Figure 2 X-ray crystal structure (ORTEP) of compound 4d (30%
probability ellipsoids)
Synthesis 2011, No. 14, 2268–2274 © Thieme Stuttgart · New York

2270
X. Yu et al.
SPECIAL TOPIC
Table 1 Silver(I) Triflate and Nickel Perchlorate Hexahydrate Co-Catalyzed Three-Component Reaction of 2-Alkynylbenzaldehydes, a Sul-
fonohydrazide and Dimethyl Cyclopropane-1,1-dicarboxylate
MeO2C
R3
Ts
CHO
AgOTf (10 mol%)
Ni(ClO4)2⋅6H2O (10 mol%)
CO2Me
CO2Me
R1
MeO2C
+
+
TsNHNH2
N
4 Å MS, 1,4-dioxane, 50 °C
N
R1
R3
R2
R2
1
2
3
4
Entry
1
R1, R2
R3
Product
4a
Yield (%)a
H, C6H5 (1a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
C6H5 (3b)
C6H5 (3b)
68
2
H, 4-ClC6H4 (1b)
H, c-Pr (1c)
4b
4c
75
3
71
4
4-F, C6H5 (1d)
4d
4e
73
5
4-F, 4-MeC6H4 (1e)
87
6
4-F, 4-MeOC6H4 (1f)
4-F, n-C4H9 (1g)
5-F, C6H5 (1h)
4f
85
7
4g
35
8
4h
4i
77
9
5-F, 4-MeC6H4 (1i)
5-F, c-Pr (1j)
80
10
11
12
13
14
15
16
17
18
4j
57
5-Cl, C6H5 (1k)
5-Cl, c-Pr (1l)
4k
4l
72
55
5-O2N, C6H5 (1m)
5-Me, C6H5 (1n)
5-Me, c-Pr (1o)
4-MeO, C6H5 (1p)
H, C6H5 (1a)
4m
4n
4o
59
61
43
4p
4q
4r
57
complex
complex
4-F, C6H5 (1d)
a Isolated yield based on 2-alkynylbenzaldehyde 1.
4m in an isolated yield of 59% (Table 1, entry 13). The ward improving the substrate scope and construction of a
structure of tetrahydroisoquinoline 4d was confirmed by related library of products are ongoing.
X-ray crystallographic analysis (Figure 2). Unfortunately,
only dimethyl cyclopropane-1,1-dicarboxylate (3a) could
All reactions were performed under a nitrogen atmosphere. Flash
be employed in this reaction to give the desired 2,3,4,11b-
tetrahydro-1H-pyridazino[6,1-a]isoquinoline products.
The reaction proved complex when dimethyl 2-phenylcy-
clopropane-1,1-dicarboxylate (3b) was utilized (Table 1,
entries 17 and 18).
column chromatography was performed using silica gel (60 Å pore
size, 32–63 mm, standard grade). Analytical thin-layer chromatog-
raphy was performed using glass plates pre-coated with 0.25 mm
230–400 mesh silica gel impregnated with a fluorescent indicator
(254 nm). Thin-layer chromatography plates were visualized by ex-
posure to ultraviolet light. Organic solutions were concentrated at
~20 Torr (house vacuum) at 25–35 °C. Solvents were re-distilled
In conclusion, we have described a three-component reac-
tion of 2-alkynylbenzaldehydes 1, sulfonohydrazide 2 and prior to use in the reactions. Other commercial reagents were used
as received. Petroleum ether (PE) refers to the fraction boiling in the
60–90 °C range.
1H and 13C NMR spectra were recorded in CDCl3 on a Bruker DRX-
dimethyl cyclopropane-1,1-dicarboxylate (3a) co-cata-
lyzed by silver(I) triflate and nickel perchlorate hexahy-
drate,
which
affords
2,3,4,11b-tetrahydro-1H-
400 spectrometer operating at 400 MHz and 100 MHz, respectively,
or on a Bruker DRX-500 spectrometer operating at 500 MHz and
125 MHz. All chemical shift values are quoted in ppm and coupling
constants quoted in Hz. High-resolution mass spectrometry
(HRMS) was carried out on a micrOTOF II instrument. Melting
pyridazino[6,1-a]isoquinolines in moderate to good
yields. A tandem 6-endo-cyclization and [3+3] cycloaddi-
tion process takes place during the reaction. Studies to-
Synthesis 2011, No. 14, 2268–2274 © Thieme Stuttgart · New York

SPECIAL TOPIC
Three-Component Synthesis of Tetrahydroisoquinolines
2271
points were determined in open capillary tubes on a WRS-1B digital
melting point apparatus. IR spectra were run on a FTIR-360 spec-
trophotometer.
Dimethyl 9-Fluoro-6-phenyl-4-tosyl-3,4-dihydro-2H-pyridazi-
no[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4d)
White solid; 201 mg, 73% yield; mp 176.6–177.2 °C.
IR (thin film): 2954, 1722, 1610, 1591, 1491, 1485, 1436 cm–1.
2,3,4,11b-Tetrahydro-1H-pyridazino[6,1-a]isoquinolines 4;
General Procedure
1H NMR (400 MHz, CDCl3): d = 2.05–2.14 (m, 1 H), 2.35–2.40 (m,
1 H), 2.50 (s, 3 H), 3.46 (s, 3 H), 3.53–3.60 (m, 1 H), 3.64 (s, 3 H),
3.71–3.77 (m, 1 H), 5.30 (s, 1 H), 5.32 (s, 1 H), 6.59 (dd, J = 9.2,
2.4 Hz, 1 H), 6.77 (td, J = 8.4, 2.4 Hz, 1 H), 7.09 (dd, J = 8.4, 5.6
Hz, 1 H), 7.20–7.34 (m, 7 H), 7.66 (d, J = 8.4 Hz, 2 H).
To a soln of 2-alkynylbenzaldehyde 1 (0.5 mmol), sulfonohy-
drazide 2 (0.5 mmol) and dimethyl cyclopropane-1,1-dicarboxylate
3 (1.5 mmol) in 1,4-dioxane (2.0 mL) were added AgOTf (10
mol%), Ni(ClO4)2·6H2O (10 mol%) and 4 Å MS. The mixture was
heated at 50 °C with vigorous stirring overnight until the reaction
was complete. The mixture was diluted with EtOAc (5.0 mL) and
quenched with H2O (5.0 ml). The organic layer was washed with
brine (2 × 5 mL), dried over Na2SO4 and concd under reduced pres-
sure. The crude residue was purified by column chromatography on
silica gel (eluent: PE–EtOAc, 16:1 to 4:1) to provide the desired
product 4.
13C NMR (125 MHz, CDCl3): d = 21.6, 30.3, 41.0, 52.0, 52.7, 54.5,
2
2
60.2, 104.3, 109.6 (d, JC–F = 23 Hz), 112.1 (d, JC–F = 22 Hz),
3
123.4, 127.5, 128.1, 128.5, 128.8, 129.1 (d, JC–F = 9 Hz), 129.8,
134.9, 135.2, 144.6, 148.1, 162.8 (d, 1JC–F = 244 Hz), 169.6, 170.1.
HRMS (ESI): m/z [M + H]+ calcd for C29H28FN2O6S: 551.1652;
found: 551.1620.
Dimethyl 9-Fluoro-6-(p-tolyl)-4-tosyl-3,4-dihydro-2H-pyridazi-
no[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4e)
White solid; 246 mg, 87% yield; mp 165.3–165.9 °C.
IR (thin film): 3064, 2952, 1723, 1611, 1496, 1432, 1359 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.05–2.11 (m, 1 H), 2.35–2.38 (m,
1 H), 2.37 (s, 3 H), 2.50 (s, 3 H), 3.45 (s, 3 H), 3.52–3.60 (m, 1 H),
3.62 (s, 3 H), 3.71–3.77 (m, 1 H), 5.26 (s, 1 H), 5.30 (s, 1 H), 6.58
(dd, J = 9.2, 2.4 Hz, 1 H), 6.76 (td, J = 8.8, 2.8 Hz, 1 H), 7.05–7.14
(m, 5 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 2 H).
Dimethyl 6-Phenyl-4-tosyl-3,4-dihydro-2H-pyridazino[6,1-
a]isoquinoline-1,1(11bH)-dicarboxylate (4a)
White solid; 181 mg, 68% yield; mp 148.2–149.2 °C.
IR (thin film): 3057, 2951, 1724, 1629, 1598, 1491, 1435 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.05–2.13 (m, 1 H), 2.34–2.39 (m,
1 H), 2.49 (s, 3 H), 3.39 (s, 3 H), 3.49–3.56 (m, 1 H), 3.62 (s, 3 H),
3.68–3.74 (m, 1 H), 5.28 (s, 1 H), 5.34 (s, 1 H), 6.87 (d, J = 7.3 Hz,
1 H), 7.04–7.09 (m, 2 H), 7.15–7.30 (m, 8 H), 7.67 (d, J = 8.2 Hz,
2 H).
13C NMR (100 MHz, CDCl3): d = 21.7, 30.4, 41.0, 52.0, 52.7, 54.5,
60.3, 105.5, 123.3, 125.8, 127.4, 127.5, 127.9, 128.0, 128.3, 128.6,
129.0, 129.9, 133.1, 135.3, 135.5, 144.5, 147.0, 169.8, 170.3.
13C NMR (125 MHz, CDCl3): d = 21.2, 21.6, 30.2, 41.0, 51.9, 52.6,
54.4, 60.1, 104.3, 109.5 (d, 2JC–F = 23 Hz), 112.0 (d, 2JC–F = 21 Hz),
3
123.3, 128.2, 128.4, 128.7, 129.1 (d, JC–F = 9 Hz), 129.8, 132.0,
135.3 (d, 3JC–F = 9 Hz), 135.4, 137.9, 144.6, 148.3, 162.8 (d, 1JC–F
=
HRMS (ESI): m/z [M + H]+ calcd for C29H29N2O6S: 533.1746;
found: 533.1742.
244 Hz), 169.5, 170.2.
HRMS (ESI): m/z [M + H]+ calcd for C30H30FN2O6S: 565.1809;
found: 565.1794.
Dimethyl 6-(4-Chlorophenyl)-4-tosyl-3,4-dihydro-2H-pyridazi-
no[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4b)
White solid; 213 mg, 75% yield; mp 146.9–147.7 °C.
Dimethyl 9-Fluoro-6-(4-methoxyphenyl)-4-tosyl-3,4-dihydro-
2H-pyridazino[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4f)
White solid; 247 mg, 85% yield; mp 168.0–169.0 °C.
IR (thin film): 2954, 1724, 1608, 1511, 1495, 1432 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.01–2.08 (m, 1 H), 2.33–2.36 (m,
1 H), 2.50 (s, 3 H), 3.43 (s, 3 H), 3.50–3.57 (m, 1 H), 3.62 (s, 3 H),
3.71–3.76 (m, 1 H), 3.82 (s, 3 H), 5.20 (s, 1 H), 5.30 (s, 1 H), 6.57
(dd, J = 9.2, 2.0 Hz, 1 H), 6.74 (td, J = 8.4, 2.0 Hz, 1 H), 6.79 (d,
J = 8.4 Hz, 2 H), 7.03 (dd, J = 8.4, 6.0 Hz, 1 H), 7.16 (d, J = 8.4 Hz,
2 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.69 (d, J = 7.6 Hz, 2 H).
IR (thin film): 3061, 2950, 1724, 1596, 1490, 1435, 1357 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.02–2.10 (m, 1 H), 2.34–2.39 (m,
1 H), 2.52 (s, 3 H), 3.39 (s, 3 H), 3.48–3.55 (m, 1 H), 3.62 (s, 3 H),
3.70–3.77 (m, 1 H), 5.16 (s, 1 H), 5.37 (s, 1 H), 6.90 (d, J = 7.2 Hz,
1 H), 7.03–7.11 (m, 2 H), 7.18–7.28 (m, 5 H), 7.34 (d, J = 8.0 Hz,
2 H), 7.72 (d, J = 8.4 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 21.6, 30.2, 41.0, 51.9, 52.6, 54.3,
60.3, 105.8, 123.3, 125.9, 127.3, 127.7, 127.8, 128.3, 128.4, 129.9,
130.5, 132.7, 133.7, 134.0, 135.3, 144.6, 145.8, 169.7, 170.1.
13C NMR (125 MHz, CDCl3): d = 21.6, 30.2, 41.0, 51.9, 52.6, 54.3,
HRMS (ESI): m/z [M + H]+ calcd for C29H28ClN2O6S: 567.1357;
found: 567.1350.
55.2, 60.1, 104.9, 109.5 (d, 2JC–F = 22 Hz), 112.0 (d, 2JC–F = 22 Hz),
3
112.9, 123.3, 127.2, 128.4, 129.1 (d, JC–F = 8 Hz), 129.8, 130.2,
135.3 (d, 3JC–F = 9 Hz), 135.4, 144.5, 147.9, 159.5, 162.8 (d, 1JC–F
=
Dimethyl 6-Cyclopropyl-4-tosyl-3,4-dihydro-2H-pyridazi-
no[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4c)
White solid; 177 mg, 71% yield; mp 149.3–150.3 °C.
IR (thin film): 2952, 1725, 1632, 1597, 1491, 1435 cm–1.
244 Hz), 169.6, 170.2.
HRMS (ESI): m/z [M + H]+ calcd for C30H30FN2O7S: 581.1758;
found: 581.1755.
1H NMR (400 MHz, CDCl3): d = 0.44–0.49 (m, 1 H), 0.55–0.66 (m,
2 H), 0.77–0.82 (m, 1 H), 1.62–1.69 (m, 1 H), 2.05–2.13 (m, 1 H),
2.43–2.45 (m, 1 H), 2.48 (s, 3 H), 3.21 (s, 3 H), 3.58 (s, 3 H), 3.98–
4.01 (m, 2 H), 4.87 (s, 1 H), 5.07 (s, 1 H), 6.79 (d, J = 7.6 Hz, 1 H),
6.87 (d, J = 7.6 Hz, 1 H), 6.96 (t, J = 7.6 Hz, 1 H), 7.11 (t, J = 7.6
Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.80 (d, J = 8.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 5.2, 7.2, 10.9, 21.6, 30.6, 40.5,
51.7, 52.5, 54.6, 60.2, 98.1, 122.8, 124.8, 126.9, 127.0, 128.0,
128.2, 129.8, 133.2, 135.1, 144.4, 148.1, 169.4, 170.3.
Dimethyl 6-Butyl-9-fluoro-4-tosyl-3,4-dihydro-2H-pyridazi-
no[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4g)
White solid; 93 mg, 35% yield; mp 152.0–153.0 °C.
IR (thin film): 2955, 2872, 1725, 1637, 1610, 1495, 1434 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.89–0.93 (m, 3 H), 1.27–1.43 (m,
4 H), 2.05–2.12 (m, 1 H), 2.15–2.18 (m, 2 H), 2.40–2.45 (m, 1 H),
2.49 (s, 3 H), 3.29 (s, 3 H), 3.60 (s, 3 H), 3.86–3.91 (m, 2 H), 4.82
(s, 1 H), 5.17 (s, 1 H), 6.53 (dd, J = 9.6, 2.4 Hz, 1 H), 6.66 (td,
J = 8.8, 2.4 Hz, 1 H), 6.86 (dd, J = 8.0, 5.6 Hz, 1 H), 7.32 (d,
J = 8.0 Hz, 2 H), 7.77 (d, J = 8.0 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C26H29N2O6S: 497.1746;
found: 497.1731.
Synthesis 2011, No. 14, 2268–2274 © Thieme Stuttgart · New York

2272
X. Yu et al.
SPECIAL TOPIC
13C NMR (125 MHz, CDCl3): d = 13.9, 21.6, 22.5, 28.6, 28.8, 30.5,
40.6, 51.8, 52.6, 54.6, 60.1, 99.2, 109.0 (d, 2JC–F = 22 Hz), 111.1 (d,
2JC–F = 22 Hz), 122.5, 128.3, 128.8 (d, 3JC–F = 9 Hz), 129.8, 134.6,
135.4 (d, JC–F = 9 Hz), 144.6, 148.5, 162.8 (d, JC–F = 244 Hz),
169.4, 170.2.
IR (thin film): 3055, 2951, 1726, 1596, 1491, 1435, 1360 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.05–2.14 (m, 1 H), 2.37–2.40 (m,
1 H), 2.51 (s, 3 H), 3.44 (s, 3 H), 3.50–3.57 (m, 1 H), 3.67 (s, 3 H),
3.70–3.76 (m, 1 H), 5.27 (s, 1 H), 5.33 (s, 1 H), 6.82 (d, J = 8.4 Hz,
1 H), 7.10–7.20 (m, 4 H), 7.24–7.28 (m, 2 H), 7.30–7.32 (m, 3 H),
7.66 (d, J = 8.0 Hz, 2 H).
3
1
HRMS (ESI): m/z [M + H]+ calcd for C27H32FN2O6S: 531.1965;
found: 531.1954.
13C NMR (125 MHz, CDCl3): d = 21.6, 30.2, 40.9, 51.9, 52.7, 54.4,
60.3, 104.3, 124.3, 127.5, 127.6, 128.1, 128.3, 128.5, 128.8, 129.3,
129.9, 130.7, 131.7, 134.9, 135.1, 144.6, 147.3, 169.4, 170.0.
HRMS (ESI): m/z [M + H]+ calcd for C29H28ClN2O6S: 567.1357;
found: 567.1339.
Dimethyl 10-Fluoro-6-phenyl-4-tosyl-3,4-dihydro-2H-pyridazi-
no[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4h)
White solid; 212 mg, 77% yield; mp 152.1–153.1 °C.
IR (thin film): 3068, 2953, 1725, 1597, 1499, 1435, 1358 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.00–2.08 (m, 1 H), 2.33–2.36 (m,
1 H), 2.48 (s, 3 H), 3.40 (s, 3 H), 3.46–3.54 (m, 1 H), 3.61 (s, 3 H),
3.66–3.72 (m, 1 H), 5.20 (s, 1 H), 5.32 (s, 1 H), 6.80–6.89 (m, 3 H),
7.20–7.30 (m, 7 H), 7.66 (d, J = 8.0 Hz, 2 H).
Dimethyl 10-Chloro-6-cyclopropyl-4-tosyl-3,4-dihydro-2H-py-
ridazino[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4l)
White solid; 146 mg, 55% yield; mp 154.5–155.1 °C.
IR (thin film): 3006, 2952, 1727, 1630, 1596, 1485, 1435 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.38–0.45 (m, 1 H), 0.52–0.65 (m,
2 H), 0.76–0.83 (m, 1 H), 1.58–1.65 (m, 1 H), 2.04–2.11 (m, 1 H),
2.42–2.47 (m, 1 H), 2.49 (s, 3 H), 3.25 (s, 3 H), 3.62 (s, 3 H), 3.96–
3.99 (m, 2 H), 4.82 (s, 1 H), 5.02 (s, 1 H), 6.71 (d, J = 8.0 Hz, 1 H),
6.88–6.89 (m, 1 H), 7.08 (dd, J = 8.0, 2.0 Hz, 1 H), 7.32 (d, J = 8.0
Hz, 2 H), 7.78 (d, J = 8.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 21.6, 30.2, 40.8, 51.9, 52.7, 54.2,
60.2, 104.5, 114.7 (d, 2JC–F = 23 Hz), 115.1 (d, 2JC–F = 22 Hz), 124.6
(d, 3JC–F = 8 Hz), 127.4, 128.0, 128.4, 129.0, 129.4, 129.7 (d, 3JC–F
=
8 Hz), 129.9, 135.1, 135.3, 144.6, 146.2, 160.9 (d, 1JC–F = 243 Hz),
169.4, 170.1.
HRMS (ESI): m/z [M + H]+ calcd for C29H28FN2O6S: 551.1652;
found: 551.1646.
13C NMR (125 MHz, CDCl3): d = 5.3, 7.3, 10.8, 21.6, 30.5, 40.4,
51.7, 52.7, 54.4, 59.9, 97.1, 123.8, 127.2, 128.1, 128.2, 128.4,
129.7, 129.8, 131.9, 134.9, 144.6, 148.7, 169.1, 170.1.
HRMS (ESI): m/z [M + H]+ calcd for C26H28ClN2O6S: 531.1357;
found: 531.1346.
Dimethyl 10-Fluoro-6-(p-tolyl)-4-tosyl-3,4-dihydro-2H-py-
ridazino[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4i)
White solid; 226 mg, 80% yield, mp 148.2–148.8 °C.
IR (thin film): 3055, 2952, 1725, 1597, 1499, 1435, 1355 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.01–2.09 (m, 1 H), 2.35–2.38 (m,
1 H), 2.37 (s, 3 H), 2.51 (s, 3 H), 3.42 (s, 3 H), 3.49–3.56 (m, 1 H),
3.64 (s, 3 H), 3.70–3.75 (m, 1 H), 5.18 (s, 1 H), 5.35 (s, 1 H), 6.84–
6.91 (m, 3 H), 7.08 (d, J = 8.0 Hz, 2 H), 7.14 (d, J = 8.0 Hz, 2 H),
7.33 (d, J = 8.0 Hz, 2 H), 7.70 (d, J = 8.4 Hz, 2 H).
Dimethyl 10-Nitro-6-phenyl-4-tosyl-3,4-dihydro-2H-pyridazi-
no[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4m)
Yellow solid; 171 mg, 59% yield; mp 184.4–185.4 °C.
IR (thin film): 3055, 2954, 1727, 1601, 1574, 1513, 1436 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.15–2.23 (m, 1 H), 2.38–2.42 (m,
1 H), 2.51 (s, 3 H), 3.47 (s, 3 H), 3.55–3.62 (m, 1 H), 3.70 (s, 3 H),
3.74–3.80 (m, 1 H), 5.38 (s, 1 H), 5.46 (s, 1 H), 6.96 (d, J = 8.4 Hz,
1 H), 7.19 (d, J = 7.6 Hz, 2 H), 7.26–7.31 (m, 4 H), 7.34–7.37 (m,
1 H), 7.58 (d, J = 8.4 Hz, 2 H), 7.99–8.00 (m, 1 H), 8.06 (dd,
J = 8.4, 2.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 21.6, 30.1, 41.5, 52.1, 52.9, 55.2,
60.6, 103.0, 123.2, 123.3, 124.1, 127.1, 128.4, 128.5, 128.8, 130.0,
134.3, 134.7, 139.7, 145.1, 145.2, 151.5, 169.2, 169.4.
13C NMR (125 MHz, CDCl3): d = 21.2, 21.6, 30.2, 40.8, 51.9, 52.7,
54.1, 60.2, 104.5, 114.6 (d, 2JC–F = 23 Hz), 115.0 (d, 2JC–F = 22 Hz),
124.5 (d, 3JC–F = 8 Hz), 128.1, 128.4, 128.9, 129.5, 129.7 (d, 3JC–F
8 Hz), 129.8, 132.2, 135.4, 137.8, 144.6, 146.3, 160.8 (d, JC–F
=
=
1
243 Hz), 169.4, 170.1.
HRMS (ESI): m/z [M + H]+ calcd for C30H30FN2O6S: 565.1809;
found: 565.1803.
Dimethyl 6-Cyclopropyl-10-fluoro-4-tosyl-3,4-dihydro-2H-py-
ridazino[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4j)
White solid; 147 mg, 57% yield; mp 142.0–143.0 °C.
IR (thin film): 3015, 2953, 1726, 1638, 1597, 1499, 1435 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.40–0.46 (m, 1 H), 0.52–0.65 (m,
2 H), 0.76–0.82 (m, 1 H), 1.59–1.66 (m, 1 H), 2.02–2.10 (m, 1 H),
2.42–2.47 (m, 1 H), 2.49 (s, 3 H), 3.24 (s, 3 H), 3.61 (s, 3 H), 3.97–
4.00 (m, 2 H), 4.81 (s, 1 H), 5.05 (s, 1 H), 6.66 (dd, J = 9.2, 2.0 Hz,
1 H), 6.75 (dd, J = 8.4, 5.6 Hz, 1 H), 6.83 (td, J = 8.4, 2.4 Hz, 1 H),
7.33 (d, J = 8.0 Hz, 2 H), 7.79 (d, J = 8.4 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C29H28N3O8S: 578.1597;
found: 578.1598.
Dimethyl 10-Methyl-6-phenyl-4-tosyl-3,4-dihydro-2H-py-
ridazino[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4n)
White solid; 167 mg, 61% yield; mp 122.1–123.1 °C.
IR (thin film): 3048, 2951, 1724, 1597, 1492, 1435, 1357 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.01–2.17 (m, 1 H), 2.33 (s, 3 H),
2.36–2.41 (m, 1 H), 2.50 (s, 3 H), 3.43 (s, 3 H), 3.51–3.58 (m, 1 H),
3.65 (s, 3 H), 3.72–3.77 (m, 1 H), 5.31 (s, 1 H), 5.35 (s, 1 H), 6.80
(d, J = 7.6 Hz, 1 H), 6.90 (s, 1 H), 7.01 (d, J = 7.6 Hz, 1 H), 7.19–
7.32 (m, 7 H), 7.68 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 21.4, 21.6, 30.4, 40.8, 51.8, 52.5,
54.6, 60.8, 105.4, 123.2, 127.4, 127.8, 127.9, 128.0, 128.5, 128.9,
129.7, 130.4, 135.3, 135.4, 135.5, 144.3, 145.9, 169.7, 170.3.
13C NMR (125 MHz, CDCl3): d = 5.2, 7.1, 10.8, 21.6, 30.6, 40.3,
51.7, 52.7, 54.3, 59.9, 97.3, 114.2 (d, 2JC–F = 23 Hz), 114.8 (d, 2JC–F
22 Hz), 124.0 (d, JC–F = 8 Hz), 128.2, 128.8 (d, JC–F = 8 Hz),
129.6, 129.8, 135.4, 144.5, 147.4, 160.3 (d, 1JC–F = 243 Hz), 169.1,
170.2.
=
3
3
HRMS (ESI): m/z [M + H]+ calcd for C26H28FN2O6S: 515.1652;
found: 515.1646.
HRMS (ESI): m/z [M + H]+ calcd for C30H31N2O6S: 547.1903;
found: 547.1896.
Dimethyl 10-Chloro-6-phenyl-4-tosyl-3,4-dihydro-2H-py-
ridazino[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4k)
White solid; 204 mg, 72% yield; mp 158.7–159.6 °C.
Dimethyl 6-Cyclopropyl-10-methyl-4-tosyl-3,4-dihydro-2H-py-
ridazino[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4o)
White solid; 110 mg, 43% yield; mp 142.5–142.7 °C.
Synthesis 2011, No. 14, 2268–2274 © Thieme Stuttgart · New York

SPECIAL TOPIC
Three-Component Synthesis of Tetrahydroisoquinolines
2273
IR (thin film): 2952, 1726, 1634, 1594, 1434, 1352 cm–1.
European Patent EP 0470578, 1992; Chem. Abstr. 1992,
117: 7943.
(2) Bailly, C. Curr. Med. Chem. Anti-Cancer Agents 2004, 4,
363.
(3) 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.; Bushman, 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.
1H NMR (400 MHz, CDCl3): d = 0.38–0.43 (m, 1 H), 0.52–0.61 (m,
2 H), 0.73–0.79 (m, 1 H), 1.54–1.61 (m, 1 H), 2.08–2.15 (m, 1 H),
2.26 (s, 3 H), 2.42–2.46 (m, 1 H), 2.48 (s, 3 H), 3.24 (s, 3 H), 3.62
(s, 3 H), 3.97–4.01 (m, 2 H), 4.90 (s, 1 H), 5.05 (s, 1 H), 6.69–6.70
(m, 2 H), 6.93 (d, J = 7.6 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.80
(d, J = 8.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 5.1, 7.0, 10.8, 21.3, 21.6, 30.7,
40.3, 51.6, 52.5, 54.6, 60.5, 98.2, 122.7, 127.1, 127.6, 128.3, 128.7,
129.7, 130.5, 134.3, 135.2, 144.2, 147.0, 169.4, 170.3.
HRMS (ESI): m/z [M + H]+ calcd for C27H31N2O6S: 511.1903;
(5) (a) Craig Hill, G.; Remers, W. A. J. Med. Chem. 1991, 34,
1990. (b) Lown, W. J.; Hanstock, C. C.; Joshua, A. V.; Arai,
T.; Takahashi, K. J. Antibiot. 1983, 36, 1184.
(6) Ingrassia, L.; Lefranc, F.; Dewelle, J.; Pottier, L.; Mathieu,
V.; Spiegl, K. S.; Sauvage, S.; Yazidi, M. E.; Dehoux, M.;
Berger, W.; Quaquebeke, E. V.; Kiss, R. J. Med. Chem.
2009, 52, 1100.
(7) For selected examples, see: (a) Yamaoka, Y.; Miyabe, H.;
Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686.
(b) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2000, 122, 6327. (c) Takamura, M.;
Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2001, 123, 6801. (d) Young, I. S.; Kerr, M. A. Angew.
Chem. Int. Ed. 2003, 42, 3023. (e) Young, I. S.; Kerr, M. A.
Org. Lett. 2004, 6, 139. (f) Young, I. S.; Williams, J. L.;
Kerr, M. A. Org. Lett. 2005, 7, 953. (g) Sibi, M. P.; Ma, Z.;
Jasperse, C. P. J. Am. Chem. Soc. 2005, 127, 5764.
(h) Kang, Y.-B.; Sun, X.-L.; Tang, Y. Angew. Chem. Int. Ed.
2007, 46, 3918. (i) Bentley, K. W. The Isoquinoline
Alkaloids, Vol 1; Harwood Academic: Amsterdam, 1998.
(j) Phillipson, J. D.; Roberts, M. F.; Zenk, M. H. The
Chemistry and Biology of Isoquinoline Alkaloids; Springer-
Verlag: New York, 1985.
found: 511.1907.
Dimethyl 9-Methoxy-6-phenyl-4-tosyl-3,4-dihydro-2H-py-
ridazino[6,1-a]isoquinoline-1,1(11bH)-dicarboxylate (4p)
White solid; 161 mg, 57% yield; mp 147.4–148.2 °C.
IR (thin film): 2954, 1723, 1604, 1493, 1433, 1357 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.06–2.13 (m, 1 H), 2.34–2.39 (m,
1 H), 2.50 (s, 3 H), 3.46 (s, 3 H), 3.52–3.60 (m, 1 H), 3.63 (s, 3 H),
3.70–3.76 (m, 1 H), 3.79 (s, 3 H), 5.26 (s, 1 H), 5.32 (s, 1 H), 6.44–
6.45 (m, 1 H), 6.65 (dd, J = 8.4, 2.4 Hz, 1 H), 7.02 (d, J = 8.8 Hz,
1 H), 7.21–7.34 (m, 7 H), 7.68 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 21.6, 30.3, 41.0, 52.0, 52.6, 54.6,
55.1, 60.3, 105.2, 108.5, 110.9, 120.3, 127.4, 127.9, 128.4, 128.5,
128.9, 129.8, 134.3, 135.3, 135.4, 144.4, 147.3, 159.6, 169.8, 170.3.
HRMS (ESI): m/z [M + H]+ calcd for C30H31N2O7S: 563.1852;
found: 563.1840.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
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(b) Reißig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
(c) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.;
Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165.
(d) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66.
(e) Corey, E. J.; Gant, T. G. Tetrahedron Lett. 1994, 35,
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1997, 38, 5949. (g) Kerr, M. A.; Keddy, R. G. Tetrahedron
Lett. 1999, 40, 5671. (h) England, D. B.; Kuss, T. D. O.;
Keddy, R. G.; Kerr, M. A. J. Org. Chem. 2001, 66, 4704.
(i) England, D. B.; Woo, T. K.; Kerr, M. A. Can. J. Chem.
2002, 80, 992. (j) Pohlhaus, P. D.; Johnson, J. S. J. Org.
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J. Am. Chem. Soc. 2005, 127, 16014. (l) Kang, Y. B.; Tang,
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2005, 61, 1893. (c) Bernard, A. M.; Frongia, A.; Piras, P. P.;
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(e) Reissig, H.-U. Tetrahedron Lett. 1981, 22, 2981.
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1989, 45, 3139.
Primary Data for this article are available online at http://
www.thieme-connect.com/ejournals/toc/synthesis and can be cited
using the following DOI: 10.4125/pd0014th.
Acknowledgment
Financial support from the National Natural Science Foundation of
China (21032007) is gratefully acknowledged.
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Synthesis 2011, No. 14, 2268–2274 © Thieme Stuttgart · New York

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SPECIAL TOPIC
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Synthesis 2011, No. 14, 2268–2274 © Thieme Stuttgart · New York