Concise synthesis of 1,2-dihydroisoquinolines and 1H-isochromenes by carbophilic lewis acid-catalyzed tandem nucleophilic addition and cyclization of 2-(1-alkynyl)arylaldimines and 2-(1-alkynyl)arylaldehydes

Article abstract of DOI:10.1021/jo070615f

(Chemical Equation Presented) By using carbophilic Lewis acids, In(OTf)₃, NiCl₂, and AuCl(PPh₃)/AgNTf ₂, a concise and efficient synthesis of 1,3-disubstituted 1,2-dihydroisoquinolines has been achieved via tandem nucleophilic addition and cyclization of 2-(1-alkynyl)arylaldimines. Addition of proton sources such as water, CF₃CH₂OH, and 2,6-di-tert-butyl-4-methoxyphenol was essential for the Lewis acid-catalyzed tandem reactions with organometallic reagents. By switching these catalysts, various types of nucleophiles such as allylstannanes, silyl enol ethers, alkenylboronic acids, and active methylene compounds could be introduced at the C₁ position of 1,2-dihydroisoquinolines in this transformation. Furthermore, this method proved to be applicable to the synthesis of 1H-isochromene derivatives via the same tandem reaction of 2-(1-alkynyl)-arylaldehydes.

Full text of DOI:10.1021/jo070615f

Concise Synthesis of 1,2-Dihydroisoquinolines and 1H-Isochromenes
by Carbophilic Lewis Acid-Catalyzed Tandem Nucleophilic Addition
and Cyclization of 2-(1-Alkynyl)arylaldimines and
2-(1-Alkynyl)arylaldehydes
†
†
†
‡
,†
Shingo Obika, Hideki Kono, Yoshizumi Yasui, Reiko Yanada, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku, Kyoto 606-8501,
Japan, and Faculty of Pharmaceutical Sciences, Hiroshima International UniVersity, Hirokoshingai, Kure,
Hiroshima 737-0112, Japan
takemoto@pharm.kyoto-u.ac.jp
ReceiVed March 24, 2007
By using carbophilic Lewis acids, In(OTf)
synthesis of 1,3-disubstituted 1,2-dihydroisoquinolines has been achieved via tandem nucleophilic addition
and cyclization of 2-(1-alkynyl)arylaldimines. Addition of proton sources such as water, CF CH OH,
3 2 3 2
, NiCl , and AuCl(PPh )/AgNTf , a concise and efficient
3
2
and 2,6-di-tert-butyl-4-methoxyphenol was essential for the Lewis acid-catalyzed tandem reactions with
organometallic reagents. By switching these catalysts, various types of nucleophiles such as allylstannanes,
silyl enol ethers, alkenylboronic acids, and active methylene compounds could be introduced at the C
1
position of 1,2-dihydroisoquinolines in this transformation. Furthermore, this method proved to be
applicable to the synthesis of 1H-isochromene derivatives via the same tandem reaction of 2-(1-alkynyl)-
arylaldehydes.
4
Introduction
of the target compounds require multiple steps. Therefore, many
synthetic problems still remain to be solved. To overcome the
lack of synthetic methods and knowledge, considerable effort
has been directed toward the development of concise and
efficient syntheses of these compounds using a wide range of
transition-metal catalysts.
Dihydroisoquinoline is an important and useful skeleton in
organic synthesis. Indeed, many total syntheses of natural
alkaloids have been achieved using 1,2-dihydroisoquinolines as
synthetic intermediates. A number of elegant approaches to
the synthesis of 1,2-dihydroisoquinolines has been developed.
The Reissert-type reaction of isoquinoline derivatives is one of
the methods for 1-substituted 1,2-dihydroisoquinolines, and
recently, its asymmetric versions have been keenly investigated.
In contrast to 1-substituted 1,2-dihydroisoquinolines, there are
only a few convenient methods for 3- and 4-substituted 1,2-
dihydroisoquinolines because most of the reported syntheses
1
(2) Miller, R. B. Tetrahedron Lett. 1998, 39, 1721. Lorsbach, B. A.;
Bagdanoff, J. T.; Miller, R. B.; Kurth, M. J. J. Org. Chem. 1998, 63, 2244.
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2
3
2
004, 2, 2170. Taylor, S. J.; Taylor, A. M.; Schreiber, S. L. Angew. Chem.,
Int. Ed. 2004, 43, 1681. Diaz, J. L.; Miguel, M.; Lavilla, R. J. Org. Chem.
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Neckers, D. C. J. Org. Chem. 2005, 70, 10653.
(3) Takamura, M.; Funbashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
*
Corresponding author. Phone: 81-75-753-4528; fax: 81-75-753-4569.
Kyoto University.
Hiroshima International University.
Soc. 2000, 122, 6327. Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2001, 123, 10784. Alexakis, A.; Amiot, F. Tetrahe-
dron: Asymmetry 2002, 13, 2117. Taylor, M. S.; Tokunaga, N.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2005, 44, 6700. Taylor, A. M.; Schreiber, S.
L. Org. Lett. 2006, 8, 143. Lu, S.; Wang, Y.; Han, X.; Zhau, Y. Angew.
Chem., Int. Ed. 2006, 45, 2260.
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Chem. 1975, 40, 733. Beugelmans, R.; Chastanet, J.; Roussi, G. Tetrahedron
1984, 40, 311. Magnus, P.; Matthew, K. S.; Lynch, V. Org. Lett. 2003, 5,
2181. Kadzimirsz, D.; Hildebrandt, D.; Merz, K.; Dyker, G. Chem. Commun.
2006, 661.
†
‡
(
1) For a review, see: Scott, J. D.; Williams, R. M. Chem. ReV. 2002,
02, 1669. For recent communications, see: Chan, C.; Heid, R.; Zheng,
S.; Guo, J.; Zhou, B.; Furuuchi, T.; Danishefsky, S. J. J. Am. Chem. Soc.
1
2
1
005, 127, 4596. Magnus, P.; Matthews, K. S. J. Am. Chem. Soc. 2005,
27, 12476. Zheng, S.; Chan, C.; Furuuchi, T.; Wright, B. J. D.; Zhou, B.;
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2
007, 46, 1517.
10.1021/jo070615f CCC: $37.00 © 2007 American Chemical Society
4
462
J. Org. Chem. 2007, 72, 4462-4468
Published on Web 05/16/2007

1
,2-Dihydroisoquinoline and 1H-Isochromene Synthesis
SCHEME 1. Synthesis of Isoquinolines and
TABLE 1. Lewis Acid-Catalyzed Tandem Reaction of 1a with
Allyltributylstannane 4Aa
1,2-Dihydroisoquinolines from 2(1-Alkynyl)arylaldimines
c
c
time yield 2aA yield 3aA
entry
catalyst
In(OTf)3
additiveb (h)
(%)
(%)
1
2
3
4
5
6
7
8
48
60
48
60
48
48
48
48
48
36
48
6
92
0
10
88
5
88
70
18
15
72
90
92
0
12
72
0
90
0
d
InBr3
Ga(OTf)3
Sn(OTf)3
dry In(OTf)3e
e,f
dry In(OTf)3
NiCl2
A
B
B
B
B
B
C
Recently, transition-metal-catalyzed 6-endo-mode cyclizations
0
of 2-(1-alkynyl)arylaldimine (Scheme 1) were discovered as
powerful synthetic tools of isoquinolines and 1,2-dihydroiso-
quinolines, and they were also successfully applied to the total
PtCl2
0d
d
9
AuCl3
AuCl(PPh3)/AgNTf2
In(OTf)3
0
g
10
11
12
0
0
0
5
synthesis of natural products. Namely, Larock found that the
In(OTf)3
dealkylative addition of tert-butylimine to a CtC triple bond
a
Reaction of 1a was carried out with allyltributylstannane 4A (1.2 equiv)
and Lewis acid (0.2 equiv) in 1,2-dichloromethane at 70 °C unless stated
proceeded cleanly in the presence of a Pd(0) catalyst to give
5
a,b
3
-substituted or 3,4-disubstituted isoquinolines (route a). In
addition, the Ag(I)- and Pd(II)/Cu(II)-promoted cyclization of
-alkynylarylimines accompanied by intermolecular nucleophilic
b
otherwise. A: H2O (1 equiv); B: CF3CH2OH (2 equiv); or C: 2,6-di-
tert-butyl-4-methoxyphenol (2 equiv). c Isolated yield. d Almost all of 1a
was left in the reaction mixture. e Commercially available In(OTf)3 was
2
f
dried by heating in vacuo before use. 0.1 equiv of In(OTf)3 was used.
Reaction was carried out at room temperature.
addition was developed by Yamamoto’s group for the synthesis
of 1,3-disubstituted or 1,3,4-trisubstituted 1,2-dihydroisoquino-
lines (route b).5 These metallic catalysts probably activated
the CtC triple bond rather than the aldimine moiety. In contrast,
quite recently, we have found that the In(III) catalyst, which
g
c,d
together with an extension of the tandem reaction to 2-alkyny-
larylaldehydes for the synthesis of 1H-isochromenes.
6
has both oxophilic and carbophilic characters, effectively
7
8
activated a CdN double bond and a CtC triple bond at the
same time to obtain the same 1,3-disubstituted 1,2-dihydroiso-
quinolines via the intermolecular nucleophilic addition to an
imine and the subsequent cyclization of the resulting amide to
Results and Discussion
Optimization of Lewis Acids and Proton Sources. We have
already reported that the reaction of 2-(1-alkynyl)arylaldimine
1a with allyltributylstannane 4A in the presence of 20 mol %
In(OTf)3 in 1,2-dichloroethane (DCE) at 70 °C yielded the
desired 1,2-dihydroisoquinoline 2aA in 92% yield after 48 h
(Table 1, entry 1). Although in the previous article, mainly In-
(III) catalysts were examined, due to our interest in indium-
mediated reactions, we re-examined the tandem reaction with
a wide range of soft or hard Lewis acids to expand their synthetic
utility and gain additional insight into this tandem process.
All reactions of 1a with allyltributylstannane 4A were carried
out under the same reaction conditions except the Lewis acids
employed (Table 1, entries 2-9). Use of InBr3 instead of In-
9
an alkyne (route c). The development of such tandem reactions
for the efficient construction of complex molecules is an
important goal of organic synthesis from the viewpoints of
1
0
operational simplicity and assembly efficiency. Herein, we
9
describe the full details of the scope and limitations of Lewis
1
1
acid-catalyzed tandem nucleophilic addition and cyclization of
-(1-alkynyl)arylaldimines with a wide range of nucleophiles,
2
(5) (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86. (b)
Dai, G.; Larock, R. C. J. Org. Chem. 2003, 68, 920. (c) Ohtaka, M.;
Nakamura, H.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 7339. (d) Asao,
N.; Yudha, S.; Nogami, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2005,
(
OTf)3 provided a small amount of addition product 3aA (12%)
along with recovery of the starting material (entry 2). This result
is in sharp contrast to the efficient InBr3-catalyzed cyclization
4
4, 5526.
6) Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. Org.
(
Lett. 2005, 7, 1363. Sakai, N.; Kanada, R.; Hirasawa, M.; Konakahara, T.
Tetrahedron 2005, 61, 9298. Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2005, 127, 13760.
8d
of 2-alkynylanilines to the corresponding indoles. Considering
(
7) Cintas, P. Synlett 1995, 1087. Chauhan, K. M.; Frost, C. G. J. Chem.
Soc., Perkin Trans. 1 2000, 3015. Ranu, B. C. Eur. J. Org. Chem. 2000,
347.
8) (a) Tsuchimoto, T.; Maeda, T.; Shirakawa, E.; Kawakami, Y. Chem.
(10) Tietze, L. F. Chem. ReV. 1996, 96, 115. Ramon, D. J.; Yus, M.
Angew. Chem., Int. Ed. 2005, 44, 1602. Pellissier, H. Tetrahedron 2006,
62, 2143. Guo, H. C.; Ma, J. A. Angew. Chem., Int. Ed. 2006, 45, 354.
Nicholau, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134. Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem.,
Int. Ed. 2007, 46, 1570.
(11) Yanada, R.; Kaieda, A.; Takemoto, Y. J. Org. Chem. 2001, 66,
7516. Yanada, R.; Obika, S.; Oyama, M.; Takemoto, Y. Org. Lett. 2004,
6, 2825. Yanada, R.; Koh, Y.; Nishimori, N.; Matsumura, A.; Obika, S.;
Mitsuya, H.; Fujii, N.; Takemoto, Y. J. Org. Chem. 2004, 69, 2417. Yanada,
R.; Obika, S.; Kobayashi, Y.; Inokuma, T.; Oyama, M.; Yanada, K.;
Takemoto, Y. AdV. Synth. Catal. 2005, 347, 1632.
2
(
Commun. 2000, 1573. (b) Tsuchimoto, T.; Hatanaka, K.; Shirakawa, E.;
Kawakami, Y. Chem. Commun. 2003, 2454. (c) Nakamura, M.; Endo, K.;
Nakamura, E. J. Am. Chem. Soc. 2003, 125, 13002. (d) Sakai, N.; Annaka,
K.; Konakahara, T. Org. Lett. 2004, 6, 1527. (e) Tsuchimoto, T.;
Matsubayashi, H.; Kaneko, M.; Shirakawa, E.; Kawakami, Y. Angew.
Chem., Int. Ed. 2005, 44, 1336. (f) Weiwer, M.; Coulombel, L.; Dunach,
E. Chem. Commun. 2006, 332.
(9) Yanada, R.; Obika, S.; Kono, H.; Takemoto, Y. Angew. Chem., Int.
Ed. 2006, 45, 3906.
J. Org. Chem, Vol. 72, No. 12, 2007 4463

Obika et al.
SCHEME 2. Plausible Reaction Mechanism of Lewis
other hard Lewis acids such as Ga(OTf)3 and Sn(OTf)2, each
reaction led to a different outcome. When Ga(OTf)3, gallium
belonging to the same group 13 metals as indium, was used as
the catalyst, 2aA was obtained as a minor product together with
the allylated adduct 3aA in 72% yield (entry 3). In contrast,
the reaction with Sn(OTf)2, tin being a member of group 12
metals, gave the desired cyclic adduct 2aA as the sole product
in 88% yield, although it required a longer reaction time (entry
Acid-Catalyzed Tandem Addition and Cyclization Reaction
4
(
). We turned our attention to soft transition-metal catalysts
group 10-and 11 metals) because AgOTf5d was only reported
to be an effective catalyst for the tandem cyclization of 2-(1-
alkynyl)arylaldimines with several active methylene compounds.
Then, we explored other carbophilic transition-metal-catalysts,
12
Ni(II) and Pt(II) as group 10 metals and Au(I or III) as a group
1
1 metal,13 for the tandem reaction of 1a. In sharp contrast to
the hard metal triflates, these catalysts did not promote the
reaction at all, and almost all the starting material was recovered
even after 24 h. Since 1 equiv of a proton source is obviously
needed as a vinyl proton for this cyclization, these results are
reasonable based on the reaction mechanism (see route b in
Scheme 1). This indicated that In(OTf)3 might contain a small
amount of water, which acted as an appropriate proton source
for this tandem reaction. To test this possibility, we tried the
reaction with dry In(OTf)3 prepared by heating in vacuo before
use. As expected, the yield of cyclic product 2aA was reduced
to only 5%, and the allylated adduct 3aA was obtained as a
major product (entry 5). Interestingly, we also found that the
addition of 1 equiv of water to the reaction mixture restored
the chemical yield to 88% (entry 6). In this case, the amount of
In(OTf)3 could be reduced to 10 mol % with no significant
effects. We examined several proton sources as additives for
the reactions with Ni, Pt, and Au catalysts. Among those
examined, including AcOH, ArOH, CF3CH2OH, t-BuOH, and
water, the highest yield of the desired product 2aA was given
by CF3CH2OH, which was obtained in good yield with Ni(II)
and Au(I) catalysts (entries 7-10). In particular, a combined
1
4
catalyst prepared from AuCl(PPh3) and AgNTf2 showed
remarkable catalytic activity, catalyzing the reaction efficiently
at room temperature, while the other catalysts required heating
at 70 °C. Furthermore, we investigated the additives for the In-
intermediate but also an activator of the allylstannane reagent
by forming an ”-ate” complex.
15
On the other hand, another aspect of the reactions with Ni,
Pt, and Au catalysts is that the allylated product 3aA was not
obtained at all, whatever the reaction time, and this is totally
different from the In(III)-catalyzed reaction. The same phenome-
(
III)-catalyzed reaction. It was found that CF3CH2OH had only
a marginal effect on the reactivity, but the addition of 2,6-di-
tert-butyl-4-methoxyphenol (2 equiv) significantly accelerated
the tandem cyclization, the reaction being complete within 6 h
at 70 °C (entries 11 and 12). The unique roles of the phenol
would be not only a proton source for the vinylindium
5d
non was observed in Yamamoto’s Ag(I)-catalyzed cyclization
(path b in Scheme 1). Unlike In(OTf)3, these soft Lewis acids
do not promote the nucleophilic addition of allylstannane to
the CdN double bond, and therefore, allylated product 3aA was
not obtained irrespective of the presence of the proton source.
In this way, the soft transition-metal-catalyzed reactions seem
to proceed via the iminium intermediate as shown in Scheme
(
12) Liu, C.; Han, X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc.
004, 126, 3700. Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem.
Soc. 2004, 126, 10546. Bender, C. F.; Widenhoefer, R. A. J. Am. Chem.
Soc. 2005, 127, 1070. Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am.
Chem. Soc. 2005, 127, 15022. Furstner, A.; Davies, P. W. J. Am. Chem.
Soc. 2005, 127, 15024.
2
2
b. Although the vinylindium species A is proposed as an
intermediate, direct protonation of the CtC triple bond with
water activated by In(OTf)3 might be involved in the tandem
addition and cyclization with the allylstananne reagent.
Tandem Addition and Cyclization of 2-(1-Alkynyl)aryla-
ldimines with Various Nucleophiles. We examined the scope
and limitations of the tandem reaction with several stannyl
reagents using three effective catalysts, In(OTf)3, NiCl2, and
AuCl(PPh3)/AgNTf2 (Table 2). Initial screening of the catalysts
with methallyltributylstannane 4B revealed that In(OTf)3 was
the best catalyst in terms of reaction rate and chemical yield
(
13) For reviews, see: Hashmi, A. S. Gold Bull. 2004, 37, 1. Hoffmann-
R o¨ der, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387. Stephen, A.;
Hashmi, K.; Hutchings, G. I. Angew. Chem., Int. Ed. 2006, 45, 7896.
Jim e´ nez-N u´ n˜ ez, E.; Echavarren, A. M. Chem. Commun. 2007, 333. Marco-
Contelles, J.; Soriano, E. Chem.sEur. J. 2007, 13, 1350. For recent
communications, see: Brouwer, C.; He, C. Angew. Chem., Int. Ed. 2006,
4
5, 1744. Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.;
LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991. Toullec,
P. Y.; Genin, E.; Leseurre, L.; Genet, J.-P.; Michelet, V. Angew. Chem.,
Int. Ed. 2006, 45, 7427. Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem. Soc.
006, 128, 1798. Gorin, D. J.; Dub e´ , P.; Toste, F. D. J. Am. Chem. Soc.
006, 128, 14480. Lee, J. H.; Toste, F. D. Angew. Chem., Int. Ed. 2007,
6, 912.
2
2
4
(15) Aspinall, H. C.; Bissett, J. S.; Greeves, N.; Levin, D. Tetrahedron
Lett. 2002, 43, 323.
(
14) M e´ zailles, N.; Richard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133.
4464 J. Org. Chem., Vol. 72, No. 12, 2007

1
,2-Dihydroisoquinoline and 1H-Isochromene Synthesis
TABLE 2. Lewis Acid-Catalyzed Tandem Reaction of 1a-k with Allylic Stannanes 4A-Ca
c
entry
1
R1
RPMP
R2
R3
X
methodb
4
time (h)
2
yield %
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
A
B
C
A
A
A
A
A
A
A
A
A
A
A
4B
4B
4B
4C
4A
4A
4A
4A
4A
4A
4A
4A
4A
4A
6
48
40
6
8
8
8
8
10
12
8
2aB
2aB
2aB
2aC
2bA
2cA
2dA
2eA
2fA
2gA
2hA
2iA
89
70
66
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
i-Bu
d
80
4-MeOPh
4-CF3Ph
n-Pr
CH2OBn
Ph
71
e
89
f
0
5-F
5-OMe
87
70
72
82
70
10
11
12
13
14
Ph
Ph
Ph
Ph
H
H
H
H
CH
CH
CH
7
9
6
Bn
2jA
2kA
d
(R)-phenytyl
Ph
85
a
Reaction was carried out with 4A-C (1.2-2.0 equiv), additive (2 equiv), and catalyst (0.2 equiv) in ClCH2CH2Cl. b A: In(OTf)3, 2,6-di-tert-butyl-4-
c
d
methoxyphenol, 70 °C; B: NiCl2, CF3CH2OH, 70 °C; C: AuCl(PPh3)/AgNTf2, CF3CH2OH, room temperature. Isolated yield. Product was obtained as
a mixture of two diastereomers in a ratio of 1:2. Reaction gave a complex mixture. Addition adduct 3eA was only obtained in 60% yield.
e
f
(
entries 1-3); thus, we selected it for further study. Sterically
hindered crotylstannane 4C also underwent the addition to imine
a, affording tandem adduct 2aC in 80% yield with moderate
TABLE 3. Lewis Acid-Catalyzed Tandem Reaction of 1a and 1j
with Silyloxy Compounds 4D-G and Alkenylboronic Acids 4H-J
a
1
diastereoselectivity (2:1) (entry 4). The reactions of various 2-(1-
alkynyl)arylaldimine 1b-k with allylstannane 4A were carried
3
out under the optimized reaction conditions. The R substituent
proved to have a significant influence on the cyclization.
Although the reaction of 1b, having a p-methoxyphenyl group
3
as the R substituent, afforded cyclic product 2bA in good yield,
the reaction of 1c, with an electron-withdrawing group (p-CF3-
phenyl), resulted in a complex mixture of products (entries 5
and 6). We assumed that these contrasting results were attribut-
able to a decrease of electronic density of the CtC triple bond,
which would be crucial for the coordination of the metal catalyst
to the alkyne. In the case of 1d, bearing an n-propyl group as
c
entry
1
methodb
4D-H
time (h)
2
yield (%)
1
2
3
4
5
6
7
8
9
1a
1j
1j
1j
1j
1a
1a
1a
1a
A
A
A
A
A
B
C
C
C
4D
4D
4E
4F
4G
4H
4H
4I
8
9
2aD
2jD
2jE
2jF
2jG
2aH
2aH
2aI
0d
90
88
78
87
0
75
80
82
3
the R substituent, the corresponding adduct 2dA was obtained
12
12
12
12
5
in 89% yield. However, the benzyloxymethyl derivative 1e did
not undergo the tandem cyclization, giving only the addition
product 3eA in 60% yield (entries 7 and 8). On the other hand,
concerning the R2 substituent, introducing either electron-
donating or -withdrawing groups to the substrate had no
influence on the tandem reaction. Even replacement of the
benzene ring by a pyridine ring was tolerated (entries 9-11).
We have used the PMP-imines 1a-h in the previous experi-
e
5
5
4J
2aJ
a
Reaction was carried out with 4D-J (2 equiv) and catalyst (0.2 equiv)
in ClCH2CH2Cl. b A: In(OTf)3, 70 °C; B: In(OTf)3, H2O (5 equiv), 70
c
°
C; C: AuCl(PPh3)/AgNTf2, H2O (5 equiv), room temperature. Isolated
yield. Addition adduct 3aD was obtained in 68% yield. Only starting
material 1a was recovered.
1
ments (R ) PMP), but it was proven that both i-butyl and
d
e
1
benzyl groups could be used as the nitrogen substituent (R )
(entries 12 and 13). To develop the diastereoselective tandem
reaction, the chiral imine 1k, prepared from (R)-phenethylamine,
was subjected to the same reaction conditions. The desired
product 2kA was obtained in 85% yield with moderate
diastereoselectivity (2:1) (entry 14).
yield (entry 2). Further study on the reactions of 1j with other
siloxy compounds 4E-G demonstrated that not only ketene silyl
acetal derived from methyl acetate but also silyl enol ethers
derived from acetone or acetopheneone could be used as
nucleophiles to give the cyclic adducts 2jE-jG in comparable
yields (entries 3-5). Encouraged by these successful results
The tandem cyclization was explored with other nucleophiles
such as ketene silyl acetals and alkenylboronic acids (Table 3).
The In(III)-catalyzed reaction of ketene silyl acetal 4D was
carried out at 70 °C with PMP-imine 1a, but only the additional
adduct 3aD was obtained (entry 1). In our attempt to make the
16
using ketene silyl acetals, we were intrigued by Petasis-type
nucleophilic cyclization using alkenylboronic acids 4H-J, by
1
R substituent more nucleophilic, we found that the benzylimine
(16) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.
derivative 1j gave the desired product 2jD selectively with 90%
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798.
J. Org. Chem, Vol. 72, No. 12, 2007 4465

Obika et al.
SCHEME 3. In(III)-Catalyzed Tandem Reaction of 1a and
j with Allylstannane 4A and Ketene Silyl Acetal 4D
TABLE 4. Lewis Acid-Catalyzed Tandem Reaction of 1a,e with
Active Methylene Compounds 4K-Na
1
nucleophile 4K-N methodb time (h)
2
yield (%)
c
entry
1
1
2
3
4
5
6
7
8
1l
CH3NO2 4K
CH3NO2 4K
CH3NO2 4K
CH2(CN)2 4L
CH2(CO2Me)2 4M
PhCCH 4N
A
B
C
C
C
C
B
C
12
24
7
6
6
6
24
8
2lK
2lK
2lK
2lL
2lM
2lN
89
86
89
75
72
91
86
83
1l
1l
1l
1l
1l
SCHEME 4. Synthesis of 1,2-Dihydroisoquinoline 2aO
1m CH3NO2 4K
1m CH3NO2 4K
2mK
2mK
a
Reaction was carried out with 4K-N (2.0 equiv) and catalyst (0.1-
which several alkenyl groups can be introduced at the C1
position of 1,2-dihydroisoquinolines. After many experiments,
the best results were obtained using AuCl(PPh3)/AgNTf2 instead
of In(OTf)3, with the addition of water, and the reaction
proceeded favorably at room temperature (entries 6 and 7). The
alkenylboronic acids with more electron-donating groups on the
benzene ring provided the corresponding products 2aH-2aJ
with slightly improved yields (entries 8 and 9).
The reaction mechanism of the Au(I)-catalyzed alkenylative
cyclization would be the same as the Ni(II)- and Au(I)-catalyzed
allylated cyclization shown in Scheme 2b. That is, the Au(I)-
catalyzed formation of the iminium intermediate occurs initially,
followed by nucleophilic addition of the alkenylboronic acids
activated by water to give the cyclized adducts 2aH-2aJ. The
detailed mechanism of the Petasis reaction is not yet clear.
To clarify the different reaction processes, depending on the
nucleophiles such as ketene silyl acetal 4D and allylstannane
.2 equiv) in ClCH2CH2Cl. b A: In(OTf)3 (0.2 equiv), 70 °C; B: NiCl2
0
(0.1 equiv), 70 °C; C: AuCl(PPh3)/AgNTf2 (0.1 equiv), room temperature.
c
Isolated yield.
organometallic reagents 4A-J took place smoothly, using
appropriate Lewis acids and proton sources, to give a wide range
of 1,3-disubstituted 1,2-dihydroisoquinolines. The proton donors
were shown to have roles not only in the regeneration of the
catalyst but also in activation of the nucleophile.
We tried the same reaction with active methylene compounds
as the nucleophile (Table 4), which would be a more benign
process from the viewpoint of atom efficiency. We first
employed activated nitromethane 4K as a nucleophile for the
tandem reaction. For this purpose, three catalytic systems were
examined. The intended tandem reaction proceeded with all
catalysts, AuCl(PPh3)/AgNTf2 being the most effective in terms
of reaction temperature and reaction rate (entries 1-3). Although
a similar Ag(I)-catalyzed tandem reaction with active methylene
compounds has been reported by Yamamoto’s group, our
reaction conditions were much milder as compared with theirs,
4
A, we monitored the distribution of the reaction products by
1
taking their H NMR spectra at appropriate intervals (Scheme
). In the case of the reaction with benzylimine 1j and 4D, non-
3
cyclized addition adduct 3jD was scarcely observed in the
reaction mixture, regardless of the reaction time. Instead of 3jD,
the starting material 1j was recovered, together with the desired
tandem product 2jD (eq 1). Indeed, 1j and 2jD were obtained
in 30 and 68% yields, respectively, after 4 h, while only 2jD
was obtained, in 92% yield, after 9 h. In sharp contrast to this
reaction, when PMP-imine 1a was reacted with 4A, it rapidly
disappeared, and both the cyclized adduct 2aA and the allylated
adduct 3aA were observed during the course of the reaction
5d
which required heating at 80 °C. For the tandem reaction, more
functionalized nucleophiles such as malononitrile 4L and
dimethyl malonate 4M could be used in the presence of a AuCl-
(PPh3)/AgNTf2 catalyst to provide the corresponding tandem
products 2lL and 2lM in good yields (entries 4 and 5). In
addition, the terminal alkyne 4N proved to be an effective
nucleophile for this tandem reaction (entry 6). These studies
prompted us to examine the scope and limitations of substrate
for this tandem reaction. The In(III)-catalyzed cyclization of
(eq 2). In a former case, the iminium intermediate should be
1
e, bearing a benzyloxymethyl group as the substituent (R), did
formed predominantly before the direct addition of 4D to the
imine 1j (tandem cyclization and nucleophilic addition mech-
anism) because the silylamide species of addition product 3aD
would not give cyclized product 2aD, even in the presence of
In(OTf)3 (entries 1 and 2, Table 3). On the other hand, the latter
reaction could be explained based on the mechanism shown in
Scheme 2a (tandem nucleophilic addition and cyclization
mechanism). The different outcomes between PMP-imine 1a
and benzylimine 1j could be attributed to the nucleophilicity
of the imine-nitrogen atoms to the CtC triple bond activated
by the In(III) catalyst. The more nucleophilic benzylimine 1j
tends to form the iminium intermediate more rapidly, resulting
in the predominant production of cyclized adduct 2jD. As
described previously, tandem nucleophilic addition and cycliza-
tion reactions of 2-(1-alkynyl)aldimines 1a-k with several
not afford the desired product (Table 2, entry 8). However, we
found that both catalysts, NiCl2 and AuCl(PPh3)/AgNTf2, are
effective enough to promote the tandem cyclization of
1
m with nitromethane, giving the product 2mK in high yields.
We assumed that both catalysts would activate the CtC triple
bond efficiently without inhibition of the imine and ether
moieties due to their more carbophilic character than
In(OTf)3.
Having established the optimal conditions for the reactions
with carbon nucleophiles, the tandem cyclization accompanied
by hydride reduction of the iminium intermediate was next
investigated using various reducing agents. Although use of Et3-
SiH was not effective for this purpose, the desired cyclic adduct
2aO was obtained in 80% yield by the reaction of 1a with 2
4466 J. Org. Chem., Vol. 72, No. 12, 2007

1
,2-Dihydroisoquinoline and 1H-Isochromene Synthesis
TABLE 5. In(III)-Catalyzed Tandem Reaction of Aldehydes 5a-d with Various Nucleophiles 4a
R1
R2
X
nucleophile 4
methodb
time (h)
6
yield (%)
c
entry
5
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5a
5b
5c
5d
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
Ph
H
H
H
H
H
H
H
Me
CH
CH
CH
CH
CH
CH
CH
CH
4A
4D
4K
4M
A
B
B
B
C
A
A
A
21
15
48
48
18
21
21
21
6aA
6aD
6aK
6aM
6aP
6bA
6cA
6dA
75
0
0
d
e
35f
92
85
85
80
n-BuOH 4P
4A
4A
4A
Ph
Ph
a
Reaction was carried out with 4 (1.2-6.0 equiv) and In(OTf)3 (0.2 equiv). b A: 4A (1.2 equiv), ClCH2CH2Cl, room temperature; B: 4D, 4K, 4M (2
equiv), 1,4-dioxane, room temperature; C: n-BuOH (6 equiv), DMF, 50 °C. Isolated yield. d Addition adduct 7aD was obtained in 72% yield. Only
starting material 5a was recovered. Starting material 5a was recovered in 30% yield.
c
e
f
equiv of Hantzsch ester 4O17 in the presence of AuCl(PPh3)/
AgNTf2 catalyst (0.1 equiv) (Scheme 4).18
Tandem Addition and Cyclization of 2-(1-Alkynyl)aryla-
ldehydes. The new catalysts such as In(OTf)3, NiCl2, and AuCl-
(
PPh3)/AgNTf2 expanded the applicability of the tandem
nucleophilic addition and cyclization with 2-(1-alkynyl)aryla-
ldimine. Therefore, we turned our attention to the tandem
reaction of 2-(1-alkynyl)arylaldehydes with the aim of concise
synthesis of 1H-isochromenes (Table 5). Although such a
transition-metal-catalyzed transformation of 2-(1-alkynyl)ary-
laldehydes 5 into 1H-isochromenes has been accomplished in
19
the presence of a proton source with Pd(0) and Cu(II) catalysts,
Au(III)- and Cu(II)-catalyzed reactions of 5 in the presence of
external alkynes or alkenes afforded polycyclic compounds via
[
4 + 2]benzannulation.20 Therefore, we examined the In(OTf)3-
catalyzed tandem reactions of 5a-d with various nucleophiles
in the absence of proton sources. In fact, the reaction with silyl
enol ether 4D provided no cyclic adduct 6aD, but the desired
product 6aA was obtained as the single product in the reaction
with allylstannane 4A (entries 1 and 2). In contrast to ni-
tromethane 4K, dimethyl malonate 4M could be introduced to
5
6
a in dioxane, furnishing the corresponding cyclic compound
aM in moderate yield (entries 3 and 4). Treatment of aldehyde
FIGURE 1. Time-dependent product distribution of 6aA and 7aA in
the reaction of aldehyde 5a with allylstannane 4A.
(
17) Ouellet, S. G.; Tuttle, J. B.; Macmillan, D. W. C. J. Am. Chem.
5
a with n-BuOH in DMF at 50 °C afforded the tandem cyclic
Soc. 2005, 127, 32. Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.;
Bolte, M. Org. Lett. 2005, 7, 3781. Stoter, R. I.; Carrera, D. E.; Ni, Y.;
Macmillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84. Martin, N. J. A.;
List, B. J. Am. Chem. Soc. 2006, 128, 13368. Ruping, M.; Antonchick, A.
P.; Thessmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683. Ruping, M.;
Antonchick, A. P.; Thessmann, T. Angew. Chem., Int. Ed. 2006, 45, 6751.
Menche, D.; Hassfeld, J.; Li, J.; Menche, G.; Ritter, A.; Rudolph, S. Org.
Lett. 2006, 8, 741. Mench, D.; Bohm, S.; Li, J.; Rudolph, S.; Zander, W.
Tetrahedron Lett. 2007, 48, 365.
product 6aP in 92% yield but not the expected dibutyl acetal
(entry 5). The reaction with allylstannane 4A has the advantages
of lower catalyst quantity and higher product yield, as compared
with reported methods. We examined the In(III)-catalyzed
tandem allylated cyclization with some 2-(1-alkynyl)arylalde-
hydes 5b,c. All tandem reactions proceeded efficiently irrespec-
tive of the R substituent and the ring system (entries 6 and 7).
Furthermore, ketone derivative 5d also underwent tandem
cyclization to give the corresponding adduct 6dA, without any
contamination by the addition product 7dA (entry 8). To
elucidate the mechanism, the reaction mixture of 5a, In(OTf)3,
19g
1
(18) Yamaguchi, R.; Hamasaki, T.; Utimoto, K. Chem. Lett. 1988, 913.
Czombos, J.; Aelterman, W.; Tkachev, A.; Martins, J. C.; Tourwe, D.; Peter,
A.; Toth, G.; Fulop, F.; Kimpe, N. D. J. Org. Chem. 2000, 65, 5469. Lu,
S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2006,
4
5, 2260.
19) (a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am.
(
Chem. Soc. 2002, 124, 764. (b) Barluenga, J.; V a´ zquez-Villa, H.; Ballesteros,
A.; Gonz a´ lez, J. M. J. Am. Chem. Soc. 2003, 125, 9028. (c) Mondal, S.;
Nogami, T.; Asao, N.; Yamamoto, Y. J. Org. Chem. 2003, 68, 9496. (d)
Zhu, J.; Germain, A. R.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2004, 43,
(20) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc.
2003, 125, 10921. Asao, N.; Kasahara, T.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2003, 42, 3504. Dyker, G.; Hildebrandt, D.; Liu, J.; Merz, K. Angew.
Chem., Int. Ed. 2003, 42, 4399. Asao, N.; Aikawa, H.; Yamamoto, Y. J.
Am. Chem. Soc. 2004, 126, 7458. Asao, N.; Sato, K.; Menggenbateer
Yamamoto, Y. J. Org. Chem. 2005, 70, 3682. Dyker, G.; Hildebrandt, D.
J. Org. Chem. 2005, 70, 6093. Asao, N. Synlett 2006, 1645.
1
239. (e) Yue, D.; C a` , N. D.; Larock, R. C. Org. Lett. 2004, 6, 1581. (f)
Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004, 69, 5139. (g) Asao, N.;
Chan, C. S.; Takahashi, K.; Yamamoto, Y. Tetrahedron 2005, 61, 11322.
(h) Yao, X.; Li, C.-J. Org. Lett. 2006, 8, 1953.
J. Org. Chem, Vol. 72, No. 12, 2007 4467

Obika et al.
1
and allylstannane 4A was monitored by H NMR (Figure 1).
General Procedure for the Au(I)-Catalyzed Tandem Reaction
of Imines with Alkenylboronic Acids as a Nucleophile. To a
solution of AuCl(PPh ) (0.016 mmol) and AgNTf (0.016 mmol)
3 2
in dioxane (0.40 mL) were added imine (0.016 mmol), alkenylbo-
ronic acid (0.32 mmol), and 6.0 µL of water, and the resulting
mixture was stirred at room temperature for 5 h. After the reaction
Almost all the starting material disappeared after 2 h, and both
allylated product 7aA and cyclic product 6aA were observed
in the reaction mixture. The amount of 7aA gradually decreased
with increasing yield of 6aA. From these results, the tandem
addition and cyclization of 2-(1-alkynyl)arylaldehydes 5a-c
with allyltributylstannane 4A seems to take place in the same
manner as that of 2-(1-alkynyl)arylimines 1.
was complete, the reaction mixture was diluted with H
and extracted with CHCl
(3 × 2 mL). The combined organic layers
were dried over anhydrous Na SO and filtered, and the solvent
2
O (3 mL)
3
2
4
was removed under reduced pressure. The residue was purified by
basic silica gel column chromatography (hexane/AcOEt ) 5:1) to
give product.
Conclusion
In conclusion, concise synthesis of 1,3-disubstituted 1,2-
dihydroisoquinolines was established by tandem nucleophilic
addition and cyclization of 2-(1-alkynyl)arylaldimines and
various nucleophiles in the presence of carbophilic Lewis acids
such as In(OTf)3, NiCl2, and AuCl(PPh3)/AgNTf2. Among these
catalysts, Ni(II) and Au(I) catalysts require appropriate proton
sources to proceed the tandem reaction, by which a wide range
of nucleophiles and substrates can be employed for these
reactions. We have demonstrated that these reactions proceeded
via two different reaction pathways depending on the character
of catalyst and the reactivity of substrate and nucleophile: one
is the initial addition of nucleophile to the CdN double bond
and the subsequent cyclization of the resulting amide species
to the CtC triple bond, and the second one is the nucleophilic
addition of imine to the CtC triple bond activated by the
catalyst and the subsequent addition of nucleophile to the
resultant iminium species. Furthermore, the In(III)-catalyzed
tandem reaction can be applied to 2-(1-alkynyl)arylaldehydes
for the efficient synthesis of 1H-isochromenes.
1
,2-Dihydro-2-(4-methoxyphenyl)-3-phenyl-1-styrylisoquino-
1
line (2aH). H NMR (500 MHz, CDCl ) δ 7.55 (d, J ) 7.7 Hz,
3
2
H), 7.32 (d, J ) 7.6 Hz, 2H), 7.26-7.17 (m, 6H), 7.09-7.07 (m,
1H), 6.90 (d, J ) 8.6 Hz, 2H), 6.65 (d, J ) 8.6 Hz, 2H), 6.60-
6.57 (m, 1H), 6.52-6.47 (m, 1H), 6.43 (s, 1H), 5.51 (d, J ) 5.2
Hz, 1H), 3.67 (s, 3H); 13C NMR (126 MHz, CDCl
3
) δ 155.1, 141.3,
1
1
41.2, 137.8, 136.9, 132.3, 130.6, 130.1, 129.0, 128.5, 128.0, 127.8,
27.5, 126.7, 126.3, 126.0, 124.1, 123.94, 113.9, 109.8, 67.2, 55.4;
IR (CHCl
-
1
3
) 3027, 2966, 2366, 1731, 1260 cm ; LRMS (EI) m/z
+
+
4
15 (M ); HRMS (EI) calcd for C19
H O
24 5
(M ) 415.1936, found
4
15.1935.
General Procedure for the In(III)-Catalyzed Tandem Reac-
tion of Aldehydes with Allyltributylstannane as a Nucleophile.
To a solution of aldehyde (1.0 mmol) in CH ClCH Cl (2 mL) were
added allyltributylstannane (1.2 mmol) and In(OTf) (0.20 mmol),
2
2
3
and the resultant mixture was stirred at room temperature for 21 h.
After the reaction was complete, the reaction mixture was diluted
with H
2
O (3 mL) and extracted with CHCl
3
(3 × 2 mL). The
combined organic layers were dried over MgSO
4
and filtered, and
the solvent was removed under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/AcOEt )
5
:1) to give product.
Experimental Section
1
1-Allyl-3-propyl-1H-isochromene (6aA). H NMR (500 MHz,
CDCl
3
) δ 7.18-7.15 (m, 1H), 7.10-7.07 (m, 1H), 6.95 (d, J )
General Procedure for the In(III)-Catalyzed Tandem Reac-
7
1
2
7
1
1
.3 Hz, 1H), 6.92 (d, J ) 7.3 Hz, 1H), 5.93-5.85 (m, 1H), 5.58 (s,
H), 5.16-5.11 (m, 2H), 5.09 (s, 1H), 2.77-2.71 (m, 1H), 2.47-
.43 (m, 1H), 2.18-2.11 (m, 2H), 1.64-1.58 (m, 2H), 0.96 (t, J )
tion of Imines with Allyltributylstannane as a Nucleophile. To
a solution of imine (0.20 mmol) in CH
added 2,6-di-tert-butyl-4-methoxyphenol (0.40 mmol), allyltribu-
tylstannane (0.24 mmol), and In(OTf) (0.040 mmol), and the
mixture was stirred at 70 °C for 6-12 h. After the reaction was
complete, the reaction mixture was diluted with H O (3 mL) and
extracted with CHCl
(3 × 2 mL). The organic layers were
combined, dried over anhydrous Na SO , and filtered, and the
2 2
ClCH Cl (0.40 mL) were
.3 Hz, 3H); 13C NMR (126 MHz, CDCl
) δ 134.3, 127.8, 125.5,
24.1, 122.8, 117.5, 100.1, 98.3, 80.2, 77.4, 38.7, 35.9, 20.0, 13.7,
3
3
-
1
3
3.5; IR (CHCl ) 3028, 2964, 2933, 2875, 1725 cm ; LRMS
2
+
+
(FAB) m/z 215 (MH ); HRMS (FAB) calcd for C15
H19O (MH )
3
2
15.1436, found 215.1431.
2
4
solvent was removed under reduced pressure. The residue was
purified by basic silica gel column chromatography (hexane/AcOEt
Acknowledgment. This work was supported by grants from
)
5:1) to give product.
-Allyl-1,2-dihydro-2-(4-methoxyphenyl)-3-phenylisoquion-
the 21st Century COE Program “Knowledge Information
Infrastructure for Genome Sciences” and a Grant-in-Aid for
Scientific Research on Priority Areas from MEXT (17035043)
and JSPS KAKENHI (16390006). S.O. thanks the JSPS for a
Fellowship.
1
1
line (2aA). H NMR (500 MHz, CDCl
H), 7.25-7.21 (m, 6H), 7.13 (t, J ) 5.4 Hz, 1H), 6.97 (d, J ) 6.3
Hz, 1H), 6.84 (d, J ) 7.0 Hz, 2H), 6.62 (d, J ) 6.3 Hz, 2H), 6.57
s, 1H), 6.15-6.11 (m, 1H), 5.23-5.17 (m, 2H), 4.83 (dd, J )
3
) δ 7.56 (d, J ) 6.7 Hz,
2
(
5
1
1
1
1
.1, 4.9 Hz, 1H), 3.65 (s, 3H), 2.75-2.72 (m, 1H), 2.30-2.25 (m,
H); 13C NMR (126 MHz, CDCl
) δ 154.9, 141.3, 140.9, 137.9,
35.8, 132.3, 131.8, 128.2, 127.7, 127.2, 126.1, 125.6, 124.2, 124.0,
17.8, 113.9, 110.7, 66.3, 55.3, 39.5; IR (CHCl ) 3643, 2960, 2360,
508 cm ; LRMS (FAB) m/z 354 (MH ); HRMS (FAB) calcd
Supporting Information Available: Product characterization
data for 1,2-dihydroisoquinolines and H NMR spectra for all new
compounds prepared. This material is available free of charge via
the Internet at http://pubs.acs.org.
3
1
3
-
1
+
+
for C25
H24NO (MH ) 354.1858, found 354.1866.
JO070615F
4468 J. Org. Chem., Vol. 72, No. 12, 2007