Pybox ligand-promoted copper(I)-catalyzed three-component tandem coupling-annulation of terminal alkynes, amines and ortho-alkynylaryl aldehydes

Article abstract of DOI:10.1016/j.tetlet.2009.09.095

Pybox ligand was utilized to promote a highly efficient, one-pot, copper(I)-catalyzed three-component tandem addition and cyclization of ortho-alkynylaryl aldehydes, primary amines, and terminal alkynes. Dihydroisoquinoline derivatives 2 were achieved with excellent to moderate yields. In some examples, water was found as an additive to activate the reaction with or without Pybox ligand. Compared with the reported methods, in which imine had to be pre-prepared and purified, the novel process provides a greener choice.

Full text of DOI:10.1016/j.tetlet.2009.09.095

Tetrahedron Letters 50 (2009) 6791–6794
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Tetrahedron Letters
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Pybox ligand-promoted copper(I)-catalyzed three-component tandem
coupling-annulation of terminal alkynes, amines and ortho-alkynylaryl
aldehydes
a,
Min Yu a, Ying Wang a, Chao-Jun Li b, , Xiaoquan Yao
*
*
a Department of Applied Chemistry, School of Material Science and Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 210016, PR China
b Department of Chemistry, McGill University, Montreal, QC, Canada H3A 2K6
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2009
Revised 14 September 2009
Accepted 18 September 2009
Available online 24 September 2009
Pybox ligand was utilized to promote a highly efficient, one-pot, copper(I)-catalyzed three-component
tandem addition and cyclization of ortho-alkynylaryl aldehydes, primary amines, and terminal alkynes.
Dihydroisoquinoline derivatives 2 were achieved with excellent to moderate yields. In some examples,
water was found as an additive to activate the reaction with or without Pybox ligand. Compared with
the reported methods, in which imine had to be pre-prepared and purified, the novel process provides
a greener choice.
Keywords:
Dihydroisoquinoline
Pybox ligand
Ó 2009 Elsevier Ltd. All rights reserved.
Three-component tandem addition and
cyclization
Dihydroisoquinolines are common structural units of natural
products and exhibit interesting biological activities such as antibi-
otic properties.1 Among the methods to construct such structures,
the nucleophilic addition to acetylenic imines, which were pre-
pared from ortho-alkynylaryl aldehydes and primary amines, fol-
lowed by amine–alkyne cyclization is the most useful.2 However,
in most of the cases, the key starting material, acetylenic imines
had to be pre-prepared from ortho-alkynylaryl aldehyde (1) and
amine (4), and then were utilized as pure compounds. To the best
of our knowledge, there are only a few examples utilizing acety-
lenic imines in situ prepared.3 Since the imines are easily decom-
posed in the presence of water, the following reactions were
usually carried out in an anhydrous solvent. Recently, Wu and
co-workers reported an ultrasound-assisted, copper-surfactant
co-catalyzed, three-component reaction of ortho-alkynylaryl alde-
hydes, primary amines, and terminal alkynes.3c As an alternative
choice, herein, we hope to report a copper(I)–Pybox complex-
catalyzed, three-component tandem coupling-annulation of termi-
nal alkynes, amines, and ortho-alkynylaryl aldehydes, in which
1-(arylethynyl)-1,2-dihydroisoquinolines (2) were achieved with
excellent to moderate yields.4
atom-economic alternative, which avoids the utilization of stoichi-
ometric amounts of metal and halides when compared to the clas-
sical methods.5 During our earlier studies on the metal acetylides
of group IB, such as Cu(I), Ag(I), and Au(I), we realized that the
reactivities of the C–M bonds in metal acetylides could be adjusted
by the introduction of N-donor and P-donor ligands, and in most
cases, water was found to be helpful to cleave the C–M bonds.6 Fol-
lowing this method, in current reaction, Pybox ligand was used
with/without water to promote a copper(I)-catalyzed three-com-
ponent tandem coupling-annulation.
2-(Phenylethynyl)benzaldehyde, aniline, and phenyl acetylene
were selected as the prototype reaction. Referring to the reported
method, in which the imine substrate had to be prepared previ-
ously, AgOTf was detected as the first attempt.2b It can be seen that
under the literature conditions, no desired product 2a was ob-
served, while 2-phenylnaphthalene (3) was isolated as the major
product with 50% of yield (Table 1, entry 1). While the loading of
catalyst was increased to 10 mol %, 3 was still the only product.
Considering the mechanism of copper-catalyzed formation of 3,
which resulted from a hetero-Diels–Alder reaction of 1a and 5a,
and followed by rearrangement at higher temperature,7 the reac-
tion temperature was then decreased to 40 °C for 2 days, and 47%
of 2a was obtained without 3. We tried to introduce water into
the system. It was shown obviously that the yield of 2a was de-
creased from 47% to 5%, and 3 became the major product (entry
4 vs entry 3). The above-mentioned results suggest that AgOTf
was not an effective catalyst in the three-component tandem
coupling-annulation reaction.
Metal-mediated Grignard-type reactions represent some of the
most common methodologies in C–C bond formations. The meth-
ods based on the catalytic reaction of C–H bonds provide a highly
* Corresponding authors. Tel./fax: +1 514 3988457 (C.-J.L.); tel.: +86 25
52112902; fax: +86 25 52112626 (X.Y.).
E-mail addresses: cj.li@mcgill.ca (C.-J. Li), yaoxq@nuaa.edu.cn (X. Yao).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.095

6792
M. Yu et al. / Tetrahedron Letters 50 (2009) 6791–6794
Table 1
Ag(I), Cu(I) and Cu(II)-catalyzed three-component tandem coupling-annulation of 1a, 4a, and 5aa
Ph
O
cat. AgOTf
Ph
Ph
H
solvent (1.5 mL)
N
+ PhNH2
+
Ph
+
additive (H2O)
Ph
Ph
1a
4a
Conditions
5a
2a
3
Entry
Yieldb (%)
2a
3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
AgOTf (5 mol %), DCE, 80 °C/6 h
AgOTf (10 mol %), DCE, 80 °C/9 h
AgOTf (10 mol %), DCE, 40 °C/2d
AgOTf (10 mol %), DCE/H2O(15:1), 40 °C/9 h
CuOTf (10 mol %), DCE, 40 °C/9 h
0
0
50
48
0
32
0
0
0
0
0
0
0
0
0
47
<5
61
53
68
76
52
17
60
33
15
82
CuOTf (10 mol %), CH2Cl2, 40 °C/9 h
CuOTf (10 mol %), CH2Cl2/H2O(15:1), 40 °C/9 h
CuOTf (5 mol %), CH2Cl2/H2O(15:1), 40 °C/2d
CuOTf (10 mol %), H2O, 40 °C/9 h
CuOTf (10 mol %), toluene, 40 °C/9 h
CuOTf (10 mol %), toluene/H2O(15:1), 40 °C/9 h
CuOTf (10 mol %), THF, 40 °C/9 h
CuOTf (10 mol %), THF/H2O(15:1), 40 °C/9 h
Cu(OTf)2 (5 mol %), CH2Cl2/H2O(20:1), 40 °C/2d
0
a
2-(Phenylethynyl)benzaldehyde (0.2 mmol), aniline (0.24 mmol, 1.2 equiv), and phenylacetylene (0.3 mmol, 1.5 equiv) in 1.5 mL of selected solvent.
Isolated yield.
b
Copper(I) and copper(II) salts were then detected in the reaction
(entries 5–14). It can be seen from Table 1 that the two catalysts
can catalyze the reaction effectively with the promotion of water
(entries 7, 8, and 14). However, compared with the reported meth-
od, with imine as a starting material,2b the yield is far from ideal.
Considering the reported methods about copper, silver, and gold-
catalyzed C–C bond formation reactions involved in the metal acet-
ylides as key intermediates, in which ligands and/or water were
believed to play the key role in adjusting the reactivities of M–C
bond in metal acetylides,6 a series of N-donor ligands in Figure 1
were detected for the reaction, and the results are listed in Table 2.
Several kinds of sp2 N-donor ligands were scanned. Pybox 8
proved to be the best of choices, and up to 97% of 2a was achieved
O
O
N
N
N
N
N
N
6
7
8
i-Pr
Pr-i
Figure 1. The ligands utilized in the reaction.
at 40 °C overnight in CH2Cl2 (Table 2, entry 3). When desiccant,
anhydrous MgSO4, was added in the reaction to remove the 1 equiv
of water produced in situ, the yield decreased (entry 4 vs entry 3).
However, with the introduction of additional water, the reaction
became worse (entry 6). It seems that a proper amount of water
might be of benefit to the reaction. Some other solvents were also
tested, and with Pybox–CuOTf as catalyst, 94% and 92% of yields
were observed in toluene and THF solutions, respectively. It should
be mentioned that in the reaction with THF as a solvent, the addi-
tion of water improved the reaction significantly, while only 72% of
2a was obtained in dried THF (entry 12 vs entry 11).
Subsequently, various acetylenic aldehydes were reacted with
terminal alkynes and anilines under the standard reaction condi-
tions (Table 3).8 Obviously, the ortho-alkynylaryl aldehydes with
the conjugated group on R1 provide much better reactivities than
the substrates with non-conjugated alkyl group (Table 3, entries
1–12 vs entries 13–15).
Table 2
Ligand-promoted, copper-catalyzed three-component tandem coupling-annulation of
1a, 4a, and 5aa
Entry
Conditions
Yieldb (%)
2a
3
1c
2d
3
CuOTf/6, CH2Cl2, 40 °C/9 h
CuOTf/7, CH2Cl2, 40 °C/9 h
CuOTf/8, CH2Cl2, 40 °C/9 h
CuOTf/8, CH2Cl2, 40 °C/9 h
CuOTf/8, CH2Cl2, rt/2d
CuOTf/8, CH2Cl2/H2O(15:1), 40 °C/9 h
CuOTf/8, DCE, 40 °C/9 h
CuOTf/8, DCE/H2O(15:1), 40 °C/9 h
CuOTf/8, DCE/H2O(1:1), 40 °C/9 h
CuOTf/8, toluene, 40 °C/9 h
CuOTf/8, THF, 40 °C/9 h
CuOTf/8, THF/H2O(15:1), 40 °C/9 h
CuOTf/8, THF/H2O(1:1), 40 °C/9 h
Cu(OTf)2/8, CH2Cl2, 40 °C/9 h
60
56
97
89
12
60
13
20
36
94
72
92
35
84
25
19
0
0
0
4e
5
With (2-phenylethynyl)aldehyde (1a) as substrate, both elec-
tron-donating and electron-deficient arylacetylenes provide good
to excellent yields for the desired products (entries 1–4), and a
>99% of yield was achieved with 1-bromo-4-ethynylbenzene (5b)
as the terminal alkyne (entry 2). On the other hand, aniline pro-
vides the best reactivity in comparison with other substituted aro-
matic amines (entry 1 vs entries 5–7). When cyclohexenyl group
was introduced on R1, ꢀ80% of yields were observed for different
substituted arylacetylenes and anilines (entries 8–12).
6
7
8
9
10
11
12
13
14
0
54
30
9
0
0
0
0
4
a
CuOTf (10 mol %), ligand (12 mol %), 2-(phenylethynyl)benzaldehyde
However, when alkyl group was introduced on R1, the reactivi-
ties were decreased obviously, only moderate yields were obtained
with n-butyl-substituted 1c as a substrate (entries 13–15).
In order to further understand the effect of ligand and water on
the reaction, copper phenylacetylide 9, which was suggested as the
(0.2 mmol), aniline (0.24 mmol, 1.2 equiv), and phenylacetylene (0.3 mmol,
1.5 equiv) in 1.5 mL of selected solvent.
b
Isolated yield.
CuOTf (10 mol %), ligand 6 (30 mol %).
CuOTf (10 mol %), ligand 7 (12 mol %).
Anhydrous MgSO4 (100 mg) was added.
c
d
e

M. Yu et al. / Tetrahedron Letters 50 (2009) 6791–6794
6793
Table 3
Pybox–CuOTf catalyzed three-component tandem coupling-annulation of 1, 4, and 5a
R3
O
H
R2
cat. Cu(I)/Pybox
+ R2
R1
+ R3
NH2
additives, sol.
up to >99% of yield
N
1
4
5
2
R1
Entry
1:R1
4:R2
5:R3
Product 2
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ph– (1a)
Ph–
Ph–
Ph–
Ph–
H (2a)
H
H
H
CH3 (2b)
Br (2c)
Br
H
H
H
Br
CH3
H
H
H (5a)
Br (5b)
Cl (5c)
CH3 (5d)
H
H
Br
H
CH3
Br
H
H
H
CH3
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
97
>99
87
85
77
93
86
83
77
76
85
84
40
49
42
Ph–
Ph–
Cyclohexenyl– (1b)
Cyclohexenyl–
Cyclohexenyl–
Cyclohexenyl–
Cyclohexenyl–
n-Bu– (1c)
n-Bu–
n-Bu–
Br
a
Conditions: CuOTf (10 mol %) and 8 (12 mol %) were mixed in 1.5 mL of CH2Cl2, stirred at room temperature for 20 min, and then ortho-alkynylaryl aldehyde (0.2 mmol),
aniline (0.24 mmol, 1.2 equiv), and arylacetylene (0.3 mmol, 1.5 equiv) were added. The mixture was then stirred at 40 °C overnight.
b
Isolated yield.
key intermediate in the reaction, was prepared and utilized as a
catalyst (or a catalyst precursor). It can be seen from Table 4 that
both water and Pybox ligand improved the reactions significantly.
Furthermore, the results in entries 2 and 5 also suggested that a
proper amount of water is helpful to the reaction, while worse re-
sults were observed with pure water (Table 4, entry 2 vs entry 3,
entry 5 vs entry 6). Therefore, we reasoned that the Pybox ligand
might be weakening and activating the copper–carbon bond in
the copper acetylide. Coordination of the electron-donating Pybox
ligand increases the electron density on copper, resulting in the
weakening of the copper–carbon bond, which was then cleaved
with the promotion of water produced in situ from the aldehydes
and anilines.
per(I) acetylide species in the presence of anilines. The acetylide
then reacts with imine formed in situ from aldehyde and aniline
to give propargylic amine, followed by the amine–alkyne cycliza-
tion to give the vinylcopper intermediate; the carbon–copper bond
is then quenched to give the final product 2 by protonolysis and
regenerates the catalyst.9
In conclusion, with the help of Pybox ligand, dihydroisoquino-
line derivatives 2 were achieved successfully via a highly efficient,
one-pot, copper(I)-catalyzed three-component tandem addition
and cyclization of ortho-alkynylaryl aldehydes, anilines, and termi-
nal alkynes. Compared with the reported methods, in which the
imine intermediate had to be pre-prepared and purified, the novel
process provides a greener choice. The three-component tandem
addition and cyclization with other nucleophiles based on this cat-
alytic system are currently under investigation.
Thus, a tentative mechanism for the Pybox–Cu(I) complex-cat-
alyzed tandem addition/cyclization is proposed: The reaction of
terminal alkynes with Pybox–Cu(I) complex generates the cop-
Table 4
Acknowledgment
Copper phenylacetylide 9 catalyzed three-component tandem coupling-annulation of
1a, 4a, and 5aa
We are grateful to the financial support from National Natural
Science Foundation of China (20602018 to X.Y.).
Ph
O
H
References and notes
Cu
Ph
9 (cat.)
Ph
Ph
+
N
Ph NH2
Ph
+
additives
CH2Cl2 (1.5 mL)
1. (a) Biber, B.; Muske, J.; Ritzan, M.; Graft, U. J. Antibiot. 1998, 51, 381; (b)
Maruse, N.; Goto, M. J. Antibiot. 1998, 51, 545; (c) Wang, W.; Breining, T.; Li, T.;
Milbum, R.; Attardo, G. Tetrahedron Lett. 1998, 39, 2459. and the references
cited therein.
Ph
4a
5a
1a
2a
2. For representative examples, see: (a) Obika, S.; Kono, H.; Yasui, Y.; Yanada, R.;
Takemoto, Y. J. Org. Chem. 2007, 72, 4462. and the references cited therein; (b)
Asao, N.; Yudha, S. S.; Nogami, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44,
5526; (c) Yanada, R.; Obika, S.; Kono, H.; Takemoto, Y. Angew. Chem., Int. Ed.
2006, 45, 3822; Some other examples involoved in the nuclophilic addition to
ortho-alkynylaryl aldehydes, see: (d) Asao, N.; Nogami, T.; Takahashi, K.;
Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 764; (e) Patil, N. T.; Yamamoto, Y. J.
Org. Chem. 2004, 69, 5139; (f) Nakamura, H.; Ohtaka, M.; Yamamoto, Y.
Tetrahedron Lett. 2002, 43, 7631; (g) Asao, N.; Chan, C. S.; Takahashi, K.;
Yamamoto, Y. Tetrahedron 2005, 61, 11322; (h) Patil, N. T.; Pahadi, N. K.;
Yamamoto, Y. J. Org. Chem. 2005, 70, 10096; (i) Wei, L.-L.; Wei, L.-M.; Pan, W.-
B.; Wu, M.-J. Synlett 2004, 1497; Some examples for the electrophilic
Entry
Conditions
9 10 mol %, CH2Cl2, 40 °C
Yieldb (%)
1
2
3
4
5
6
32
56
26
54
81
15
9 10 mol %, H2O 1 equiv, CH2Cl2, 40 °C
9 10 mol %, H2O, 40 °C
9 10 mol %, 8 12 mol %, CH2Cl2, 40 °C
9 10 mol %, 8 12 mol %, H2O 1 equiv, CH2Cl2, 40 °C
9 10 mol %, 8 12 mol %, H2O, 40 °C
a
2-(Phenylethynyl)benzaldehyde (0.2 mmol), aniline (0.24 mmol, 1.2 equiv), and
phenylacetylene (0.3 mmol, 1.5 equiv) in 1.5 mL of selected solvent.
b
Isolated yield.

6794
M. Yu et al. / Tetrahedron Letters 50 (2009) 6791–6794
cyclization: (j) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. J.
Am. Chem. Soc. 2003, 125, 9028; (k) Yue, D.; Ca, N. D.; Larock, R. C. Org. Lett.
2004, 6, 1581.
2005, 7, 4395; (d) Wei, C.; Li, Z.; Li, C.-J. Synlett 2004, 1472; (e) Wei, C.; Mague, J.
T.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5749; (f) Wei, C.; Li, C.-J. J. Am.
Chem. Soc. 2002, 124, 5683; (g) Wei, C. M.; Li, C.-J. J. Am. Chem. Soc. 2003, 125,
9584; (h) Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003, 5, 4473; (i) Li, Z.; Wei, C.; Chen, L.;
Varma, R. S.; Li, C.-J. Tetrahedron Lett. 2004, 45, 2443; (j) Li, C.-J.; Wei, C. Chem.
Commun 2002, 268; (k) Li, C.-J. Acc. Chem. Res. 2002, 35, 533; (l) Li, C.-J.; Wei, C.
Green Chem. 2002, 39; For recent review about the ligand effects in IB metals-
catalyzed reactions, see: (m) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev.
2008, 108, 3351.
3. (a) Ding, Q.; Wu, J. Org. Lett. 2007, 9, 4959; (b) Ding, Q.; Wang, B.; Wu, J.
Tetrahedron 2007, 63, 12166; (c) Ye, Y.; Ding, Q.; Wu, J. Tetrahedron 2008, 64,
1378; (d) Ye, S.; Zhou, H.; Wu, J. Tetrahedron 2009, 65, 1294.
4. The CuOTf/Pybox catalytic system was utilized with TBHP as oxidiant in a CDC
reaction to synthesize the similar tetrahydoisoquinoline derivatives, see: Li, Z.;
MacLeod, P. D.; Li, C.-J. Tetrahedron: Asymmetry 2006, 17, 590.
5. Recent reviews on C–H activations, see: (a) Dyker, G. Angew. Chem., Int. Ed. 1999,
38, 1698; (b) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai,
S. J. Am. Chem. Soc. 2001, 123, 10935; (c) Chen, H.; Schlecht, S.; Semple, T. C.;
Hartwig, J. F. Science 2000, 287, 1995; (d) Goldman, A. S. Nature 1993, 366, 514;
(e) Crabtree, R. H. J. Organomet. Chem. 2004, 689, 4083; (f) Jia, C.; Kitamura, T.;
Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633; For atom-economy, see: (g) Trost, B.
M. Science 1991, 254, 1471; (h) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34,
259; (i) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford
University Press: New York, 2000; About Grignard-type reactions utilizing C–H
bonds directly in water, see: (j) Herrerías, C. I.; Yao, X.; Li, Z.; Li, C.-J. Chem. Rev.
2007, 107, 2546.
7. (a) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 10921;
(b) Asao, N.; Sato, K.; Menggenbateer; Yamamoto, Y. J. Org. Chem. 2005, 70,
3682.
8. General procedure: Copper(I) trifluoromethanesulfonate benzene complex
(0.0050 g, 10 mol % to copper(I)) and 8 (0.0072 g, 12 mol %) were mixed in
1.5 mL of CH2Cl2, stirred at room temperature for 20 min, and then, ortho-
alkynylaryl aldehyde
1 (0.2 mmol), aniline 4 (0.24 mmol, 1.2 equiv), and
arylacetylene (0.3 mmol, 1.5 equiv) were added. The mixture was then
5
stirred at 40 °C overnight. The reaction mixture was purified by flash column
chromatography to give dihydroisoquinoline derivatives 2.
9. See Refs. 6a–c and e,f.
6. (a) Yu, M.; Skouta, R.; Zhou, L.; Jiang, H.-F.; Yao, X.; Li, C.-J. J. Org. Chem. 2009, 74,
3378; (b) Yao, X.; Li, C.-J. Org. Lett. 2006, 8, 1953; (c) Yao, X.; Li, C.-J. Org. Lett.