The First Silver-Catalyzed Three-Component Coupling of Aldehyde, Alkyne, and Amine

Article abstract of DOI:10.1021/ol035781y

(Equation presented) Silver iodide catalyzed the three-component coupling of aldehyde, alkyne, and amines to generate propargylic amines with high efficiency in water. The silver-catalyzed reaction is especially effective for reactions involving aliphatic

Full text of DOI:10.1021/ol035781y

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4473-4475
The First Silver-Catalyzed
Three-Component Coupling of Aldehyde,
Alkyne, and Amine
,†,§
Chunmei Wei,†,‡ Zigang Li,†,‡ and Chao-Jun Li*
Department of Chemistry, Tulane UniVersity, New Orleans, Louisiana 70118,
and Department of Chemistry, McGill UniVersity, 801 Sherbrooke St. West,
Quebec H3A 2K6 Canada
cjli@tulane.edu; cj.li@mcgill.ca
Received September 15, 2003
ABSTRACT
Silver iodide catalyzed the three-component coupling of aldehyde, alkyne, and amines to generate propargylic amines with high efficiency in
water. The silver-catalyzed reaction is especially effective for reactions involving aliphatic aldehyde. No additional cocatalyst or activator is
required.
In comparison with other transition metals, silver has been
virtually untouched as a catalyst for coupling purposes. Very
recently, a few silver-catalyzed reactions such as aza-Diels-
Alder reaction,1 asymmetric aldol reaction,2 addition,3 cou-
pling,4 cyclization,5 and allylation6 have been reported;
however, in most cases, the silver species served as either a
cocatalyst or a Lewis acid. Silver “catalysts” in a “transition
metal” sense are commonly considered to have low efficiency
and not to be as good as other late transition metals. On the
other hand, the development of environmentally friendly
synthetic methods has become an increasingly important
consideration for many chemists.7 One such subject is the
development of the Barbier-Grignard-type reaction in water.
With the low atom economy of the classical Barbier-
Grignard-type reaction generating stoichiometric amounts of
metal ions and halides, an alternative reaction via catalytic
C-H activation would provide a greener approach for such
reactions. Recently, we8 and others9,10 have described the
direct addition of terminal alkyne to aldehyde and imines to
† Tulane University.
‡ Wei, C. M. and Li, Z. G. contributed equally to this research.
§ McGill University.
(1) (a) Loncaric, C.; Manabe, K.; Kobayashi, S. AdV. Synth. Catal. 2003,
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F.; Frost, C. G.; Weller, A. S. Chem. Eur. J. 2002, 8, 2088-2098. (c)
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(7) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice,
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10.1021/ol035781y CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/18/2003

Scheme 1
Table 2. Coupling of Aldehyde, Alkyne, and Amine Catalyzed
by AgI in Water
afford propargyl alcohol and propargylamines. With Cu(I)-
pybox as a chiral catalyst, a highly enantioselective imine
addition in either water or toluene was developed.11 We also
developed the coupling of alkynes with N-acylimines and
N-acyliminiun ions mediated by a CuBr catalyst.12 Because
of our continued interest in synthesizing propargylamine via
activation of alkynes, we found that gold can be used as a
highly efficient catalyst for a three-component coupling
reaction of aldehyde, alkyne, and amine in water.13 However,
previous success in such three-component couplings has been
largely limited to the aromatic aldehydes. Aliphatic aldehyes
have led to both low yields and conversions.
Herein we wish to report that AgI is a highly effective
catalyst for the three-component coupling of aldehyde,
alkyne, and amine to generate propargylamines in water,
without using any other cocatalyst or additives (Scheme 1).
Furthermore, a reversal of the reactivity of aliphatic and
aromatic aldehydes was observed compared to our early
reported systems, in which aliphatic aldehydes were often
much more reactive than aromatic aldehydes.
In an effort to seek a more effective catalyst for the
coupling of aldehyde, alkyne, and amines, water-soluble or
partially soluble salts such as AgNO3, Ag2O, AgOAc, Ag2-
SO4, AgOTf, AgBF4 were all found to catalyze the reaction
of benzaldehyde, piperidine, and phenylacetylene with low
conversion (ca. 25-45%) together with the formation of
some carboxylic acid. Metal silver did not show any catalytic
activity. To reduce the consumption of the catalyst due to
reduction by aldehyde, we screened some water-insoluble
Table 1. Silver-Catalyzed Reaction of Benzaldehyde,
Piperidine and Phenylacetylene in Watera
entry
catalyst (3 mol %)
time (h)
conversion (%)
a Isolated yields based on aldehyde were reported; carried out on a 2
mmol scale with aldehyde/amine/alkyne ) 1:1.2:1.5 and 1.5 mol % AgI,
100 °C, 1 mL of water. b Carried out on a 1 mmol scale with 3% AgI under
the same conditions.
1
2
3
4
5
6
7
8
9
AgOTf
AgBF4
Ag2O
Ag2SO4
AgNO3
AgF
AgCl
AgBr
AgI
14
14
14
14
14
14
14
14
14
40
35
40
42
40
40
55
60
75
Ag salts. No desired product was found with Ag2S. However,
AgCl, AgBr, and AgI showed good results, and AgI was
found to be the most effective in catalyzing the three-
component coupling. No other additive was needed for this
reaction. The reaction did not proceed in the absence of AgI
or under an air atmosphere.
a All reactions were carried out on 1 mmol scale based on aldehyde;
conversions were based on 1H NMR measurement of crude reaction
mixtures.
Subsequently, various aldehydes, alkynes, and dialky-
lamines were similarly coupled and the results were sum-
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Org. Lett., Vol. 5, No. 23, 2003

marized in Table 2. Both aromatic and aliphatic aldehydes
were able to undergo addition to afford the corresponding12
three-component propargylic amines effectively. While only
a trace amount of product was obtained with acyclic amines
(such as diallylamine), cyclic dialkylamines and various
terminal alkynes reacted well in these conditions. However,
the reaction was found to be highly affected by the nature
of the aldehyde. Aryl aldehyde decreased the reactivity of
the reaction, required a longer reaction time for reaction
completion, and gave lower conversions and lower yields.
Aliphatic aldehydes, on the other hand, displayed higher
reactivity and cleaner reactions. The reactions involving
aliphatic aldehydes gave both higher conversions and greater
yields. While unwanted trimerization of aldehyde was a
major limitation of the reactions catalyzed by gold and
copper, almost no trimer was formed with aliphatic aldehydes
when using AgI as the catalyst. The reactions proceeded very
well in either water or an organic solvent such as toluene
and DMF. The conversions of coupling cyclohexylcarbox-
aldehyde, piperidine, and phenylacetylene in toluene and
DMF were 95 and 98%, respectively. Even when only 0.2
mol % AgI was used as a catalyst, the reaction in water still
led to more than 95% conversion and an isolated yield of
92%. A tentative mechanism was proposed involving the
exchange of H of the C-H bond of alkyne by a Ag(I)
species. The silver acetylide intermediate thus generated
reacted with the iminium ion generated in situ from aldehydes
and secondary amines to give the corresponding propargy-
lamine and regenerate the Ag(I) catalyst for further reactions
(Scheme 2).
Scheme 2
In conclusion, we have developed a highly effective three-
component coupling of aldehyde, alkyne, and amine with
silver as the catalyst. This process is simple and provides a
diverse range of propargylamines in high yields. Aliphatic
aldehydes are particularly effective for the reaction, which
provides an effective complement of gold- and copper-
catalyzed A3 coupling. The scope, mechanism, and synthetic
application of other silver-catalyzed couplings are under
further investigation.14
(11) (a) Wei, C. M.; Li, C. J. J. Am. Chem. Soc. 2002, 124, 5638-5639.
(b) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002,
41, 2535-2538.
(12) Zhang, J. H.; Wei, C. M.; Li, C. J. Tetrahedron Lett. 2002, 43.
5731-5733.
(13) Wei, C. M.; Li, C. J. J. Am. Chem. Soc. 2003, 125, 9584-9585.
(14) A representative procedure: A mixture of AgI (7 mg, 0.03 mmol),
cyclohexylcarboxaldehyde (244 µL, 2.0 mmol), piperidine (210 µL, 2.2
mmol), phenylacetylene (300 µL, 3 mmol) in water (1 mL) was stirred at
100 °C oil-bath for 2 h under N2. The reaction mixture was cooled, extracted
with ether (3 × 15 mL) and dried over MgSO4. Analysis of the crude
mixture by 1H NMR showed a quantitative conversion of aldehyde. The
product was isolated by flash chromatography on silica gel (eluent:
hexanes-EtOAc) to give propargylamine in almost quantitative yield (540
mg, 96%).
Acknowledgment. We are grateful to NSF and the NSF-
EPA joint program for a sustainable environment for partial
support of our research.
Supporting Information Available: Representative ex-
perimental procedure and characterization of all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL035781Y
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