Indium-catalyzed highly efficient three-component coupling of aldehyde, alkyne, and amine via C-H bond activation

Article abstract of DOI:10.1021/jo900507v

(Chemical Equation Presented) In this paper, indium(III) chloride was found to be a highly effective catalyst for the three-component coupling reactions of aldehydes, alkynes, and amines (A³-coupling) via C-H activation. The reactions could be

Full text of DOI:10.1021/jo900507v

are frequent skeletons3 and synthetically versatile key intermedi-
ates4 for the preparation of many nitrogen-containing biologi-
cally active compounds such as ꢀ-lactams, oxotremorine
analogues, conformationally restricted peptides, isosteres, natural
products, and therapeutic drug molecules.3b,5 Classical methods
for the preparation of propargylamines have usually exploited
the relatively high acidity of a terminal acetylenic C-H bond
to form alkynylmetal reagents by reaction with strong bases
such as butyllithium,6a organomagnesium compounds,6b or
LDA7 in a separate step. Unfortunately, these reagents are
required in stoichiometric quantities, are highly moisture sensi-
tive, and require strictly controlled reaction conditions.
Indium-Catalyzed Highly Efficient
Three-Component Coupling of Aldehyde, Alkyne,
and Amine via C-H Bond Activation
Yicheng Zhang,† Pinhua Li,† Min Wang,† and Lei Wang*,†,‡
Department of Chemistry, Huaibei Coal Teachers College,
Huaibei, Anhui 235000, P. R. China, and State Key
Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
leiwang@hbcnc.edu.cn
In recent years, enormous progress has been made in ex-
panding the scope of the direct addition of alkynes to carbon-
nitrogen double bonds either from prepared imines or from
aldehydes and amines in one-pot procedure by several noble
transition-metal catalysts via C-H activation of terminal
alkynes. AgI salts,8 AuI/AuIII salts,2,9 AuIII-salen complexes,10
CuI salts,11 Ir complexes,12 Hg2Cl2,13 and Cu/RuII bimetallic
system14 have all been used for this reaction under homogeneous
conditions, where water is the only theoretical byproduct.
Recently, AuI, AgI, and CuI in ionic liquids and supported AuIII,
AgI, and CuI were successfully used to catalyze three-component
coupling reactions under heterogeneous reaction conditions with
recyclability and reusability of the transition-metal catalysts.15
ReceiVed March 6, 2009
In this paper, indium(III) chloride was found to be a highly
effective catalyst for the three-component coupling reactions
of aldehydes, alkynes, and amines (A3-coupling) via C-H
activation. The reactions could be applied to both aromatic
and aliphatic aldehydes and alkynes. Nearly quantitative
yields of the desired products were obtained in most cases.
No cocatalyst or activator is required, and water is the only
byproduct in the reactions. Furthermore, a tentative mech-
anism of the InCl3-catalyzed one-pot, three-component
coupling of aldehyde, alkyne, and amine is proposed.
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Multicomponent coupling reactions (MCRs) are a powerful
synthetic tool to access complex structures from simple precur-
sors via a one-pot procedure, and in general, those reported
exhibit high atom economy and selectivity.1 Three-component
coupling of an aldehyde, an alkyne, and an amine (A3-coupling)
is one of the best examples of such a process, and this
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Synlett 2001, 676. For enantioselective syntheses of propargylamines through
CuI-catalyzed one-pot, three-component coupling reactions of aldehydes, alkynes,
and amines, see: (d) Wei, C.; Li, C. J. J. Am. Chem. Soc. 2002, 124, 5638. (e)
Wei, C.; Mague, J. T.; Li, C. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5749.
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† Huaibei Coal Teachers College.
‡ Shanghai Institute of Organic Chemistry.
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A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29,
123. (c) Ugi, I.; Domling, A.; Werner, B. J. Heterocycl. Chem. 2000, 37, 647.
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Steinbrueckner, C. Chem. Ber. 1961, 94, 2802. (f) Strecker, A. Ann. Chem. 1850,
75, 27. (g) Mannich, C.; Kosche, W. Arch. Pharm. 1912, 250, 647. (h) Hantzsch,
A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474.
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10.1021/jo900507v CCC: $40.75 2009 American Chemical Society
Published on Web 05/07/2009

TABLE 1. Screening of Catalysts for A3-Coupling Reactionsa
SCHEME 1
entry
indium source
yieldb (%)
The utility of indium(III) salts as Lewis acids in organic
synthesis has received a great deal of interest due to their
relatively low toxicity, stability in air and water, recyclability,
operational simplicity, and strong tolerance to oxygen- and
nitrogen-containing substrates and functional groups.16 Their
potential as Lewis acid catalysts for fundamental reactions, such
as the Diels-Alder,17 Friedel-Crafts,18 Mukaiyama aldol,19 and
Sakurai-Hosomi allylation reactions,20 has been extensively
investigated.21 However, indium-catalyzed three-component
coupling reactions of aldehydes, terminal alkynes, and amines
has not so far been described. As a part of our program aiming
to develop selective and environmental friendly methods for
the preparation of fine chemicals and in continuation of our
interest in exploring novel synthetic strategies for the synthesis
of propargylamines via activation of terminal alkynes,15g,h,22
herein we report InCl3 as an inexpensive, high-yielding catalyst
for the three-component coupling of aldehydes, alkynes, and
amines (A3-coupling) without any cocatalyst or activator. The
reactions generated the corresponding products in nearly
quantitative yields in most cases. This method provided a wide
range of substrate applicability and could be applied to both
aromatic and aliphatic aldehydes and alkynes (Scheme 1).
At the outset, the catalytic activity of a variety of indium
salts were examined in a model reaction of phenylacetylene,
isobutyraldehyde, and dibenzylamine in toluene under an argon
atmosphere at 120 °C for 20 h, and the results are summarized
in Table 1. To our delight, the three-component coupling
reaction proceeded smoothly and generated the desired product
propargylamine in 98% yield, representing one of the best results
when 10 mol % of InCl3 was used as catalyst without any
cocatalyst or activator (Table 1, entry 1). Other indium salts,
such as InBr3, InI3, In(CF3SO3)3, and In(CH3COO)3, were
inferior and generated the desired product in 53, 78, 71, and
72% yields, respectively (Table 1, entries 2-5). In(I) salts
seemed slightly better than In(III) salts, and the corresponding
product was obtained in 99% yield (Table 1, entry 6). Consider-
ing that InCl3 is relatively cheap compared to other indium salts
1
2
3
4
InCl3
InBr3
InI3
In(CF3SO3)3
In(CH3COO)3
InCl
InCl3
InCl3
98
53
78
71
72
99
78
95
98
5
6
7c
8d
9e
InCl3
a Reaction conditions: phenylacetylene (1.2 equiv), isobutyraldehyde
(1.2 equiv), dibenzylamine (1.0 equiv), indium source (0.10 equiv),
toluene (1.0 mL ·mmol-1), 120 °C, under argon, 20 h. b Yield of isolated
product after flash chromatography. c In the present of InCl3 (0.05
equiv). d In the present of InCl3 (0.05 equiv) for 36 h. e In the present of
InCl3 (0.20 equiv).
TABLE 2. Effect of Solvent on InCl3-Catalyzed A3-Coupling
Reactionsa
entry
solvent/T (°C)
yieldb (%)
1
2
3
4
5
6
7
8
toluene/120
benzene/80
1,4-dioxane/100
DCE/83
CH3CN/82
C2H5OH/78
CH3OH/68
H2O/100
PEG-400/120
DMA/120
DMSO/120
DMF/120
98
83
81
87
78
50
56
65
53
0
9
10
11
12
13
0
0
0
BmimBF4/120
a Reaction conditions: phenylacetylene (1.2 equiv), isobutyraldehyde
(1.2 equiv), dibenzylamine (1.0 equiv), InCl3 (0.10 equiv), solvent (1.0
mL·mmol-1) at the temperature indicated in Table 2, under argon, 20 h.
b Yield of isolated product after flash chromatography.
(16) Reviews for indium Lewis acids: (a) Frost, C. G.; Chauhan, K. K.
J. Chem. Soc., Perkin Trans. 1 2000, 3015. (b) Fringuelli, F.; Piermatti, O.;
Pizzo, F.; Vaccaro, L. Curr. Org. Chem. 2003, 7, 1661. (c) Frost, C. G.; Hartley,
J. P. Mini-ReV. Org. Chem. 2004, 1, 1. (d) Zhang, Z.-H. Synlett 2005, 711.
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Perumal, P. T. Tetrahedron Lett. 1998, 39, 3225.
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(19) Loh, T.-P.; Wei, L.-L. Tetrahedron Lett. 1998, 39, 323.
(20) (a) Friestad, G. K.; Korapala, C. S.; Ding, H. J. Org. Chem. 2006, 71,
281. (b) Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A. Eur. J. Org. Chem. 2002,
1578.
(21) For allylation of carbonyl compounds with allyltributylstannanes, see:
(a) Teo, Y.-U.; Goh, J.-D.; Loh, T.-P. Org. Lett. 2005, 7, 2743. (b) Lu, J.; Ji,
S.-J.; Teo, Y.-C.; Loh, T.-P. Org. Lett. 2005, 7, 159. (c) Marshall, J. A.; Hinkle,
K. W. J. Org. Chem. 1995, 60, 1920. For other reactions, see: (d) Harada, S.;
Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4365.
(e) Yanada, R.; Obika, S.; Kobayashi, Y.; Inokuma, T.; Oyama, M.; Yanada,
K.; Takemoto, Y. AdV. Synth. Catal. 2005, 347, 1632. (f) Yanada, R.; Obika,
S.; Oyama, M.; Takemoto, Y. Org. Lett. 2004, 6, 2825. (g) Dobbs, A. P.; Guesne´,
S. J. J.; Martinovic´, S.; Coles, S. J.; Hursthouse, M. B. J. Org. Chem. 2003, 68,
7880. (h) Onishi, Y.; Ogawa, D.; Yasuda, M.; Baba, A. J. Am. Chem. Soc. 2002,
124, 13690. (i) Cho, Y. S.; Kim, H. Y.; Cha, J. H.; Pae, A. N.; Koh, H. Y.;
Choi, J. H.; Chang, M. H. Org. Lett. 2002, 4, 2025. (j) Yasuda, M.; Onishi, Y.;
Ueba, M.; Miyai, T.; Baba, A. J. Org. Chem. 2001, 66, 7741.
and the most effective, it was therefore chosen as the catalyst
for the following experiments. With respect to the catalyst
loading, 10 mol % of InCl3 was found to be optimal. When 5
mol % of InCl3 was used, the reaction did not go to completion,
and excellent yield of the product was obtained as the reaction
time was prolonged (Table 1, entries 7 and 8). However, no
significant improvement was observed with 20 mol % of InCl3
(Table 1, entry 9).
We next screened the effect of solvent on A3-coupling of
model substrates by using 10 mol % of InCl3 as catalyst at 120
°C, and the nature of solvent significantly affects the reaction
(Table 2). Among the solvents tested in Table 2, toluene was
the most suitable reaction medium for the A3-coupling reaction
(Table 2, entry 1). Benzene, 1,4-dioxane, 1,2-dichloroethane
(DCE), and CH3CN were inferior and generated the correspond-
ing products in 83, 81, 87, and 78% yields, respectively (Table
2, entries 2-5), whereas C2H5OH, CH3OH, H2O, and PEG-
400 afforded moderate yields of the desired products (Table 2,
(22) (a) Li, P.; Wang, L.; Zhang, Y.; Wang, M. Tetrahedron Lett. 2008, 49,
6650. (b) Li, P.; Zhang, Y.; Wang, L. Chem.sEur. J. 2009, 15, 2045.
J. Org. Chem. Vol. 74, No. 11, 2009 4365

TABLE 3. InCl3-Catalyzed A3-Coupling Reactionsa
SCHEME 2
entry
R
R1
i-C3H7
R2, R3
yieldb (%)
1
2
3
4
5
6
7
8
C6H5
2 (C6H5CH2)
2 (C6H5CH2)
2 (C6H5CH2)
2 (C6H5CH2)
2 (C6H5CH2)
2 (C6H5CH2)
2 (C6H5CH2)
2 (C6H5CH2)
2 (C6H5CH2)
2 (C6H5CH2)
2 (C6H5CH2)
2 (C6H5CH2)
2 (C6H5CH2)
2 (C6H5CH2)
(CH2)5
(CH2)2O(CH2)2
2 (i-C3H7)
(CH2)5
2 (c-C6H11)
(CH2)5
(CH2)5
(CH2)5
(CH2)5
98
99
97
98
96
89
87
95
p-CH3C6H4
p-FC6H4
p-ClC6H4
p-C6H5C6H4
n-C8H17
n-C6H13
C6H5
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
n-C3H7
i-C4H9
H
SCHEME 3. Possible Mechanism of InCl3-Catalyzed
Three-Component Coupling of Aldehyde, Alkyne, and
Amine
9
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
94
99
10
11
12
13
14
15
16
17
18
19
20
21
22
23
c-C6H11
C6H5
98
99c
92c
83c
76
p-CH3C6H4
p-ClC6H4
i-C3H7
i-C3H7
H
H
H
C6H5
85
78
80
68
96c
97c
90c
87c
p-CH3C6H4
p-CH3OC6H4
p-ClC6H4
such as methyl and chloro groups, afforded the corresponding
products in good yields in the presence of 4 Å molecular sieves
(Table 3, entries 12-14 and 20-23). In the absence of 4 Å
molecular sieves, the yields were moderate.
To expand the scope of amine substrates, phenylacetylene
was used as a model substrate and various amines with different
aldehydes were examined (Table 3, entries 1 and 15-23). The
results indicated that cyclic, heterocyclic, and acyclic secondary
aliphatic amines gave excellent yields of products under the
standard reaction conditions. However, no A3-reaction product
was isolated when an aromatic secondary amine, such as
N-benzylaniline or N-methylaniline, was served as amine
substrate.
Considering that chiral propargylamines are widely present
in many important bioactive compounds, we subsequently
investigated a novel substrate-controlled asymmetric indium-
catalyzed A3-coupling. A chiral amine, (S)-N-benzyl-1-phenyl-
ethylamine, was selected for examination using benzaldehyde
and phenylacetylene as model substrates, as depicted in Scheme
2. It was interesting to note that (S)-N-benzyl-1-phenylethy-
lamine exhibited good diastereoselectivity (75:25), and a very
high yield (99%) of the product was isolated when an A3-
coupling reaction of phenylacetylene, formaldehyde, and (S)-
N-benzyl-1-phenylethylamine was carried out under the present
reaction conditions.
A tentative mechanism of the InCl3-catalyzed one-pot, three-
component coupling of aldehyde, alkyne, and amine is proposed
in Scheme 3. The catalyst InCl3 would be first reacted with
terminal alkyne to form a stable InIII alkynyl-ate complex and
release HCl.23 When PhCt CInCl2 prepared according to the
literature23 was used instead of PhCt CH to react with immo-
nium salt in the absence of additional InCl3 at 120 °C in toluene,
97% yield of the desired product was isolated. On the other
hand, we hypothesize that the generated HCl accelerates the
formation of immonium salt from aldehyde and secondary
amine,24 and InCl3 as a Lewis acid plays a role in increasing
a Reaction conditions: amine (1.0 mmol), aldehyde (1.2 mmol),
alkyne (1.2 mmol), InCl3 (0.10 mmol), toluene (1.0 mL), 120 °C, under
argon, 20 h. b Yield of isolated product after flash chromatography. c In
the present of 4 Å molecular sieves (100 mg), which are thought to
scavenge water.
entries 6-9). Unfortunately, no desired product was isolated
when the reactions were carried out in N,N-dimethylacetamide
(DMA), dimethyl sulfoxide (DMSO), N,N-dimethylformamide
(DMF), and 1-n-butyl-3-methylimidazolium tetrafluoroborate
(BmimBF4) (Table 2, entries 10-13). During the course of our
further optimization of the reaction conditions, the reaction was
generally completed within 20 h when it was performed at 120
°C by using 10 mol % of InCl3 in toluene without any cocatalyst
or activator.
On the basis of the previously optimized reaction conditions,
the scope of this three-component coupling reaction was
evaluated. The results are outlined in Table 3. At the beginning
of the investigation into the alkyne substrate scope, isobutyral-
dehyde and dibenzylamine were used as model substrates and
a variety of alkynes were examined for the A3-coupling reactions
(Table 3, entries 1-7). As can be seen from Table 3, aromatic
alkynes were often much more reactive than aliphatic alkynes.
Aromatic alkynes, with either electron-donating or electron-
withdrawing groups attached to the benzene rings, were able
to undergo three-component coupling smoothly and generated
the corresponding products in excellent yields (Table 3, entries
1-5). Fortunately, aliphatic alkynes also gave the corresponding
propargylamines in good yields (Table 3, entries 6 and 7).
To expand the scope of aldehyde substrates, a combination
of phenylacetylene-dibenzylamine-aldehydes was chosen, and
various aldehydes were surveyed. Aliphatic aldehydes, acyclic
or cyclic, such as isobutyraldehyde, n-butyraldehyde, isovaler-
aldehyde, cyclohexanecarboxaldehyde, and formaldehyde, dis-
played high reactivity under the optimized reaction conditions
and generate the desired products in high yields (Table 3, entries
1, and 8-11). Fortunately, aromatic aldehydes with both
electron-donating and electron-withdrawing functional groups,
(23) Takami, K.; Usugi, S. I.; Yorimitsu, H.; Oshima, K. Synthesis 2005,
824.
4366 J. Org. Chem. Vol. 74, No. 11, 2009

reaction vessel was placed in an oil bath at 120 °C, the mixture
was stirred for 20 h and then cooled to room temperature, the
solvent was filtered and concentrated under reduced pressure, and
the residue was purified by flash chromatography on silica gel
(eluant: hexane/ethyl acetate) to give the corresponding A3-coupling
product.
the electrophilic character of the starting aldehyde and stabilizing
the immonium salt by the coordination of oxygen or nitrogen
lone electron pair with In(III).25 The resulting indium acetylide
intermediate subsequently reacted with immonium salt generated
in situ to give the corresponding propargylamine and regenerate
InIII catalyst.
In conclusion, a highly efficient indium-catalyzed three-
component coupling of aldehydes, alkynes, and amines via C-H
bond activation has been achieved in toluene. The process was
simple and generated a diverse range of propargylamines in
excellent yields. The reaction is applicable to both aromatic and
aliphatic aldehydes and alkynes. Water is the only byproduct
in this novel three-component reaction. The scope, mechanism,
stereoselectivity, and synthetic applications of this reaction are
under investigation.
Acknowledgment. We gratefully acknowledge financial
support by the National Natural Science Foundation of China
(No. 20772043).
Supporting Information Available: Representative experi-
1
mental procedure, analytical data, and copies of H and 13C
NMR spectra of all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO900507V
Experimental Section
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General Procedure for the Indium-Catalyzed Three-Compo-
nent Coupling Reactions. In argon atmosphere, a sealable reaction
tube with a Teflon-coated screw cap equipped with a magnetic stir
bar was charged with alkyne (1.2 mmol), aldehyde (1.2 mmol),
amine (1.0 mmol), InCl3 (0.1 mmol), and toluene (1.0 mL). The
J. Org. Chem. Vol. 74, No. 11, 2009 4367