Development of a copper(II)-catalyzed three-component tandem synthesis of isoindolinone derivatives

Article abstract of DOI:10.1139/v11-108

Isoindolinone derivatives are important pharmaceutical building blocks in medicinal chemistry. Isoindolo[2,1-a]quinolines are a class of interesting compounds that possess protective effects against N₂-induced hypoxia and inhibitory activities against human topoisomerase II and bacterial DNA-gyrase. The conventional methods for synthesizing these compounds are unsatisfactory because of their harsh reaction conditions, complex starting materials, and multistaged purification procedures. This synthesis of the propargyl-isoindolinone core features an aldehyde-alkyne-amine (A³) coupling-based tandem strategy using methyl 2-formylbenzoate, primary aryl amine, and terminal alkyne under Cu(OTf)₂ catalysis.

Full text of DOI:10.1139/v11-108

92
Development of a copper(II)-catalyzed three-
component tandem synthesis of isoindolinone
derivatives
Leon Xuetong Sun, Tieqiang Zeng, Dong Jiang, Li-Yi Dai, and Chao-Jun Li
Abstract: Isoindolinone derivatives are important pharmaceutical building blocks in medicinal chemistry. Isoindolo[2,1-a]
quinolines are a class of interesting compounds that possess protective effects against N2-induced hypoxia and inhibitory ac-
tivities against human topoisomerase II and bacterial DNA-gyrase. The conventional methods for synthesizing these com-
pounds are unsatisfactory because of their harsh reaction conditions, complex starting materials, and multistaged purification
procedures. This synthesis of the propargyl-isoindolinone core features an aldehyde–alkyne–amine (A3) coupling-based tan-
dem strategy using methyl 2-formylbenzoate, primary aryl amine, and terminal alkyne under Cu(OTf)2 catalysis.
Key words: aldehyde–alkyne–amine (A3) coupling, propargyl-isoindolinone, isoindolo[2,1-a]quinoline, copper(II) catalysis,
tandem reaction.
Résumé : Les dérivés de l’isoindolinone sont d’importants synthons en chimie médicinale. Les isoindolo[2,1-a]quinoléines
font partie d’une classe intéressante de composés qui possèdent effets protecteurs contre l’hypoxie induite par N2 et des acti-
vités inhibitrices contre la topoisomérase II humaine et la gyrase d’ADN bactérienne. Les méthodes de synthèse convention-
nelles de ces composés ne sont pas satisfaisantes en raison de la sévérité de leurs conditions réactionnelles, de la nature
complexes de leurs produits de départ et des méthodes de purification en plusieurs étapes. Cette synthèse du synthon propar-
gyl-isoindolinone comporte un couplage d’aldéhyde, d’alcyne et d’amine (A3) à base d’une stratégie en tandem impliquant
du 2-formylbenzoate de méthyle, une amine aromatique primaire et un alcyne terminal sous l’influence d’un catalyseur de
Cu(OTf)2.
Mots‐clés : couplage d’aldéhyde, d’alcyne et d’amine (A3), propargyl-isoindolinone, isoindolo[2,1-a]quinoléine, catalyse par
le cuivre(II), réaction en tandem.
[Traduit par la Rédaction]
zide.3 Furthermore, isoindolylalkylphosphonium salts possess
Introduction
antitumour activities and have displayed substantial activity
in the P-388 lymphocytic leukemia screen.4 In some recent
reports, these salts have been demonstrated to possess herbi-
cidal activity5 and to act as antagonists of the 5-hydroxy-
tryptamine 2C (5-HT2C) receptor,6 as well as being
candidates to treat various cancers.7 There have also been
some recent studies in applying isoindoline derivatives in
pigments.8
One of the most common isoindoline derivatives is isoin-
dolinone, which has also attracted much research interest ow-
ing to its substantial biological activities. N-Substituted
isoindolinones of general structure 1 possess anxiolytic activ-
ity and are commonly applied as sedatives, hypnotics, and
muscle relaxants.9 Some examples, such as anxiolytics
pazinaclone, pagoclone (Sanofi-Aventis and Pfizer, phase III
A tandem reaction, also called a cascade or domino reac-
tion, is defined as a consecutive series of reactions that usu-
ally proceed via highly reactive intermediates; the product of
each reaction acts as the substrate of subsequent reactions.1
These reactions possess high synthetic value in the sense
that they not only allow efficient construction of complex
structures from simple precursors but also display overall re-
duced operations and better step economy, which translates
into reduced labor time, energy input, and waste; therefore,
they have been the subject of extensive investigations in re-
cent years.2
Isoindoline derivatives are important pharmaceutical build-
ing blocks that possess unique medicinal properties. For in-
stance, the diuretic activity of sulfonamide-functionalized
isoindoline in Fig. 1 is 100 times more than for chlorothia-
Received 27 April 2011. Accepted 14 June 2011. Published at www.nrcresearchpress.com/cjc on 10 November 2011.
L.X. Sun, T. Zeng, and C.-J. Li. Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 2K6.
Canada.
D. Jiang. Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 2K6. Canada; Center for the
Chemistry of Ionic Liquids, East China Normal University, Shanghai 20006, P. R. China.
L.-Y. Dai. Center for the Chemistry of Ionic Liquids, East China Normal University, Shanghai 20006, P. R. China.
Corresponding author: Chao-Jun Li (e-mail: CJ.Li@McGill.ca).
This article is part of a Special Issue dedicated to Professor Tak-Hang Chan.
Can. J. Chem. 90: 92–99 (2012)
doi:10.1139/V11-108
Published by NRC Research Press

Sun et al.
93
Fig. 1. Early discoveries of isoindoline and isoindolinone deriva-
blocks for the preparation of many nitrogen-containing com-
pounds that possess valuable biological activities. It has been
proven that the A3 coupling can be catalyzed by various
types of transition-metal catalysts, including Cu(I), Cu(II),
Ag(I), Au(I), and Au(III) salts and Cu/Ru bimetallic systems,
etc.12 Depending on the nature of the substrates, the reaction
can proceed in organic solvent, water, or neat. We rational-
ized that from simple commercially available starting materials
5, 6, and 7, under transition-metal catalysis, the A3-coupling
product 8 would quickly form in situ, and upon intramolec-
ular cyclization, the isoindolinone core 9 would be con-
structed in one step (Scheme 2).
tives.3,4
O
Cl
N
N
Ph
Ph
Ph
O
S
P
H2N
O
O
Isoindolinone synthesized in 1977
with substantial activity in the P-388
lymphocytic leukemia screen
Isoindoline synthesized in 1963
with high diuretic activity
Fig. 2. Important N-substituted isoindolinone derivatives as pharma-
ceuticals.9
Our initial examination started by using 2-carboxybenzal-
dehyde, aniline, and phenyl acetylene as the starting materi-
als, all of which are inexpensive readily available
commercial substrates. Unfortunately, no desired product was
O
O
O
R
N
O
1
obtained. H NMR studies showed that 2-carboxybenzalde-
N Ar
N
hyde mainly exists in its fused bicyclic form (Scheme 3). We
believe that this form obstructs the formation of imine and
thus prevents A3 coupling from occurring. Another factor
possibly responsible for the failure of the reaction is that the
substrate does not contain a good leaving group to facilitate
the cyclization of the amido ring.
N
O
O
N
1
2
Cl
Isoindolinones
O
Pazinaclone
O
N
Me
N
To render a good leaving group into the substrate as well
as converting it into its “open” form, we decided to use its
methyl ester, “methyl 2-formylbenzoate”, and re-subject it to
the same sets of conditions examined previously; in this case,
all metal catalysts offered the desired product in different
yields, among which Cu(OTf)2 had the highest product:im-
purities ratio. Upon systematic screening, the optimized con-
ditions were determined to be 15 mol % of Cu(OTf)2 at 100 °C
for 12 h in toluene. One noteworthy fact is that the solvent
is an essential component of the reaction, without which the
conditions provided would be too harsh for the substrates
used, and in most cases the phenylacetylene would be con-
verted into acetophenone.
Various types of aniline derivatives were examined. Exper-
imental results (Table 1) indicated that any ortho substituent
on the aniline ring (9g–9m) impedes the formation of the de-
sired product with no reaction observed, most likely because
of steric hindrance. The presence of electron-withdrawing
groups on the meta or para position (9b–9f) can reduce the
yield compared with electron-donating groups.
Screening of the acetylene substrates proved to be chal-
lenging using this methodology. The results for the reactions
tend to vary upon repetitions; thus, each yield reported in Ta-
ble 2 is the averaged isolated yield among a few trials. Simi-
lar to the results of anilines, ortho-substitution patterns in
aryl acetylenes (9u and 9z) do not favour formation of de-
sired products; most importantly, electronic characters of the
aryl cycles do not seem to play a crucial role in the yield,
despite the fact that in the para-substituted cases, electron-
donating groups seem to offer a better yield than electron-
withdrawing groups. Alkyl acetylenes (9v and 9w) always
provide higher yields than aryl acetylenes (9n–9t).
Two special situations have been observed. Firstly, when
the aryl acetylene contains a nitrogen heterocycle, the yield
diminishes to nearly zero. Based on the colour of the catalyst
and the amount of starting materials recovered, we can
clearly conclude that the catalyst is not turning over. We
suspect that this is caused by the strong coordination and
N
N
N
N
O
Cl
N
N
N
O
Cl
3
4
Zopiclone
Pagoclone
clinical trials), and the anticonvulsant zopiclone, are shown in
Fig. 2.10
Conventional synthetic methods adopted in approaching
polysubstituted isoindolinone derivatives are usually unsatis-
factory because of their harsh reaction conditions, complex
starting materials, and lengthy synthetic sequence.11 In recent
years, more and more cascade reactions have been devoted to
the construction of the isoindolinone skeletons. For example,
an elegant palladium(0)-catalyzed three-component carbon-
ylation – amination – Michael addition was used by Grigg
and et al.9a in 2005 in their synthesis of various isoindoli-
nones. Nevertheless, the applications of cascade reactions are
still quite limited.
While working on the aldehyde–alkyne–amine (A3) meth-
odology (A3 coupling; Scheme 1) for the synthesis of mo-
nopropargyl amines,12 we envisioned that the secondary
amine formed in the product could also be utilized as a nu-
cleophile to perform consecutive reactions. Under proper
conditions, this nucleophilic nitrogen can be treated as the
building block for a lactam ready to access various isoindoli-
none derivatives.
Results and discussion
Li and co-workers13 developed the first copper-catalyzed
addition as well as asymmetric addition of acetylenes to vari-
ous imine and acylimines. This discovery has attracted much
attention and also triggered intensive research in this area14
because the final products are synthetically versatile building
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94
Can. J. Chem. Vol. 90, 2012
Scheme 1. Three-component coupling of aldehyde, alkyne, and amine (A3 coupling).
R1
R
R2
N
cat
R1
NH
R2
R-CHO
+
+
R3
H2O or organic solvent
R3
Scheme 2. Proposed isoindoline synthesis via the A3-coupling strategy.
O
O
R'
OR''
H
N
N
O
R'
NH2
OR''
cat
cyclization
+
+
R
R'
CHO
A3
R = alkyl, H
R
R
5
6
7
9
8
Scheme 3. Equilibrium of 2-carboxybenzaldehyde.
core (9) can also be transformed into a series of biologically
active compounds.
O
O
OH
H
O
Experimental
OH
All glassware used for moisture-sensitive reactions was
flame-dried under vacuum and subsequently purged with ni-
trogen. All reagents were commercially available materials
and were used without further purification unless specified.
Standard column chromatography was performed on 20–
60 µm silica gel (obtained from Silicycle Inc.) or on Sorbent
silica gel (30–60 µm) using standard flash column chroma-
tography techniques. Infrared analyses were recorded as a
thin film on NaCl plates and solid compounds as KBr pel-
O
complexation between the heterocyclic nitrogen and copper(II),
which prevents the formation of copper acetylide. An ele-
vated temperature or the addition of a catalytic amount of
acid does not solve this problem. Secondly, when using
propiolate as the alkyne, the desired isoindolinone core
does not form; in this case, the mechanistic pathway is al-
tered and the reaction exclusively yields the 1,4-dihydropyr-
idine system (>90% isolated yield), as shown in Scheme 4.
Initially, we were quite impressed by this outcome because
previously known synthesis of 1,4-dihydropyridines either
requires a microwave apparatus15 or preformation of the
imine with a rare earth metal catalyst (RE triflates, RE =
Sc, Y, La, Ce, Pr, Nd, Sm, or Yb).16 Unfortunately, upon
careful review of the synthetic literature, we concluded that
this methodology is not the greenest approach to date; as
with our studies, Mai et al.17 in 2009 used Brønsted acid
as the catalyst and completed the same transformation in a
one-pot tandem manner in the absence of any transition
metal.
1
lets. H and 13C NMR spectra were recorded on a Varian
1
400 MHz or 300 MHz spectrometer. Chemical shifts for H
NMR spectra were reported in parts per million (ppm) from
tetramethylsilane with the solvent resonance as the internal
standard (deuterated chloroform: d 7.26 ppm, DMSO: d
2.50 ppm). Chemical shifts for 13C NMR spectra were re-
ported in ppm from tetramethylsilane with the solvent reso-
nance as the internal standard (deuterated chloroform: d
77.0 ppm). Mass spectrometry (MS) data were obtained by
using a Kratos MS25RFA mass spectrometer. High-resolution
mass spectrometry electrospray ionization (HR-MS-ESI)
measurements were performed at the McGill University MS
Laboratory.
Conclusion
General procedure for the synthesis of isoindolinones
Under an argon atmosphere, acetylene (0.36 mmol), ani-
line (0.36 mmol), methyl 2-formylbenzoate (0.30 mmol), Cu
(OTf)2 (15 mol %), and anhydrous toluene (1 mL) were
added into a tube and stirred at 75 °C for 12 h. After the re-
action, 15 mL of ethyl acetate was added into the tube and
the entire reaction mixture was filtered through a short plug
of silica. The filtrate was concentrated in vacuo and then sub-
jected to liquid column chromatography (hexane/EtOAc =
7:1 to 5:1 gradient elution). The solvent of the combined
fractions was removed under reduced pressure to afford the
desired isoindolinone compound as a viscous light yellow oil
or semisolid.
In summary, we have demonstrated a one-pot synthesis of
the pharmaceutically interesting propargyl-isoindolinone core
(9) based on the tandem A3-coupling methodology, starting
from methyl 2-formylbenzoate, aniline derivative, and al-
kynes as the precursors. Such methodology provides a simple
and efficient access to a variety of isoindolinone building
blocks from inexpensive starting materials readily. Within
the scope of this reaction, two exceptions were observed: (i)
using propiolates as the acetylene source provides 1,4-dihy-
dropyridine as the only product and (ii) heterocyclic amines
do not favour the formation of the desired product. For future
work, chiral ligands shall be introduced into the reaction to
generate enantio- or diastereo-selectivity. the isoindolinone
Published by NRC Research Press

Sun et al.
95
Table 1. The effect of various anilines on the reaction.
O
FG
FG
CO2Me
N
NH2
cat
+
+
PhMe
CHO
75 °C
12 h
7b
5a
6
9a-9m
Entry
Aniline
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
C6H5NH2
3-F-C6H4NH2
3-Cl-C6H4NH2
4-Cl-C6H4NH2
4-Br-C6H4NH2
4-NO2-C6H4NH2
2-I-C6H4NH2
2-NO2-6-Me-C6H3NH2
2-Cl-4-Cl-6-Cl-C6H2NH2
2-OMe-5-OMe-C6H3NH2
2-i-Pr-6-i-Pr-C6H3NH2
2-Cl-4-Cl-C6H3NH2
9a
9b
9c
9d
9e
9f
9g
9h
9i
75
70
55
52
66
60
N.R.
N.R.
N.R.
N.R.
N.R.
<5
9
10
11
12
13
9j
9k
9l
2-OMe-4-OMe-C6H3NH2
9m
<5
Note: N.R. = no reaction. Conditions: phenylacetylene (0.36 mmol), aniline (0.36 mmol), methyl 2-formylbenzoate
(0.30 mmol), and Cu(OTf)2 (15 mol %) in 1 mL toluene, reacted for 12 h at 75 °C under argon.
Table 2. The effect of alkynes on the reaction.
O
CO2Me
CHO
N
NH2
cat
+
R
+
PhMe
75 oC
12 h
7b
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
5
6a
9n-9z
R
Acetylene
Product
9n
9o
9p
9q
9r
9s
9t
9u
Isolated yield (%)
4-Me-phenylacetylene
4-OMe-phenylacetylene
4-t-Bu-phenylacetylene
4-n-Bu-phenylacetylene
4-CF3-phenylacetylene
4-Ph-phenylacetylene
3-F-phenylacetylene
2-NO2-phenylacetylene
Tetradec-1-yne
31
25
35
45
20
20
44
N.R.
55
60
32
0
9v
5-Methylhex-1-yne
Ethynyl-triisopropylsilane
Methyl propiolate
9w
9x
9ya
9z
2-Ethynylpyridine
N.R
Note: N.R. = no reaction. Conditions: acetylene (0.36 mmol), aniline (0.36 mmol), methyl 2-formylbenzoate
(0.30 mmol), and Cu(OTf)2 (15 mol %) in 1 mL toluene, reacted for 12 h at 75 °C under argon.
aProduct 9y does not bear an isoindolinone structure, instead it is a 1,4-dihydropyridine structure, noted as
compound 10.
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96
Can. J. Chem. Vol. 90, 2012
Scheme 4. Formation of 1,4-dihydropyridine structural scaffolds.
O
N
X
NH2
O
O
5 mol% Cu(OTf)2
OMe
OMe
+
+
Not observed
PhMe
100 °C
12 h
CHO
7b
O
X
MeO
6
5b
9y
X = H
X = Br
X = CN
CO2Me
CO2Me
10
10a
, X = H
N
10b, X = CN
10c
MeO2C
, X= Br
X
1,4-dihydropyridine system
90~95%
Characterization of products
86.5, 83.0, 53.1. HR-MS (ESI) exact mass calcd. for
C22H13FNO ([M – H]) m/z: 326.0987; found m/z: 326.0988.
O
O
N
N
Cl
9a
9c
1H NMR (400 MHz, CDCl3, ppm) d: 7.96 (d, 1H, J =
7.6 Hz), 7.86 (dd, 2H, J = 7.8, 1.0 Hz), 7.72–7.68 (m, 2H),
7.58–7.45 (m, 3H), 7.32–7.26 (m, 6H), 6.04 (s, 1H). 13C
NMR (100 MHz, CDCl3, ppm) d: 166.7, 141.8, 137.7,
132.8, 131.8, 131.7, 129.3, 129.0, 128.9, 128.3, 125.3,
124.2, 123.0, 122.2, 121.7, 86.2, 83.5, 53.2. HR-MS (ESI)
exact mass calcd. for C22H16NO ([M + H]) m/z: 310.1237;
found m/z: 310.1230.
1H NMR (400 MHz, CDCl3, ppm) d: 7.94 (d, 1H, J =
7.6 Hz), 7.84 (d, 2H, J = 8.8 Hz), 7.71–7.69 (m, 2H), 7.59–
7.57 (m, 1H), 7.43 (d, 2H, J = 8.8 Hz), 7.33–7.26 (m, 5H),
5.99 (s, 1H). 13C NMR (100 MHz, CDCl3, ppm) d: 166.6,
141.6, 138.9, 134.6, 133.1, 131.8, 131.3, 129.9, 129.4,
129.0, 128.3, 125.1, 124.4, 123.1, 121.7, 121.5, 119.5, 86.6,
82.9, 53.0. HR-MS (ESI) exact mass calcd. for C22H15ClNO
([M + H]) m/z: 344.0837; found m/z: 344.0842.
O
N
F
O
N
Cl
9d
9b
1H NMR (400 MHz, CDCl3, ppm) d: 7.94 (d, 1H, J =
7.6 Hz), 7.84 (d, 2H, J = 8.8 Hz), 7.72–7.69 (m, 2H), 7.57–
7.56 (m, 1H), 7.43 (dd, 2H, J = 7.0, 2.0 Hz), 7.30–7.26 (m,
5H), 6.00 (s, 1H). 13C NMR (100 MHz, CDCl3, ppm) d:
166.6, 141.6, 136.3, 132.9, 131.8, 131.3, 130.4, 129.4,
129.1, 128.8, 128.3, 124.3, 123.1, 122.9. HR-MS exact mass
calcd. for C22H14ClNONa ([M + Na]) m/z: 366.0656; found
m/z: 366.0664.
1H NMR (400 MHz, CDCl3, ppm) d: 7.96 (d, 1H, J =
7.6 Hz), 7.82–7.56 (m, 5H), 7.44–7.24 (m, 6H), 6.94 (td,
1H, J = 10.8, 2.6 Hz), 6.00 (s, 1H). 13C NMR (100 MHz,
CDCl3, ppm) d: 165.6 (d, J = 211.8 Hz), 161.3, 141.6,
139.3 (d, J = 13.9 Hz), 133.1, 131.8, 131.3, 130.1, 129.9,
129.4, 129.0, 128.3, 124.4, 123.1, 121.7, 116.6 (d, J =
4.3 Hz), 111.8 (d, J = 27.9 Hz), 108.9 (d, J = 35.2 Hz),
Published by NRC Research Press

Sun et al.
97
O
O
N
Br
N
9e
9w2
1H NMR (400 MHz, CDCl3, ppm) d: 8.18 (d, 1H, J =
2 Hz), 8.02 (dd, 1H, J = 8.8, 2.4 Hz), 7.96–7.84 (m, 4H),
7.67 (dd, 1H, J = 2.8, 1.2 Hz), 7.58–7.44 (m, 3H), 5.94 (s,
1H), 2.10–2.06 (m, 2H), 1.38–1.33 (m, 1H), 1.25–1.18 (m,
2H), 0.68–0.64 (m, 6H). 13C NMR (75 MHz, CDCl3, ppm)
d: 166.6, 142.5, 135.3, 133.6, 132.6, 131.6, 131.1, 129.1,
128.6, 127.9, 127.5, 126.3, 125.5, 124.1, 122.9, 121.4,
119.8, 87.5, 74.5, 53.2, 36.9, 26.8, 21.8, 16.6. HR-MS (ESI)
exact mass calcd. for C25H24NO ([M + H]) m/z: 354.1852;
found m/z: 354.1851.
1H NMR (400 MHz, CDCl3, ppm) d: 7.94 (d, 1H, J =
7.2 Hz), 7.80 (d, 2H, J = 8.8 Hz), 7.79–7.67 (m, 2H), 7.59–
7.56 (m, 3H), 7.33–7.25 (m, 5H), 5.99 (s, 1H). 13C NMR
(100 MHz, CDCl3, ppm) d: 166.6, 141.6, 136.8, 133.0,
131.9, 131.8, 131.3, 129.4, 129.0, 128.3, 124.3, 123.2,
123.1, 121.5, 118.2, 86.5, 82.9, 52.9. HR-MS (ESI) exact
mass calcd. for C22H15BrNO ([M + H]) m/z: 388.0332; found
m/z: 388.0338.
O
O
N
NO2
N
9f
OMe
9o
1H NMR (400 MHz, CDCl3, ppm) d: 8.34 (dd, 2H, J =
7.2, 2.0 Hz), 8.19 (dd, 2H, J = 9.6, 2.0 Hz), 7.90–7.50 (m,
4H), 7.34–7.29 (m, 5H), 6.09 (s, 1H). 13C NMR (100 MHz,
CDCl3, ppm) d: 166.9, 143.6, 143.5, 141.5, 133.8, 131.8,
130.7, 129.7, 129.3, 128.4, 124.8, 124.6, 123.2, 121.1,
119.9, 87.1, 82.4, 52.7. HR-MS (ESI) exact mass calcd. for
C22H13N2O3 ([M – H]) m/z: 353.0932; found m/z: 353.0953.
1H NMR (400 MHz, CDCl3, ppm) d: 7.95 (d, 1H, J =
7.2 Hz), 7.86 (d, 2H, J = 8 Hz), 7.73–7.65 (m, 2H), 7.59–
7.45 (m, 3H), 7.26–7.22 (m, 3H), 6.77 (d, 2H, J = 7.6 Hz),
6.02 (s, 1H), 3.77 (s, 3H). 13C NMR (75 MHz, CDCl3, ppm)
d: 166.7, 159.9, 142.0, 137.7, 133.3, 132.7, 131.6, 129.2,
128.9, 125.3, 124.2, 123.0, 122.2, 113.9, 86.2, 82.0, 80.2,
55.3, 53.4. HR-MS (ESI) exact mass calcd. for C23H18NO2
([M + H]) m/z: 340.1332; found m/z: 340.1333.
O
O
N
N
9w
Me
9n
1H NMR (400 MHz, CDCl3, ppm) d: 7.91 (d, 1H, J =
7.6 Hz), 7.79 (d, 2H, J = 7.6 Hz), 7.67–7.62 (m, 2H), 7.58–
7.51 (m, 1H), 7.46–7.42 (m, 2H), 7.26–7.21 (m, 1H), 5.79 (s,
1H), 2.13–2.09 (m, 2H), 1.51–1.43 (m, 1H), 1.28–1.23 (m,
2H), 0.86–0.76 (m, 6H). 13C NMR (75 MHz, CDCl3, ppm)
d: 166.6, 142.4, 137.7, 132.6, 131.6, 128.9, 128.8, 125.1,
124.1, 122.9, 122.2, 87.3, 74.4, 52.9, 36.9, 26.9, 22.0, 21.9,
16.6. HR-MS (ESI) exact mass calcd. for C21H22NO ([M +
H]) m/z: 304.1707; found m/z: 304.1698.
1H NMR (400 MHz, CDCl3, ppm) d: 7.95 (d, 1H, J =
7.6 Hz), 7.87 (d, 2H, J = 8 Hz), 7.73–7.65 (m, 2H), 7.59–
7.44 (m, 4H), 7.26–7.19 (m, 2H), 7.06 (d, 2H, J = 7.6 Hz),
6.02 (s, 1H), 3.31 (s, 3H). 13C NMR (75 MHz, CDCl3, ppm)
d: 166.7, 141.9, 139.1, 137.7, 132.7, 131.7, 129.2, 129.1,
129.0, 128.9, 125.3, 124.2, 123.1, 122.2, 119.4, 118.7, 86.4,
82.8, 53.3. HR-MS (ESI) exact mass calcd. for C23H16NO
([M – H]) m/z: 322.1237; found m/z: 322.1231.
Published by NRC Research Press

98
Can. J. Chem. Vol. 90, 2012
141.5, 137.5, 132.8, 131.6, 129.9, 129.3, 129.2, 129.1,
129.0, 127.7, 127.6, 125.4, 124.3, 122.9, 122.1, 119.4, 118.6
(d, J = 22.5 Hz), 116.4, 116.3 (d, J = 21.9 Hz), 84.5 (d, J =
29 Hz), 53.1. HR-MS (ESI) exact mass calcd. for
C22H13FNO ([M – H]) m/z: 326.0987; found m/z: 326.0995.
O
N
O
N
9p
5
1H NMR (400 MHz, CDCl3, ppm) d: 7.95 (d, 1H, J =
Me
9v
7.6 Hz), 7.86 (d, 2H, J = 7.6 Hz), 7.73–7.65 (m, 2H), 7.57
(t, 1H, J = 7.6 Hz), 7.46 (t, 2H, J = 8.4 Hz), 7.30–7.22 (m,
5H), 6.03 (s, 1H), 1.27 (s, 9H). 13C NMR (75 MHz, CDCl3,
ppm) d: 166.7, 152.2, 141.9, 137.7, 132.7, 131.7, 131.6,
129.2, 128.9, 125.3, 125.2, 124.2, 123.0, 122.2, 118.7, 86.3,
82.8, 53.4, 34.8, 31.1. HR-MS (ESI) exact mass calcd. for
C26H23NONa ([M + Na]) m/z: 388.1672; found m/z:
388.1679.
1H NMR (400 MHz, CDCl3, ppm) d: 7.91 (d, 1H, J =
7.6 Hz), 7.80 (d, 2H, J = 7.6 Hz), 7.64 (d, 2H, J = 2.4 Hz),
7.55–7.52 (m, 1H), 7.46–7.42 (m, 2H), 7.26–7.20 (m, 1H),
5.80 (s, 1H), 2.13–2.08 (m, 2H), 1.38–1.78 (m, 20H), 0.93–
0.87 (m, 3H). 13C NMR (75 MHz, CDCl3, ppm) d: 166.7,
142.4, 137.7, 134.4, 132.6, 131.5, 128.9, 128.8, 126.6,
125.1, 124.1, 123.7, 122.9, 122.1, 87.4, 74.5, 52.9, 31.9,
29.6, 29.4, 29.0, 28.6, 28.2, 22.7, 18.6, 14.1. HR-MS (ESI)
exact mass calcd. for C28H36NO ([M + H]) m/z: 402.2791;
found m/z: 402.2801.
O
N
CO2Me
CO2Me
N
MeO2C
9q
10a
1H NMR (400 MHz, CDCl3, ppm) d: 7.95 (d, 1H, J =
7.6 Hz), 7.87 (d, 2H, J = 8 Hz), 7.73–7.65 (m, 2H), 7.59–
7.55 (m, 1H), 7.49–7.45 (m, 2H), 7.26–7.22 (m, 3H), 7.07
(d, 2H, J = 8 Hz), 6.03 (s, 1H), 2.58–2.54 (m, 2H), 1.67–
1.50 (m, 2H), 1.35–1.26 (m, 2H), 0.91–0.86 (m, 3H). 13C
NMR (75 MHz, CDCl3, ppm) d: 166.7, 144.1, 141.9, 137.7,
132.7, 131.7, 131.6, 129.2, 128.9, 128.4, 125.3, 124.2, 123.1,
122.2, 118.9, 86.4, 82.8, 53.3, 35.5, 33.3, 22.2, 13.9. HR-MS
(ESI) exact mass calcd. for C26H23NONa ([M + H]) m/z:
388.1672; found m/z: 388.1678.
1H NMR (500 MHz, CDCl3, ppm) d: 7.75 (dd, 1H, J =
8 Hz, 1.5 Hz), 7.68 (s, 2H), 7.48–7.40 (m, 5H), 7.32–7.28
(m, 2H), 7.21 (m, 1H), 6.10 (s, 1H), 3.99 (s, 3H), 3.60 (s,
6H). 13C NMR (75 MHz, CDCl3, ppm) d: 168.5, 167.0,
146.8, 143.0, 136.1, 131.9, 130.2, 130.1, 129.9, 129.7,
126.4, 126.3, 120.6, 111.4, 51.9, 51.4, 32.9. HR-MS (ESI)
exact mass calcd. for C23H22NO6 ([M + H]) m/z: 408.1442;
found m/z: 408.1439.
CO2Me
CO2Me
O
N
N
MeO2C
CN
10b
1H NMR (400 MHz, CDCl3, ppm) d: 7.78–7.73 (m, 5H),
7.43–7.36 (m, 3H), 7.25–7.21 (m, 2H), 6.14 (s, 1H), 3.98 (s,
3H), 3.62 (s, 6H). 13C NMR (75 MHz, CDCl3, ppm) d:
168.3, 166.5, 145.8, 145.7, 134.1, 134.0, 131.9, 130.3,
130.2, 129.9, 126.6, 119.8, 118.1, 113.5, 109.1, 52.02,
51.66, 32.97, 31.58, 22.65, 14.12. HR-MS (ESI) exact mass
calcd. for C24H20N2O6Na ([M + Na]) m/z: 455.1214; found
m/z: 455.1206.
F
9t
1H NMR (400 MHz, CDCl3, ppm) d: 7.97–7.83 (m, 3H),
7.71–7.66 (m, 1H), 7.60–7.41 (m, 4H), 7.27–7.20 (m, 2H),
7.07 (d, 1H, J = 8 Hz), 7.02–6.03 (m, 2H), 6.03 (s, 1H),
4.86 (s, 1H). 13C NMR (75 MHz, CDCl3, ppm) d: 166.6,
Published by NRC Research Press

Sun et al.
99
(8) Sasaki, D.; Fujiwara, T. Jpn. Kokai Tokkyo Koho JP
2005304565, 2006; Chem. Abstr. 2007, 146, 472371.
(9) (a) Grigg, R.; Gai, X.; Khamnaen, T.; Rajviroongit, S.;
Sridharan, V.; Zhang, L.; Collard, S.; Keep, A. Can. J. Chem.
2005, 83 (6–7), 990. doi:10.1139/v05-111; (b) Takahashi, I.;
Kawakami, T.; Hirano, E.; Yokota, H.; Kitajima, H. Synlett
1996, 1996 (04), 353. doi:10.1055/s-1996-5438.
(10) (a) Sorbera, L. A.; Leeson, P. A.; Silvestre, J.; Castaner, J.
Drugs Future 2001, 26 (7), 651. doi:10.1358/dof.2001.026.07.
630003; (b) Anzini, M.; Cappelli, A.; Vomero, S.; Giorgi, G.;
Langer, T.; Bruni, G.; Romeo, M. R.; Basile, A. S. J. Med.
Chem. 1996, 39 (21), 4275. doi:10.1021/jm960325j; (c) Gotor,
V.; Limeres, F.; García, R.; Bayod, M.; Brieva, R. Tetrahedron
Asymmetry 1997, 8 (7), 995. doi:10.1016/S0957-4166(97)
00090-6.
CO2Me
CO2Me
N
MeO2C
Br
10c
1H NMR (500 MHz, CDCl3, ppm) d: 7.75 (d, 1H, J =
8 Hz), 7.62 (s, 2H), 7.57 (dd, 2H, J = 6.8, 2 Hz), 7.42 (d,
2H, J = 4.4 Hz), 7.21–7.18 (m, 3H), 6.10 (s, 1H), 3.98 (s,
3H), 3.60 (s, 6H). 13C NMR (75 MHz, CDCl3, ppm) d:
168.4, 166.9, 146.5, 142.0, 135.5, 133.0, 131.9, 130.2,
130.1, 129.7, 129.4, 126.4, 122.0, 111.9, 51.9, 51.5, 32.8.
HR-MS (ESI) exact mass calcd. for C23H20BrNO6Na ([M +
Na]) m/z: 508.0366; found m/z: 508.0371.
(11) (a) Zhu, C.; Falck, J. R. Org. Lett. 2011, 13 (5), 1214. doi:10.
1021/ol200093f; (b) Moreau, A.; Couture, A.; Deniau, E.;
Grandclaudon, P.; Lebrun, S. Tetrahedron 2004, 60 (29), 6169.
doi:10.1016/j.tet.2004.05.033.
References
(12) Chen, L.; Li, C.-J. Adv. Synth. Catal. 2006, 348 (12–13), 1459.
doi:10.1002/adsc.200606090.
(1) For reviews, see (a) Tietze, L. F.; Brasche, G.; Gericke, K. M.
Domino Reactions in Organic Synthesis; Wiley-VCH: Wein-
heim, Germany, 2006; p 3; (b) Tietze, L. F.; Beifuss, U.
Angew. Chem. Int. Ed. Engl. 1993, 32 (2), 131. doi:10.1002/
anie.199301313; (c) Tietze, L. F. Chem. Rev. 1996, 96 (1),
115. doi:10.1021/cr950027e; (d) Pellissier, H. Tetrahedron
2006, 62 (10), 2143. doi:10.1016/j.tet.2005.10.041; (e) Ho, T.
L. Tandem Organic Reactions; Wiley: New York, 1992; p 502;
(f) Bunce, R. A. Tetrahedron 1995, 51 (48), 13103. doi:10.
1016/0040-4020(95)00649-S.
(2) (a) Ikeda, S. Acc. Chem. Res. 2000, 33 (8), 511. doi:10.1021/
ar9901016; (b) Enders, D. C.; Wang, J. W.; Bats, J. W. Angew.
Chem. 2008, 120 (39), 7649. doi:10.1002/ange.200802532.
(3) Cornish, E. J.; Lee, G. E.; Wragg, W. R. Nature 1963, 197
(4874), 1296. doi:10.1038/1971296b0.
(4) (a) Dubois, R. J.; Lin, C.-C.; Beisler, J. A. J. Med. Chem.
1978, 21 (3), 303. doi:10.1021/jm00201a016; (b) Bonfield, E.
R.; Li, C.-J. Adv. Synth. Catal. 2008, 350 (3), 370. doi:10.
1002/adsc.200700500.
(5) Huang, M. Z.; Huang, K. L.; Ren, Y. G.; Lei, M. X.; Huang,
L.; Hou, Z. K.; Liu, A. P.; Ou, X. M. J. Agric. Food Chem.
2005, 53 (20), 7908. doi:10.1021/jf051494s.
(6) Hamprecht, D.; Micheli, F.; Tedesco, G.; Checchia, A.; Donati,
D.; Petrone, M.; Terreni, S.; Wood, M. Bioorg. Med. Chem.
Lett. 2007, 17 (2), 428. doi:10.1016/j.bmcl.2006.10.029.
(7) (a) Muller, G. W.; Man, H. W. PCT Int. Appl. WO
2006025991, 2006; Chem. Abstr. 2006, 144, 269911; (b)
Murakata, C.; Amishiro, N.; Atsumi, T.; Tamashita, Y.;
Tanahashi, T.; Nakai, R.; Tagaya, H.; Takahashi, H.;
Funahashi, J.; Yamamoto, J.; Fukuda, Y. PCT Int. Appl. WO
2006112479, 2006; Chem. Abstr. 2006, 145, 454932; (c)
Funk, L. A.; Johnson, M. C.; Kung, P. P.; Meng, J. J.; Zhou, J.
Z. PCT Int. Appl. WO 2006117669, 2006; Chem. Abstr. 2006,
145, 489014.
(13) (a) Li, C.-J.; Wei, C. Chem. Commun. (Camb.) 2002, 2002 (3),
268. doi:10.1039/B108851N; (b) Wei, C.; Li, C.-J. J. Am.
Chem. Soc. 2002, 124 (20), 5638. doi:10.1021/ja026007t; (c)
Wei, C.; Mague, J. T.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A.
2004, 101 (16), 5749. doi:10.1073/pnas.0307150101; (d)
Zhang, J.; Wei, C.; Li, C.-J. Tetrahedron Lett. 2002, 43 (33),
5731. doi:10.1016/S0040-4039(02)01197-8.
(14) For reviews and recent examples, see (a) Li, C.-J. Acc. Chem.
Res. 2010, 43 (4), 581. doi:10.1021/ar9002587; (b) Wei, C.;
Li, Z.; Li, C.-J. Synlett 2004, 2004 (9), 1472. doi:10.1055/s-
2004-829531; (c) Zeng, T.; Yang, L.; Hudson, R.; Song, G.;
Moores, A. R.; Li, C.-J. Org. Lett. 2011, 13 (3), 442. doi:10.
1021/ol102759w; (d) Shore, G.; Yoo, W.-J.; Li, C.-J.; Organ,
M. G. Chem. Eur. J. 2010, 16 (1), 126. doi:10.1002/chem.
200902396; (e) Zhang, Y.; Donahue, J. P.; Li, C.-J. Org. Lett.
2007, 9 (4), 627. doi:10.1021/ol062918m; (f) Bonfield, E. R.;
Li, C.-J. Org. Biomol. Chem. 2007, 5 (3), 435. doi:10.1039/
b613596j; (g) Zani, L.; Bolm, C. Chem. Commun. (Camb.)
2006, 2006 (41), 4263. doi:10.1039/b607986p; (h) Yoo, W.-J.;
Zhao, L.; Li, C.-J. Aldrichim. Acta 2011, 44 (2), 43; (i) Zeng,
T.; Chen, W.-W.; Cirtiu, C. M.; Moores, A.; Song, G.; Li, C.-J.
Green Chem. 2010, 12 (4), 570. doi:10.1039/b920000b; (j)
Huang, B.; Yao, X.; Li, C.-J. Adv. Synth. Catal. 2006, 348 (12–
13), 1528. doi:10.1002/adsc.200606118.
(15) Balalaie, S.; Kowsari, E. Monatsh. Chem. 2001, 132 (12),
1551. doi:10.1007/s007060170012.
(16) Kikuchi, S.; Iwai, M.; Murayama, H.; Fukuzawa, S. Tetra-
hedron Lett. 2008, 49 (1), 114. doi:10.1016/j.tetlet.2007.11.
003.
(17) Mai, A.; Valente, S.; Meade, S.; Carafa, V.; Tardugno, M.;
Nebbioso, A.; Galmozzi, A.; Mitro, N.; De Fabiani, E.;
Altucci, L.; Kazantsev, A. J. Med. Chem. 2009, 52 (17), 5496.
doi:10.1021/jm9008289.
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