A highly efficient three-component coupling of aldehyde, alkyne, and amines via C-H activation catalyzed by gold in water

Article abstract of DOI:10.1021/ja0359299

A highly efficient three-component-coupling of aldehyde, alkyne, and amine (A³ Coupling) catalyzed by gold via C-H activation was developed in water. The reaction is general, and nearly quantitative yields of the corresponding propargylamines were obtained in most cases. Both aromatic and aliphatic aldehydes and amines can be used for the reaction. No additional cocatalyst or activator is required. A mechanistic rationale for the reaction has been proposed. Copyright

Full text of DOI:10.1021/ja0359299

Published on Web 07/19/2003
A Highly Efficient Three-Component Coupling of Aldehyde, Alkyne, and
Amines via C-H Activation Catalyzed by Gold in Water
Chunmei Wei and Chao-Jun Li*
Department of Chemistry, Tulane UniVersity, New Orleans, Louisiana 70118, and
Department of Chemistry, McGill UniVersity, 801 Sherbrooke St. West, Montreal, QC H3A 2K6 Canada
Received May 2, 2003; E-mail: cjli@tulane.edu
Table 1. Three-component Coupling of Benzaldehyde, Piperidine,
and Phenylacetylene Catalyzed by Gold in Water
The increasing environmental consciousness of the chemical
community has led to the search for more efficient and environ-
mentally friendly methods for chemical syntheses.1 One of the
related research areas has been the development of Barbier-
Grignard type reactions in water.2 Representative examples include
allylation,3 propargylation,4 benzylation,5 arylation/vinylation,6 and
the aldol-type reaction.7 A Barbier-Grignard type carbonyl alkyl-
ation with nonactivated halides in water has also been developed.8
On the other hand, an alternative reaction via catalytic C-H
activation9 in water by using a water-soluble catalyst would provide
an atom-economical approach10 for such reactions.
Recently, we11 and others12 have described Grignard-type reac-
tions of alkyne to aldehyde and imines to generate propargyl
alcohols and via catalytic C-H activation in water and organic
media. A highly enantioselective addition of alkynes to imines to
generate optically propargylamines in water by using a chiral copper
catalyst has also been developed by us.13 However, the previous
methods in water are largely limited to imines generated from
arylamines and aromatic aldehydes. As a continued interest to
develop efficient synthesis of propargylamines via activation of
alkynes, herein we report a highly efficient three-component-
coupling of aldehyde, alkynes, and amines (A3 Coupling) catalyzed
by gold in water (Scheme 1). The reaction is general and can be
applied to both aromatic and aliphatic aldehydes and amines. Nearly
quantitative yields were obtained in most cases. Furthermore, no
cocatalyst or activator (as in the ruthenium- and copper-catalyzed
imine additions) is required, less than 1 mol % of catalyst is needed,
and water is the only byproduct for the reaction.
entry
catalyst (mol %)
solvent/temp (°C)/time (h)
conversion (%)a
1
2
3
4
5
6
7
8
AuCl (5)
AuCl (1)
AuI (1)
H2O/100/12
H2O/100/12
H2O/100/12
H2O/100/12
H2O/100/12
H2O/100/12
H2O/100/12
H2O/100/2
H2O/100/5.5
H2O/r.t./72
THF/r.t./48
toluene/100/12
DMF/100/12
99
99
99
100
100
0
AuBr3 (1)
AuCl3 (1)
Au0 sponge (3)
AuBr3 (0.25)
AuBr3 (1)
AuBr3 (1)
AuBr3 (1)
AuBr3 (1)
AuBr3 (1)
AuBr3 (1)
99
93
9
100
81
10
11
12
13
55b
78b
62b
a Conversions were determined by 1H NMR of the crude reaction mixture.
b Various byproducts were observed.
to 13% conVersion during the same reaction period. As AuBr3 is
relatively cheaper among these gold salts and the most effective, it
was therefore chosen as the catalyst for other substrates. Gold metal
itself did not show any catalytic activity. No reaction was observed
in the absence of Au(I) or Au(III) or when the reaction was carried
out under an atmosphere of air. The nature of the reaction media
significantly affects the reaction. Whereas reactions proceeded
cleanly in water, the use of organic solvent such as THF, toluene,
and DMF resulted in a low conversion and more byproducts.
The catalysis was then applied to various aldehydes and
dialkylamines as summarized in Table 2. Both aromatic and
aliphatic aldehydes, including those bearing functional groups such
as alkoxy, chloro, bromo, and trifluoromethyl additions, were able
to undergo the corresponding three-component-coupling. Aryl
aldehydes with electron-donating groups (entries 2, 3, 4, and 5)
reacted smoothly; however, as 4-methoxybenzaldehyde and 4-alkyl-
benzaldehyde showed, electron-rich groups bound to the benzene
ring decreased the reactivity and required a longer reaction time.
Electron-withdrawing groups (entries 5, 6, 7, 8, 9, and 10) displayed
high reactivities; reactions were completed at a lower temperature
and gave higher conversions. The decreased yield for aliphatic
aldehydes is caused by the trimerization of aliphatic aldehydes. The
corresponding amine also has an effect on the reaction: whereas
dialkylamines reacted smoothly in these conditions, aniline formed
the corresponding product in lower yields, and N-alkylanilines and
1° amines were inert for the reactions. Aliphatic alkynes also worked
effectively (entries 15 and 16).
Scheme 1
Compared to other late transition metals, gold has not been
extensively explored as a catalyst. However, recent work by Ito,14
Hashmi,15 and others16 has demonstrated unique catalytic properties
of gold in several reactions. Whereas only ca. 10% of the corre-
sponding product was obtained by using CuBr, the three-component
coupling of benzaldehyde, piperidine, and phenylacetylene in the
presence of 5 mol % AuCl afforded quantitative yield of the desired
propargylic amine as shown by the 1H NMR of the crude reaction
mixture (see Table 1). No other additive was needed for this
reaction. Subsequently, gold salts such as AuCl, AuI, AuBr3, and
AuCl3 were tested, and all showed excellent catalytic activities.
Au(III) salts seemed slightly better than Au(I) salts. Even when
only 0.25 mol % AuBr3 was used as the catalyst, the conversion of
the reaction still was as high as 99% (the yield, 98%). EVen with
only 0.01 mol % AuBr3 used as the catalyst, the reaction still led
A tentative mechanism was proposed (see Scheme 2) involving
the activation of the C-H bond of alkyne by a Au(I) species17
(for AuBr3-catalyzed, Au(I) can be generated in situ from
reduction of Au(III) by the alkyne). The gold acetylide intermediate
thus generated reacted with the immonium ion generated in situ
9
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J. AM. CHEM. SOC. 2003, 125, 9584-9585
10.1021/ja0359299 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Coupling of Aldehyde, Alkyne, and Amine Catalyzed by
Gold in Water
Scheme 2. Tentative mechanism for the gold-catalyzed reaction
in water
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 experimental
procedure and characterization of all new compounds (PDF). This
material is available free of charge via the Internet at http:/pubs.acs.org.
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In conclusion, a highly efficient gold-catalyzed three-component-
coupling of aldehyde, alkyne, and amine via C-H activation has
been achieved in water. 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 amines.
Water is the only byproduct in this novel three-component reaction.
The scope, mechanism, stereoselectivity, and synthetic applications
of this reaction are under investigation.
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