Smaller, faster, better: Modular synthesis of unsymmetrical ammonium salt-tagged NHC-gold(i) complexes and their application as recyclable catalysts in water

Article abstract of DOI:10.1039/c5ob01286d

Facile access towards a small library of unsymmetrical ammonium salt-tagged N-heterocyclic carbene gold(i) complexes is described, and their application as recyclable catalysts in cyclization reactions of acetylenic carboxylic acids and amides to lactones and lactams, respectively, in aqueous media is demonstrated. Catalyst 1ab was applied in the synthesis of 2-epi-clausemarine A (16).

Full text of DOI:10.1039/c5ob01286d

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Smaller, faster, better: modular synthesis of
unsymmetrical ammonium salt-tagged
NHC–gold(I) complexes and their application
as recyclable catalysts in water†
Cite this: DOI: 10.1039/c5ob01286d
Katrin Belger and Norbert Krause*
Received 24th June 2015,
Accepted 8th July 2015
Facile access towards a small library of unsymmetrical ammonium salt-tagged N-heterocyclic carbene
gold(I) complexes is described, and their application as recyclable catalysts in cyclization reactions of
acetylenic carboxylic acids and amides to lactones and lactams, respectively, in aqueous media is demon-
strated. Catalyst 1ab was applied in the synthesis of 2-epi-clausemarine A (16).
DOI: 10.1039/c5ob01286d
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Introduction
Sustainable chemistry is a frequently used term which indi-
cates economic, ecological friendly and safe transformations.
Accordingly, the development of new chemical reactions
should combine waste prevention, use of nonhazardous sol-
vents, and renewable raw materials.1 In organometallic chem-
istry, main objectives are reusable catalysts, easy separation of
products, and prevention of side reactions.2 To achieve these
goals, the use of water-soluble catalysts represents a desirable
pathway. For this purpose, N-heterocyclic carbene (NHC) metal
complexes were linked to water-soluble polymers3,4 or silica-
based surfaces4 and carbohydrates.5 Moreover, they were
functionalized with hydrophilic groups, such as carboxylates6,7
or sulfonates,7,8 resulting in improved water solubility and
consequently an easier separation of the product and the cata-
lyst, and also the opportunity for catalyst recycling.9,10
Fig. 1 Modular system for the synthesis of ammonium salt-tagged gold
catalysts 1.
allenic and acetylenic alcohols in aqueous medium.11 More-
over, we could successfully demonstrate their high stability
and recyclability in water.
Since the first synthesis of
a sulfonated NHC–metal
Here, we report an even more facile access towards
ammonium salt-functionalized NHC–gold complexes. A shor-
tened synthetic pathway is achieved by the application of a
modular system which provides access to a small library of
gold catalysts 1. These ligands consist of an arylimidazole and
a benzylic linker with an attached ammonium group (Fig. 1).
The ammonium salt is introduced by aminoalkylation with tri-
methyl-, triethyl-, or tributylamine.
complex by Herrmann et al., the number of reports about
water-soluble NHC ligands has been increasing steadily.
However, ammonium salt-tagged NHC ligands still play a
minor role in transition metal catalysis,8 and only a limited
number of publications deal with a direct synthesis of the
ammonium function.11,12 More often, an amino group of the
final NHC–metal complex is quaternized with a Brønsted
acid.13–15 Recently, we reported the direct synthesis of
ammonium salt-tagged IMesAuCl complexes and demon-
strated their catalytic activity in cycloisomerization reactions of
Results and discussion
Organic Chemistry, Dortmund University of Technology, Otto-Hahn-Str. 6, D-44227
The synthesis of the ammonium salt-tagged NHC–gold com-
plexes 1 started with the formation of N-arylimidazoles 2a and
2b (Scheme 1). These were obtained from commercially avail-
able 2,4,6-trimethylaniline and 2,6-diisopropylaniline, respect-
Dortmund, Germany. E-mail: norbert.krause@tu-dortmund.de;
Fax: (+)49 231 755 3884
†Electronic supplementary information (ESI) available: Experimental details and
NMR spectra. See DOI: 10.1039/c5ob01286d
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Table 1 Cycloisomerization of carboxylic acid 10a to lactone 11a in the
presence of gold catalyst 1ab
Medium
Cycle
Water
Buffer solutiona
Conv.b (%)
Yieldc (%)
Conv.b (%)
Yieldc (%)
1
2
3
4
5
99
98
87
84
79
78
73
72
66
63
>99
>99
>99
99
89
87
88
84
81
Scheme 1 Synthesis of building blocks 2 and 3 (DIBAL-H = diisobutyl-
aluminum hydride; DCM = dichloromethane; DHP = 3,4-dihydro-2H-
pyran; PPTS = pyridinium p-toluenesulfonate).
97
a 1.0 M triethylammonium acetate solution (pH = 7). b Determined by
1H NMR. c Isolated yield.
ively, according to a literature procedure with similar yields to
those reported.16 The second building block 3 was formed by
reduction of methyl 4-(chloromethyl)benzoate 5 with diiso-
butylaluminum hydride (DIBAL-H; 96% yield) and tetrahydro-
pyranyl-(THP)-protection of alcohol 6 (63% yield).
pyridinium groups. Related studies were reported by Navarro
Ranninger18 who applied platinum complexes and also investi-
gated the hydrolysis of the lactone and its mechanism. Fur-
thermore, copper and palladium complexes were also used in
lactonization reactions of unsaturated carboxylic acids in
aqueous medium.19,20 The corresponding cyclization of acety-
lenic amides to lactams was mainly performed in the presence
of TBAF or bases in organic solvents.21,22 The only example of
a metal-catalyzed cyclization was published by Nagasaka who
used a lithium hexamethyldisilazide/AgOTf system.23 As far as
we know, this reaction has not yet been carried out in water.
As a benchmark reaction, we first investigated the cycliza-
tion of 4-pentynoic acid (10a) to lactone 11a in the presence of
gold catalyst 1ab at room temperature in water (Table 1). A
recycling of catalyst 1ab after product extraction with diethyl
ether showed decreasing conversions (99–79%) and yields
(78–63%) over five cycles. As the measured pH value of penty-
noic acid (pKa = 4.21 (ref. 24)) in water is 2.44, the gold
complex slowly decomposed with the formation of a black pre-
cipitate in the acidic medium. The use of a triethylammonium
acetate buffer solution with pH = 7 led to high conversions
over five cycles and enhanced yields of 89–81%. Notably, an
activation of the gold catalyst with a silver salt is not necessary.
At present, it is not clear whether complex 1 or a cationic gold
species formed by dissociation of chloride is the catalytically
active species, even though the rather high concentration of
the strongly coordinating chloride anion (from the ammonium
chloride side chain) in the reaction mixture certainly disfavors
the latter.25
The coupling of these building blocks was performed by
heating 2a or 2b in acetonitrile in the presence of 3 to form
the imidazolium salts 7a and 7b with 78% and 76% yield,
respectively (Scheme 2). Here, the THP ether was cleaved
during the acidic work-up. The alcohols 7 were chlorinated
with thionyl chloride (90/96% yield) and an aminoalkylation
with trimethyl-, triethyl-, or tributylamine gave the desired
carbene precursors 9 (66–86% yield). These imidazolium salts
were transformed into the corresponding gold(I) complexes in
the presence of (Me2S)AuCl and potassium tert-butoxide. The
NHC gold complexes 1 were obtained with 71–86% yield.
The catalytic activity of the new unsymmetrical ammonium
salt-tagged gold catalysts 1 was investigated in cycloisomeriza-
tion reactions of acetylenic carboxylic acids and amides. The
gold-catalyzed lactonization of acetylenic carboxylic acids in
water was previously examined by Cadierno et al.17 who used
zwitterionic water-soluble gold complexes with sulfonate and
Next, we applied the full library of ammonium salt-tagged
gold catalysts 1 to the cycloisomerization of different acetylenic
carboxylic acids in aqueous buffer solution (Table 2). It turned
out that the mesityl-substituted catalysts 1aa–ac gave better
results than their 2,6-diisopropylphenyl-substituted counter-
parts 1ba–1bc. In particular, catalyst 1ab gave high yields of
lactones 11 (84–94%) in all cases. Even though the corres-
ponding complex 1aa showed a similar reactivity, it gave lower
yields (69–86%) than 1ab. These results were similar to 1bb
Scheme 2 Synthesis of unsymmetrical ammonium salt-tagged gold(I)
complexes 1.
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Table 2 Cycloisomerization of carboxylic acids 10 to lactones 11 in the
presence of gold catalysts 1 in aqueous buffer solutiona
Scheme 3 Gold-catalyzed cycloisomerization of 4-pentynoic acid
(10a) and hydrolytic ring-opening of lactone 11a.
Catalyst
1aa
1ab
1ac
1ba
1bb
1bc
Substrate
R1, R2
Yieldb (%)
Table 4 Cycloisomerization of amides 13 to lactams 14 in the presence
of gold catalysts 1 in aqueous buffer solutiona
10a
H, H
69
77
86
72
81
89
85
94
84
84
85
83
91
77d
72
77
67
72
77
71
78
71
78
86
76
77
65
71
74d
69
10b
Me, H
iPr, H
Ph, H
Ph, Ph
10cc
10dc
10ec,d
a Reaction times required for full conversion are given in the ESI.
b Isolated yield. c 0.5 M solution of the carboxylic acid in THF was
used. d At 50 °C.
Catalyst
1aa
1ab
1ac
1ba
1bb
1bc
Substrateb
R
Yieldc (%)
13a
13b
13c
13d
H
95
84
85
77
92
89
80
82
89
86
87
78
81
90
79
84
92
92
72
75
91
Me
iPr
Ph
78
80
90
Table 3 Cycloisomerization of carboxylic acid 10a to lactone 11a in the
presence of different amounts of gold catalyst 1ab in aqueous buffer
solution
a Reaction times required for full conversion are given in the ESI. b 0.3
M solution of the amide in THF was used. c Isolated yield.
Entry
1ab (mol%)
Conversiona (%)
Yielda (%)
detected the formation of ketoacid 12a from 10a with gold
complexes within 1 h at rt, which led to moderate yields of
lactone 11a (50%) in pure water (ratio of 11a/12a = 3 : 1). With
our catalyst 1ab, however, there were no traces of 12a or any
other side product within this time (Table 1). Only after a pro-
longed reaction time of 24 h in pure water, we could isolate
21% of ketoacid 12a together with 50% of lactone 11a
(Scheme 3). In the triethylammonium acetate buffer solution,
similar yields were obtained after 24 h (12a: 18%; 11a: 54%).
After 3 days in buffer solution, 43% of 12a and 23% of 11a
could be isolated, whereas in the absence of a gold catalyst,
there was no formation of 12a. If we assume that the cycliza-
tion of 10a to 11a is irreversible, the ketoacid 12a is not
formed by hydration of 10a but rather by a slow gold-catalyzed
hydrolytic ring-opening of the lactone 11a. Accordingly, we
could not observe any formation of acetophenone when
phenylacetylene was heated to 60 °C for 24 h with gold
complex 1ab in water. Under these conditions, only the more
electron-rich 1-ethynyl-4-methoxybenzene gave 2% of the
corresponding ketone.
In analogy to the acetylenic carboxylic acids 10, the corres-
ponding tosylamides 13 26 can be smoothly cyclized to the
lactams 14 with the unsymmetrical ammonium salt-tagged
gold catalysts 1 in aqueous medium (Table 4). As the measured
pH value of amide 13a in water is 3.72 (calcd pKa = 6.31), we
again used a buffer solution to avoid degradation of the cata-
lyst. In general, all gold catalysts afforded high yields of
lactams 13. Only complexes 1ac/1bc with tributylammonium
groups needed extended reaction times of 2–4 h which has
1
2
3
4
2.5
1.0
0.5
0.1
>99
97
90
89
83
63
37
57
a Determined by 1H NMR (standard toluene).
(71–86%). The addition of THF as the cosolvent to carboxylic
acids 10c–e was necessary in order to dissolve the (otherwise
insoluble) substrates. Moreover, for carboxylic acid 10e the
temperature had to be raised to 50 °C to decrease the reaction
time to 0.5–4 h (otherwise, full conversion was obtained only
after 24 h at room temperature).
In order to render the transformation even more sustain-
able, we decreased the catalyst loading. As shown in Table 3,
similar results were obtained for the cycloisomerization of car-
boxylic acid 10a to lactone 11a with 1 mol% of 1ab instead of
2.5 mol% (entry 2 vs. 1). Even lower catalyst loadings of 0.5 or
0.1 mol% afforded incomplete conversion within 1 h (entries
3 and 4). However, increasing the reaction time to 3 h (with
0.5 mol% of 1ab; 79% yield) or 7 h (with 0.1 mol% 1ab; 74%
yield) was sufficient to give a full conversion of 10a to 11a.
A possible side reaction to the cyclization is the gold-cata-
lyzed hydration of the triple bond of the acetylenic acid in the
aqueous reaction medium. This has been observed previously
by other groups,17,18 but not (to this point) with the
ammonium salt-tagged gold catalysts 1. Cadierno et al.17 have
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of their unsymmetrical structure. The modular approach
allowed the synthesis of a small library of catalysts 1 with
overall yields of 32–47% starting from building blocks 2 and 3.
Gold complexes 1 catalyze the cycloisomerization of acetylenic
carboxylic acids and amides to the corresponding lactones and
lactams in aqueous medium with good to excellent yields. An
activation of the gold catalyst with a silver salt is not necessary.
The acid-promoted degradation of the catalysts in pure water
can be prevented by adjustment of the pH value to 7. The
recyclability of gold catalyst 1ab was demonstrated for the
benchmark reaction of carboxylic acid 10a to lactone 11a. In
contrast to previous gold catalysts operating in water, for-
mation of ketoacids as a side product can be avoided with gold
complexes 1. Moreover, we could successfully apply catalyst
1ab in the synthesis of 2-epi-clausemarine A (16). Further
examples of sustainable gold catalysts will be reported in due
course.
Fig. 2 Furanocoumarin clausemarine A (15) isolated from Clausena
lansium, and its 2-epimer 16.
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Scheme 4 Synthesis of 2-epi-clausemarine A (16).
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