An efficient synthesis of propargylamines via C-H activation catalyzed by copper(I) in ionic liquids

Article abstract of DOI:10.1039/b416268d

A readily available copper(I) catalyst, in an ionic liquid, can effect three-component coupling of aldehydes, amines and alkynes to generate propargylamines in high yields. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b416268d

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An efficient synthesis of propargylamines via C–H activation catalyzed
by copper(I) in ionic liquids
Soon Bong Park and Howard Alper*
Received (in Corvallis, OR, USA) 20th October 2004, Accepted 20th December 2004
First published as an Advance Article on the web 20th January 2005
DOI: 10.1039/b416268d
coupling of benzaldehyde, piperidine and phenylacetylene
(Table 1).
A readily available copper(I) catalyst, in an ionic liquid, can
effect three-component coupling of aldehydes, amines and
alkynes to generate propargylamines in high yields.
The coupling process proceeded well in the presence of 2 mol%
of copper compounds (CuI, CuBr, CuCl, CuCN, Cu(OAc)2 and
Cu powder) to give propargylamines in 60–98% conversion.
Whereas about 10% of the corresponding product, N-(1,3-
diphenyl-2-propynyl) piperidine (4), was obtained by using CuBr
in water,5a the same catalyst, after 2 h, afforded 4 in 95% yield
using [bmim]PF6 as the ionic liquid (Table 1, entry 5). All Cu(I)
species (entries 1–6) showed excellent catalytic properties and
slightly better than those of Cu(II) or copper powder. Nevertheless
hydrated cupric acetate (entry 7) and 800 mesh of copper powder,
afforded 4 in 60–77% yield. No reaction occurred in the absence of
a copper-containing catalyst (entry 9). The [bmim]PF6 is a better
ionic liquid than, for example, a phosphonium ionic liquid such
as trihexyl(tetradecyl) phosphonium hexafluorophosphate for this
reaction (entry 10). In addition, no other additive was needed
for this system, and the experimental process was quite simple
and easy.
The transition metal-catalyzed multi-component reaction is a
powerful synthetic tool to access complex structures from simple
precursors by a one-pot procedure. Activation of a terminal alkyne
C–H bond by transition metal catalysts1 is a reaction of
fundamental interest in organic synthesis because, for example,
the unique properties of acetylenic arrays are of value in non-linear
optical devices2 and natural product synthesis.3 Propargylic amines
are important intermediates for organic synthesis and reliable
methods for their synthesis are relatively few. Thus, there is a need
for a general and efficient synthetic protocol that would be
applicable to a wide range of propargylamines.4 Recently, Li,5 Tu,6
and co-workers reported interesting propargylamine syntheses
through three-component coupling of aldehydes, alkynes and
amines (A3 coupling) via transition metal (for example gold, silver,
ruthenium or copper with microwaves) catalysis in water or
organic media. Even though these systems are general, environ-
mentally friendly and applicable to both aliphatic and aromatic
aldehydes and amines, there are no reports of the recyclability of
the catalyst. It is a considerable drawback that an expensive metal
catalyst (silver, gold etc.) is often lost at the end of the reaction.
Hence, a process for recycling the catalyst system is of importance.
Different strategies have been used to separate and reuse
homogeneous catalysts, such as aqueous biphasic systems,7
fluorous biphasic systems,8 soluble polymer-based ligands9 and
ionic liquids.10 In continuation of our studies on recyclable
catalysts in ionic liquids,11 we now report an efficient recyclable A3
coupling reaction via C–H activation catalyzed by a copper(I)
compound in an ionic liquid.
Having optimized the reaction conditions, the recyclability of
the A3 coupling reaction with copper(I) catalysts in [bmim]PF6
was examined (Table 2). Reactions using an aliphatic aldehyde
(entry 2), electron-rich (entry 4) or electron-poor (entry 5) styrenes,
or a heteroaromatic (entry 6) aldehyde gave the desired products in
Table 1 A3 Coupling reaction with copper catalysts in [bmim][PF6]a
Temp. (uC)/
Time (h)
Conversion
(%)b
Initially, we examined the A3 coupling reaction using various
palladium catalysts, as we previously found that Sonogashira
coupling could be effected using a palladium catalyst in an ionic
liquid in the absence of both a copper co-catalyst and extra
phosphine ligands. It was found that palladium catalysts (i.e.,
PdCl2, PdCl2(PPh3)2, (cod)PdCl2, Pd(PPh3)4, Pd2(dba)3) were not
useful to obtain the desired propargylamines, despite the known
activity of Pd to catalyze terminal C–H bond activation.12
Entry
Cu cat.
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuCN
CuBr
CuCl
Cu(OAc)2 monohydrate
Copper powder
—
CuCN
100/5
120/2
120/4
120/2
120/2
120/2
120/4
120/4
120/12
120/2
78
86
98
85
95
85
60
77
0
We then turned our attention to the use of copper compounds
as catalysts for the A3 coupling reaction because they are readily
available and much cheaper than silver,5b gold,5a ruthenium,5c or
other additives6 in an ionic liquid as the solvent. The catalytic
activity of various copper complexes was examined for the A3
10
a
60c
All reactions were carried out using 1 mmol of benzaldehyde,
1.2 eq. of piperidine, 1.5 eq. of phenylacetylene and 2 mL of the
ionic liquid. Conversions were determined by 1H NMR of the
crude reaction mixture. Trihexyl(tetradecyl)phosphonium hexa-
b
c
fluorophosphate was used as the ionic liquid. Various by-products
were observed.
*howard.alper@uottawa.ca
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Chem. Commun., 2005, 1315–1317 | 1315

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Table 2 Recyclable A3 coupling reaction with copper catalysts in [bmim][PF6]a
Cycle no. (time, h)b
Corresponding yield (%)
Entry
R1
R2
Ph
Ph
Ph
Cu cat.
CuI
1
2
3
C6H5
C7H15
C6H5
1 (2)
86
1 (2)
82
1 (2)
86
6 (2)
83
1 (2)
79
1 (2)
74
1 (2)
83
1 (2)
69
2 (2)
84
2 (2)
80
2 (2)
85
7 (2)
77
2 (2)
73
2 (2)
87
2 (2)
82
2 (2)
79
3 (2)
76
3 (2)
78
3 (2)
84
8 (2)
82
3 (2)
73
3 (2)
89
3 (2)
82
3 (2)
83
4 (4)
83
4 (4)
84
4 (2)
85
9 (2)
81
4 (4)
85
4 (4)
77
4 (4)
78
4 (2)
68
5 (4)
77
5 (4)
78
5 (2)
78
10(2)
78
5 (4)
63
5 (4)
75
5 (4)
80
5 (2)
68
CuCN
CuCN
4
5
6
7
a
4-(MeO)C6H5
4-ClC6H5
2-Thiophene
C6H5
Ph
CuCN
CuCN
CuCN
CuCN
Ph
Ph
n-C5H11
b
All reactions were carried out using 1 mmol of aldehyde, 1.2 eq. of piperidine, 1.5 eq. of the alkyne and 2 mL of [bmim]PF6. Values given
for each cycle are based on GC yields (%).
high yields using only 2 mol% of the copper catalyst. CuI (entry 1)
and CuCN (entry 3) show similar catalytic activity. It is important
to stress that the catalyst was recycled and reused for five or ten
runs (entry 3) with only a slight drop in activity.
Furthermore, aliphaticaldehydeshavingana-hydrogen(entry10)
also display high reactivity and clean reactions under standard
conditions. The reaction is sensitive to steric effects, as 2-methoxy-
benzaldehyde afforded a trace amount of product (entry 4) while
electronic effects are minimal in this reaction (entries 2, 3, 5 and 6).
Use of different (aliphatic, aromatic) amines in reaction with
phenylacetylene and benzaldehyde (entries 11–16) gave results
demonstrating again the sensitivity to steric factors, e.g., using
2-methyl piperidine as the amine gave the propargylamine in 68%
Having established the recyclability and reusability of this
system, we next examined its performance for the coupling
reaction of a variety of aldehydes, amines, and alkynes (Table 3).
Entries 1–3 and 5–9 of Table 3 indicate that the coupling reactions
gave 4 in 74–98% yields.
Table 3 A3 Coupling reaction with copper catalyst in [bmim][PF6]a
Entry
R1
Amine (R2, R3)
R4
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
C6H5
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
n-C5H11
(EtO)2CH
TIPS
2
2
3
5
2
2
2
2
2
2
2
2
2
2
2
3
2
2
2
85
79
84
trace
74
98
95
95
83
82
95
88
68
0
4-(MeO)C6H4
3-(MeO)C6H4
2-(MeO)C6H4
4-ClC6H4
4-BrC6H4
4-Biphenyl
1-Naphthyl
2-Thiophene
C7H15
C6H5
C6H5
C6H5
C6H5
Piperidine
Piperidine
10
11
12
13
14
15
16
17
18
19
a
Morpholine
R2 5 R3 5 allyl
2-Methyl piperidine
cis-2,6-Dimethyl piperidine
R2 5 R3 5 Ph
R2 5 Ph, R3 5 H
Morpholine
Morpholine
Morpholine
C6H5
C6H5
C6H5
C6H5
C6H5
56
90
87
79
54
b
All reactions were carried out using 1 mmol of aldehyde, 1.2 eq. of amine, 1.5 eq. of acetylene and 2 mL of [bmim]PF6. Isolated yield.
1316 | Chem. Commun., 2005, 1315–1317
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Soon Bong Park and Howard Alper*
Centre for Catalysis Research and Innovation, Department of
Chemistry, University of Ottawa, 10 Marie Curie Ottawa, ON, Canada
K1N 6N5. E-mail: howard.alper@uottawa.ca
Notes and references
1 For reviews see: (a) C.-J. Li, Acc. Chem. Res., 2002, 35, 533; (b)
K. Sonogashira, in Handbook of Organopalladium Chemistry for
Organic Synthesis, ed. E. Negishi, John Wiley & Sons, New York,
2002, 493; (c) G. Dyker, Angew. Chem. Int. Ed., 1999, 38, 1698.
2 (a) J. J. Wolff, F. Siegler, R. Matschiner and R. Wortmann, Angew.
Chem. Int. Ed., 2000, 39, 1436; (b) N. Matsumi, K. Naka and Y. Chunjo,
J. Am. Chem. Soc., 1998, 120, 5112.
3 (a) B. Jiang and Y.-G. Si, Angew. Chem. Int. Ed., 2004, 43, 216; (b)
I. Paterson, R. D. Davies and R. Marquez, Angew. Chem. Int. Ed.,
2001, 40, 603; (c) M. Toyota, C. Komori and U. Ihara, J. Org. Chem.,
2000, 65, 7110.
Scheme 1 Tentative mechanism for A3 coupling reaction.
yield, while no reaction occurred in the case of cis-2,6-dimethyl
piperidine. Finally, the A3 coupling reaction proceeded well using
alkyl and aryl-substituted acetylenes (entries 17–19).
On the basis of these results, together with several literature
publications,5,6 it is believed that the A3 coupling reaction proceeds
by terminal alkyne C–H bond activation by copper catalysts
(Scheme 1). The copper acetylide intermediate thus generated
can react with the iminium ion prepared in situ from the aldehyde
and the amine, to form the corresponding propargylamine. The
released Cu(I) species is then able to be recycled. Because [bmim]PF6
is a hydrophobic room temperature ionic liquid, it is possible to
exclude water which is only by-product formed in these reactions.
This new method offers the following competitive advantages:
(i) recyclability of the catalyst without significant loss of catalytic
activity; (ii) use of readily available, cheap copper catalysts without
further purification, or without using other additives; (iii) lower
catalyst loading (2 mol%); (iv) broad substrate applicability; (v)
high yields attained in short reaction times; and (vi) simple and
easy operation.
4 (a) C. Koradin, N. Gommermann, K. Polborn and P. Knochel, Chem.
Eur. J., 2003, 9, 2797; (b) L. C. Akullian, M. L. Snapper and
A. H. Hoveyda, Angew. Chem. Int. Ed., 2003, 42, 4244; (c) C. Fisher and
E. M. Carreira, Org. Lett., 2001, 3, 4319; (d) G. S. Kauffman,
G. D. Harris, R. L. Dorow, B. P. R. Stone, R. L. Parsons, J. Pesti, Jr.,
N. A. Magnus, J. M. Fortunak, P. N. Confalone and W. A. Nugent,
Org. Lett., 2000, 2, 3119; (e) K. B. Aubrecht, M. D. Winemiller and
D. B. Callum, J. Am. Chem. Soc., 2000, 122, 11084.
5 (a) C. Wei and C.-J. Li, J. Am. Chem. Soc., 2003, 125, 9584; (b) C. Wei,
Z. Li and C.-J. Li, Org. Lett., 2003, 5, 4475; (c) C.-J. Li and C. Wei,
Chem. Commun., 2002, 268; (d) C. Wei and C.-J. Li, J. Am. Chem. Soc.,
2002, 124, 268; (e) Z. Li, C. Wei, L. Chen, R. S. Varma and C.-J. Li,
Tetrahedron Lett., 2004, 45, 2443.
6 L. Shi, Y.-Q. Tu, M. Wang, F.-M. Zhang and C.-A. Fan, Org. Lett.,
2004, 6, 1001.
7 (a) W. A. Herrmann and C. W. Kohlpaintner, Angew. Chem. Int. Ed.
Engl., 1993, 32, 1524; (b) B. Cornils and W. A. Herrmann, Aqueous-
Phase Organometallic Catalysis, Wiley-VCH, Weinheim, 1998.
8 (a) I. T. Horvath and J. Rabai, Science, 1994, 266; (b) I. T. Horvath,
Acc. Chem. Res., 1998, 31, 641; (c) E. de Wolf, G. van Koten and
B. J. Deelman, Chem. Soc. Rev., 1999, 28, 37; (d) Q. Zhang,
Z. Luo and D. P. Curren, J. Org. Chem., 2000, 65, 8866; (e)
M. Wende and J. A. Gladysz, J. Am. Chem. Soc., 2003, 125, 5861.
9 (a) D. E. Bergbreiter, P. L. Osburn, A. Wilson and E. M. Sink, J. Am.
Chem. Soc., 2000, 122, 9058; (b) D. E. Bergbreiter, Chem. Rev., 2002,
102, 3345; (c) T. Mizugaki, M. Murata, M. Ooe, K. Ebitani and
K. Kaneda, Chem. Commun., 2002, 52.
10 For reviews see: (a) A. R. Sethi, P. Smith, N. Srinivasa and T. Walton,
in Green Industrial Applications of Ionic Liquids, eds. R. D. Rogers,
K. R. Seddon and S. Volkov, Kluwer, Boston, 2002, vol. 92; (b)
J. Dupont, R. F. de Souza and P. A. Z. Suarez, Chem. Rev., 2002, 102,
3367; (c) R. Sheldon, Chem. Commun., 2001, 2399; (d) P. Wasserscheid
and W. Keim, Angew. Chem. Int. Ed., 2000, 39, 3772.
11 (a) S. B. Park and H. Alper, Org. Lett., 2003, 5, 3209; (b) S. B. Park and
H. Alper, Chem. Commun., 2004, 1306; (c) S. B. Park and H. Alper,
Tetrahedron Lett., 2004, 45, 5515.
12 (a) A. Soheili, J. Albaneze-Walker, J. A. Murry, P. G. Dormer and
D. L. Hughes, Org. Lett., 2003, 5, 4191; (b) K. Onitsuka, S. Yamamoto
and S. Takahashi, Angew. Chem. Int. Ed., 1999, 38, 174; (c) L. G. Bruk
and O. N. Temkin, Inorg. Chim. Acta, 1998, 280, 202; (d) B. M. Trost,
M. T. Sorum, C. Chan, A. E. Harms and G. Ruhter, J. Am. Chem. Soc.,
1997, 119, 698; (e) Q. Liu and D. J. Burton, Tetrahedron Lett., 1997, 38,
4371.
In summary, we have developed an efficient synthesis of
propargylamines through three-component coupling of aldehydes,
amines and alkynes via C–H activation by a copper catalyst in the
ionic liquid, [bmim]PF6. This system can be recycled five times
without any significant loss of catalytic activity.
A representative procedure for the coupling reaction follows: a
mixture of [bmim][PF6] (2 mL) and CuCN (2.0 mg, 0.02 mmol)
was degassed under reduced pressure at 80 uC for 30 min, and then
nitrogen gas was introduced. To the solution was added piperidine
(0.12 mL, 1.5 mmol), benzaldehyde (106 mg, 1.0 mmol) and
phenylacetylene (0.16 mL, 1.2 mmol), and the resulting mixture
was heated at 120 uC for 2 h. The product was extracted from the
reaction mixture by addition of diethyl ether and the recovered
ionic liquid layer was reused without any pretreatment. The
combined organic layer was concentrated and the desired product
was isolated by short-path silica gel column chromatography.
We are indebted to the Natural Sciences and Engineering
Research Council of Canada (NSERC) for support of this
research.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 1315–1317 | 1317