'Auto-click' functionalization for diversified copper(i) and gold(i) NHCs

Article abstract of DOI:10.1039/c4dt00429a

Azide-tagged Cu^I-NHC reacts in an 'auto-click' process to furnish complexes functionalized by 1,2,3-triazoles bearing diverse substituents. The resulting Cu^I complexes are amenable to further transmetallation to Au^I. The w

Full text of DOI:10.1039/c4dt00429a

Dalton
Transactions
View Article Online
View Journal | View Issue
COMMUNICATION
‘Auto-click’ functionalization for diversified
copper(I) and gold(I) NHCs†
Cite this: Dalton Trans., 2014, 43,
6981
Houssein Ibrahim,a Clémentine Gibard,a Cédric Hesling,b Régis Guillot,c
Received 10th February 2014,
Accepted 14th February 2014
Laurent Morel,b,d,e Arnaud Gautier*a,f and Federico Cisnetti*a
DOI: 10.1039/c4dt00429a
www.rsc.org/dalton
Azide-tagged CuI-NHC reacts in an ‘auto-click’ process to furnish
complexes functionalized by 1,2,3-triazoles bearing diverse substi-
tuents. The resulting CuI complexes are amenable to further trans-
metallation to AuI. The whole strategy proceeds with mild
conditions and constitutes an efficient entry to functionalised
metal-NHCs with biorelevant moieties.
Fig. 1 Synthetic strategy.
rarely reported with preformed metal complexes and most of
the examples consist of ‘metal-chelating’ azides (metal = PdII,
CuI).5 Thus, this remains restricted to organometallics of
limited stability. Combining this auto-functionalization with a
subsequent transmetallation6 would be highly valuable for the
rising demand for new stable metal-NHCs of high structural
diversity (Fig. 1).
There are scarce examples of biomolecule-tagged metal-
NHCs4a,b whereas such complexes currently receive great inter-
est as anti-cancer drug candidates. For example, by targeting
the mitochondrial proteins TxR, an important enzyme regulat-
ing the redox system, AuI and AuIII-NHCs offer important
opportunities to circumvolve the cisplatin resistances.7 Herein
we report a straightforward synthetic route for architecturally
sophisticated CuI and AuI-NHCs bearing bio-relevant
pendants. The reaction products could bear a coumarin or a
glucose moiety (without the need of any protection–deprotec-
tion sequence). Special attention was paid to the SIPr ligand as
it has been shown that its complexes display good biological
activities.8
Introduction
Metal-NHCs (M-NHCs) have attracted considerable interest
over the last decades as a leading familyof contemporaryorgano-
metallic materials for catalytic purposes and more recently
as metal-based drugs.1,2 Therefore, it is highly desirable to
develop concise synthetic routes permitting both straight-
forward variations of the metal and ligand (for reactivity, stability
or solubility purposes). For the modulation of the organic
core, two strategies are routinely used to access new metal
NHC complexes: (i) pre-functionalization3 consisting of (i-1)
the elaboration of the functionalized azolium precursor, then
(i-2) the introduction of the metal and (ii) post-functionali-
zation,4 consisting of (ii-1) the introduction of the metal, then
(ii-2) the chemical modification of the carbene ligand. We have
recently reported that NHCs can react as catalysts for their own
functionalization in a CuAAC model reaction giving a so-called
‘auto-click’ behaviour.4e This auto-functionalization has been
aClermont Université, Université Blaise Pascal, Institut de Chimie de Clermont-
Ferrand, BP 10448, F-63000 Clermont-Ferrand, France.
E-mail: federico.cisnetti@univ-bpclermont.fr
bClermont Université, Université Blaise Pascal, GReD, BP 10448, F-63000 Clermont-
Ferrand, France
cInstitut de Chimie Moléculaire et des Matériaux d’Orsay, Bât. 420, Université Paris-
Sud, UMR CNRS 8182, F-91405 ORSAY Cedex, France
dCNRS, UMR 6293, GReD, F-63001 Clermont-Ferrand, France
eInserm, UMR 1103, GReD, F-63001 Clermont-Ferrand, France
fCNRS, UMR 6296, ICCF, F-63171 AUBIERE, France.
Results and discussion
In this article, we investigate the ‘auto-click products’ of the
symmetric bis-azido Cu complex 6b4e along with its mono-
azido analogue 6a (Scheme 1). The symmetric imidazolinium
salt 5b was obtained by a known protocol4e while the new dis-
symmetric mono-N3 imidazolinium salt 5a was obtained in a
4-step sequence (Scheme 1) without any chromatographic
purification.
E-mail: arnaud.gautier@univ-bpclermont.fr
†Electronic supplementary information (ESI) available: NMR and crystallo-
graphic details. CCDC 977560. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4dt00429a
This journal is © The Royal Society of Chemistry 2014
Dalton Trans., 2014, 43, 6981–6989 | 6981

View Article Online
Communication
Dalton Transactions
Scheme 1 Synthesis of copper precursor 6a and 6b. Reagents and
conditions: (a) 4-iodo-2,6-diisopropylaniline, K2CO3, DCM, 92%. (b)
BF3·Et2O, NaBH4, THF; then EtOH, HCl, 69%. (c) NaN3, CuI (10 mol%),
MeNH(CH2)2NHMe (15 mol%), sodium ascorbate (20 mol%), DMSO–H2O
(v/v) 9 : 1, 70 °C, 83%; then EtOH, HCl, 69%. (d) HC(OEt)3, EtOH, reflux,
88%. (e) Ag2O, DCM; then CuCl, 64%. (f) CuCl, NH3 (aq.), 6a: 77%, 6b:
89%.
Fig. 2 Kinetic profile at 70 °C in CD3CN for auto-click reaction of 6a
(open symbols) to 7a (closed symbols).
Table 1 Conversion determined by 1H NMRa
Solvent
Temp.
Time (h)
Conversion (%)
CHCl3
MeOH
DMSO (1% H2O)
DMSO (1% H2O)
Acetonitrile
Acetonitrile
50
50
50
70
35
70
19
19
19
19
19
2
0
0
74
Decomposition
100
100
a [6]: 0.03 M; propargyl alcohol: 2.0 eq.
Scheme 2 Isolated yields of ‘auto-clicked’ copper-NHCs.
The known oxalamide derivative 29a was obtained in good
yield from the condensation9b of compound 1 and 4-iodo-2,6-
diisopropylaniline.9c 2 was converted into the 1,2-diamine bis
hydrochloride (3) after reduction by in situ generated diborane
and treatment with HCl.10 Copper catalysed iodine substi-
tution11 efficiently furnished the azido diamine hydrochloride
4 which, after a classical orthoformate cyclization, afforded the
imidazolinium chloride 5a. The imidazolinium salts 5a and 5b
were converted into the targeted CuI-NHCs on average to good
yields either by the standard silver route (6a: 64%) or by a
newly reported direct metallation protocol using aqueous
ammonia (6a: 77%, 6b: 89%).12
sition or formation of the 1,5 isomer (careful examination of
the 1H and 13C spectra). Indeed, we have previously shown that
thermal Huisgen reaction (leading to a mixture of isomers) between
non-activated alkynes and azolium bearing azides did not
occur even at higher temperature. In the case of gold(I)-NHC
and dimethyl acetylene dicarboxylate (as an activated alkyne),
the thermal [2 + 3] cycloaddition yields only 65% at 60 °C after
10 days.3f In comparison to acetonitrile, wet DMSO was less
efficient at low temperature and induces decomposition at
higher temperatures. The kinetic profile of this ‘auto-click’
1
With 6a, the conditions required for the ‘auto-click’ reac-
tion were evaluated by 1H NMR (Table 1). Previous studies
using symmetric bis-azido CuI-NHC 6b were made difficult by
reaction was examined by H NMR at 70 °C by monitoring the
disappearance of the azide 6 (aromatic protons at 7.0 ppm)
and the appearance of the 1,2,3-triazole of 7a (H-triazole at
8.4 ppm and aromatic protons at 7.8 ppm), Fig. 2 and ESI.†
The kinetic profile clearly shows that the reaction occurs after
an induction period, indicating that 6a is not the active cata-
lytic species. The fact that the reaction occurs in coordinating
conditions, i.e., wet DMSO and acetonitrile (at lower tempera-
ture for the latter) suggests that solvolysis of the copper–chlor-
ide bond could lead to the formation of a cationic CuI-NHC
that acts as the real catalytic species.
1
the overlap of H NMR signals precluding a clear view of the
process.4e
Other CuI-NHCs could be synthesized efficiently from 6a,b
using the same protocol (Scheme 2). Indeed, the method is
not limited to the functionalization by simple alcohol pen-
dants but also applies to biologically relevant substituents as
shown by complexes 7b–e possessing glucose or a fluorescent
A total lack of reactivity in chloroform and methanol was
observed whereas conversions occurred in DMSO and aceto-
nitrile. Interestingly, acetonitrile proved to be the solvent of
choice as the reaction could take place from fairly low (35 °C)
to higher (70 °C) temperatures without noticeable decompo-
6982 | Dalton Trans., 2014, 43, 6981–6989
This journal is © The Royal Society of Chemistry 2014

View Article Online
Dalton Transactions
Communication
Fig. 3 Ellipsoid plot (50% probability) of CuI complex 7c. d(C–Cu) =
1.887 Å. d(Cu–Cl) = 2.103 Å. (C–Cu–Cl) = 174.5° (hydrogens and sol-
vents not shown for clarity).‡
Fig. 5 Isolated yields of gold-NHCs and fluorescence of 8c under UV
excitation.
gave higher amounts of the expected AuI-NHC 8a at room
temperature; however, completion was not reached even after
an extended period of 3 days. Increasing the temperature to
50 °C was deleterious as shown by the increased proportion of
imidazolinium 9a. When the reaction was performed in
DMSO, a larger amount of 9a was formed. However, we finally
found that a mixture of DMSO and MeCN (1/1) allowed a clean
and complete conversion to 8a (without any detectable for-
mation of 9a).
Fig. 4 Transfer process leading to gold(I) complex and imidazolinium
as a side-product.
As earlier work reported that the transfer reaction occurred
well with all classical NHCs ligands (SIMes, IMes, IPr) but
SIPr, these optimized conditions are likely to extend the scope
of copper-to-gold transmetalations.6 Thus, the success for the
transfer reaction seems to be ligand- and solvent- dependent.
Following this protocol, we were also able to obtain AuI com-
plexes 8b,§ 8c and 8d in average to good yield (Fig. 5). It is
noteworthy that 8b and 8d are obtained in a one pot-two step
procedure from their CuI carbene precursors 7b,d bearing
unprotected glucose moiety. However we were unable to obtain
a total and clean transmetallation from the CuI-NHC 7e, prob-
ably because of its high insolubility.
Table 2 NMR conversion
Temp.
(°C)
Time
(h)
Product ratioa
(%) 7a/8a/9a
Solvent
CH2Cl2
MeCN
MeCN
DMSO
50
25
50
30
30
16
72
16
16
16
0/43/57
29/62/9
20/53/27
52/48/0
DMSO–MeCN (1/1)
0/100(63)b/0
a NMR conversion. b Yield of isolated pure 8a.
Compound 8c (and 7c) are fluorescent due to their cou-
marin substituents as shown in Fig. 6 (10−5 M in HEPES
buffer–1% DMSO) under UV irradiation. Therefore, the fluo-
rescence data of copper and gold complexes 7c and 8c were
determined (Fig. 6 and Table 3).
In view of the fluorescent properties of the gold(I)-NHC 8c
that fall into classical DAPI filters wavelengths, we investigated
its uptake and intracellular distribution in human prostate
cancer (PC3) cell line. After incubating PC3 cells with 8c for
18 h (10 µM), a significant blue fluorescence was detected in
the cytoplasm but not in the nucleus. It could be specifically
localized in mitochondria as could be shown by the merge of
almost all luminescent spots due to 8c fluorescence with those
caused by red-MitoTracker dye (Fig. 7).16
coumarin appendages. It is important to note that 7b and 7d
are synthesized from an unprotected sugar precursor.13
Structural proof of the coumarin derivative 7c was provided
by X-ray diffraction.‡Distances and angles fall into the classical
ranges of what was reported for the CuCl(SIPr) complex
(Fig. 3).14 The dihedral angles between the triazole and both
2,6-diisopropyl aniline and coumarin are low (11° and 8°,
respectively) which allows an extended conjugation.
Then, we tested the CuI complex 7a as carbene transfer
agent for synthesizing the corresponding gold(I) complex 8a
using gold(I) chloride-dimethyl sulfide complex as reported by
Furst and Cazin (Fig. 4).6 The conversion was estimated by
integrating the signals corresponding to the cyclic methylene
protons (N–CH2–CH2–N) for 7a vs. 8a and 9a. The screened
conditions are gathered in Table 2.
Conclusion
In our hands, the carbene transfer in dichloromethane
proved to be difficult as a large amount of imidazolinium 9a
was formed. Switching to acetonitrile as a coordinating solvent
We have reported that the combination of the ‘auto-click’ reac-
tion with a transmetallation process constitutes an efficient
This journal is © The Royal Society of Chemistry 2014
Dalton Trans., 2014, 43, 6981–6989 | 6983

View Article Online
Communication
Dalton Transactions
dissolved in acetonitrile prior to the measurement. IR spectra
were recorded on a Shimadzu Fourier Transform Infrared
Spectrophotometer FTIR-8400S. Elemental analyses were per-
formed at the Service de Microanalyse, Université Henry Poin-
caré, Vandoeuvre-les-Nancy, France.
Synthesis
(2,6-Diisopropylphenylcarbamoyl)formyl chloride (1). 2,6-
Diisopropylphenylamine (20 mL, 0.107 mol) was added to
500 mL of dry toluene. A solution of oxalyl chloride (25 mL,
0.29 mol) in 150 mL of dry toluene was added dropwise while
stirring vigorously at 0 °C (ice-water bath) during 15 min. The
mixture was further stirred for 1 h and was filtered to remove
the white solid that forms. The filtrate evaporated under
reduced pressure, giving a yellow solid which was triturated
with a minimum amount of n-pentane to give a white solid;
10.44 g were obtained after drying under vacuum (36% Yield).
1H NMR (DMSO-d6, 400 MHz) δ = 10.22 (s, 1H, NH), 7.29 (t,
1H, J = 7.0 Hz, HAr), 7.17 (d, 1H, J = 7.0 Hz, HAr), 2.98 (sept,
2H, J = 6.4 Hz, CH(CH3)2), 1.11 (d, 12H, J = 6.4 Hz, CH(CH3)2).
This product was used without any further purification in
the next step.
Fig. 6 Excitation and emission spectra of compounds 7c and 8c, 10−5
mol L−1 HEPES buffer–1% DMSO.
Table 3 Fluorescence data
Excitation λmax (nm)
Emission λmax (nm)
Φa (%)
7c
8c
333
336
418
418
8
18
N-(2,6-Diisopropylphenyl)-N′-(4-iodo-2,6-diisopropylphenyl)
oxalamide (2). According to a modified literature procedure.9b
At first, 4-iodo-2,6-diisopropylaniline was azeotroped 3 times
with cyclohexane to remove water that may crystallize with this
material (when stored for a long period, and that will dramati-
cally reduce the yield). Then, 4-iodo-2,6-diisopropylaniline3e,9c
(20.0 g, 66.0 mmol, 1.0 eq.) was dissolved in 500 mL
anhydrous dichloromethane under argon. Na2CO3 (17.5 g,
165 mmol, 2.5 eq.) was added followed by 1 (19.4 g,
72.4 mmol, 1.1 eq.) in one portion (slight heating and gas evol-
ution were apparent). After 2 h at room temperature the reac-
tion mixture was filtered over a fritted glass. The solid residue
was washed with boiling dichoromethane until no more solid
dissolved. The combined organic fractions were evaporated
under reduced pressure to yield 32.5 g of a white solid
(60.8 mmol, 92% yield). Spectroscopic characterizations identi-
cal to literature.17
a Fluorescence quantum yield (quinine sulfate as standard).15
Fig. 7 Co-localization of 8c and MitoTracker. Left: PC3 cell visualized
with DAPI filters (λex: 365 nm; λem: 397 nm). Centre: PC3 cell visualized
with DsRED filter (λex: 565 nm; λem: 620 nm). Right: merged images.
tool for the construction of functionalized gold-NHCs of high
diversity, for example bearing a fluorescent biomarker or an
unprotected sugar. Thus, this synthetic route avoids the need
of a tedious protection–deprotection sequence. Other appli-
cations are currently under investigation in our laboratory.
N-(2,6-Diisopropylphenyl)-N′-(4-iodo-2,6-diisopropylphenyl)
ethane-1,2-diamine
dihydrochloride
(3). Compound
2
(16.00 g, 29.93 mmol, 1.0 eq.) and NaBH4 (6.8 g, 180 mmol,
6.0 eq.) were added to 160 mL anhydrous THF. The solution
was cooled at 0 °C and BF3·Et2O (30 mL, 33.6 g, 237 mmol,
7.9 eq.) was added dropwise over 20 min. The reaction mixture
was stirred at room temperature for 2 h and then refluxed over-
night. The mixture was cooled to 0 °C and treated with a
Experimental
General remarks
NMR spectra were recorded in Fourier transform mode with a 50 mL of a 1 : 4 v/v mixture of 36% aq. HCl and methanol
Bruker AVANCE 400 spectrometer (1H at 400 MHz, 13C at under vigorous stirring and then evaporated to dryness, 1 M
100 MHz) at 298 K. Data are reported as chemical shifts (δ) in NaOH (200 mL) was added and extraction with 3–200 mL Et2O
ppm. Residual solvent signals were used as internal references was performed. Drying over Na2SO4 and evaporation in vacuo
(1H, 13C). Electrospray (positive mode) high resolution mass afforded a brownish oil. This material was treated under vigor-
spectra were recorded on a Q-TOF microspectrometer (Waters), ous stirring with an ethanolic HCl solution – freshly prepared
using internal (H3PO4) and external lock masses (leucine- by adding with caution at 0 °C 6.4 mL (89.8 mmol) of acetyl
enkephalin [M + H]+: m/z = 556.2766). Metal complexes were chloride to 65 mL anhydrous ethanol. After a few min a solid
6984 | Dalton Trans., 2014, 43, 6981–6989
This journal is © The Royal Society of Chemistry 2014

View Article Online
Dalton Transactions
Communication
separated from the supernatant. Filtration afforded 12.01 g of
an off-white powder (20.75 mmol, 69% yield).
1H NMR (DMSO-d6, 400 MHz) δ = 9.60 (s, 1H, CHImidazolinium),
7.56 (t, 1H, J = 7.7 Hz, HAr), 7.43 (d, 2H, J = 7.7 Hz, HAr),
1H NMR (DMSO-d6, 400 MHz) δ = 7.45 (s, 2H, HAr), 7.39 7.11 (s, 2H, HAr), 4.54 (s, 4H, CH2), 3.12–3.05 (m, 4H, CH
(t, 1H, J = 7.0 Hz, HAr), 7.32 (d, 1H, J = 7.0 Hz, HAr), 3.47–3.38 (CH3)2), 1.35 (d, 12H, J = 6.6 Hz, CH(CH3)2), 1.20 (d, 12H, J =
(m, 6H, CH2 + 2CH(CH3)2), 3.32–3.26 (m, 2H, CH(CH3)2), 1.18 6.6 Hz, CH(CH3)2).
(d, 12H, J = 6.4 Hz, CH(CH3)2), 1.12 (d, 12H, J = 6.4 Hz,
CH(CH3)2).
13C NMR (DMSO-d6, 100 MHz) δ = 160.4 (NCHN), 148.5
(CqAr), 146.1 (CqAr), 142.1 (CqAr), 131.1 (CAr–H), 129.8 (CqAr),
13C NMR (DMSO-d6, 100 MHz) δ = 145.7 (CqAr), 142.8 (CqAr), 126.7 (CqAr), 124.8 (CAr–H), 115.5 (CAr–H), 53.7 (CH2), 53.6
137.7 (CqAr), 133.2 (CAr–H), 130.7 (CqAr), 129.3 (CAr–H), 125.6 (CH2), 28.5 (CH), 28.2 (CH), 25.0 (CH3), 24.6 (CH3), 23.3 (CH3),
(CAr–H), 92.3 (CqAr), 50.8 (CH2), 47.3 (CH2), 27.3 (CH), 27.2 23.0 (CH3).
(CH), 24.5 (CH3), 24.1 (CH3).
IR (ν, cm−1): 2965, 2100 (N3), 1610, 1264, 804, 758.
HRMS (ESI+): calculated for C26H40IN2 [M − H − 2Cl]+:
507.2236, found: 507.2240.
HRMS (ESI+): calculated for C27H38N5 [M − Cl]+: 432.3127,
found: 432.3191
N-(4-Azido-2,6-diisopropylphenyl)-N′-(2,6-diisopropylphenyl)
(N-(4-Azido-2,6-diisopropylphenyl)-N′-(2,6-diisopropylphenyl)
imidazolin-2-ylidene)-chlorocopper(I) (6a)
ethane-1,2-diamine
dihydrochloride
(4). Compound
3
Using silver oxide method. 1 – Synthesis of silver carbene:
compound 5a (1.50 g, 3.20 mmol, 1.0 eq.) was dissolved in
130 mL dichloromethane, silver oxide (482.7 mg, 2.08 mmol,
0.65 eq.) was added and the solution was stirred overnight at
room temperature in the dark. The resulting suspension was
filtered over celite and evaporated. 1.60 g (2.79 mmol, 88%
yield) of white solid was obtained. This material was used
without any further purification in the next step.
(11.00 g, 19.00 mmol, 1.0 eq.) was treated with 140 mL sat. aq.
NaHCO3, extracted with 3 × 140 mL Et2O and the joint organic
phases evaporated (Na2SO4). To the resulting oil were added
H2O (10 mL) and DMSO (90 mL). Ascorbic acid (670.1 mg,
3.80 mmol, 20 mol%), sodium hydroxide (152.2 mg,
3.80 mmol, 20 mol%), sodium azide (2.470 g, 38.0 mmol, 2.0
eq.) and N,N′-dimethylethane-1,2-diamine (307 µL, 251.5 mg,
2.8 mmol, 15 mol%) were subsequently added and the result-
ing solution was degassed by argon bubbling for 20 min. CuI
(362.3 mg, 1.9 mmol, 10 mol%) was added and the reaction
mixture was stirred at 70 °C for 3 h. After cooling to room
temperature, brine (220 mL) was added and extraction was per-
formed with 3 × 110 mL of diethyl ether. The combined
organic phases were washed with saturated aq. NH4Cl (2 ×
110 mL) and water (2 × 110 mL). Drying (Na2SO4) and solvent
evaporation furnished a brownish oil which was treated with
ethanolic HCl solution – freshly prepared by adding with
caution at 0 °C 5.7 mL (76 mmol) of acetyl chloride to 55 mL
anhydrous ethanol. After 20 min of vigorous stirring a precipi-
tate was formed. Filtration and washing with ice-cold metha-
nol afforded 7.70 g (15.57 mmol, 83% yield) of 4 as a white
powder.
1H NMR (CDCl3, 400 MHz) δ = 7.42 (t, 1H, J = 7.7 Hz, HAr),
7.25 (d, 2H, J = 7.7 Hz, HAr), 6.86 (s, 2H, HAr), 4.08–4.04 (m,
4H, CH2), 3.08–2.99 (m, 4H, CH(CH3)2), 1.35–1.33 (m, 24H,
CH(CH3)2).
13C NMR ((CD3)2CO, 100 MHz) δ = 208.5 (2d, J = 215 Hz,
248 Hz, Ccarbene), 150.7 (CqAr), 148.3 (CqAr), 142.6 (CqAr), 136.4
(CqAr), 133.5 (CqAr), 131.1 (CAr–H), 125.9 (CAr–H), 116.6 (CAr–H),
55.5 (d, J = 8.4 Hz, CH2), 55.3 (d, J = 8.4 Hz, CH2), 30.1 (CH),
29.8 (CH), 26.3 (CH3), 25.9 (CH3), 24.7 (CH3), 24.4 (CH3).
2 –Synthesis of copper carbene (6a) 1.10 g (1.92 mmol,
1.0 eq.) of the preceding solid and CuCl (569.9 mg, 5.76 mmol,
3.0 eq.) were dissolved in 110 mL dichloromethane. The result-
ing mixture solution was stirred 3 h at room temperature in
the dark. The resulting suspension was filtered over celite and
evaporated obtain a solid. This material was taken up in
CH2Cl2 and n-pentane added dropwise while stirring until a
white solid formed. This material was recovered by filtration
and washed with n-pentane: 738.9 mg (1.39 mmol, 73% yield).
Using direct metallation with ammonia. 5a (468 mg,
1.0 mmol, 1.0 eq.) was suspended in 10 mL of water. Freshly
prepared copper(I) chloride (149 mg, 1.50 mmol, 1.5 eq.) was
added and the solution was degassed by bubbling argon for
5–10 min. Then, under vigorous stirring, aqueous ammonia
(14.0 mol L−1, 430 μL, 6.0 mmol, 6, 6.0 eq.) was added with a
syringe through the stopper and the solution was stirred for
2 h. The solution was extracted with 3 × 10 mL of dichloro-
methane, dried over K2CO3 and evaporated under reduced
pressure. The crude product was dissolved in 5 mL of dichloro-
methane and 30 mL of pentane was added dropwise under
stirring. The resulting white precipitate was filtered, washed
with n-pentane and dried to give 409 mg (77%).
1H NMR (DMSO-d6, 400 MHz) δ = 7.38–7.27 (m, 3H, HAr),
6.88 (s, 2H, HAr), 3.47–3.34 (m, 8H, CH2 + CH(CH3)2), 1.19 (d,
12H, J = 6.4 Hz, CH(CH3)2), 1.15 (d, 12H, J = 6.4 Hz, CH(CH3)2).
13C NMR (DMSO-d6, 100 MHz) δ = 145.3 (CqAr), 142.8 (CqAr),
137.7 (CqAr), 131.7 (CqAr), 128.9 (CAr–H), 125.4 (CAr–H), 125.3
(CqAr), 115.3 (CAr–H), 50.3 (CH2), 48.0 (CH2), 27.5 (CH), 27.3
(CH), 24.5 (CH3), 24.1 (CH3).
IR (ν, cm−1): 2965, 2115 (N3), 1569, 1463, 772.
HRMS (ESI+): calculated for C26H40N5: [M − H − 2Cl]+
422.3284, found 422.3261.
N-(4-Azido-2,6-diisopropylphenyl)-N′-(2,6-diisopropylphenyl)
imidazolinium chloride (5a). Compound
4
(2.00 g,
4.04 mmol) was suspended in a mixture of 20 mL HC(OEt)3
and 10 mL absolute ethanol. 1 drop of formic acid was added
and the reaction mixture was refluxed. After 2 h a clear solu-
tion was obtained. Concentration under reduced pressure
affords a white solid which was filtered and washed with
methyl-tert-butyl ether to give 1.67 g (3.57 mmol, 88% yield) of
white powder.
1H NMR ((CD3)2CO, 400 MHz) δ = 7.44 (t, 1H, J = 7.0 Hz,
HAr), 7.34 (d, 2H, J = 7.0 Hz, HAr), 7.02 (s, 2H, HAr), 4.23 (broad
This journal is © The Royal Society of Chemistry 2014
Dalton Trans., 2014, 43, 6981–6989 | 6985

View Article Online
Communication
Dalton Transactions
s, 4H, CH2), 3.31–3.22 (m, 4H, CH(CH3)2), 1.38–1.33 (m, 24H, 0.377 mmol, 1.05 eq.) was dissolved in 10 mL acetonitrile, and
CH(CH3)2).
propargyl α-D-glucopyranoside13 (2.45 mL from a solution pre-
13C NMR ((CD3)2CO, 100 MHz) δ = 204.6 (Ccarbene), 150.7 pared in methanol (0.146 M), 0.359 mmol, 1.0 eq.) was added.
(CqAr), 148.3 (CqAr), 142.4 (CqAr), 136.3 (CqAr), 133.4 (CqAr), The mixture was heated to 50 °C for 16 h. The solution was fil-
131.0 (CAr–H), 125.7 (CAr–H), 116.5 (CAr–H), 55.3 (CH2), 55.1 tered over celite and evaporated. The solid was taken up with
(CH2), 30.2 (CH), 29.9 (CH), 26.3 (CH3), 26.0 (CH3), 24.5 (CH3), 5 mL of dichloromethane and 20 mL of n-pentane was added
24.3 (CH3).
IR (ν, cm−1) = 2970, 2108 (N3), 1485, 1458, 1270, 644.
E. A. Calcd for C27H39N5Cl C: 61.12%, H: 7.03%, N: 13.20%;
found C: 61.36%, H: 7.06%, N: 12.89%.
dropwise while stirring to give 248 mg of a white powder
(0.331 mmol, 92% yield).
1H NMR (CD3CN, 400 MHz) δ = 8.56 (s, 1H, CHtriazole), 7.74
(s, 2H, HAr), δ = 7.44 (t, 1H, J = 7.7 Hz, HAr), 7.32 (d, 2H, J =
(N,N′-Bis-[4-azido-2,6-diisopropylphenyl]imidazolin-2-ylidene)- 7.7 Hz, HAr), 4.96 (d, 1H, J = 3.1 Hz, CHanomeric), [4.85 (d, 1H,
chlorocopper(I) (6b)
J = 12.1 Hz), 4.70 (d, 1H, J = 12.1 Hz), CH2OC], 4.07 (s, 4H,
CH2–CH2), 3.83–3.59 (m, 6H, CH2OH + 2CHOH + 2OH),
3.46–3.30 (m, 3H, 2 CHOH + 1OH), 3.26–3.12 (m, 5H,
CH(CH3)2 + CH2OH), 1.38–1.28 (m, 24H, CH(CH3)2).
13C NMR (CD3CN, 100 MHz) δ = 203.1 (Ccarbene), 151.0
(CqAr), 148.5 (CqAr), 139.2 (CqAr), 136.4 (CqAr), 136.0 (CqAr),
131.1 (CAr–H), 125.8 (CAr–H), 123.9 (CHtriazole), 118.1 (CAr–H),
99.6 (CHanomeric), 75.2 (CHOH), 73.8 (CHOH), 73.4 (CHOH),
71.8 (CHOH), 62.9 (CH2OH), 61.8 (CH2OC), 55.1 (CH2), 54.9
(CH2), 30.2 (CH), 29.7 (CH), 26.1 (CH3), 25.8 (CH3), 24.4 (CH3),
24.2 (CH3); one quaternary carbon not detected.
Using direct metallation with ammonia. 5b (1.50 g,
2.95 mmol, 1 eq.) was dissolved in 30 mL of water and
degassed for 20 min. Then, copper(I) chloride (436 mg,
4.43 mmol, 1.5 eq.) was added and the flask was stoppered
and degassed by bubbling argon for 5 min. Then, concentrated
aqueous ammonia (15.7 mol L−1, 1.13 mL, 17.7 mmol, 6.0 eq.)
was added with a syringe through the stopper, and the reaction
vessel was degassed for 1 more minute. The mixture was
stirred vigorously for 4 h at RT. The reaction mixture was trans-
ferred to a separating funnel containing 30 mL of dichloro-
methane. Extraction was performed three times. The
combined organic phases were dried over K2CO3, and evapor-
ated. The crude was recrystallized in DCM (80 mL) by the drop-
wise addition of n-pentane (200 mL) to afford 1.49 g of a pale
yellow product (89%).
IR (ν, cm−1): 3396 (br), 2966, 2868, 1631, 1599, 1485, 1456,
1277, 1147, 1037.
HRMS (ESI+): calculated for C36H51N5O6Cu [M − Cl]+:
712.3135, found: 712.3162.
(N-[2,6-Diisopropyl-4-(4-(2-oxo-2H-chromen-6-yl)-1H-1,2,3-
triazol-1-yl)phenyl]-N′-(2,6-diisopropylphenyl)imidazolin-2-ylidene)-
chlorocopper(I) (7c). Compound 6a (250 mg, 0.471 mmol,
1.0 eq.) was dissolved in 6 mL acetonitrile, and 6-ethynyl-2H-
chromen-2-one18 (88.2 mg, 0.518 mmol, 1.1 eq.) was added.
The mixture was heated to 50 °C for 16 h during which white
solid precipitated. After cooling to room temperature, the solid
was filtered and washed with ice-cooled acetonitrile: 285 mg
(0.407 mmol, 86% yield).
1H, 13C NMR and IR according to literature precedent.4e
(N-(2,6-Diisopropylphenyl)-N′-[4-(4-(hydroxymethyl)-1H-1,2,3-
triazol-1-yl)-2,6-diisopropylphenyl]imidazolin-2-ylidene)-chloro-
copper(I) (7a). Compound 6a (250 mg, 0.471 mmol, 1 eq.)
was dissolved in 5 mL of acetonitrile, and propargyl alcohol
(55.6 µL, 0.942 mmol, 2 eq.) was added. The mixture was
heated to 50 °C for 16 h during which a solid precipitated.
After cooling the reaction mixture to 0 °C for 2 h, the resulting
powder was recovered by filtration. The mother liquor was
cooled again overnight at 0 °C and filtered again to furnish a
second crop: 220 mg (0.374 mmol, 80% yield).
1H NMR (DMSO-d6, 400 MHz) δ = 9.64 (s, 1H, CHtriazole),
8.12 (d, 1H, J = 9.6 Hz, HAr), 7.98 (d, 1H, J = 7.8 Hz, HAr), 7.95
(s, 1H, HAr), 7.92 (s, 2H, HAr), 7.89 (d, 1H, J = 7.8 Hz, HAr), δ =
7.47 (t, 1H, J = 7.8 Hz, HAr), 7.36 (d, 2H, J = 7.8 Hz, HAr), 6.54
(d, 1H, J = 9.6 Hz, HAr), 4.16 (s, 4H, CH2), 3.26–3.21 (m, 2H,
CH(CH3)2), 3.16–3.09 (m, 2H, CH(CH3)2), 1.44–1.28 (m, 24H,
CH(CH3)2).
1H NMR (CD3CN, 400 MHz) δ = 8.34 (s, 1H, CHtriazole), 7.73
(s, 2H, HAr), δ = 7.46 (t, 1H, J = 7.7 Hz, HAr), 7.34 (d, 2H, J =
7.7 Hz, HAr), 4.72 (d, 2H, J = 5.3 Hz, CH2OH), 4.09 (s, 4H, CH2),
δ = 3.38 (t, 1H, J = 5.3 Hz, OH), 3.29–3.14 (m, 4H, CH(CH3)2),
1.40–1.31 (m, 24H, CH(CH3)2).
13C NMR (HSQC, DMSO-d6, 100 MHz) δ = 143.3 (CAr–H),
129.2 (CAr–H), 129.0 (CAr–H), 124.1 (CAr–H), 121.3 (CHtriazole),
121.0 (CAr–H), 115.9 (CAr–H), 116.0 (CAr–H), 112.2 (CAr–H), 53.3
(CH2), 28.3 (CH), 28.0 (CH), 24.8 (CH3), 24.3 (CH3), 23.4 (CH3),
22.9 (CH3).
Insufficient solubility of 7c in common NMR solvents pre-
vented the recording of a standard 13C NMR spectrum.
IR (ν, cm−1): 1722 (CvO), 1620, 1483, 1244, 1113, 1045,
937, 848.
13C NMR (CD3CN, 100 MHz)
δ = 203.1 (Ccarbene),
151.0 (CqAr), 150.3 (CqAr), 148.5 (CqAr), 139.4 (CqAr),
136.3 (CqAr), 136.0 (CqAr), 131.1 (CAr–H), 125.8 (CAr–H), 122.3
(CHtriazole), 118.1 (CAr–H), 56.9 (CH2), 55.1 (CH2), 54.9 (CH2),
30.2 (CH), 29.7 (CH), 26.1 (CH3), 25.8 (CH3), 24.4 (CH3),
24.1 (CH3).
IR (ν, cm−1): 3477, 2966, 1601, 1486, 1462, 1329, 1277,
1034.
HRMS (ESI+): calculated for C32H44N6OCu [M − Cl +
HRMS (ESI+): calculated for C40H46N6O2Cu [M − Cl +
CH3CN]+: 591.2873, found: 591.2875
CH3CN]+: 705.2978, found: 705.2954.
(N-[2,6-Diisopropyl-4-(4-(α-D-glucopyranosyloxy)methyl)-1H-
1,2,3-triazol-1-yl)phenyl]-N′-(2,6-diisopropylphenyl)imidazolin-
2-ylidene)-chlorocopper(I) (7b). Compound 6a (200 mg,
(N,N′-Bis[2,6-diisopropyl-4-(4-(α-D-glucopyranosyloxy)methyl)-
1H-1,2,3-triazol-1-yl)phenyl]-imidazolin-2-ylidene)-chlorocopper(I)
(7d). Compound 6b (200 mg, 0.349 mmol, 1.05 eq.) was dis-
6986 | Dalton Trans., 2014, 43, 6981–6989
This journal is © The Royal Society of Chemistry 2014

View Article Online
Dalton Transactions
Communication
solved in 6 mL acetonitrile, and 6 mL of propargyl α-D-gluco- recovered by filtration and washed with n-pentane: 46.0 mg
pyranoside (183 mg, 0.838 mmol, 2.4 eq.) was added. The (0.064 mmol, 63% yield).
mixture was heated to 50 °C for 3.5 h. The solution was filtered
1H NMR ((CD3)2CO, 400 MHz) δ = 8.60 (s, 1H, CHtriazole),
over celite and evaporated. The solid was taken up with 6 mL 7.88 (s, 2H, HAr), 7.46 (t, 1H, J = 7.7 Hz, HAr), 7.34 (d, 2H, J =
of dichloromethane and 25 mL of n-pentane was added drop- 7.7 Hz, HAr), 4.77 (d, 2H, J = 5.7 Hz, CH2OH), 4.43 (t, 1H, J =
wise while stirring to give 320 mg of a white powder 5.77 Hz, OH), 4.35–4.31 (m, 4H, CH2), 3.41–3.33 (m, 2H, CH
(0.317 mmol, 91% yield).
(CH3)2), 3.31–3.24 (m, 2H, CH(CH3)2), 1.50 (d, 6H, J = 6.8 Hz,
1H NMR (MeOD, 400 MHz) δ = 8.74 (s, 2H, CHtriazole), 7.82 CH(CH3)2), 1.43 (d, 12H, J = 6.8 Hz, CH(CH3)2), 1.34 (d, 6H, J =
(s, 2H, HAr), 4.99 (d, 2H, J = 3.7 Hz, CHanomeric), 4.94 (d, 2H, J = 6.8 Hz, CH(CH3)2).
12.6 Hz), 4.78 (d, 2H, J = 12.6 Hz), CH2OC], 4.23 (s, 4H, CH2–
13C NMR ((CD3)2CO, 100 MHz) δ = 197.1 (Ccarbene), 150.8
CH2), 3.72–3.64 (m, 8H, CH2OH + 2CHOH), 3.45 (dd, 2H, J1 = (CqAr), 148.2 (CqAr), 139.7 (CqAr), 136.0 (CqAr), 135.9 (CqAr),
9.7 Hz, J2 = 3.7 Hz, CHOH), 3.29 (hept, 4H, J = 6.8 Hz, CH(CH3)2), 131.2 (CAr–H), 125.9 (CAr–H), 121.9 (CHtriazole), 117.7 (CAr–H),
1.45 (m, 24H, CH(CH3)2).
57.3 (CH2), 55.2 (CH2), 54.9 (CH2), 30.5 (CH), 30.0 (CH), 25.9
13C NMR (MeOD, 100 MHz) δ = 203.1 (Ccarbene), 151.2 (CqAr), (CH3), 25.6 (CH3), 24.8 (CH3), 24.6 (CH3).
139.6 (CqAr), 136.5 (CqAr), 124.0 (CHtriazole), 118.1 (CAr–H), 100.0
IR (ν, cm−1): 3323, 2962, 1604, 1502, 1464, 1280, 1055,
(CHanomeric), 75.2 (CHOH), 74.2 (CHOH), 73.7 (CHOH), 72.0 1018, 887.
(CHOH), 62.9 (CH2OH), 61.7 (CH2OC), 55.2 (CH2), 30.6 (CH),
25.8 (CH3), 24.1 (CH3).
HRMS (ESI+): calculated for C32H44N6OAu [M − Cl +
CH3CN]+: 725.3242, found: 725.3275.
IR (ν, cm−1) = 3400(br), 2962, 1633, 1603, 1483, 1329, 1258,
1029.
E. A. Calcd for C30H41AuClN5O, 1H2O C: 48.82%, H: 5.87%,
N: 9.49%; found C: 49.10%, H: 5.70%, N: 9.47%.
(N-[2,6-Diisopropyl-4-(4-(α-D-glucopyranosyloxy)methyl)-1H-
(N,N′-Bis[2,6-diisopropyl-4-(4-(2-oxo-2H-chromen-6-yl)-1H-1,2,3-
triazol-1-yl)phenyl)imidazolin-2-ylidene)-chlorocopper(I) (7e). 1,2,3-triazol-1-yl)phenyl]-N′-(2,6-diisopropylphenyl)imidazolin-
Compound 6b (200 mg, 0.35 mmol, 1.0 eq.) was dissolved in 2-ylidene)-chlorogold(I) (8b). Compound 7b (100 mg,
2.5 mL acetonitrile and 2.5 mL of methanol, and 6-ethynyl-2H- 0.134 mmol, 1.0 eq.) and AuCl·Me2S (58.8 mg, 0.200 mmol,
chromen-2-one (131 mg, 0.77 mmol, 2.2 eq.) was added. The 1.5 eq.) were dissolved in 6 mL of 50/50 acetonitrile–DMSO.
mixture was heated to 50 °C for 24 h. After cooling to room The resulting mixture solution was stirred overnight at 30 °C.
temperature, the orange solid was filtered and washed with The resulting suspension was stirred for 30 min with a small
acetonitrile, methanol and small part of DMSO: 205.2 mg amount of silica and potassium carbonate and then was fil-
(0.23 mmol, 64% yield).
tered over celite and evaporated. The resulting solid was dis-
1H NMR (DMSO-d6, 400 MHz) δ = 9.64 (s, 2H, CHtriazole), solved in 1 mL of acetone and n-pentane (7 mL) was added
8.12 (d, 2H, J = 9.5 Hz, HAr), 7.98 (d, 2H, J = 7.8 Hz, HAr), 7.94 dropwise while stirring to give of a white solid recovered by fil-
(s, 4H, HAr), 7.89 (d, 2H, J = 7.8 Hz, HAr), 6.53 (d, 2H, J = tration and washed with ice-cooled methanol: 58.0 mg,
9.5 Hz, HAr), 4.22 (s, 4H, CH2), 3.26 (hept, 4H, J = 6.8 Hz, 0.066 mmol, 49% yield).
CH(CH3)2), 1.44 (d, 12H, J = 6.8 Hz, CH(CH3)2), 1.39 (d, 12H,
J = 6.8 Hz, CH(CH3)2).
1H NMR (CD3CN, 400 MHz) δ = 8.52 (s, 1H, CHtriazole), 7.74
(s, 2H, HAr), δ = 7.48 (t, 1H, J = 7.7 Hz, HAr), 7.33 (d, 2H, J =
13C NMR (HSQC, DMSO-d6, 100 MHz) δ = 144.9 (CAr–H), 7.7 Hz, HAr), 4.98 (d, 1H, J = 3.1 Hz, CHanomeric), [4.88 (d, 1H,
130.5 (CAr–H), 122.7 (CHtriazole), 122.2 (CAr–H), 117.3 (CAr–H), J = 12.6 Hz) 4.73 (d, 1H, J = 12.6 Hz), CH2OC], 4.12 (s, 4H,
117.2 (CAr–H), 113.6 (CAr–H), 54.7 (CH2), 29.7 (CH), 24.7 (CH3), CH2–CH2), 3.76 (s, 1H, OH), 3.66–3.53 (m, 3H, CH2OH +
25.9 (CH3).
1CHOH), 3.46–3.35 (m, 3H, 2CHOH + 1OH), 3.30–3.21 (m, 3H,
Insufficient solubility of 7e in common NMR solvents pre- 1CHOH + 2CH(CH3)2), 3.19–3.10 (m, 3H, 2CH(CH3)2 + 1OH),
vented the recording of a standard 13C NMR spectrum.
IR (ν, cm−1) = 2963, 1723, 1603, 1483, 1258, 1105, 1044,
939, 847.
2.91 (s, 1H, OH), 1.43–1.32 (m, 24H, CH(CH3)2).
13C NMR (CD3CN, 100 MHz) δ = 196.0 (Ccarbene), 151.1
(CqAr), 148.4 (CqAr), 139.5 (CqAr), 136.1 (CqAr), 135.7 (CqAr),
HRMS (ESI+): calculated for C51H51N9O4Cu [M − Cl + 131.3 (CAr–H), 125.9 (CAr–H), 123.9 (CHtriazole), 118.1 (CAr–H),
CH3CN]+: 916.3360, found: 916.3400.
99.6 (CHanomeric), 75.2 (CHOH), 73.8 (CHOH), 73.4 (CHOH),
(N-(2,6-Diisopropylphenyl)-N′-[4-(4-(hydroxymethyl)-1H-1,2,3- 71.8 (CHOH), 62.9 (CH2OH), 61.8 (CH2OC), 55.1 (CH2), 54.9
triazol-1-yl)-2,6-diisopropylphenyl]imidazolin-2-ylidene)-chloro- (CH2), 30.2 (CH), 29.7 (CH), 26.1 (CH3), 25.8 (CH3), 24.4 (CH3),
gold(I) (8a). Compound 7a (60.0 mg, 0.102 mmol, 1.0 eq.) and 24.2 (CH3); one quaternary carbon not detected.
AuCl·Me2S (45.0 mg, 0.153 mmol, 1.5 eq.) were dissolved in
6 mL of 50/50 acetonitrile–DMSO. The resulting mixture solu-
IR (ν, cm−1): 3385(br), 2966, 1627, 1485, 1458, 1277, 1037.
HRMS (ESI+): calculated for C40H46N6O2Au [M − Cl]+:
tion was stirred overnight at 30 °C. The resulting suspension 836.3505, found: 836.3478.
was stirred for 30 min with a small amount of silica and pot-
(N-[2,6-Diisopropyl-4-(4-(2-oxo-2H-chromen-6-yl)-1H-1,2,3-
assium carbonate in dichloromethane and then was filtered triazol-1-yl)phenyl]-N′-(2,6-diisopropylphenyl)imidazolin-2-ylidene)-
over celite. The solvent was removed under high vacuum. The chlorogold(I) (8c). Compound 7c (90.0 mg, 0.128 mmol,
resulting solid was taken up in CH2Cl2 and n-pentane was 1.0 eq.) and AuCl·Me2S (56.6 mg, 0.192 mmol, 1.5 eq.) were
added dropwise while stirring. A white powder was formed, dissolved in 7 mL of 50/50 acetonitrile–DMSO. The resulting
This journal is © The Royal Society of Chemistry 2014
Dalton Trans., 2014, 43, 6981–6989 | 6987

View Article Online
Communication
Dalton Transactions
mixture solution was stirred for 72 h at 30 °C. The resulting Localization of 8c in PC3 cell line
suspension was stirred for 30 min with a small amount of
Cells were plated on a glass slide and cultured in red phenol
free RPMI 1640 until reaching 60% of confluence. Then, they
were incubated with 10 µM of 8c for 18 h at 37 °C, 5% CO2.
Cells were washed three times by PBS 1X at 37 °C and treated
by 200 nM MitoTracker (M7513, Life Technologies) for 30 min.
Cells were washed again three times by PBS 1X at 37 °C then
fixed using 4% PFA for 15 min at room temperature. After
three additional washes by PBS 1X, cells were stocked in PBS
1X–glycerol (50/50) and fluorescence was captured by a
Zeiss axioplan2 microscope using Zeiss filter sets #01 and
#31 for visualizing 8c and red-MitoTracker respectively
(100× magnification).
silica and potassium carbonate in dichloromethane and then
was filtered over celite. The solvent was removed under high
vacuum. The resulting solid was taken up in CH2Cl2 and
MeOH was added dropwise while stirring. A white powder
formed and was recovered by filtration and washed with
methanol: 74.1 mg (0.089 mmol, 70% yield).
1H NMR (DMSO-d6, 400 MHz) δ = 9.64 (s, 1H, CHtriazole),
8.12 (d, 1H, J = 9.4 Hz, HAr), 7.98 (d, 1H, J = 8.0 Hz, HAr), 7.95
(s, 1H, HAr), 7.92 (s, 2H, HAr), 7.89 (d, 1H, J = 8.0 Hz, HAr), δ =
7.48 (t, 1H, J = 7.9 Hz, HAr), 7.36 (d, 2H, J = 7.9 Hz, HAr), 6.54
(d, 1H, J = 9.4 Hz, HAr), 4.20 (s, 4H, CH2), 3.25–3.20 (m, 2H,
CH(CH3)2), 3.15–3.10 (m, 2H, CH(CH3)2), 1.44–1.42 (m, 12H,
CH(CH3)2), 1.35–1.33 (m, 12H, CH(CH3)2).
Fluorescence spectroscopy
13C (HSQC) NMR (DMSO-d6, 100 MHz) δ = 143.6 (CAr–H),
129.5 (CAr–H), 129.0 (CAr–H), 124.1 (CAr–H), 121.2 (CHtriazole),
120.7 (CAr–H), 115.9 (CAr–H), 115.6 (CAr–H), 112.0 (CAr–H), 53.2
(CH2), 28.2 (CH), 27.8 (CH), 24.5 (CH3), 23.6 (CH3), 23.5 (CH3),
22.9 (CH3).
Insufficient solubility of 8c in common NMR solvents pre-
vented the recording of a standard 13C NMR spectrum.
IR (ν, cm−1): 1743 (CvO), 1620, 1492, 1396, 1219, 1099,
1026.
Stock solutions of compounds 7c and 8c were prepared in
DMSO at 10−2 mol L−1. 30 µL of each stock solution was added
to 2970 µL of pH = 7.2, 0.5 mol L−1 HEPES-NaOH buffer (final
concentration 10−5 mol L−1).
Quantum yields were determined using a solution of
quinine sulfate 0.5 mol L−1 aqueous H2SO4 and used as stan-
dard for quantum yield determination.19
Fluorescence spectra were recorded with a Cary Eclipse
fluorimeter. The spectra were recorded in 1 cm luminescence
cells. The slits were set to 2.5/2.5 nm (excitation/emission) for
all measurements. Absorption spectra for quantum yields
determination were recorded with a Cary spectrophotometer.
HRMS (ESI+): calculated for C40H46N6O2Au [M − Cl +
CH3CN]+: 839.3348, found: 839.3369.
E. A. Calcd for C38H43AuClN5O2, 3/2 dmso C: 51.76%, H:
5.51%, N: 7.36%; found C: 51.57%, H: 5.30%, N: 7.51%.
(N,N′-Bis[2,6-diisopropyl-4-(4-(α-D-glucopyranosyloxy)methyl)-
1H-1,2,3-triazol-1-yl)phenyl]-imidazolin-2-ylidene)-chlorogold(I)
(8d). Compound 7d (50 mg, 0.05 mmol, 1.0 eq.) was dissolved
in 2.5 mL of 50/50 acetonitrile–DMSO and the resulting
mixture solution was stirred for 24 h at 50 °C. The resulting
suspension was stirred for 30 min with a small amount of
silica and potassium carbonate, then filtered over celite and
evaporated. The resulting solid was taken-up with 5 mL of
methanol, filtered over a millipore filter and evaporated.
The resulting solid was dissolved in 1 mL of methanol
then 5 mL of acetone was added dropwise and the product
was precipitated by a slow addition of n-pentane (5 mL)
while stirring. The resulting off-white solid was recovered by
filtration and washed with acetone: 34.0 mg, 0.066 mmol, 60%
yield.
Acknowledgements
Region Auvergne (PNC) is acknowledged for financial support.
Notes and references
‡CCDC 977560 for 7c. The unit cell contains two very similar but non-equivalent
molecules. Thus, values of Fig. 3 correspond to the average.
§The complex 8b shows only moderate cytotoxicity: 35% of inhibition of cell
growth on MCF-7 cells at 10 μM.
1 (a) S. Díez-González, N. Marion and S. P. Nolan, Chem.
Rev., 2009, 109, 3612–3676; (b) O. Schuster, L. Yang,
H. G. Raubenheimer and M. Albrecht, Chem. Rev., 2009,
109, 3445–3478; (c) N-Heterocyclic Carbenes in Synthesis, ed.
S. P. Nolan, Wiley-VCH, Weinheim, 2006; (d) N-Heterocyclic
Carbenes From Laboratory Curiosities to Efficient Synthetic
Tools, ed. S. Díez-González, RSC Publishing, 2010.
2 (a) K. M. Hindi, M. J. Panzner, C. A. Tessier, C. L. Cannon
and W. J. Youngs, Chem. Rev., 2009, 109, 3859–3884;
(b) L. Oehninger, R. Rubbiani and I. Ott, Dalton Trans.,
2013, 42, 3269–3284; (c) W. Lui and R. Gust, Chem. Soc.
Rev., 2013, 42, 755–773; (d) A. Gautier and F. Cisnetti,
Angew. Chem., Int. Ed., 2013, 52, 11976–11978.
1H NMR (MeOD, 400 MHz) δ = 8.75 (s, 2H, CHtriazole), 7.82
(s, 2H, HAr), 5.0 (d, 2H, J = 3.7 Hz, CHanomeric), 4.96 (d, 2H, J =
12.6 Hz), 4.79 (d, 2H, J = 12.6 Hz), CH2OC], 4.26 (s, 4H, CH2–
CH2), 3.72–3.64 (m, 8H, CH2OH + 2CHOH), 3.45 (dd, 2H, J1 =
9.7 Hz, J2 = 3.7 Hz, CHOH), 3.29–3.26 (hept, J = 6.8 Hz, 4H,
CH(CH3)2), 1.50 (d, 12H, J = 6.8 Hz, CH(CH3)2), 1.46 (d, 12H,
J = 6.8 Hz, CH(CH3)2).
13C NMR (MeOH-d4, 100 MHz) δ = 196.6 (Ccarbene), 151.1
(CqAr), 140.4 (CqAr), 136.0 (CqAr), 118.2 (CAr–H), 100.0
(Canomeric), 75.0 (CHOH), 74.3 (CHOH), 73.6 (CHOH), 71.9
(CHOH), 62.5 (CH2OH), 61.7 (CH2OC), 55.4 (CH2), 54.9 (CH2),
30.5 (CH), 25.3 (CH3), 24.3 (CH3), C triazole missing.
3 For azide–alkyne pre-functionalization of metal NHCs, see:
(a) S. Warsink, R. M. Drost, M. Lutz, A. L. Spek and
C. J. Elsevier, Organometallics, 2010, 29, 3109–3116;
IR (ν, cm−1) = 3400 (br), 2967, 1603, 1483, 1348, 1279, 1038.
6988 | Dalton Trans., 2014, 43, 6981–6989
This journal is © The Royal Society of Chemistry 2014

View Article Online
Dalton Transactions
Communication
(b) H. Chayanant, H.-L. Su, H. S. Bazzi and
D. E. Bergbreiter, Org. Lett., 2009, 11, 665–667; (c) S. Gu,
H. Xu, N. Zhang and W. Chen, Chem.–Asian J., 2010, 5,
1677–1689; (d) Y. He and C. Cai, Chem. Commun., 2011, 47,
12319–12321; (e) C. Gaulier, A. Hospital, B. Legeret,
A. F. Delmas, V. Aucagne, F. Cisnetti and A. Gautier, Chem.
Commun., 2012, 48, 4005–4007; (f) A. Hospital, C. Gibard,
C. Gaulier, L. Nauton, V. Thery, M. El-Ghozzi, D. Avignant,
F. Cisnetti and A. Gautier, Dalton Trans., 2012, 41, 6803–
6812.
4 For post-functionalization of metal NHCs see representa-
tive examples: (a) RuAAC: E. Chardon, G. L. Puleo,
G. Dahm, G. Guichard and S. Bellemin-Laponnaz, Chem.
Commun., 2011, 47, 5864–5866; (b) RuAAC: E. Chardon,
G. L. Puleo, G. Dahm, S. Fournel, G. Guichard and
S. Bellemin-Laponnaz, ChemPlusChem, 2012, 77, 1028–
1038; (c) Photochemical: V. W. W. Yam, J. K. W. Lee,
C. C. Ko and N. Zhu, J. Am. Chem. Soc., 2009, 131, 912–913;
(d) CuAAC (also for prefunctionalisation): S. Warsink,
R. M. Drost, M. Lutz, A. L. Spek and C. J. Elsevier, Organo-
metallics, 2010, 29, 3109–3116; (e) CuAAC (catalyst and sub-
A. Meyer, J. Lemke, J. Wimberg, N. Metzler-Nolte, F. Meyer,
F. Mohr and I. Ott, Med. Chem. Commun., 2013, 4, 942–948;
(d) R. Rubbiani, S. Can, I. Kitanovic, H. Alborzinia,
M. Stefanopoulou, M. Kokoschka, S. Mönchgesang,
W. S. Sheldrick, S. Wölfl and I. Ott, J. Med. Chem., 2011, 54,
8646–8657; (e) J. L. Hickey, R. A. Ruhayel, P. J. Barnard,
M. V. Baker, S. J. Berners-Price and A. Filipovska, J. Am.
Chem. Soc., 2008, 130, 12570–12571.
8 For silver, see: (a) L. Eloy, A.-S. Jarrousse, M.-L. Teyssot,
A. Gautier, L. Morel, C. Jolivat, T. Cresteil and S. Roland,
ChemMedChem, 2012, 7, 805–814 For copper, see:
(b) M.-L. Teyssot, A.-S. Jarrousse, A. Chevry, A. De Haze,
C. Beaudoin, M. Manin, S. P. Nolan, S. Diez-Gonzalez,
L. Morel and A. Gautier, Chem.–Eur. J., 2009, 15, 314–318.
9 (a) T. Makino, H. Masu, K. Katagiri, R. Yamasaki,
I. Azumaya and S. Saito, Eur. J. Inorg. Chem., 2008, 4861–
4865; (b) E. Tzur, A. Ben-Asuly, C. E. Diesendruck,
I. Goldberg and N. G. Lemcoff, Angew. Chem., Int. Ed., 2008,
47, 6422–6425; (c) H. Ibrahim, C. Gibard, A. Hospital,
C. Gaulier, N. Hewitt, A. Gautier and F. Cisnetti, Protocol
Exchange, 2012, DOI: 10.1038/protex.2012.058.
strate): C. Gibard, D. Avignant, F. Cisnetti and A. Gautier, 10 H. C. Brown, Organic synthesis via borane, Aldrich Chemical
Organometallics, 2012, 31, 7902–7908; (f) CuAAC: Co., Inc., Milwaukee, 1997.
S. Gauthier, N. Weisbach, N. Bhuvanesh and J. A. Gladysz, 11 J. Andersen, U. Madsen, F. Björkling and X. Liang, Synlett,
Organometallics, 2009, 28, 5597–5599; (g) Enolate reactivity: 2005, 2209–2213.
L. Benhamou, N. Vujkovic, V. César, H. Gornitzka, 12 C. Gibard, H. Ibrahim, A. Gautier and F. Cisnetti, Organo-
N. Lugan and G. Lavigne, Organometallics, 2010, 29, 2616– metallics, 2013, 32, 4279–4283.
2630; (h) Enolate reactivity: L. Benhamou, V. César, 13 A. S. Rowan, N. I. Nicely, N. Cochrane, W. A. Wlassoff,
H. Gornitzka, N. Lugan and G. Lavigne, Chem. Commun.,
2009, 4720–4722; (i) Huisgen and SPAAC: ref. 3f
A. Claiborne and C. J. Hamilton, Org. Biomol. Chem., 2009,
7, 4029–4036.
( j) Nucleophilic substitution: H. V. Huynh and Q. Teng, 14 S. Díez-González, E. D. Stevens and S. P. Nolan, Chem.
Chem. Commun., 2013, 49, 4244–4246. Commun., 2008, 4747–4749.
5 (a) M. Barz, E. Herdtweck and W. R. Thiel, Angew. Chem., 15 (a) D. F. Eaton, Pure Appl. Chem., 1988, 60, 1107–1114;
Int. Ed., 1998, 37, 2262–2264; (b) D. Urankar and J. Kosmrlj,
J. Comb. Chem., 2008, 10, 981–985; (c) W. S. Brotherton,
H. A. Michaels, J. T. Simmons, R. J. Clark, N. S. Dalal and
L. Zhu, Org. Lett., 2009, 11, 4954–4957; (d) S. A. Ingale and
F. Seela, J. Org. Chem., 2013, 78, 3394–3399;
(b) A. M. Brouwer, Pure Appl. Chem., 2011, 83, 2213–2228;
(c) Fluorescence quantum yields found here are compatible
with what is reported for other ‘clicked’ coumarin:
J. A. Key, S. Koh, Q. K. Timerghazin, A. Brown and
C. W. Cairo, Dyes Pigm., 2009, 82, 196–203.
(e) C. Uttamapinant, A. Tangpeerachaikul, S. Grecian, 16 Many gold-NHCs are known to localize at the mitochondria
S. Clarke, U. Singh, P. Slade, K. R. Gee and A. Y. Ting,
Angew. Chem., Int. Ed., 2012, 51, 5852–5856.
6 M. R. L. Furst and C. S. J. Cazin, Chem. Commun., 2010, 46,
6924–6925.
7 (a) T. Zou, C. T. Lum, S. S.-Y. Chui and C.-M. Che, Angew.
Chem., Int. Ed., 2013, 52, 2930–2933; (b) J. Lemke, A. Pinto,
vicinity, for selected examples, see: ref. 7a,e.
17 T. Makino, H. Masu, K. Katagiri, R. Yamasaki, I. Azumaya
and S. Saito, Eur. J. Inorg. Chem., 2008, 4861–4865.
18 M. Chtchigrovsky, A. Primo, P. Gonzalez, K. Molvinger,
M. Robitzer, F. Quignard and F. Taran, Angew. Chem., Int.
Ed., 2009, 48, 5916–5920.
P. Niehoff, V. Vasylyevaa and N. Metzler-Nolte, Dalton 19 (a) D. F. Eaton, Pure Appl. Chem., 1988, 60, 1107–1114;
Trans., 2009, 7063–7070; (c) R. Rubbiani, E. Schuh,
(b) A. M. Brouwer, Pure Appl. Chem., 2011, 83, 2213–2228.
This journal is © The Royal Society of Chemistry 2014
Dalton Trans., 2014, 43, 6981–6989 | 6989