Synthesis of 1,2-dihydroisoquinolines via palladium(0)-catalyzed addition-cyclization of chloroform to ortho-alkynylaldimines

Article abstract of DOI:10.1016/j.tetlet.2008.02.156

Addition-cyclization of chloroform to ortho-alkynylaldimines proceeded in the presence of PdCl₂(PPh₃)₂/dppe or Pd₂dba₃·CHCl₃/dppe at 100 °C to afford the corresponding 1-(trichloromethyl)-1

Full text of DOI:10.1016/j.tetlet.2008.02.156

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2697–2700
Synthesis of 1,2-dihydroisoquinolines via palladium(0)-catalyzed
addition–cyclization of chloroform to ortho-alkynylaldimines
Hiroyuki Nakamura *, Hiroyuki Saito, Masato Nanjo
Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Tokyo 171-8588, Japan
Received 8 February 2008; revised 26 February 2008; accepted 29 February 2008
Available online 4 March 2008
Abstract
Addition–cyclization of chloroform to ortho-alkynylaldimines proceeded in the presence of PdCl2(PPh3)2/dppe or Pd2dba3ꢀCHCl3/
dppe at 100 °C to afford the corresponding 1-(trichloromethyl)-1,2-dihydroisoquinolines in good to high yields.
Ó 2008 Elsevier Ltd. All rights reserved.
The Lewis acid and transition metal-catalyzed C–H
bond activation of carbon pronucleophiles is one of the
important requirements in regard to ‘atom economy’ for
a C–C bond forming reaction in organic synthesis.1 Espe-
cially, addition reactions of the activated pronucleophiles
to imines have been developed for the synthesis of various
organoic amines in recent years.2,3 Although 1,2-dihydro-
isoquinolines have been synthesized by tandem addition–
cycloadditions of organometallic compounds (M–Nu) to
alkynylaldimines under transition-metal catalyzed condi-
tion and the resulting organometallic species were able to
be trapped by electrophiles (X–R3), metal salts were often
generated as side products in the transformations (Scheme
1).4 The tandem addition–cyclization of carbon pronucleo-
philes to ortho-alkynylaldimines catalyzed by AgOTf was
first developed by Asao, Yamamoto, and their co-workers.
In this transformation, AgOTf as a Lewis acid would acti-
vate the C–C triple bond, which undergoes the intramole-
cular attack of the imine nitrogen to generate highly
electrophilic iminium cations as a reactive species. This is
highly potent from environmental and atom-economical
points of view, because various carbon pronucleophiles
(H–Nu), such as nitroalkanes, acetylacetone, malononiti-
R1
R2
R3
R1
R2
cat.
R3
+
+
M
Nu
+
MX
X
N
N
Nu
H
R1
R1
R2
cat. Lewis acid
H
Nu
+
N
or cat. Pd
N
R2
Nu
Scheme 1. Synthesis of 1,2-dihydroisoquinolines via tandem addition–
cyclizations of M–Nu and H–Nu to ortho-alkynylaldimines.
rile, and dimethylmalonate, can be introduced into an
1,2-dihydroisoquinoline framework without generating
any waste metal salts (Scheme 1).
Furthermore, three-component coupling reaction with
ortho-alkynylbenzaldehydes, primary amines, and pronu-
cleophiles was also investigated in the presence of mole-
cular sieves.6 We found that pronucleophiles, such as
chloroform, nitromethane, and acetonitrile, react with
ortho-alkynylaldimines 1 in the presence of palladium cat-
alysts under essentially neutral conditions to give the corre-
sponding 1,2-dihydroisoquinolines in good to high yields.
This is a first example of the C–H activation of chloroform
by palladium catalysts.
*
Corresponding author. Tel.: +81 3 3986 0221; fax: +81 3 5992 1029.
E-mail address: hiroyuki.nakamura@gakushuin.ac.jp (H. Nakamura).
Present address. Department of Material Science, Faculty of
Engineering, Tottori University, Tottori 680-8552, Japan.
We first examined the addition–cyclization with the
ortho-alkynylaldimine 1a in chloroform under various
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.156

2698
H. Nakamura et al. / Tetrahedron Letters 49 (2008) 2697–2700
Table 1
Table 2
Addition–cyclization of chloroform to ortho-alkynylaldimine 1aa
Synthesis of various 1,2-dihydroisoquinolines 2
R1
n
-Bu
R1
R2
n
-Bu
cat. Pd
CHCl3
cat. Pd
N
N
Ph
N
N
CHCl3,100 ºC
R2
Ph
CCl3
CCl3
1a
2a
1
2
R1
R2
Conditiona
Yield (%)
Entry
Pd cat. (mol %)
Ligand (mol %)
Yieldb (%)
Entry
1
2
3
4
5
6
7
a
PdCl2(PPh3)2 (10)
PdCl2(PPh3)2 (10)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (3)
PdCl2(PPh3)2 (5)
Pd(PPh3)4 (10)
None
73
97
96
92
86
1
2
3
4
5
6
7
8
9
10
11
12
a
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Ph
Ph
Ph
Ph
Cy2NCH2
Cy2NCH2
Ph
A
A
A
A
A
B
2a
2b
2c
2d
2e
2f
96
70
65
53
45
>99
95
95
97
87
32
40
dppe (10)
dppe (5)
dppe (3)
PPh3 (5)
None
2-MeOC6H4
4-MeOC6H4
3-ClC6H4
n-Pr
3-Pyridyl
Ph
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-MeOC6H4CH2
Bn
70
>99
Pd(PPh3)4 (10)
dppe (10)
B
2g
2h
2i
A
A
A
C
C
All reactions were carried out in chloroform at 100 °C for 8 h using a
vial tube.
b
2j
Isolated yield based on 1a.
2k
2l
palladium catalysts. The results are summarized in Table 1.
The ortho-alkynylaldimine 1a underwent the addition–
cyclization in the presence of PdCl2(PPh3)2 (10 mol %) at
100 °C to give the corresponding 1,2-dihydroisoquinoline
2a in 73% yield (entry 1). The addition of bisdiphenylphos-
phinoethane (dppe) as a ligand to the reaction was effective
and the yield of 2a increased to 97% (entry 2). Less
amounts of catalysts or the addition of triphenylphosphine
instead of dppe gave lower yields of the product (entries
3–5). Although Pd(PPh3)4 (10 mol %) was not effective
and 2a was obtained in 70% yield (entry 6), the combina-
tion of Pd(PPh3)4 (10 mol %) and dppe (10 mol %) dramati-
cally increased the yield, and 2a was obtained
quantitatively (entry 7).
We next examined the addition–cyclization of chloro-
form to various ortho-alkynylaldimines 1. The results are
summarized in Table 2. The ortho-alkynylaldimines, which
were prepared from 2-(hex-1-ynyl)benzaldehyde (R1 =
n-Bu) with aniline (1a), 2-aminoanisole (1b), 4-amino-
anisole (1c), 3-chloroaniline (1d), and n-propylamine (1f),
underwent the addition–cyclization in the presence of
PdCl2(PPh3)2 (5 mol %) and dppe (5 mol %) at 100 °C
(condition A) to give the corresponding 1-(trichloro-
methyl)-1,2-dihydroisoquinolines 2a–e in good to high
yields (entries 1–5). The ortho-alkynylaldimine (1f) derived
from 2-(hex-1-ynyl)benzaldehyde and 2-pyridylamine gave
2f, quantitatively (entry 6). In this case, a combination of
Pd2dba3ꢀCHCl3 (2.5 mol %) and dppe (5 mol %) was effec-
tive (condition B). The reaction of ortho-alkynylaldimines
1g–j, which were prepared from 2-(phenylethynyl)benzal-
dehyde (R1 = Ph) with aniline and aminoanisoles, gave
2g–j in 87–97% yields (entries 7–10). We also examined
the ortho-alkynylaldimines, 1k and 1l, which have a N,N-
dicyclohexylaminomethyl group at R1. In these cases,
[(C6F5)2PCH2–]2 was employed as a ligand (condition C)
and the corresponding 1-(trichloromethyl)-1,2-dihydroiso-
quinolines (2k and 2l) were obtained in 32% and 40%
yields, respectively (entries 11 and 12). The structure of
2k was confirmed by X-ray crystallographic analysis and
The reaction was carried out in the presence of PdCl2(PPh3)2/dppe
(5 mol %) (condition A), Pd2dba3ꢀCHCl3 (2.5 mol)/dppe (5 mol %)
(condition B), or Pd2dba3ꢀCHCl3 (2.5 mol)/[(C6F5)2PCH2–]2 (5 mol %)
(condition C) in CHCl3 at 100 °C for 6–8 h in a vial tube.
the ORTEP diagram in Figure 1 confirms the disubstituted
1,2-dihydroisoquinoline framework.7
Typical procedure for the synthesis of 1,2-dihydroiso-
quinoline 2a via the palladium-catalyzed addition–cycliza-
tion of chloroform to ortho-alkynylaldimine 1a (condition
A) is as follows: A mixture of 1a (128 mg, 0.49 mmol),
PdCl2(PPh3)2 (17 mg, 0.025 mmol), and dppe (10 mg,
0.0025 mmol) was dissolved in CHCl3 (1 mL) under Ar
and stirred at 100 °C until 1a was consumed (ꢁ6 h) in a vial
tube. The reaction progress was monitored by TLC and
GC. When 1a was consumed, the solvent was removed
under the reduced pressure, and the residue was purified
by silica gel column chromatography with hexane/ethyl
Fig. 1. The X-ray crystallographic structure of 2k.

H. Nakamura et al. / Tetrahedron Letters 49 (2008) 2697–2700
2699
-Bu
H
D
n
PdCl2(PPh3)2 (10 mol %)
dppe (10 mol %)
PdCl2(PPh3)2 (10 mol %)
dppe (10 mol %)
n
-Bu
n
-Bu
N
Ph
1a
1a
+
N
N
CDCl3,100
94%
º
C,
H-Nu, 100 ºC
Ph
Ph
Nu
CCl3
CCl3
2a
2a'
6a: Nu = CH2NO2, 43%
b:
(3 : 1)
Nu = CH2CN, 35%
Scheme 2. Deuterium labeling study.
Scheme 4. Addition–cyclization of nitromethane and acetonitrile to ortho-
alkynylaldimine 1a.
acetate (30:1) to give 3-butyl-2-phenyl-1-(trichloromethyl)-
1,2-dihydroisoquinoline 2a (179 mg, 0.47 mmol, 96% yield)
as a white solid.
Since the AgOTf-catalyzed addition–cyclization of pro-
nucleophiles, such as nitromethane, malononitrile, acetyl-
acetone, and dimethylmalonate, to ortho-alkynylaldimines
has been reported,3 we employed nitromethane and aceto-
nitrile as pronucleophiles for the current reaction. How-
ever, these were not suitable pronucleophiles under
palladium-catalyzed conditions and the corresponding
adducts 6a and 6b were obtained in 43% and 35% yields,
respectively (Scheme 4).
In conclusion, we found that the palladium-catalyzed
addition–cyclization of pronucleophiles to ortho-alkynyl-
aldimines to affords the functionalized 1,2-dihydro-
isoquinolines. Chloroform underwent the C–H insertion
by palladium in this transformation. Since various trans-
formations from a trichloromethyl group have been
reported, such as the C–Cl addition of olefins,8 ester forma-
tion,9 and alkene and alkyne formations,10 we believe that
the current finding enables us to conduct new atom-
economical strategy for carbon–carbon bond formation
in organic synthesis.
In order to clarify the mechanism of the current 1,2-
dihydroisoquinoline formation reaction, a deuterium label-
ing study was performed as shown in Scheme 2. The reac-
tion of 1a was carried out in CDCl3 to give a 3:1 mixture of
1-(trichloromethyl)-1,2-dihydroisoquinoline 2a and 4-
deuterio-1-(trichloromethyl)-1,2-dihydroisoquinoline 2a0.
Based on the result of the deuterium labeling study, the
proposed mechanism is shown in Scheme 3. The oxidative
insertion of palladium(0) to C–H bond of chloroform fol-
lowed by p-coordination with 1 at a carbon–carbon triple
bond would form complex 3, and the intramolecular nucle-
ophilic attack of the imine nitrogen to alkyne would gener-
ate the palladium anion species 4. There would be
equilibrium between 3 and 4. The migration of the hydride
on a palladium to the isoquinoline ring followed by the
nucleophilic attack of a trichloromethyl anion to the imin-
ium ion of 5 would give 2 and the palladium(0) is
regenerated.
In the previous report by Asao et al.,6 chloroform
underwent hydrogen absorption by the zwitterionic iso-
quinoline species directly in the reaction course, which
resulted in higher D content of the product in their deute-
rium labeling study. In the current reaction, the hydrogen
on the trichloromethylpalladium hydride complex gener-
ated by the C–H insertion of palladium to chloroform
would be readily be exchanged from other hydrogen
sources in the reaction mixture. Therefore, the D content
of the product in Scheme 2 became low.
Acknowledgments
This work was supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas ‘Advanced Molecular
Transformations of Carbon Resources’ from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan.
References and notes
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2
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Tetrahedron Lett. 1995, 36, 5023.
H
CCl3
Pd0
PdII
H
R1
3. (a) Kumagai, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 13632; (b) Xu, L.-W.; Xia, C.-G.; Li, L. J. Org. Chem.
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2004, 126, 5356; (e) Matsunaga, S.; Kumagai, N.; Harada, S.;
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Kjrsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Eur.
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Chem., Int. Ed. 2001, 40, 2995; (i) Nugent, B. M.; Yoder, R. A.;
Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418; (j) Nishiwaki, N.;
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H PdII CCl3
N
R2
5
Cl3C Pd
1
CCl3
R1
CCl3
R1
H
Pd
Pd
H
N
N
R2
R2
4
3
Scheme 3. Proposed mechanism.

2700
H. Nakamura et al. / Tetrahedron Letters 49 (2008) 2697–2700
2001, 42, 4673; (l) Yamada, K.; Harwood, S. J.; Gro¨ger, H.;
Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 3504.
10H); 13C NMR (75 MHz, CDCl3) d 156.4, 135.5, 129.7, 128.6, 127.8,
127.5, 126.1, 124.1, 123.2, 122.0, 120.5, 109.7, 106.5, 103.8, 78.2, 56.5,
54.9, 53.1, 49.1, 32.6, 29.9, 26.5, 26.3, 26.2; IR (KBr) 2926, 2851, 1624,
1601, 1564, 1450, 1421, 1254, 1231, 1151, 1103, 893, 824 cmꢂ1; MS
(EI) m/z 561 (M+); Anal. Calcd for C31H39Cl3N2O: C, 66.25; H, 6.99;
N, 4.98. Found: C, 66.45; H, 7.08; N, 4.92. Crystal data:
4. Recent papers for the synthesis of 1,2-dihydroisoquinolines from
ortho-alkynylaldimines: (a) Ohtaka, M.; Nakamura, H.; Yamamoto,
Y. Tetrahedron Lett. 2004, 45, 7339; (b) Huang, Q.; Larock, R. C. J.
Org. Chem. 2003, 68, 980; (c) Dai, G.; Larock, R. C. J. Org. Chem.
2003, 68, 920; (d) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org.
Chem. 2002, 67, 3437; (e) Roesch, K. R.; Zhang, H.; Larock, R. C. J.
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1999, 1, 553; (g) Yanada, R.; Obika, S.; Kono, H.; Takemoto, Y.
Angew. Chem., Int. Ed. 2006, 45, 3822.
5. Asao, N.; Yudha, S.; Nogami, T.; Yamamoto, Y. Angew. Chem., Int.
Ed. 2005, 44, 5526.
6. Three-component reaction with ortho-alkynylaldehydes, amines, and
chloroform in the presence of MS4A was recently reported: Asao, N.;
Iso, K.; Yudha, S. Org. Lett. 2006, 8, 4149.
C
31H39Cl3N2O, M = 561.99, Crystal system, space group, mono-
˚
clinic, C2/c, a = 17.4590(17), b = 14.1930(14), c = 24.4150(12) A,
V = 5955.8(9) A , Z = 8, Dc = 1.254 g/cm , l(Mo-Ka) = 0.71073 A,
l = 0.334 mmꢂ1
F(000) = 2384, T = 200 K. The sample
3
3
˚
˚
,
(0.25 ꢃ 0.25 ꢃ 0.20 mm) was studied on a Oxford Diffraction Xcal-
ibur Saphir 3 diffractometer with graphite monochromatized Mo-Ka
radiation. Reflections were collected (2.65° < h < 26.79°), of which
5957 had I > 2.0r(I). Final results: R1 = 0.0506, wR2 = 0.1507,
goodness of fit 1.146, 335 parameters, Largest diff. peak and hole:
0.251 and ꢂ0.335 e Aꢂ3, extinction coefficient: 0.0011(3).
˚
7. Spectral data of compound 2k: White solid: mp 120–121 °C: 1H NMR
(400 MHz, CDCl3) d 7.31 (t, J = 7.6 Hz, 2H), 7.09–7.14 (m, 3H), 6.77
(d, J = 8.0 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.47 (d, J = 7.2 Hz, 1H),
5.78 (br s, 2H), 5.10 (s, 1H), 4.53 (d, J = 18.8 Hz, 2H), 3.71 (s, 1H),
3.25–3.38 (m, 1H), 2.78 (br s, 2H), 1.53–1.80 (m, 10H), 0.95–1.34 (m,
8. Seigal, B. A.; Fajardo, C.; Snapper, M. L. J. Am. Chem. Soc. 2005,
127, 16329.
9. Habay, S. A.; Schafmeister, C. E. Org. Chem. 2004, 6, 3369.
10. Aggarwal, V. K.; Mereu, A. J. Org. Chem. 2000, 65, 7211.