A three-component approach to isoquinoline derivatives by cycloaddition/Heck reaction sequence

Article abstract of DOI:10.1016/j.tetlet.2007.04.082

Here, we report a three-component coupling reaction approach between an aldehyde, an allyloxyamine, and a maleimide toward isoquinoline derivatives. At first, an oxime O-allylic ether, prepared by dehydrative condensation of the aldehyde and the allyloxya

Full text of DOI:10.1016/j.tetlet.2007.04.082

Tetrahedron Letters 48 (2007) 4255–4258
A three-component approach to isoquinoline derivatives
by cycloaddition/Heck reaction sequence
Masato Oikawa,a,* Yoshiyuki Takeda,a Shinya Naito,a Daisuke Hashizume,b
Hiroyuki Koshinob and Makoto Sasakia
aLaboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku University, Tsutsumidori-Amamiya,
Aoba-ku, Sendai 981-8555, Japan
bMolecular Characterization Team, Advanced Development and Supporting Center, RIKEN, Hirosawa 2-1, Wako,
Saitama 351-0198, Japan
Received 13 February 2007; revised 10 April 2007; accepted 13 April 2007
Available online 21 April 2007
Abstract—Here, we report a three-component coupling reaction approach between an aldehyde, an allyloxyamine, and a maleimide
toward isoquinoline derivatives. At first, an oxime O-allylic ether, prepared by dehydrative condensation of the aldehyde and the
allyloxyamine, was reacted with the maleimide in the presence of a Pd2+ species. The cycloadduct obtained was then subjected
to the Heck cyclization employing a Pd0 species to give thermodynamically stable diastereomer of isoquinoline derivatives selectively
in 25–78% yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Not only frequently found in naturally occurring alka-
loids, the di- and tetrahydroisoquinoline nuclei are but
also an important pharmacophore. Typical examples
include papaverine (smooth muscle relaxant),1 saframy-
cin-B (antitumor agent),2 indenoisoquinoline (topoiso-
action of Pd2+, followed by 1,3-dipolar cyclization with
the dipolarophilic maleimides 5 to give iodoolefin 6.
Upon exposure to Pd0, 6 underwent intramolecular
Heck cyclization to the isoquinoline derivative 8.
merase
I
inhibitor),3 and narciclasine (antitumor
Two questions arose in this work: (1) does the isomeri-
zation toward nitrone (3!4) proceed intramolecularly?
and (2) is the stereochemistry of the isoquinoline deriv-
ative 8 controlled throughout the synthesis? The first
question is particularly important if the synthesis is
attempted in a split-pool manner, and the second issue
arose since stereocontrol of oxime formation and 1,3-
dipolar cycloaddition is generally quite poor.
agent).4 Several methods have been reported to construct
the isoquinoline framework, including the Bischler–
Napieralski reaction approach on b-phenethylamine
derivatives toward dihydroisoquinolines.5
We have been interested in the construction of the
isoquinoline scaffold by multicomponent coupling reac-
tions so that a library of diverse isoquinoline derivatives
can be accessible by a split-pool synthesis on insoluble
polymer beads. Our approach is shown in Scheme 1.
The components employed in this study are iodobenzal-
dehydes 1, allyloxyamines 2, and maleimides 5. These
components were coupled sequentially leading to di-
or tetrahydroisoquinolines 8 as follows. First, aldehyde
1 and allyloxyamine 2 were dehydratively condensed
to the chemically stable oxime O-allylic ether 3, which
was then subjected to isomerization to nitrone 4 by the
The 1,3-dipolar cycloaddition was performed by the pro-
cedure originally reported by Grigg et al.6 Since they
have examined only the oxime O-allyl ether and O-crotyl
ether, we at first synthesized benzoxime O-(a-methyl)al-
lyl ether (11)7 by a dehydrative condensation (Na2SO4,
THF, 60 °C) of benzaldehyde (9) with (a-methyl)allyl-
oxyamine (10)8 in 93% isolated yield (trans/cis = 86:14)
to investigate the reaction course (Scheme 2). By expo-
sure to 0.15 equiv of PdCl2(CH3CN)2 in the presence of
N-methylmaleimide (12), nitrone formation from 11 fol-
lowed by the cycloaddition took place smoothly to give
cycloadduct 13 in 85% yield with no significant stereose-
lectivity (54:46).9 However, the a-methylallyl group in 11
*
Corresponding author. Tel./fax: +81 22 7178827; e-mail: mao@
bios.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.082

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M. Oikawa et al. / Tetrahedron Letters 48 (2007) 4255–4258
X1
H
I
H
I
H2N
O
X3
Pd2+
CHO
I
O
X1
X2
O
X2
N
N
R
R
R
formal
allyloxyamine 2
X1
X3
[2,3]-sigmatropic
rearrangement
X3
X2
1
oxime O-allylic ether 3
nitrone intermediate 4
R
R
O
R
R
*
R
R
R
R
Pd0
elimination
O
O
N
N
*
*
N
R
Heck
R
R
maleimide 5
X3
X3
I
reaction
X1
X2
Pd
X2
X3
1,3-dipolar
X2
cycloaddition
X1
X1
isoquinoline 8
6
7
Scheme 1.
amounts of crossover products (18 and 19 in the former
reaction, and 13 and 15 in the latter reaction) were de-
tected, indicating that nitrone formation proceeds com-
pletely in an intramolecular fashion.
Me
H
H2N
O
10
O
Me
CHO
N
a
Efficient conditions for the Heck cyclization of iodoole-
fin 2012 leading to the dihydroisoquinoline scaffold were
next investigated. After several experiments with various
catalysts, ligands, bases, additives, and solvents, the best
result was found to be achieved by employing a simple
combination of 0.15 equiv of Pd(PPh3)4 and 2.0 equiv
i-Pr2NEt in N,N-dimethylacetamide (DMA) at 100 °C
for 4 h (Scheme 4). It should be especially noted that tri-
phenylphosphine, frequently used as an additive, causes
significant reductive decomposition presumably at the
N–O bond to lower the yield to 49%. Another finding
in this reaction is that the diastereomeric ratio of the cyc-
lized product 21, a-H/b-H = 80:20, is inconsistent with
that of iodoolefin 20 (a-H/b-H = 53:47) employed. Since
thermodynamic equilibrium was suspected from the re-
sult, we carried out several experiments, and finally
found that b-isomer 21b completely isomerizes into a-
isomer 21a just upon heating to 100 °C for 5 h in
DMA. A prolonged reaction (22 h) for the Heck reaction
of 20 gave 21a with complete stereoselectivity but in low-
er yield (68%) because of the decomposition. The struc-
ture of product 21a was unambiguously determined by
a single crystal X-ray diffraction analysis.13,14 Although
the mechanistic comprehension of this isomerization re-
quires further study, this is reasonably accounted for by
the energy difference (3.33 kcal/mol) between 21a and
21b calculated at the MMFF94S force field (CON-
FLEX).14,15 By this procedure, other dihydroisoquino-
lines 22a and 23a, being different at the imide moiety,
were also synthesized in 62% and 61% yields, respec-
tively, also in a diastereoselective manner (Fig. 1).11
9
11 (trans/cis = 86:14)
Me
N
Me
O
O
N
O
O
H
H
12
O
N
H
b
13
(α-H/β-H = 46:54)
Me
Scheme 2. Reagents and conditions: (a) Na2SO4, THF, 60 °C, 24 h,
93%, (b) PdCl2(CH3CN)2 (0.15 equiv), CHCl3, 60 °C, 50 h, 85%.
was completely transformed into the crotyl group in 13,
indicating that the nitrone formation proceeds by a for-
mal [2,3]-sigmatropic rearrangement process obviously
through addition/elimination of the Pd2+ species.
We then synthesized three oxime O-allylic ethers 14, 1610
and 17 for crossover experiments to know if the nitrone
formation has possibilities to allow scrambling of the
partners (Scheme 3). At first, equimolar amounts of 11
and 14 were mixed and subjected to the cycloaddition
with N-methylmaleimide. After 72 h, two products were
chromatographically separated, and the less polar and
the polar products were determined to be 13 (96%, a-
H/b-H = 57:43) and 15 (65%, a-H/b-H = 57:43), respec-
tively.11 Another combination (16 and 176,7) was next
subjected to the reaction, and two products 18 (polar,
58%, a-H/b-H = 50:50)11 and 19 (less polar, 99%, a-H/
b-H = 56:44)6 were also isolated cleanly. Not even trace
Finally, iodoolefins with substituents on the allyl moiety
were subjected to the Heck cyclization (Scheme 5). As
compared to the unsubstituted substrate 20, these reac-

M. Oikawa et al. / Tetrahedron Letters 48 (2007) 4255–4258
4257
Me
N
Me
N
OMe
O
O
OMe
O
O
O
O
H
2
2
Br
H
H
O
Me
a
O
Br
H
H
O
H
N
O
O
O
N
O
O
N
H
N
H
11
MeO
(trans/cis = 86:14)
MeO
14
Me
15
13
65% (α-H/β-H = 43:57)
96% (α-H/β-H = 43:57)
Me
Me
OMe
O
N
O
O
OMe
N
O
O
2
O
H
2
Br
O
Br
H
H
O
N
a
H
H
O
H
O
O
O
N
O
O
Me
N
H
N
H
17
MeO
(trans/cis = 95:5)
MeO
16
Me
18
58% (α-H/β-H = 50:50)
19
99% (α-H/β-H = 44:56)
Scheme 3. Reagents and conditions: (a) N-methylmaleimide (12), PdCl2(CH3CN)2 (0.15 equiv), CHCl3, 60 °C, 72 h.
Me
N
Me
N
Me
N
O
O
O
O
O
O
a
H
H
H
H
H
H
O
O
O
N
N
N
H
I
H
H
78% : 20%
b
20
21α
21β
α-H/β-H = 53:47
Scheme 4. Reagents and conditions: (a) Pd(PPh3)4 (0.15 equiv), i-Pr2NEt (2.0 equiv), N,N-dimethylacetamide, 100 °C, 4 h, 21a/21b = 78%:20%, (b)
N,N-dimethylacetamide, 100 °C, 5 h, 92%.
tions on 24–26 were found to be sluggish, and the yields
for 27–29 were apparently lower (33–63%). However,
the point that should be much emphasized is that the
stereoselectivity is completely controlled in these cases;
(1) the stereochemistry of the carbon a to the N–O func-
tionality is a-orientated as in the cases for 21a–23a,16,17
(2) the double bond takes trans configuration, and (3)
another benzylic carbon nearby the allyl group is also
controlled to be R*. These stereochemistries, determined
from NMR analysis, are the thermodynamically most
stable configurations from the molecular modeling at
α-orientation
Me
N
Me
N
O
O
O
O
H
H
H
H
a
O
O
N
N
H
I
H
R
R*
N
O
O
trans
R'
R
H
H
O
24 (R = Me)
25 (R = n-hexyl)
26 (R = 2-phenylethyl)
27α (R' = H)
N
H
28α (R' = n-pentyl)
29α (R' = benzyl)
22α (R = H): 62%
23α (R = Bn): 61%
Scheme 5. Reagents and conditions: (a) Pd(PPh3)4 (0.15 equiv), i-
Pr2NEt (3.0 equiv), N,N-dimethylacetamide, 100 °C, <48 h, 63% (27a),
33% (28a), 44% (29a).
Figure 1. Dihydroisoquinolines 22a and 23a synthesized by the
cycloaddition/Heck reaction approach.

4258
M. Oikawa et al. / Tetrahedron Letters 48 (2007) 4255–4258
the MMFF94S force field (CONFLEX).14,15 In all cases,
unreacted iodoolefins were recovered after the reaction.
procedure, see: Irie, H.; Katayama, I.; Mizuno, Y.;
Koyama, J.; Suzuta, Y. Heterocycles 1979, 12, 771–773;
Koyama, J.; Sugita, T.; Suzuta, Y.; Irie, H. Chem. Pharm.
Bull. 1983, 31, 2601–2606.
In summary, we have developed a stereoselective three-
component coupling approach to isoquinoline deriva-
tives. Though the intermediary cycloadducts 6 were
obtained as a diastereomeric mixture, the finally synthe-
sized isoquinolines 8 were diastereomerically controlled
to one isomer under thermodynamic conditions by an
as yet unclear mechanism. In addition, we have given
clear evidence for the intramolecular, formal [2,3]-sig-
matropic rearrangement of the Pd2+-catalyzed nitrone
formation. Work is in progress toward realization of a
di- and tetrahydroisoquinoline library, and application
of the present methodology to biologically important
natural products.
9. The change of the diastereomeric ratio in this 1,3-dipolar
cycloaddition would be attributed to the isomerization of
the intermediary nitrone.6 The stereochemistries of these
products (13a,13b) were determined by 1H–1H J-coupling
constants and NOESY experiments, and finally confirmed
by X-ray diffraction analysis of 21a.
10. Oxime O-allylic ethers 14 and 16 were prepared from 2-
bromo-3-hydroxy-4-methoxybenzaldehyde over 4 and 5
steps for 60% and 46% yields, respectively.
11. The stereochemistries of these products were determined
by 1H–1H J-coupling constants and NOESY experiments,
and finally confirmed by analogy with the synthesis of
21a.
12. Prepared from 2-iodobenzaldehyde as for 13 shown in
Scheme 2 over 2 steps (66% yield).
References and notes
13. The crystallographic data for 21a have been deposited at
the Cambridge Crystallographic Data Centre and allo-
cated the deposition number, CCDC 620027. Dihydroiso-
quinoline 21a has been also recently synthesized by an
alternative four-component coupling approach, see: Don-
das, H. A.; Fishwick, C. W. G.; Gai, X. J.; Grigg, R.;
Kilner, C.; Dumrongchai, N.; Kongkathip, B.; Kongka-
thip, N.; Polysuk, C.; Sridharan, V. Angew. Chem., Int.
Ed. 2005, 44, 7570–7574.
14. The details will be reported in the full account of this
research.
15. Calculated on BARISTA software (BARISTA, version
1.2.2; CONFLEX Co., Yotsuya 4-30, Shinjuku-ku, Tokyo
160-0004, Japan).
1. Kaneda, T.; Takeuchi, Y.; Matsui, H.; Shimizu, K.;
Urakawa, N.; Nakajyo, S. J. Pharmacol. Sci. 2005, 98,
275–282.
2. Mikami, Y.; Yokoyama, K.; Tabeta, H.; Nakagaki, K.;
Arai, T. J. Pharm. Dyn. 1981, 4, 282–286.
3. 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, 287–295.
4. 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, 995–1002.
5. Whaley, W. M.; Govindachari, T. R. The Preparation of
3,4-Dihydroisoquinolines and Related Compounds by the
Bischler–Napieralski Reaction. In Organic Reactions;
1951; Vol. 6, pp 74.
16. A considerable amount (30%) of the trisubstituted, olefin
isomer of 27a was also detected in the Heck cyclization of
24.
17. In the cases for the synthesis of 28a and 29a, unreacted b-
isomer of 25 (33%) and 26 (33%) were recovered after the
reaction, indicating these b-isomers are less reactive than
the a-isomer. Because prolonged reaction was found to
cause decomposition from the experiment of 20, we are
currently optimizing the other reaction conditions for this
transformation.
6. Grigg, R.; Markandu, J. Tetrahedron Lett. 1991, 32, 279–
282.
7. Davies, S. G.; Fox, J. F.; Jones, S.; Price, A. J.; Sanz, M.
A.; Sellers, T. G. R.; Smith, A. D.; Teixeira, F. C. J. Chem.
Soc., Perkin Trans. 1 2002, 1757–1765.
8. Prepared from 2-but-3-enyl chloride and N-hydroxy-
phthalimide over 2 steps (34% yield) by a reported