Light-Stable Silver N-Heterocyclic Carbene Catalysts for the Alkynylation of Ketones in Air

Article abstract of DOI:10.1002/cctc.201500869

N-Heterocyclic carbene (NHC) silver(I) complexes were employed efficiently in the alkynylation of ketones. These cationic complexes were highly active and efficient under mild conditions and in air without the need for an additive. The mechanism of this transformation was investigated. Experiments suggest that the formation of a silver acetylide key intermediate and the release of one ligand from the silver centre enable the transformation.

Full text of DOI:10.1002/cctc.201500869

DOI: 10.1002/cctc.201500869
Full Papers
Light-Stable Silver N-Heterocyclic Carbene Catalysts for
the Alkynylation of Ketones in Air
Faïma Lazreg, Mathieu Lesieur, Andrew J. Samson, and Catherine S. J. Cazin*[a]
N-Heterocyclic carbene (NHC) silver(I) complexes were em-
ployed efficiently in the alkynylation of ketones. These cationic
complexes were highly active and efficient under mild condi-
tions and in air without the need for an additive. The mecha-
nism of this transformation was investigated. Experiments sug-
gest that the formation of a silver acetylide key intermediate
and the release of one ligand from the silver centre enable the
transformation.
Introduction
Propargylic alcohols are well-known building blocks in organic
chemistry.[1] Easily functionalised, these precursors lead to a va-
riety of molecules, such as allenes, alkenes and vinylsilanes,[1]
and find useful applications in the synthesis of natural prod-
ucts or pharmaceutical agents such as Efavirenz[2] or
Donaxarine[3] (Figure 1).
trifluoromethyl ketones in toluene at 1008C (or THF at 608C)
for 12–24 h.[9] In parallel, Deng and Li described an aqueous
process that showcased silver(I)/phosphine as an efficient
system for such a transformation. However, long reactions
times (1–2 days) were required, and the reaction had to be
conducted under an inert atmosphere.[10]
During the last decade, metal-N-heterocyclic carbene (NHC)
systems have become catalysts of choice that present out-
standing reactivity and stability.[13] Recently, Li and co-workers
reported an “on water” alkynylation of isatin using 5 mol% of
[Ag(Cl)(IMes)] (IMes=N,N’-bis[2,4,6-(trimethyl)phenyl]imidazol-
2-ylidene) in the presence of di-iso-propylethylamine (DIPEA,
10 mol%).[11] McQuade and co-workers demonstrated [Cu-
(Cl)(IPr)] (IPr=N,N’-bis[2,6-(di-iso-propyl)phenyl]imidazol-2-yli-
dene) and sodium tert-butoxide as a catalytically active system
for the alkynylation of trifluoromethyl ketones.[12] However, as
a result of the formation of a tert-butoxide species, an inert
atmosphere was required.
Figure 1. Examples of natural product and pharmaceutical reagents.
Propargylic alcohols are principally synthesised by the alky-
nylation of aldehydes or ketones, but their assembly usually re-
quires the presence of a zinc, lithium or Grignard reagent to
activate the alkyne.[4,5] Interestingly, numerous advances have
been reported in the area of CÀH activation of alkynes.[6] De-
spite the recent work reported on the direct alkynylation of al-
dehydes, ketones have remained a more challenging function-
ality to activate.[4,5,7] Amongst ketones, much less attention has
focused on trifluoromethyl ketone and isatin (1H-indole-2,3-
dione) derivatives.[8–12] In 2007, Shibasaki and co-workers re-
ported a methodology using a copper salt with Xantphos or
phenanthroline as the ligand (10 mol%) in the presence of po-
tassium tert-butoxide, which allowed the direct alkynylation of
Recently, our group reported the synthesis of heteroleptic
bis-NHC copper(I) and silver(I) complexes.[14,15] Although the
latter have not yet been tested in catalysis, the former have
shown excellent activity in the [3+2] cycloaddition of alkynes
and azides.[14] Mechanistic studies have shown that the reac-
tion likely proceeds through an acetylide complex, which
could also be a key intermediate in the alkynylation of ke-
tones.[9] Therefore, we reasoned that heteroleptic bis-NHC Cu
and Ag complexes could be efficient catalysts in such a trans-
formation.
Herein, we report the high efficiency of such complexes for
the alkynylation of trifluoromethyl ketones and isatin deriva-
tives using water or methanol/water mixtures as the solvent in
air and without the need for any additive.
[a] Dr. F. Lazreg, M. Lesieur, A. J. Samson, Dr. C. S. J. Cazin
EaStCHEM School of Chemistry
Results and Discussion
University of St Andrews
KY16 9ST, St Andrews (U.K.)
E-mail: cc111@st-andrews.ac.uk
N-Benzylisatin and phenylacetylene were selected as bench-
mark substrates for the optimisation of the reaction conditions.
[Cu(IPr)(ICy)]BF4 (1; ICy=N,N’-dicyclohexylimidazol-2-ylidene)
and [Cu(IPr)(ItBu)]BF4 (2; ItBu=N,N’-di-tert-butylimidazol-2-yli-
Supporting Information and ORCID(s) from the author(s) for this article
are available on the WWW under http://dx.doi.org/10.1002/
cctc.201500869.
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dene) were chosen as they are efficient catalysts for the [3+2]
cycloaddition and permit the direct CÀH activation of alkynes
without additives.[14] The silver analogues [Ag(IPr)(ICy)]BF4 (3)
and [Ag(IPr)(ItBu)]BF4 (4) were also evaluated (Figure 2).
Solvent optimisation was performed (see the Supporting In-
formation), which led us to a mixture of MeOH and H2O in
a 1:1 ratio as the optimal reaction medium. Under such condi-
tions, complex 3 provides superior catalytic activity than its
ItBu analogue 4 (Table 1, entries 10 and 11). A further decrease
of the catalyst loading to 0.5 mol% leads to a good conversion
if the reaction mixture is heated to 608C (Table 1, entry 17).
The scope of the reaction was examined (Scheme 1). N-Ben-
zylisatin was converted successfully in a series of propargylic
alcohols using aryl- and alkyl-substituted alkynes. In all cases,
quantitative conversion is observed with isolated yields that
ranged from 90 to 99%, which demonstrates the selectivity of
the process. Phenyl acetylene derivatives substituted with
a range of functional groups (F, OMe, Me, tBu, CF3) are convert-
ed efficiently (7aa–i). This is also the case with alkynes substi-
tuted with a heterocycle (7aj), alkyl and amino groups (7ak–l).
N-Methylated isatin can also be converted, however, in this
case, no methanol was used and the reaction was performed
in water (7ba). The versatility of the methodology is further
showcased by the reactivity of isatins substituted by electron-
donating and withdrawing groups (7ca, 7cd, 7da, 7db, 7eb).
All these reactions lead to the complete conversion to the al-
kynylation product in air in the presence of light using 2 mol%
of catalyst (for 7aa-c and 7eb, only 1 mol% was used). Nota-
bly, ethyltrimethylsilane as well as prop-2-yn-1-ol were tested,
however, no conversion towards the desired products was
observed.
Figure 2. Bis-NHC copper(I) and silver(I) complexes used in this study.
A
comparison of the four complexes in water using
2.5 mol% loading shows that, although the Cu catalysts are
moderately active, the Ag analogues lead to the propargylic al-
cohol quantitatively (Table 1, entries 1–4). No particular precau-
tion was taken to avoid the presence of light on using silver(I)
complexes 3 and 4. A decrease of the catalyst loading to
2 mol% showed no loss in catalytic activity. A further decrease
to 1 mol% Ag led to poor conversion (Table 1, entries 7–9).
Next, we turned our attention to the acyclic trifluoromethyl
ketone trifluoroacetophenone. In this case, the reaction is cata-
lysed efficiently using only 1 mol% of 3 in water and air and in
the presence of light (Scheme 2). The scope of the reaction
was investigated, and a series of propargylic alcohols was syn-
thesised in good to excellent isolated yields (75–99%). Phenyl
acetylene derivatives that bear electron-withdrawing and -do-
nating groups (F, CF3, Me, tBu, OMe) are well tolerated. Alkynes
other than phenyl acetylene derivatives can be used as shown
with 4-phenyl-1-butyne (9ak, 9bk), which extends the scope
to alkyl-substituted alkynes.
Table 1. Optimisation of bis-NHC silver(I) and copper(I) complexes.[a]
Entry
Complex
Catalyst
[mol%]
MeOH/H2O
Conversion
[%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1
2
3
4
3
4
3
4
4
3
4
3
4
3
4
3
3
2.5
2.5
2.5
2.5
2
2
1
1
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0:1
0:1
0:1
0:1
0:1
0:1
0:1
0:1
1:0
1:1
1:1
8:2
8:2
2:8
2:8
1:1
1:1
15
15
>99
>99
>99
98
30
26
30
40
Mechanistic studies
To obtain information on the nature of the organometallic in-
termediates involved in these reactions, 3 was reacted with an
excess of phenylacetylene at 608C in methanol/water for 15 h
(Scheme 3). This led to the formation of the silver acetylide
complex A with the concomitant loss of the imidazolium salt
ICy·HBF4 B (Scheme 3, and the Supporting Information). The in-
termediate acetylide
A can itself catalyse the reaction
10
8
4
20
(Scheme 4). The species A was reacted with N-benzylisatin,
which interestingly leads to the formation of an unstable new
species, presumably intermediate C (Scheme 5).
Based on these observations, a catalytic cycle is proposed
(Scheme 5) in which the bis-NHC Ag pre-catalyst leads to the
acetylide derivative A that can then react with the ketone to
form an alkoxide intermediate. The latter can be protonated
by the imidazolium salt B released during the first step, which
liberates the product and regenerates the catalyst. An alterna-
20
10[c]
73[d]
[a] Reaction
conditions:
N-benzylisatin
(0.25 mmol,
59.3 mg),
phenylacetylene (0.37 mmol, 41.2 mL), solvent (1 mL), 408C, 15 h, in air.
[b] Conversion determined by 1H NMR spectroscopy based on N-benzyli-
satin, minimum average of four reactions. [c] RT. [d] 608C.
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Scheme 2. Scope of trifluoromethyl ketones. Reaction conditions: Trifluoro-
methyl ketone (0.25 mmol), alkyne (0.375 mmol), 3 (1 mol%), water (1 mL),
1
60 8C, 15 h. Conversion determined by H NMR based on the isatin deriva-
tive, average of two reactions. Isolated yield is shown in parentheses.
Scheme 3. Stoichiometric reaction between 3 and phenylacetylene.
Scheme 4. Catalytic reaction involving the acetylide silver(I) complex A.
Scheme 1. Alkynylation of isatin derivatives. Reaction conditions: Isatin
(0.25 mmol), alkyne (0.375 mmol), 3 (2 mol%), methanol/water (1:1, 1 mL),
60 8C, 15 h. Conversion determined by H NMR based on the isatin deriva-
tive, average of two reactions. Isolated yield is shown in parentheses.
[a] 1 mol% of catalyst 3. [b] Only in water.
1
tive catalytic cycle might also be operative in which the proton
that leads to the liberation of the alcohol product comes from
the alkyne itself (Scheme 5, right-hand side). On-going compu-
tational studies are directed to answer these questions about
the preferred reaction pathway.
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Experimental Section
General procedure for catalysis: A vial was charged with [Ag(I-
Pr)(ICy)]BF4 (1.0 mol%), the ketone (0.25 mmol), the alkyne
(0.375 mmol) and the solvent (1 mL). The reaction mixture was
stirred at 608C for 15 h. The reaction mixture was allowed to cool
to RT. The aqueous layer was extracted with ethyl acetate (2”
10 mL). The combined organic layers were washed with brine
(20 mL). The organic phase was dried over MgSO4, filtered and the
solvent was evaporated. The crude product was purified by recrys-
tallisation or flash chromatography (SiO2).
Acknowledgements
The authors gratefully acknowledge the Royal Society (University
Research Fellowship to C.S.J.C.) for funding. We also thank the
EPSRC National Spectrometry Centre in Swansea for HRMS
analysis.
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Keywords: alkynes · carbene ligands · copper · ketones · silver
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Received: August 4, 2015
Published online on November 10, 2015
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