Permethylated NHC-Capped α- and β-Cyclodextrins (ICyDMe) Regioselective and Enantioselective Gold-Catalysis in Pure Water

Article abstract of DOI:10.1002/chem.202001990

A series of water-soluble encapsulated copper(I), silver(I) or gold(I) complexes based on NHC-capped permethylated cyclodextrins (ICyD^Me) were developed and used as catalysts in pure water for hydration, lactonization, hydroarylation and cycloisomerization reactions. ICyD^Me ligands gave cavity-based high regioselectivity in hydroarylations, and high enantioselectivities in gold-catalyzed cycloisomerizations reactions giving up to 98 % ee in water. These ICyD^Me are therefore useful ligands for selective catalysis in pure water.

Full text of DOI:10.1002/chem.202001990

Accepted Article
Accepted Article
Title: Permethylated NHC-capped a - and b -cyclodextrins (ICyDMe)
Regioselective and enantioselective gold-catalysis in pure water
Authors: Xiaolei Zhu, Guangcan Xu, Lise-Marie Chamoreau, Yongmin
Zhang, Virginie Mansuy, Louis Fensterbank, Olivia Bistri-
Aslanoff, Sylvain Roland, and Matthieu Sollogoub
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202001990
Link to VoR: https://doi.org/10.1002/chem.202001990
01/2020

10.1002/chem.202001990
Chemistry - A European Journal
Permethylated NHC-capped
Regioselective and enantioselective gold-catalysis in pure water
- and
a b
-cyclodextrins (ICyDMe)
Xiaolei Zhu,a† Guangcan Xu,a† Lise-Marie Chamoreau,a Yongmin Zhang,a Virginie Mouriès-Mansuy,a Louis
Fensterbank,a Olivia Bistri-Aslanoff,a Sylvain Roland,*a Matthieu Sollogoub*a
aSorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), UMR 8232, 4, place Jussieu, 75005
Paris, France
emails : sylvain.roland@sorbonne-universite.fr, matthieu.sollogoub@sorbonne-universite.fr
Abstract
A series of water-soluble encapsulated copper(I), silver(I) or gold(I) complexes based on NHC-capped
permethylated cyclodextrins (ICyDMe) were developed and used as catalysts in pure water for hydration,
lactonization, hydroarylation and cycloisomerization reactions. ICyDMe ligands gave cavity-based high
regioselectivity in hydroarylations, and high enantioselectivities in gold-catalyzed cycloisomerizations reactions
giving up to 98% ee in water. These ICyDMe are therefore useful ligands for selective catalysis in pure water.
Keywords Cyclodextrin, N-heterocyclic carbene, cavity, catalysis, water
Introduction
Encapsulation of metal centers inside molecular cavities is classically viewed as a way to imitate metallo-
enzymes.1 This strategy actually allowed selectivities in chemical reactions resembling those of enzymes:
regioselectivity,2 enantioselectivity,3 substrate selection4… However, only a few reactions are operating in the
solvent of enzymes: water.5 Some time ago, we uncovered a series of N-heterocyclic carbene (NHC)-capped
cyclodextrins (CDs) which encapsulate metal centers inside the cavity.6 The structure/properties of these
complexes are flexible and can be modulated by changing the nature of the NHC (imidazolyl, benzimidazolyl or
triazolyl), the size of the CD macrocycle (a, b or g-CD), the structure of the embedded metal complex, or the
nature of O-protecting groups (-OR, R = H, Ac or Bn), these latter affecting metal surroundings and solubility. In
organic solvents, we demonstrated that the outcome of some metal-catalyzed reactions was dependent on the
nature of the CD (a-, b- or g-CD) and could be linked to the shape of the cavity. Particularly, benzyl-protected
CD–imidazolyl ligands, called ICyD, were found to induce CD-dependent enantioselectivity or variation of
product distribution in gold-catalyzed cycloisomerizations,6,7 CD-dependent regioselectivity in copper-catalyzed
hydroboration,8 and chemoselectivity in a hydrosylilation controlled by the cavity size.9 An obvious
development, when using CD scaffolds, is their application in water. Water-soluble CD–NHC–silver complexes
were previously obtained by generation of a free hydroxy ligand (non-protected CD) from a-ICyD.6 Another
classical way to get water-soluble CDs is to partially or fully methylate the hydroxyl groups. A benzimidazolyl-
capped a-CD ligand having full OH protection by methyl groups was recently reported.10 The catalytic
properties of the corresponding gold complex was evaluated in organic solvents. This methylated ligand (a-
BiCyDMe) was found to behave similarly to the previously described benzylated one (a-BiCyD)7 in standard
gold-catalyzed cycloisomerization reactions.6,7
† These authors contributed equally to this work.
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10.1002/chem.202001990
Chemistry - A European Journal
We present here applications in water of a series of water-soluble (ICyDMe)MCl complexes (M = Au, Ag, Cu)
derived from a- and b-CD. The preparation and full structural study of ICyDMe-based complexes is reported
with NMR structural analyses both in water and organic solvents and X-ray structures obtained from
crystallization both in water and organic solvents. More importantly, we present our investigations concerning
the catalytic applications of encapsulated (ICyDMe)MCl complexes in pure water over a variety of reactions:
hydrations, lactonizations, hydroarylations and enantioselective cycloisomerizations, with a particular focus on
gold-catalyzed reactions.
Results and discussion
Synthesis of water-soluble (ICyDMe)MCl complexes
Synthesis of water-soluble a- and
b
-ICyDMe metal complexes started with the classical perbenzylation/double-
debenzylation sequence,11,12 followed by an optimized conversion of the as-obtained perbenzylated diol into
the corresponding permethylated one.13 Hence THP protection, hydrogenolysis, methylation and THP cleavage,
yielded diols 1
smoothly to give 2
conditions previously used for the formation of the perbenzylated ICyD azoliums (imidazole 20 equiv, DMF,
120 °C, overnight) were found not operative here as they gave the expected (
-ICyDMe)HCl salt 3α in very low
a
and 1
a
b
in 30% and 54% yields over four steps, respectively. Mesylation of both diols proceeded
and 2
b
in high yields. The next step was formation of imidazolium derivatives. The reaction
a
yields together with partial hydrolysis and formylated products. This result was also observed by Armspach in
attempts to use these conditions to cap the same CD derivative, but with benzimidazole.10 However, upon
analysis of the secondary products, we attributed this problem to the predominance of a non-expected
reaction with DMF and to the large excess of imidazole. Hence, DMF was replaced with toluene and
acetonitrile to favor imidazole solubilization; the amount of imidazole was decreased from 20 to 3 equivalents
and triethylamine was used as the base. Subsequent heating for 3 days allowed to obtain imidazolium (
ICyDMe)HCl 3α after ion exchange in 62% yield. The bridging of the b-CD 2 -ICyDMe)HCl 3
into (
required even longer reaction times probably due to the larger size of the cavity. Both silver complexes (
ICyDMe)AgCl 4α and ( -ICyDMe)AgCl 4
a
-
b
b
b
(55% yield)
a
-
b
b
were obtained quantitatively upon action of Ag2O on the corresponding
imidazolium salts. To get the corresponding copper and gold complexes two distinct routes had to be taken for
α-CD and b-CD derivatives. The direct metalation was used to get ( and (
-ICyDMe)AuCl 5 -ICyDMe)CuCl 6
-ICyDMe)AuCl 5α and ( -ICyDMe)CuCl
b
b
b
b
,
while transmetalations from silver complexes were required to obtain (
a
a
6α. (Scheme 1)
Scheme 1. Synthesis of (
-ICyDMe)MCl and ( -ICyDMe)MCl (M=Ag, Cu, Au).
a b
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10.1002/chem.202001990
Chemistry - A European Journal
Structure of (ICyDMe)MCl complexes.
All (ICyDMe)MCl complexes were first characterized by NMR in organic solvents (CDCl3 or CD3CN). As for
1
previously reported (ICyD)MCl complexes, the H NMR spectra of all ICyDMe-based complexes displayed
deshieldings of H-5 and H-3 protons typical of a M-Cl complex confined inside the CD cavity. Owing to the
water solubility of the permethylated CDs, NMR spectra in D2O were also recorded for the silver complexes (
a
-
ICyDMe)AgCl 4α and ( -ICyDMe)AgCl 4
b
b
. Interestingly, significant differences with the spectra in organic solvents
1
have been found. For comparison, the H NMR spectra of 4α in CDCl3 and D2O are displayed on Figure 1. In
CDCl3, the most deshielded intra-cavity protons are H-5A,D and H-3C,F, as observed with the benzylated complex
( -ICyD)AgCl 4α, which indicates that the shape of the cavity is probably the same in both cases. However, in
a
D2O, the order of chemical shifts between H-3s is changed, and H-3A,D becomes more deshielded than H-3C,F.
This observation suddenly rises questions, in particular about the shape of the cavity in water, or even on the
validity of our assumption concerning the relationship between distance of internal Hs and the metal complex
with their deshielding. It therefore became compulsory to obtain a crystal structure of ICyD-based metal
complexes.
Figure 1. 1H NMR spectra of (α-ICyDMe)AgCl (4α,400 MHz) in CDCl3 and in D2O.
Single crystals of (α-ICyDMe)AgCl (4α) could be obtained through slow diffusion of pentane and cyclohexane
into a solution of the complex in CDCl3. Interestingly enough, 4α also crystallized from deuterated water. Both
structures were resolved and are displayed on Figure 2. At first glance, the structures obtained are identical,
and confirm the encapsulation of the metal inside the CD torus. However, upon closer examination, striking
differences could be detected in particular when examining the H-3…Cl distances. The structure issued from
crystallization in organic solvents was symmetrical, as expected, and the distances between H-5s and the
metal, and those between the H-3s and the chlorine were in the same order as their chemical shifts as
previously hypothesized the closer to the metal or the halogen, the more deshielded.7 The examination of the
structure issued from crystallization in water revealed an asymmetry of the cavity, all distances between H-3s
and chlorine are different, a feature which is not apparent from the NMR spectrum. Furthermore, H-3A and H-
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10.1002/chem.202001990
Chemistry - A European Journal
3D are further away from chlorine than H-3C and H-3F on the structure but they are the most deshielded on the
NMR spectrum. This contradiction with our previous assumptions needed to be resolved. Upon careful
examination of both crystal structures, two molecules of water could be found in the cavity of the CD in each
case, even when (α-ICyDMe)AgCl (4α) was crystalized from organic solvents. Interestingly, these water
molecules are not situated exactly at the same place in both structures but they are both close to H-3A and H-
3D. In the solid phase these water molecules are in interaction through hydrogen bonding with both the
chlorine atom and these H-3s. The presence of water hence nicely explains the geometry and the NMR in which
the H-3A,D are deshielded because of their interaction with water molecules in aqueous solution but not in
organic solvents (although they are present in the crystal packing).
Figure 2. X-ray crystal structure of (α-ICyDMe)AgCl 4α from CDCl3/Pentane/Cyclohexane (A) and from D2O (B), distances
between H-3s and Cl are given in Å and as the average of those found in crystal.
To further support this hypothesis, a temperature-dependent NMR analysis was performed with 4α in D2O.
Upon heating, a shielding of H-3A,D was observed while H-3C,F chemical shift remained constant (Figure 3),
demonstrating that the shielding of H-3A,D is brought by an exchange process, while that of H-3C,F is
independent of the temperature and therefore is not brought by a dynamic process. We therefore propose
that the water–H-3A,D interaction is present in aqueous solution and that this is responsible for the strong
deshielding of this proton.
H-3A,D H-3C,F
362 K
353 K
338 K
323 K
313 K
300 K
Figure 3. Temperature-dependent 1H NMR of (α-ICyDMe)AgCl (4α, 600 MHz, D2O). Comparison of H-3A,D and H-3C,F chemical
shifts at different temperatures.
Catalysis in pure water with (ICyDMe)MCl complexes
In this study, the catalytic properties of water-soluble (ICyDMe)MCl complexes with encapsulated Ag, Cu, or Au,
have been investigated in a series of reactions with a particular focus on the use of water as the sole solvent
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10.1002/chem.202001990
Chemistry - A European Journal
and on gold-catalyzed reactions. Water has been shown to have a particular effect on reactivity and/or
selectivity in some reactions. It has also been seen as an alternative reaction medium to reduce the
environmental impact of (organic) synthesis,14 although other factors such as extraction and purification have
to be taken into consideration here. More importantly, the development of water-compatible gold-, silver-, or
copper-based catalytic systems, is highly interesting for in vivo applications.15 One of the main limitations for
developing catalytic reactions in pure water is the inherently low solubility of most organic materials, including
reaction substrates and catalysts. In many studies, an organic co-solvent was added to circumvent these
solubility issues. Alternatively, hydrophilic ligands have been developed for catalyst solubilization, and many
examples have been reported in copper and gold homogeneous catalysis.14,16 To the best of our knowledge,
this strategy was not particularly explored for silver-based catalysis in water.14,17 Furthermore, the increasing
importance of N-heterocyclic carbenes (NHC) as ligands has induced increasing efforts to develop hydrophilic
NHCs for metal-based catalysis in aqueous media,18,19,20,21,22 and medical applications.23 Ionic salt-tagged NHC
ligands have been designed for gold-catalyzed alkyne hydration,24,25,26,27 cycloisomerization reactions,26,28,29,30
and copper-catalyzed azide-alkyne cycloadditions (CuAAC).31,32 Although, water-soluble silver–NHCs have been
described since 2004 as antibacterial agents,33 they have mainly been used as carbene transfer agents,24,34 and
their application in homogeneous catalysis in water remains underexplored.35 In addition, examples of
encapsulated Cu, Ag or Au-based catalytic systems operating in water are scarce or nonexistent. To the best of
our knowledge, only two systems with encapsulated gold atoms operating in water are reported.36,37 A gold-
catalyzed hydroalkoxylation reaction with a phosphane-gold(I) complex confined in a (supra)molecular cage
was described in a 6:4 D2O/MeOH mixture.38 One example using a NHC-Au complex was reported with a
supramolecular capsule. This system was used for alkyne hydration in benzene-d6 with small amounts of
H2O.39,40 Encapsulated sulfonated copper phthalocyanine complexes in a protein cavity (BSA) were reported for
Diels-Alder reactions in aqueous medium.41 Recently, a bio-inspired imidazole-functionalized copper cage
complex was developed for benzylic alcohol oxidation in water.42
Hydration reactions:
In a first series of experiments, the potential of (α-ICyDMe)MCl and ( -ICyDMe)MCl complexes (M = Au, Ag, Cu)
b
was evaluated in the classical alkyne hydration reaction with different alkynes (7-10) (Scheme 2). All reactions
were first tested using D2O as the sole solvent. The reactions were run at 20 or 50 °C in NMR tubes and
monitored by 1H NMR. Yields were directly determined by comparison with the internal reference. The results
are summarized in Table 1. At 20 °C, both gold complexes (α-ICyDMe)AuCl 5α and ( -ICyDMe)AuCl 5
b b
(0.5 mol%)
were found to allow efficient hydration43 of water-soluble substrate 5-hexyn-1-ol 7 without pre-activation of
the catalyst by a silver salt,27,44 to give the corresponding bis-deuterated methyl ketone 11 in 92-99% yields
(Table 1, entries 1-2). The b-CD-derived catalyst 5 appeared more active than the a-CD-based 5α, leading to
b
complete conversion and quantitative NMR yield after 14 h. This result is similar to that reported for the
hydration of 7 in neat water using ammonium-tagged water-soluble NHC-gold complexes at the same catalyst
loading (0.5 mol%).27 The alkyne 8 reacted slowly at 20 °C with both 5α and 5
b
as gold catalysts, to give 12 in 8-
10% yield after 24 h under similar conditions (data not shown). Increasing the temperature to 50 °C was
necessary to obtain the bis-deuterated ketone 12 in 88-95% yields (Table 1, entries 3-4). As observed with
alkyne 7, the hydration of 8 is faster when catalyzed by ( , that leads to a complete conversion
-ICyDMe)AuCl 5
b b
after 24 h. The limitation of using deuterated water as the sole solvent appeared with the more lipophilic
alkyne substrates 9 and 10. In contrast to 7, the terminal alkyne 9 was found to react hardly in neat water, but
gave good yields by using deuterated methanol as co-solvent to give bis-deuterated ketone 13 in 85-99% NMR
yields (Table 1, entries 7-8).45 Here also, the larger b-ICyDMe ligand afforded better yields, probably due to
easier accessibility of the substrate to the metal.46 This trend was clearly confirmed with internal alkyne 10.
Hence, under standard conditions (50 °C), 10 did not react with a-CD-based catalyst 5α, while (b-ICyDMe)AuCl
5 allowed its hydration, to give ketone 14 in 26% yield, demonstrating some size selection of the substrate by
b
the ICyD-based catalysts albeit not in water but in methanol (Table 1, entries 9-10). With terminal alkynes and
Au catalysts, Markovnikov addition of water is usually observed to give the methyl ketones.44 However, an
encapsulated NHC–Au complexes was previously shown by Reek an co-workers to give detectable amounts
(4%) of the aldehyde regioisomer in the hydration of 4-phenyl butyne 9 in a water-saturated benzene-d6
solution.47 To compare with this result, the regioselectivity of the hydration of 9 catalyzed by encapsulated
(ICyDMe)AuCl complexes was studied in H2O. Over prolonged heating at 50 °C for 7 days, both a and b-CD-
derived (ICyDMe)AuCl complexes were found to induce non-negligible formation of aldehyde (up to 3 %), along
with 20-27% of the expected methyl ketone 12 (see Figure and Table S1 in the supporting information). This
result is comparable to that previously observed by Reek and co-workers.39
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10.1002/chem.202001990
Chemistry - A European Journal
Very few examples of silver-based catalytic systems have been reported for hydration reactions in water.17
Silver nanoparticles were used for the selective hydration of nitriles,48 and a silver salt of heteropolytungstate
was reported for hydration of alkynes.49 Both systems involve heterogeneous catalysis. Silver nitrate (AgNO3) in
water was shown to give slow hydration of phenylacetylene at 100 °C (15% conversion).49 Therefore, the
catalytic activity of (ICyDMe)AgCl complexes was investigated in the hydration reaction of alkynes 7-10 in water
(Table 1, entries 11-15). In contrast to the corresponding gold complexes, both (
ICyDMe)AgCl 4
were found to be inactive for the hydration of water-soluble alkyne 7 at 20 °C (data not shown).
-ICyDMe)AgCl 4α and (
a b
-
b
However, at 50 °C, 4α (0.5 mol%) efficiently induced the formation of the expected bis-deuterated methyl
ketone 11 which was obtained in 92% NMR yield (Table 1, entry 11). Here also, a significant difference with
gold complexes was observed, since 4
(Table 1, entry 12). To investigate why (b-ICyDMe)AgCl was less effective, we followed the reaction by NMR
(with 7) and showed that in water at 50 °C the b-CD-based silver catalyst 4 was decomposing. In contrast, 4α is
b
was found ineffective in the same reaction, leading to no conversion
b
stable under these conditions and allows the reaction to take place, hence demonstrating the high stabilizing
effect of the CD cavity in this latter case. (a-ICyDMe)AgCl 4α also catalyzes the conversion of 8 into the methyl
ketone 12 (49% yield, Table 1, entry 13). As for gold complexes, the reaction is difficult with lipophilic alkynes,
and both 4α and 4 were found to be inefficient for the transformation of 9 and 10, even in the presence of
b
methanol (Table 1, entries 14-15). Finally, (a-ICyDMe)CuCl 6α and (b-ICyDMe)CuCl 6
b
did not allow the hydration
of the studied alkynes under the same conditions (Table 1, entries 16-18).
Scheme 2. Hydration reaction of alkynes 7-10 with D2O catalyzed by (ICyDMe)MCl complexes (M = Au, Ag, Cu). (A) Terminal
alkynes, (B) internal alkyne. Methanol-d4 was used as co-solvent in some reactions.
(A)
O
(α- or β-ICyDMe)MCl (0.5 mol%)
D2O / (CD3OD)
H(D)
D(H)
R
R
(H)D
7: R = (CH2)4OH
8: R = CH2OH
11: R = (CH2)4OH
12: R = CH2OH
13: R = (CH2)2Ph
9: R = (CH2)2Ph
(B)
O
(α- or β-ICyDMe)MCl (0.5 mol%)
Et
Et
Et
Et
D
D
D2O / (CD3OD)
10
14
Table 1. Hydration of alkynes 7-10 in D2O catalyzed by (ICyDMe)MCl complexes.
co-
solvent
Entry alkyne
Ligand
a-ICyDMe
b-ICyDMe
M
Complex
T (°C)
Time (h) Convn (%)[b] Yield (%)[c]
1
2
7
7
Au
Au
5α
-
-
R.T.
R.T.
22
14
>99
>99
92
99
5
b
a-ICyDMe
b-ICyDMe
a-ICyDMe
b-ICyDMe
a-ICyDMe
b-ICyDMe
a-ICyDMe
b-ICyDMe
a-ICyDMe
b-ICyDMe
a-ICyDMe
a-ICyDMe
a /b-ICyDMe
a-ICyDMe
b-ICyDMe
a /b-ICyDMe
3
4
5
6
7
8
8
9
9
9
Au
Au
Au
Au
Au
Au
Au
Au
Ag
Ag
Ag
Ag
Ag
Cu
Cu
Cu
5α
-
-
-
-
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
120
24
48
48
120
70
96
90
41
14
120
48
48-72
96
12
28
>99
>99
8
17
95
>99
<1
92
>99
<1 [d]
60
88
95
<1
<1
85
99
<1
27
92
<1
49
<1
<1
<1
<1
<1
5
b
5α
5
b
5α
CD3OD[a]
8
9
9
CD3OD[a]
5
b
10
10
7
7
8
9
9/10
7
7
9/10
5α
CD3OD[a]
10
11
12
13
14
15
16
17
18
CD3OD[a]
5
b
4α
-
-
-
-
4
b
4α
4α
4α/4
6α
<1
<1
CD3OD[a]
b
b
-
-
<1
<1[d]
<1[d]
6
b
CD3OD[a]
6α/6
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10.1002/chem.202001990
Chemistry - A European Journal
[a] Ratio D2O/CD3OD = 1:10; [b] Conversion of the alkyne determined by 1H NMR by comparison of the amount of residual
alkyne with the internal reference (butadiene sulfone); [c] NMR yield of methylketone determined by 1H NMR by
comparison with the internal reference; [d] A precipitate was observed for b-ICyDMe-based catalysts.
Gold-catalyzed lactonization reactions in pure water:
Another classical gold-catalyzed reaction is the intramolecular addition of carboxylic acids to alkynes,50 which
has been developed in aqueous media,51 and with water-soluble NHC ligands.26,28,30,52 Therefore, the catalytic
activity of both 5α and 5 was tested in the lactonization of three g-alkynoic acids (15-17), in pure water
b
(Scheme 3). At 20 °C, both catalysts allowed formation of the corresponding lactones 18-20 with no detectable
formation of the methyl ketone resulting from competitive hydration reaction (Table 2, entries 1-6).26 The
reaction is relatively slow with variable yields ranging from 33 to 85% after 14 or 36 h. The b-CD derivative 5
b
gave higher yields in shorter reaction times than the a-CD 5α with alkynes 15 (14h vs 36 h), 16 (55% vs 33%)
and 17 (85% vs 76%) probably due to its larger cavity and therefore easier access to the metal (entries 2, 4 and
6). By comparison, the lactonization of 4-pentynoic acid in neat water was reported to give complete
conversion within 1 h with ammonium-tagged NHC-gold(I) complexes under similar conditions (2.5 mol% of
catalyst, r.t.).30 This shows (although the substrates are not identical) that encapsulation of the reactive gold
center in the CD cavity in 5α and 5
5α and 5 catalysts could be reused in a second cyclization reaction after extraction of organic compounds, to
give lactone 19 in comparable yields (25 and 55%) from alkyne 16 (Table 2, entries 7-8), suggesting in
b
likely leads to lower reaction rates. Importantly, aqueous solutions of both
b
particular, that the more accessible b-CD-based catalyst 5 remains stable in the (acidic) aqueous medium of
b
the reaction.53 All the reactions presented in Table 2 were conducted without silver(I) salts.
Scheme 3. Lactonization reaction of g-alkynoic acids 15-17 catalyzed by (ICyDMe)AuCl complexes.
COOR1
COOR1
R2
R2
O
O
(α- or β-ICyDMe)AuCl (2 mol%)
O
OH
H2O, 20 °C
15: R1 = H, R2 = CH2C≡CH
16: R1 = Me, R2 = CH2C≡CH
17: R1 = Me, R2 = CH2CH=CH2
18: R1 = H, R2 = CH2C≡CH
19: R1 = Me, R2 = CH2C≡CH
20: R1 = Me, R2 = CH2CH=CH2
Table 2. Lactonization reactions catalyzed by (ICyDMe)AuCl complexes in pure water.
Entry Substrate
Ligand
Complex
Time (h)
36
Yield (%)[a]
a-ICyDMe
b-ICyDMe
a-ICyDMe
b-ICyDMe
a-ICyDMe
b-ICyDMe
a-ICyDMe
b-ICyDMe
5α
1
2
3
4
5
15
15
16
16
17
17
16
16
58
58
33
55
76
85
25
55
5
b
14
36
14
14
14
36
14
5α
5
b
5α
6
b
5
7[b]
8[b]
5α
5
b
[a] Isolated yields; [b] Reactions performed after recycling of (α-ICyDMe)AuCl and (b-ICyDMe)AuCl (second run).
Regioselective hydroarylation in pure water:
Recently, Mascareñas15 reported a Gold-catalyzed hydroarylation54,55 in pure water, and even in cellulo, using
water-soluble phosphine with AuI and no silver salts. In his study, aryl 21 was used and gave 12% yield of
product 22 in pure water; this yield was improved up to 99% using acetonitrile as co-solvent. We therefore
tried this reaction with 5α and 5 in pure water and could observe an increase in yield when using the larger b-
b
CD derivative (31%). We also used a compound with a smaller substituent on the alkyne, 23, and observed
better yields of 24 with both our catalysts probably due to both a better water-solubility of the substrate and
an easier reaction with the catalyst. (Scheme 4, Table 3)
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Scheme 4. Hydroarylation of compounds 21 and 23 catalyzed by (ICyDMe)AuCl complexes.
N
O
O
N
O
O
(α- or β-ICyDMe)AuCl (5 mol%)
H2O, 37 °C, 42h
R
R
21: R=Ph
23: R=Me
22: R=Ph
24: R=Me
Table 3. Hydroarylation of compounds 18 and 20 catalyzed by (ICyDMe)AuCl complexes in pure water.
Entry Substrate
R
Ligand
Complex
Yield (%)[a]
a-ICyDMe
b-ICyDMe
a-ICyDMe
b-ICyDMe
5α
1
2
3
4
21
21
23
23
Ph
Ph
Me
Me
14
31
19
52
5
b
5α
5
b
[a] Isolated yields.
Substrate 21 was initially designed by Mascareñas to avoid regioselectivity problems in the hydroarylation
reaction.15 Indeed, the use of compound 25c with no substituents on both ortho-positions to the ester, was
reported by the same group to give a mixture of both 26c and 27c (ratio from 1.5:1 to 10:1 depending on the
gold catalyst used).15 We therefore probed our catalysts in this reaction with a series of aryl 25a-c and
observed a good regioselectivity in all cases in favor of compounds 26a-c. The best regioselectivity (16:1) was
obtained with 25b and b-ICyDMe as ligand (entry 4). Encapsulation of AuI inside the ICyDMe ligands therefore
promotes regioselectivity in this hydroarylation reaction in pure water without silver salts. (Scheme 5, Table 4)
Scheme 5. Hydroarylation of compounds 25a-c catalyzed by (ICyDMe)AuCl complexes.
Et2N
O
O
R
O
Et2N
O
O
(α- or β-ICyDMe)AuCl (5 mol%)
Et2N
O
H2O, 37 °C, 42h
R
R
25a: R=Me
25b: R=Et
25c: R=Ph
26a: R=Me
26b: R=Et
26c: R=Ph
27a: R=Me
27b: R=Et
27c: R=Ph
Table 4. Hydroarylation of compounds 25a-c catalyzed by (ICyDMe)AuCl complexes in pure water.
Yield (%)[a]
26x 27x
26:27
ratio
Entry Substrate
Ligand
Complex
a-ICyDMe
b-ICyDMe
a-ICyDMe
b-ICyDMe
a-ICyDMe
b-ICyDMe
5α
12
12
7:1
7:1
1
2
3
4
5
6
25a
25a
25b
25b
25c
25c
85
82
80
80
53
77
5
b
5α
5
14
5
7
6:1
16:1
8:1
b
5α
9
9:1
5
b
[a] Isolated yields.
Enantioselective gold-catalyzed cycloisomerizations in pure water:
Examples of asymmetric gold catalysis in water or in the presence of water, involving chiral ligands, remain
scarce.56,57,58,59,60 Michelet and co-workers reported enantioselective hydroxy-cyclizations of 1,6-enynes in
dioxane/H2O (6:1).57,58 An enantioselectivity up to 72% was reached with chiral phosphane ligands in
combination with silver salts. Chiral phosphoramidites (with AgBF4) were reported by Toste and co-workers to
give 96% ee in allene-ene hydroxycyclization in water.59 An enantioselective intramolecular cyclization of allenic
acids in aqueous nanomicelles was reported by Lipshutz and co-workers to give up to 96% ee with chiral biaryl
phosphane ligands.60 To the best of our knowledge, enantioselective gold-catalyzed reactions in pure water
with chiral hydrosoluble NHC ligands have not been reported. The potential of both (a-ICyDMe)AuCl 5α and (b-
ICyDMe)AuCl 5
b
to induce enantioselectivity in water was first studied in the cycloisomerization of N-tethered
enyne 28 (Scheme 6 and Table 5).61 In contrast to the previous hydration and lactonization reactions, the
reaction was found not to proceed in the absence of silver salts, regardless of the complex used (Table 5, entry
1). In the presence of AgSbF6, however, the cyclized product 29 was obtained in 13-25% yields after 16 h
(entries 2 and 3). A higher temperature of 50 °C was required with catalyst 5α likely due to the superior steric
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10.1002/chem.202001990
Chemistry - A European Journal
constraint imposed by the a-CD cavity. Although the yields are low, satisfactory enantioselectivities of 60 and
81% were obtained 5α and 5 , respectively (Table 3, entries 2 and 3). The highest ee for 29 was obtained at
20 °C with the larger b-CD-based catalyst 5
b
b
. We previously reported the enantioselective cycloisomerization of
the same enyne 28 in an organic solvent (CH2Cl2), with the perbenzylated analogues of ICyDMe ligands.7
Interestingly, both water-soluble a-ICyDMe and b-ICyDMe ligands in water were found to give significantly higher
enantioselectivity than the previous standard a-ICyD and b-ICyD ligands in organic medium (compare entries
2/4 and 3/5) (Scheme 6, Table 5)
Scheme 6. Enantioselective enyne cycloisomerization of 28.
Ts
Ts
(α- or β-ICyDMe)AuCl (2 mol%)
N
N
additive (2 mol%)
H2O (or CH2Cl2)
28
(+)-(R,R)-29
Table 5. Enantioselective enyne cycloisomerization of 28 in pure water or CH2Cl2.
Entry
1
2
Ligand
a /b-ICyDMe
a-ICyDMe
b-ICyDMe
a-ICyD
Complex
Solvent
H2O
H2O
H2O
CH2Cl2
CH2Cl2
Additive
-
AgSbF6
AgSbF6
AgSbF6
AgSbF6
T (°C)
50
50
20
40
Yield (%)[a]
ee (%)[b]
<1
13
25
83
77
-
5α/5
5α
b
60
81
43
59
3
5
b
4[c]
5α
5[c]
20
b-ICyD
5
b
[a] Isolated yields after 16 h of reaction; [b] Enantiomeric excess determined by chiral HPLC; [c] Previous results with
benzyl-protected CD ligands (ICyD) see ref. 7.
The role of silver salts in this particular reaction remains unclear. To the best of our knowledge, enyne
cycloisomerization reactions have not been reported in the absence of silver salts,62 even in aqueous
media.18,19,21 Gold catalysis in water was shown to be possible in the absence of silver salts,15a,63 which are often
added as activating agents, in particular to generate active cationic species. To better understand the level of
ionization of both 5α and 5
solubilization of the complexes in deionized water were made. This study demonstrated the partial but
b
complexes in water, measurement of molar conductivities after 2 and 72 h of
significant ionization of both 5α and 5
b
complexes since L values ranging from 29.1 to 43.9 S.cm2.mol–1,
consistent with the formation of active cationic AuI complexes in H2O, were observed (Figure and Table S2 in
the supporting information). Therefore, this suggests that the lack of activity observed in the absence of silver
salts in enyne cyclization is likely not related to low ionization of (ICyDMe)AuCl 5α complexes but rather to a
possible implication of silver in the mechanism of the reaction.64
The hydroxycyclization reaction of enyne 30 was also tested with both (ICyDMe)AuCl catalysts in pure water
(Scheme 7).65 In a first set of reactions performed in the presence AgSbF6, both a-CD and b-CD-derived
catalysts 5α and 5
b
were found to be efficient in forming the expected cyclized alcohol 31, which was isolated in
74 and 63% yield, respectively (Table 6, entries 1-2). In addition, the b-CD-derived catalyst 5
b
was also found to
induce a high control of enantioselectivity, leading to the formation of 31 with 95% ee (entry 2). A second set of
experiments was conducted in the absence of silver salts (entries 3-6). No conversion was observed with 5α
b
(entry 3). However, when 5 was used, the hydroxycyclization product 31 was obtained at room temperature in
up to 79% yield and 98% ee (entries 4 and 5). Increasing the temperature to 50 °C allowed to significantly
decrease the reaction time to 4 h to give 31 in 74% yield while keeping the same level of enantioselectivity (ee
96%, entry 6). Therefore, the results show that no silver salts are required in the hydroxycyclization reaction, in
contrast to the previous enyne cycloisomerization reaction, and that high enantioselectivity is obtained in
water.
Scheme 7. Enantioselective hydroxylation-cyclization reaction of 1,6-enyne 30.
CO2Me
CO2Me
MeO2C
MeO2C
(α- or β-ICyDMe)AuCl (2 mol%)
additive (2 mol%)
H2O
H
OH
31
30
Table 6. Enantioselective hydroxylation-cyclization reaction of 1,6-enyne 30 in pure water.
Entry
1
Ligand
Complex
Additive
AgSbF6
T (°C)
50
t (h)
18
Yield (%)[a]
74
ee (%)[b]
54 (-)
a-ICyDMe
5α
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10.1002/chem.202001990
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b-ICyDMe
5
b
5α
2
3
4
5
AgSbF6
20
50
20
20
50
18
40
23
45
4
63
1
47
79
74
95 (-)
-
98 (-)
97 (-)
96 (-)
a-ICyDMe
-
-
-
-
b-ICyDMe
5
5
5
b
b
b
b-ICyDMe
b-ICyDMe
6
[a] Isolated yields; [b] Enantiomeric excess determined by chiral HPLC.
Conclusion
A series of water-soluble complexes with encapsulated copper(I), silver(I) or gold(I) centers were obtained by
covalent capping of permethylated CDs with NHC ligands. The corresponding (ICyDMe)MCl were found to have
different catalytic behaviors in water with an important effect of the nature of the CD (a or b). The use of the
smaller a-ICyDMe ligand in most cases induces a decrease in reactivity due to steric bulk, but at the same time
induces an increase of stability of the metal complex. For instance, this allowed efficient hydration reaction of
alkynes with (a-ICyDMe)AgCl 5α whereas (b-ICyDMe)AgCl 5
In contrast, both 5α and 5
ICyDMe)AuCl 5
, in which the CD cavity is larger, was found to be a very efficient and selective catalyst in gold-
b
is inactive due to degradation of the metal complex.
b
gold complexes are stable and active in hydration reactions. More generally, (b-
b
catalyzed reactions. The size of the cavity clearly matters as larger substrates react significantly faster with b-
ICyDMe affording some degree of substrate selectivity for a-ICyDMe with methanol as co-solvent. Hydroarylation
reactions in pure water were also performed and found to be regioselective. Finally, these water-soluble
complexes induce high control of enantioselectivity in gold-catalyzed cycloisomerizations in water giving up to
81% ee and 5 was found to be particularly efficient in promoting the enantioselective hydroxycyclization
b
reaction of 1,6-enynes, leading to the cyclized alcohols in up to 98% ee. ICyDMe are therefore useful ligands for
selective catalysis in pure water that will be further explored.
Acknowledgements
The authors thank LabEx MiChem part of French state funds managed by the ANR within the Investissements
d’Avenir programme under reference ANR-11-IDEX-0004-02 for support, the CSC (PhD grants for XZ and GX)
and Cyclolab (Hungary) for generous supply of cyclodextrin.
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Chemistry - A European Journal
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