A novel and convenient copper-catalyzed three-component coupling of aldehydes, alkynes, and hydroxylamines leading to propargylamines

Article abstract of DOI:10.1016/j.tetlet.2012.03.009

The first copper-catalyzed direct three-component coupling reaction of aldehydes, alkynes, and hydroxylamines for the synthesis of propargylamines has been developed under mild conditions, which has the advantages of ready availability of catalyst as well as operation simplicity. The present protocol provides an appealing alternative for the construction of propargylamines in a simple and one-pot procedure.

Full text of DOI:10.1016/j.tetlet.2012.03.009

Tetrahedron Letters 53 (2012) 4797–4801
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel and convenient copper-catalyzed three-component coupling
of aldehydes, alkynes, and hydroxylamines leading to propargylamines
Na Guo a,b, Jian-Xin Ji a,
⇑
a Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
b Graduate University of the Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first copper-catalyzed direct three-component coupling reaction of aldehydes, alkynes, and hydrox-
ylamines for the synthesis of propargylamines has been developed under mild conditions, which has the
advantages of ready availability of catalyst as well as operation simplicity. The present protocol provides
an appealing alternative for the construction of propargylamines in a simple and one-pot procedure.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 31 October 2011
Revised 10 February 2012
Accepted 2 March 2012
Available online 9 March 2012
Keywords:
Copper catalysis
Three-component
Aldehyde
Alkyne
Hydroxylamine
Propargylamine
Multicomponent reactions (MCRs) are one of the most powerful
and versatile tools to assemble molecular complexity and diversity
from simple and readily available starting materials.1 The develop-
ment of novel MCRs to construct libraries of structurally complex
compounds for the evaluation of biological activities is a contin-
uing interest at the forefront of synthetic organic chemistry.
Propargylamines are important structural elements of drug mol-
ecules and versatile synthetic intermediates, which have attracted
increasingly synthetic pursuit of chemists due to their wide appli-
cations in the synthesis of a variety of nitrogenous compounds.2,3
Traditionally, propargylamines are prepared by amination of prop-
argylic halides,4 propargylic phosphates,5 and propargylic triflates,6
or through nucleophilic attack of lithium acetylides, Grignard
reagents on imines or their derivatives.7 However, these methods
suffer from issues of moisture sensitivity and the requirement
of strictly controlled reaction conditions. Recently, transition-
metal-catalyzed coupling reactions of aldehydes, alkynes, and
amines (A3 coupling reaction) to propargylamines have received
much attention due to their simple operation and high efficiency,
which employ amines as nitrogen sources. Li and others have re-
ported various A3 coupling reactions under homogeneous condi-
tions catalyzed by CuI salts,8 Cu/RuII bimetallic systems,9 IrI
complexes,10 AuI/AuIII salts,11 AuIII salen complexes,12 AgI salts,13
InIII salts,14 NiII salts,15 and FeIII salts16 as well as heterogeneous con-
ditions catalyzed by AgI,17 and CuI,8d in ionic liquids, Zn dust,18 sup-
ported AuIII,19a AgI,19b–d and CuI.19e–h Herein, we report a novel and
convenient copper catalyzed direct three-component coupling
reactions of aldehydes, alkynes, and hydroxylamines for the con-
struction of propargylamines under mild conditions (Eq. 1), in
which hydroxylamines were used as nitrogen sources. Approach
described in this communication provides a convenient and appeal-
ing alternative for the synthesis of propargylamines in a simple and
one-pot procedure.
ð1Þ
During the course of our continued interests in investigating
transition-metal-catalyzed multicomponent tandem reactions
to assemble complex and diverse hetero atom-containing com-
pounds,20,21 propargylamine 4a was discovered when the reaction
of butyraldehyde 1a, phenylacetylene 2a, and N,N-diethylhydr-
oxylamine 3a were performed in the presence of CuBr2 (Table 1,
entry 1), which enlightened us to develop a new method for
the synthesis of propargylamines from aldehydes, alkynes, and
hydroxylamines.
Initially, butyraldehyde 1a, phenylacetylene 2a, and N,N-diet-
hylhydroxylamine 3a were chosen as model substrates to examine
the catalytic activity of various metal catalysts. As shown in Table
1, among various metals screened, copper salts could catalyze the
⇑
Corresponding author. Tel.: +86 28 82855463; fax: +86 28 82855223.
E-mail address: jijx@cib.ac.cn (J.-X. Ji).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.009

4798
N. Guo, J.-X. Ji / Tetrahedron Letters 53 (2012) 4797–4801
Table 1
Screening of the catalystsa
Entry
Catalyst
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
CuBr2
CuCl2
Cu(OTf)2
Cu(OAc)2
(CH3CN)4CuPF6
CuBr
CuCl
CuI
5
5
5
5
5
5
5
5
61
62
37
36
41
66
64
49
0c
In(OTf)2, FeCl2, BiI3, IrCl3
AgOTf, AuClPPh3, Pd(OAc)2
AuBr3
12
12
5
10
11
12
Tracec
19
0
None
12
a
Reaction conditions: Compound 1a (1.0 mmol), 2a (1.5 mmol), 3a (1.5 mmol), 70 °C, under N2.
Isolated yields based on 1a.
Transition metals were used individually.
b
c
reaction and CuBr exhibited the best catalytic activity (entries 1–
8). Other metal complexes including In, Fe, Bi, Ir, Ag, Au(I), and
Pd salts were not effective for this transformation (entries 9 and
10). A low yield of 4a was obtained when AuBr3 was used as cata-
lyst (entry 11). No product was detected in the absence of catalyst
(entry 12).
Next, solvents, temperatures, and the proportions of the sub-
strates were examined using CuBr as catalyst (Table 2). Among
various solvents tested, toluene was found to be the optimal reac-
tion medium (entries 1–7). The best yield of 4a was obtained when
the reaction was performed at 70 °C (entries 1, 8, 9 and 10). The
appropriate proportion of the butyraldehyde 1a, phenylacetylene
2a, and N,N-diethylhydroxylamine 3a was1:1.5:1.5 (entries 11–
13).
and 1-hydroxypiperidine were compatible with this reaction and
1-hydroxypiperidine showed the best reactivity (4a–4c). Both
aliphatic and aromatic aldehydes were suitable substrates and
aliphatic aldehydes showed superior activity (4d–4k). With re-
spect to alkynes, both electron-rich and electron-deficient aro-
matic alkynes in our reaction system could be transformed into
the desired products (4l–4o). Heteroaryl alkyne and naphthyl
alkyne were also well tolerated, affording the corresponding prod-
ucts in moderate to good yields (4p and 4q).
Although the detailed reaction mechanism is not clear at the
present stage, the possibility that propargylamines were produced
through A3 coupling reaction (coupling reaction of aldehydes,
amines, and alkynes) has been excluded. It is known that propar-
gylamines could be obtained through copper catalyzed coupling
reactions of A3 coupling reaction.8,1
With the optimal reaction conditions in hand, the scope and
generality of this reaction were investigated with various combina-
tions of aldehydes, alkynes, and hydroxylamines. As shown in
Table 3, N,N-diethylhydroxylamine, N,N-dibenzylhydroxylamine,
In our system, a trace amount of dibenzylamine was detected
when the reaction of butyraldehyde 1a, phenylacetylene 2a, and
N,N-dibenzylhydroxylamine 3b22 was conducted under standard
Table 2
Optimization of the reactiona
Entry
T (°C)
Solvent
1a (mmol)
2a (mmol)
3a (mmol)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
70
70
70
70
70
70
70
rt
50
90
70
70
70
Toluene
THF
MeOH
Dioxane
CH3CN
DCE
1
1
1
1
1
1
1
1
1
1
1.5
1.5
1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1
66
40
32
38
10
60
52
32
55
58
49c
42d
65
Neat
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1.5
2
2
a
b
c
Reaction conditions: CuBr (5 mol %), compound 1a (indicated amount), 2a (indicated amount), 3a (indicated amount), solvent (1.0 mL), under N2, 5 h.
Isolated yields based on 1a.
Isolated yields based on 2a.
Isolated yields based on 3a.
d

N. Guo, J.-X. Ji / Tetrahedron Letters 53 (2012) 4797–4801
4799
Table 3
Results for the copper-catalyzed three-component coupling reactions of aldehydes, alkynes, and hydroxylaminesa
Products (yieldsb) Products (yieldsb) Products (yieldsb)
‘
a
Reaction conditions: CuBr (5 mol %), aldehyde (1.0 mmol), alkyne (1.5 mmol), hydroxylamine (1.5 mmol), toluene (1.0 mL), under
N2, 4–10 h.
b
Isolated yields based on aldehydes.
Scheme 1. Postulated reaction pathway.

4800
N. Guo, J.-X. Ji / Tetrahedron Letters 53 (2012) 4797–4801
conditions (Eq. 2). To investigate whether copper catalyzed A3
coupling reaction was involved in the present catalytic system,
the following control experiments were performed. When N,N-dib-
enzylhydroxylamine 3b was directly stirred with CuBr in the ab-
sence of butyraldehyde 1a and phenylacetylene 2a under the
standard conditions, only a trace amount of dibenzylamine was de-
tected by HPLC even after 24 h (Eq. 3). Furthermore, the addition of
butyraldehyde 1a (Eq. 4) or phenylacetylene 2a (Eq. 5) could not
improve the yield of dibenzylamine. Nevertheless, a 58% yield of
the desired product 4b could be obtained when the reaction of
butyraldehyde 1a, phenylacetylene 2a, and N,N-dibenzylhydroxyl-
amine 3b was conducted under the standard conditions for 6 h (Eq.
2). These results suggested that propargylamines 4 might not be
produced through the coupling reactions of aldehydes, alkynes,
and amines (A3 coupling reaction) in our reaction system. In addi-
tion, previous reports23 indicated that the addition reaction of
hydroxylamine with aldehyde might occur in our reaction system
In summary, we have developed the first copper catalyzed di-
rect three-component coupling reactions of aldehydes, alkynes,
and hydroxylamines leading to propargylamines. The present pro-
tocol, which utilizes simple and cheap catalyst and readily avail-
able starting materials, provides an attractive approach to
propargylamines. Investigations of the detailed reaction mecha-
nism and the synthetic application are currently underway.
Acknowledgment
We are grateful for the financial support from the National Nat-
ural Science Foundation of China (20802072).
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
03.009.
to produce a-hydroxyl-N-oxide (5, Scheme 1), which could be re-
duced with another molecule of hydroxylamine to generate aminal
(7, Scheme 1) and nitrone (6, Scheme 1). Indeed, nitrone 6b was
isolated from the reaction system of butyraldehyde 1a, phenylacet-
ylene 2a, and N,N-dibenzylhydroxylamine 3b under standard con-
ditions (Eq. 6).
ð2Þ
ð3Þ
ð4Þ
ð5Þ
ð6Þ
On the basis of the above experiments and previous reports,23,8c,d
a postulated reaction pathway was outlined in Scheme 1. The
addition reaction of aldehyde 1 and hydroxylamine 3 gave amine
N-oxides 5, which was reduced by another molecule of hydroxyl-
amine to give nitrone 6 and aminal 7. Next, 7 was transformed to
iminium ion 8. Then, the nucleophilic attack of copper acetylide
intermediate 9 on iminium ion 8 produced the desired propargyl-
amine 4 in a similar manner of the addition of the copper acetylide
intermediate on iminium ion in A3 coupling reaction, which was
also proved by the deuterium labeling studies Eq. 7. 8c,d
References and notes
1. (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A.
Acc. Chem. Res. 1996, 29, 123–131; (b) Weber, L.; Illgen, K.; Almstetter, M.
Synlett 1999, 366–374; (c) Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P.
Chem. Eur. J. 2000, 6, 3321–3329; (d) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed.
2000, 39, 3168–3210.
2. (a) Abeles, R. H.; Maycock, A. L. Acc. Chem. Res. 1976, 9, 313–319; (b) Ohmomo,
S.; Hirata, M.; Murakami, K.; Magata, Y.; Tanaka, C.; Yokoyama, A. Chem. Pharm.
Bull. 1991, 39, 1038–1040; (c) Manfré, F.; Kern, J.-M.; Biellmann, J.-F. J. Org.
Chem. 1992, 57, 2060–2065; (d) Swett, L. R.; Martin, W. B.; Taylor, J. D.; Everett,
G. M.; Wykes, A. A.; Gladish, Y. C. Ann. N.Y. Acad. Sci. 1963, 107, 891–898.
3. (a) Yoshitake, Y.; Yamaguchi, K.; Kai, C.; Akiyama, T.; Handa, C.; Jikyo, T.;
Harano, K. J. Org. Chem. 2001, 66, 8902–8911; (b) Hong, F.-E.; Tsai, Y.-T.; Chang,
Y.-C.; Ko, B.-T. Inorg. Chem. 2001, 40, 5487–5488; (c) Takayama, H.; Suzuki, T.;
Nomoto, T. Chem. Lett. 1978, 865–866; (d) Matsuda, I.; Fukuta, Y.; Itoh, K. Inorg.
Chimica Acta 1999, 296, 72–79; (e) Neunhoeffer, H.; Werner, G. Liebigs Ann.
Chem. 1974, 1190–1194.
4. Kopka, I. E.; Fataftah, Z. A.; Rathke, M. W. J. Org. Chem. 1980, 45, 4616–
4622.
ð7Þ

N. Guo, J.-X. Ji / Tetrahedron Letters 53 (2012) 4797–4801
4801
5. Imada, Y.; Yuasa, M.; Nakamura, I.; Murahashi, S.-I. J. Org. Chem. 1994, 59,
2282–2284.
17. Li, Z.; Wei, C.; Chen, L.; Varmab, R. S.; Li, C.-J. Tetrahedron Lett. 2004, 45, 2443–
2446.
6. Czernecki, S.; Valéry, J.-M. J. Carbohydr. Chem. 1990, 9, 767–770.
7. (a) Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc. 2004, 126,
5968–5969; (b) Ryan, C. W.; Ainsworth, C. J. Org. Chem. 1961, 26, 1547–1550;
(c) Jung, M. E.; Huang, A. Org. Lett. 2000, 2, 2659–2661; (d) Tubéry, F.; Grierson,
D. S.; Husson, H.-P. Tetrahedron Lett. 1987, 28, 6457–6460.
8. (a) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed.
2003, 42, 5763–5766; (b) Bisai, A.; Singh, V. K. Org. Lett. 2006, 8, 2405–2408; (c)
Shi, L.; Tu, Y.-Q.; Wang, M.; Zhang, F.-M.; Fan, C.-A. Org. Lett. 2004, 6, 1001–
1003; (d) Park, S. B.; Alper, H. Chem. Commun. 2005, 1315–1317; (e)
Gommermann, N.; Knochel, P. Chem. Commun. 2004, 2324–2325; (f)
Gommermann, N.; Knochel, P. Synlett 2005, 2799–2801.
18. Kantam, M. L.; Balasubrahmanyam, V.; Shiva Kumar, K. B.; Venkanna, G. T.
Tetrahedron Lett. 2007, 48, 7332–7334.
19. (a) Zhang, X.; Corma, A. Angew. Chem., Int. Ed. 2008, 47, 4358–4361; (b)
Kantam, M. L.; Prakash, B. V.; Reddy, C. R. V.; Sreedhar, B. Synlett 2005, 15,
2329–2332; (c) Maggi, R.; Bello, A.; Oro, C.; Sartori, G.; Soldi, L. Tetrahedron
2008, 64, 1435–1439; (d) Reddy, K. M.; Babu, N. S.; Suryanarayana, I.; Prasad, P.
S. S.; Lingaiah, N. Tetrahedron 2006, 47, 7563–7566; (e) Wang, S.; He, X.; Song,
L.; Wang, Z. Synlett 2009, 3, 447–450; (f) Li, P.; Wang, L. Tetrahedron 2007, 63,
5455–5459; (g) Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Sreedhar, B.
Tetrahedron Lett. 2004, 45, 7319–7321; (h) Wang, M.; Li, P.; Wang, L. Eur. J. Org.
Chem. 2008, 2255–2261.
9. Li, C.-J.; Wei, C. Chem. Commun. 2002, 268–269.
10. Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319–4321.
20. Zhang, Q.; Cheng, M.; Hu, X.; Li, B.-G.; Ji, J.-X. J. Am. Chem. Soc. 2010, 132, 7256–
7257.
11. Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584–9585.
12. Lo, V. K.-Y.; Liu, Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2006, 8, 1529–1532.
13. Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003, 5, 4473–4475.
14. (a) Zhang, Y.; Li, P.; Wang, M.; Wang, L. J. Org. Chem. 2009, 74, 4364–4367; (b)
Yadav, J. S.; Subba Reddy, B. V.; Hara Gopal, A. V.; Patil, K. S. Tetrahedron Lett.
2009, 50, 3493–3496.
15. Samai, S.; Nandi, G. C.; Singh, M. S. Tetrahedron Lett. 2010, 51, 5555–5558.
16. Li, P.; Zhang, Y.; Wan, L. Chem. Eur. J. 2009, 15, 2045–2049.
21. Cheng, M.; Zhang, Q.; Hu, X.; Li, B.-G.; Ji, J.-X.; Chan, A. S. C. Adv. Synth. Catal.
2011, 353, 1274–1278.
22. Dibenzylhydroxylamine was purchased from Aldrich company and no
dibenzylamine was detected by HPLC and HRMS from this reagent.
23. (a) Laughlin, R. G. J. Am. Chem. Soc. 1973, 95, 3295–3299; (b) Moran, J.;
Gorelsky, S. I.; Dimitrijevic, E.; Lebrun, M.-E.; Bédard, A.-C.; Séguin, C.;
Beauchemin, A. M. J. Am. Chem. Soc. 2008, 130, 17893–17906.