reactivities of these complexes in catalyzing organic reactions
remain sparse.11
In the present work, five gold(III) salen complexes 1a-e
were synthesized and characterized according to a known
literature procedure9b with minor modifications. In brief,
1a-e were prepared by treatment of K[AuIIICl4] (1 equiv)
with the corresponding salen ligand (5 equiv) in refluxing
CH2Cl2/EtOH in the presence of NH4PF6 (6 equiv) for 20
min (Supporting Information).
At the outset, we set out to examine the catalytic activity
of 1a in the three-component coupling reaction. The reaction
was conducted by heating 1a (0.02 mmol), benzaldehyde (2
mmol), piperidine (2.2 mmol), and phenylacetylene (3 mmol)
in water (1 mL) under a nitrogen atmosphere at 40 °C for
24 h in the absence of light. On the basis of 1H NMR analysis
of the crude reaction mixture, 99% conversion of benzalde-
hyde was found, and propargylamine 2a was isolated in 94%
yield (Table 1, entry 1).12 Reducing the catalyst loading of
Here, we report the first three-component coupling reaction
of aldehydes, amines, and alkynes catalyzed by gold(III)
salen complexes in water at 40 °C affording a variety of
propargylamines in excellent yields (Scheme 1). When chiral
Table 1. Effect of Temperature and Catalyst Screeninga
Scheme 1. Gold(III) Salen Complex-Catalyzed
Three-Component Coupling Reaction
temperature
(°C)
substrate
conversion (%)b
yield
(%)c
entry catalyst
1
1a
1a
1a
1a
1b
1c
1d
1e
40
40
99
41
54
78
75
92
64
35
94
88
78
72
72
90
64
80
prolinol derivatives were employed as the amine component,
excellent diastereoselectivity (up to 99:1) was achieved. In
addition, this three-component coupling reaction has been
successfully applied to the synthesis of a series of propar-
gylamine-modified artemisinin derivatives, which were found
to exhibit cytotoxicities with IC50 values up to 1.1 µM against
a human hepatocellular carcinoma cell line (HepG2). It is
worth noting that the delicate endoperoxide bridge of the
artemisinin derivatives remains intact after the coupling
reactions.
2d
3
room temperature
room temperature
40
40
40
40
4e
5
6
7
8
a Catalyst/benzaldehyde/piperidine/phenylacetylene ) 0.01:1:1.1:1.5.
b Determined by 1H NMR analysis of the crude reaction mixture. c Isolated
yield based on benzaldehyde conversion. d 1a (0.05 mol %). e Reaction time
was 72 h.
(5) For reviews on gold-catalyzed organic reactions, see: (a) Dyker, G.
Angew. Chem., Int. Ed. 2000, 39, 4237. (b) Hashmi, A. S. K. Gold Bull.
2004, 37, 51. (c) Arcadi, A.; di Giuseppe, S. Curr. Org. Chem. 2004, 8,
795. (d) Hoffmann-Ro¨der, A.; Krause, N. Org. Biomol. Chem. 2005, 3,
387. For selected examples on gold-catalyzed C-C bond formation reactions
through activation of alkynes, see: (e) Hashmi, A. S. K.; Frost, T. M.;
Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553. (f) Dyker, G.; Hildebrandt,
D.; Liu, J.; Merz, K. Angew. Chem., Int. Ed. 2003, 42, 4399. (g) Shi, Z.;
He, C. J. Org. Chem. 2004, 69, 3669. (h) Kennedy-Smith, J. J.; Staben, S.
T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526. (i) Staben, S. T.;
Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2004, 43, 5350.
(j) Luzung, M. R.; Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004,
126, 10858. (k) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126,
15978. (l) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925.
(m) Me´zailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133. (n)
Kim, N.; Kim, Y.; Park, W.; Sung, D.; Gupta, A. K.; Oh, C. H. Org. Lett.
2005, 7, 5289. (o) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 5802. (p) Nieto-Oberhuber, C.; Lo´pez, S.; Echavarren, A. M. J.
Am. Chem. Soc. 2005, 127, 6178. (q) Zhang, L.; Kozmin, S. A. J. Am.
Chem. Soc. 2005, 127, 6962. (r) Markham, J. P.; Staben, S. T.; Toste, F.
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1a to 0.05 mol % gave 2a with 41% conversion and 88%
isolated yield (entry 2), respresenting a product TON of 820.
In addition, the reactions could be performed at room
temperature with good catalytic activity (54% conversion
with 78% yield in 24 h, entry 3; 78% conversion with 72%
yield in 72 h, entry 4).
We also examined the catalytic activities of gold(III) salen
complexes 1b-e. With catalyst 1b bearing -OEt groups on
the aromatic rings, a decrease in substrate conversion (75%)
and yield (72%) of 2a resulted (entry 5). Yet, for 1c with a
cyclohexylamine moiety, comparable conversion (92%) and
yield (90%) with catalyst 1a were obtained (entry 6). For
1d (-Cl) and 1e (-Me), a further reduction in conversions
and yields resulted (entry 7 for 1d, 64% conversion, 64%
yield based on conversion; entry 8 for 1e, 35% conversion,
80% yield based on conversion). Our findings suggest that
these substituents on the aromatic rings of the salen ligands
may exert unfavorable effects on the substrate conversion.
On the contrary, no adverse effect was observed for 1c
bearing a cyclohexylamine moiety. Apart from gold(III) salen
(6) (a) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584. (b) Kantam,
M. L.; Prakash, B. V.; Reddy, C. R. V.; Sreedhar, B. Synlett 2005, 15,
2329.
(7) (a) Li, G.-Y.; Chen, J.; Yu, W.-Y.; Hong, W.; Che, C.-M. Org. Lett.
2003, 5, 2153. (b) Li, Y.; Chan, P. W. H.; Zhu, N.-Y.; Che, C.-M.; Kwong,
H.-L. Organometallics 2004, 23, 54. (c) Xu, H.-W.; Li, G.-Y.; Wong, M.-
K.; Che, C.-M. Org. Lett. 2005, 7, 5349.
(8) Zhou, C.-Y.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2006, 8, 325.
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Org. Lett., Vol. 8, No. 8, 2006