Well-defined (N-heterocyclic carbene)-Ag(i) complexes as catalysts for A3 reactions

Article abstract of DOI:10.1039/c2ob06900h

The use of well-defined (N-heterocyclic carbene)-Ag(i) complexes for the A³ reaction allows for the coupling of unactivated aldehydes at room temperature and very short reaction times. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob06900h

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Organic &
Biomolecular
Chemistry
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Volume 10 | Number 11 | 21 March 2012 | Pages 2177–2340
ISSN 1477-0520
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Oscar Navarro et al.
Well-defined (N-heterocyclic carbene)–Ag(I) complexes as catalysts for A3
reactions
1477-0520(2012)10:11;1-J

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COMMUNICATION
Well-defined (N-heterocyclic carbene)–Ag(I) complexes as catalysts for
A3 reactions†‡
Ming-Tsz Chen, Brant Landers and Oscar Navarro*
Received 10th November 2011, Accepted 19th December 2011
DOI: 10.1039/c2ob06900h
Ag, activating the Ag–C bond towards the nucleophilic addition
to the carbonyl. In contrast to those results, it has been shown
that the use of Ag complexes bearing even more electron donat-
ing N-heterocyclic carbenes (NHCs)9 instead of phosphines
allows for a switch back of the reactivity towards the A3
coupling.10,11
Despite this different reactivity, the use of NHCs as ligands
for the A3 reaction has barely been explored. To the best of our
knowledge, only two (NHC)–Ag(I) catalytic systems have been
reported: one of them using well-defined complexes in air and
at high temperature,10 and another using recyclable, polymer-
supported (NHC)–Ag(I) complexes, which can operate at room
temperature, under N2 and needing long reaction times.11 In both
cases, the ligands and the corresponding complexes were specifi-
cally synthesized for this reaction. We report herein that the use
of well-defined complexes derived from commercially available
NHC ligands allows for A3 coupling reactions to take place at
room temperature, in air and in much shorter reaction times
(Scheme 1).
The synthesis of the (NHC)–Ag(I) complexes used in this
study (Fig. 1) was done according to very straightforward pro-
cedures reported in the literature and starting from commercially
available NHCs or their precursors, imidazolium salts.12 After
determining that the use of methanol as solvent afforded the
highest yields when 1 mol% of (IPr)AgCl (1) was used as cata-
lyst (Table 1, entry 11), variations of this complex were screened
for activity towards the same set of substrates, using even lower
catalyst loading (Table 2). We observed that changing the
carbene IPr to its saturated counterpart SIPr did not have a con-
siderable effect in the formation of product (Table 2, entry 2).
On the other hand, the activity of the catalyst was notably
affected by the nature of the anion in the order OAc > Cl > Br
≫ I. This trend had been observed previously (for the halides
The use of well-defined (N-heterocyclic carbene)–Ag(I) com-
plexes for the A3 reaction allows for the coupling of unacti-
vated aldehydes at room temperature and very short reaction
times.
The use of the A3 coupling reaction has gained a lot of attention
since the first examples of this protocol were reported in the
early 2000s by Ishii,1 Carreira2 and Li.3 This highly efficient
multicomponent coupling involves the combination of an alde-
hyde, and amine and an alkyne in the presence of a transition
metal catalyst, leading to the formation of propargylamines,
which are recurrent components of biologically active pharma-
ceuticals and natural products, as well as valuable intermediates
for the synthesis of nitrogen-containing compounds.4 A wide
variety of transition metal catalysts have been used in this reac-
tion, such as Ru, Re, Ir, Au, Cu, and more recently Fe, Co, Ni
and Zn.5
Li and co-workers reported in 2003 the first examples of Ag-
catalyzed A3 reactions.6 The particularity of this catalytic system
was that it was especially effective towards aliphatic aldehydes,
in contrast to Cu and Au systems, more effective towards aro-
matic aldehydes, and less undesired trimerization of the aldehyde
was observed. Reactions were carried out in water at 100 °C,
under N2 and for several hours. When (PR3)–Ag(I) complexes
were used instead,7 the authors observed a switch in activity,
obtaining exclusively the aldehyde–alkyne coupling product
(Scheme 1).8 The authors postulated that a phosphine–Ag–acety-
lide was a key intermediate in the reaction, and suggested that
the coordination of the ligand increased the electron density on
Department of Chemistry, University of Hawaii at Manoa, 2545
McCarthy Mall, Honolulu, HI 96822-2275, USA. E-mail: oscarnf@
hawaii.edu; Fax: +1 808 956 5908; Tel: +1 808 956 5904
†Electronic supplementary information (ESI) available: Product charac-
terisation. See DOI: 10.1039/c2ob06900h
‡General Procedure for the A3reaction: All reactions were set up in
air. The catalyst (n mol%) was added to a vial equipped with a magnetic
bar, followed by the aldehyde (1 mmol), amine (1.1 mmol), alkyne
(1.1 mmol) and solvent (0.5 mL). The vial was then sealed with a screw
cap fitted with a septum and the mixture allowed to stir on a stirring
plate at the corresponding temperature. The reaction was monitored by
gas chromatography. When it was determined that the reaction was
finished, the solvent was evaporated in vacuum and the product isolated
by flash chromatography. The amount of product shown is the average
of two runs.
Scheme 1 Ligand-controlled alkynylation of carbonyls and imines.
2206 | Org. Biomol. Chem., 2012, 10, 2206–2208
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Fig. 1 (NHC)–Ag(I) complexes tested in this study.
Table 1 Solvent selection
Entry
Solvent
Time (h)
Yield (%)a,b
1
2
3
4
5
6
7
8
neat
acetone
DCM
MeCN
toluene
DMF
3
3
3
3
3
3
3
1
62
63
69
96
9
57
19
88
98
68
94
water
isopropanol
methanol
isopropanol
methanol
9
10
11
1
0.25
0.25
a Reaction conditions: aldehyde, 1 mmol; amine, 1.1 mmol; alkyne,
1.1 mmol; solvent, 0.5 mL b GC yield (hexamethylbenzene as internal
standard); average of 2 runs.
Table 2 Catalyst selection
Entry
Complex
Time (min)
Yield (%)a,b
1
2
3
4
5
6
1
2
3
4
5
6
20
20
20
20
20
20
86
88
70
9
91
96
Scheme 2 Substrate scope.
a Reaction conditions: aldehyde, 1 mmol; amine, 1.1 mmol; alkyne,
1.1 mmol; methanol, 0.5 mL. b GC yield (hexamethylbenzene as
internal standard); average of 2 runs.
1 mol% of (SIPr)Ag(OAc) (6) allowed for the coupling to occur
in only 20 min (Table 2, entry 6). It is worth mentioning that all
reactions were set up in open air, in technical grade methanol
and without any purification of the coupling partners.
only) by Zou and co-workers, who used it to suggest that the
first step of the catalytic cycle involves the coordination of the
alkyne to an (NHC)AgX complex, followed by the formation of
the corresponding silver alkynide.10 This coordination would
be favoured with a less bulky anion.13 We found that the use of
Following this optimized protocol, we were able to couple a
variety of aldehydes, amines and alkynes to obtain the corre-
sponding propargylamines in very good yields (Scheme 2). In
agreement with Li’s results using AgI,6 the use of our (NHC)–
Ag system was more effective towards the coupling of aliphatic
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2206–2208 | 2207

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D. Harris, R. L. Dorow, B. R. P. Stone, R. L. Parsons Jr., J. A. Pesti, N.
A. Magnus, J. M. Fortunak, P. N. Confalone and W. A. Nugent, Org.
Lett., 2000, 2, 3119.
5 For a very recent review, see: W.-J. Yoo, L. Zhao and C.-J. Li, Aldrichi-
mica Acta, 2011, 44, 43.
aldehydes (Scheme 2, compounds 7–17). A distinctive feature
of this protocol is that, in contrast to other (NHC)–Ag(I)
systems,10,11 the use of complex 6 allows for the coupling of
unactivated aryl aldehydes at room temperature, albeit requiring
much longer reaction times (Scheme 2, compounds 18–22).
These reaction times can be decreased considerably by increas-
ing the temperature and/or the catalyst loading.
In summary, we have developed a general (NHC)–Ag(I) cata-
lyzed protocol for the A3 coupling of unactivated alkyl and aryl
aldehydes, at room temperature and using low catalyst loadings.
Studies on expanding the scope of the reaction and the develop-
ment of an enantioselective protocol are currently ongoing in
our labs.
6 C. Wei, Z. Li and C.-J. Li, Org. Lett., 2003, 5, 4473.
7 X. Yao and C.-J. Li, Org. Lett., 2005, 7, 4395.
8 In that report there is one reaction carried out at room temperature invol-
ving the coupling of p-trifluoromethylbenzaldehyde and phenylacetylene,
and using twice as much catalyst loading (10 mol%).
9 Heterocyclic Carbenes in Transition Metals Catalysis and Organocataly-
sis, ed. C. S. J. Cazin, Springer, London, 2010; N-Heterocyclic Carbenes
in Transition Metal Catalysis, ed. F. Glorius, Springer, Berlin, 2007.
10 Y. Li, X. Chen, Y. Song, L. Fang and G. Zou, Dalton Trans., 2011, 40,
2046.
11 P. Li, L. Wang, Y. Zhang and M. Wang, Tetrahedron Lett., 2008, 49,
6650.
12 T. Ramnial, C. D. Abernethy, M. D. Spicer, I. D. McKenzie, I. D. Gay
and J. A. C. Clyburne, Inorg. Chem., 2003, 42, 1391; P. de Frémont,
N. M. Scott, E. D. Stevens, T. Ramnial, O. C. Lightbody,
C. L. B. Macdonald, J. A. C. Clyburne, C. D. Abernethy and S. P. Nolan,
Organometallics, 2005, 24, 6301; D. Partyka and N. Deligonul, Inorg.
Chem., 2009, 48, 9463; D. V. Partyka, T. J. Robilotto, J. B. Updegraff III,
M. Zeller, A. D. Hunter and T. G. Gray, Organometallics, 2009, 28, 795;
C. A. Citadelle, E. L. Nouy, F. Bisaro, A. M. Z. Slawin and
C. S. J. Cazin, Dalton Trans., 2010, 39, 4489.
13 To the best of our knowledge there are not any reported crystal structures
of (NHC)Ag(OAc) complexes, which would allow us to make a true
comparison with the halide-bearing counterparts to explain the higher
reactivity of 6. The crystal structure of the analogous (SIPr)Cu(OAc)
suggests a more accessible metal centre when compared to (SIPr)CuCl:
L. A. Goj, E. D. Blue, S. A. Delp, T. B. Gunnoe, T. R. Cundari and
J. L. Petersen, Organometallics, 2006, 25, 4097.
Acknowledgements
The authors acknowledge the National Science Foundation
(CHE 0924324) for support.
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This journal is © The Royal Society of Chemistry 2012