Asymmetric induction afforded by chiral azolylidene N-heterocyclic carbenes (NHC) catalysts

Article abstract of DOI:10.1016/j.tetasy.2012.09.004

Screening studies of new chiral imidazolium and triazolium based NHC salts I-VIII as ligands in asymmetric organometallic catalysis and as organocatalysts showed that these catalysts efficiently promoted the reactions. Moderate enantioselectivities (55-57% ee) were obtained in the asymmetric Cu-NHC catalysed conjugate additions of diethylzinc to cyclohexenone, in accordance with most previous studies. The chiral induction afforded in the gold(I)-NHC catalysed cyclopropanation reactions was low (<28% ee). However, these results represent the first reported chiral gold(I)-NHC catalysed olefin cyclopropanation. The NHC-organocatalysed asymmetric cross-annulation of cinnamaldehyde and trifluoroacetophenone gave lower enantioselectivity (<50% ee) but higher yields of the γ-lactone product relative to previous reports. The enantioselectivities obtained varied considerably, even within a group of structurally closely related NHCs. This study demonstrates the challenge of designing NHCs with a general ability to induce asymmetry in a broader range of reactions.

Full text of DOI:10.1016/j.tetasy.2012.09.004

Tetrahedron: Asymmetry 23 (2012) 1350–1359
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric induction afforded by chiral azolylidene N-heterocyclic
carbenes (NHC) catalysts
⇑
Ragnhild B. Strand, Trygve Helgerud, Tina Solvang, Amund Dolva, Christian A. Sperger, Anne Fiksdahl
Department of Norwegian, University of Science and Technology, NTNU, NO-7491 Trondheim, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 July 2012
Screening studies of new chiral imidazolium and triazolium based NHC salts I–VIII as ligands in asym-
metric organometallic catalysis and as organocatalysts showed that these catalysts efficiently promoted
the reactions. Moderate enantioselectivities (55–57% ee) were obtained in the asymmetric Cu-NHC cat-
alysed conjugate additions of diethylzinc to cyclohexenone, in accordance with most previous studies.
The chiral induction afforded in the gold(I)-NHC catalysed cyclopropanation reactions was low (<28%
ee). However, these results represent the first reported chiral gold(I)-NHC catalysed olefin cyclopropana-
tion. The NHC-organocatalysed asymmetric cross-annulation of cinnamaldehyde and trifluoroacetophe-
none gave lower enantioselectivity (<50% ee) but higher yields of the
c-lactone product relative to
previous reports. The enantioselectivities obtained varied considerably, even within a group of structur-
ally closely related NHCs. This study demonstrates the challenge of designing NHCs with a general ability
to induce asymmetry in a broader range of reactions.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
NHCs as chiral organocatalysts, there is a large potential for new
chiral NHCs in novel areas of stereoselective synthesis. With the
N-Heterocyclic carbenes (NHCs) represent a versatile class of
compounds due to their favourable role in transition metal cata-
lysed reactions.1 Over the last decade, they have been developed
as a powerful supplement to the traditional phosphine ligands.2
Similar to asymmetric transformations using chiral phosphine me-
tal complexes, reports on chiral NHC ligands and their applications
in asymmetric catalysis are growing steadily. The development of
this field has recently been reviewed.3 Typical concepts for
enantioselective metal catalysed reactions performed with chiral
NHC ligands are represented by allylic Pd-catalysed alkylations
intention of exploring the possibilities afforded by chiral imidaz-
ole- and triazole-based NHCs and to show their potential as
catalysts in stereoselective reactions, we have previously prepared
a number of chiral imidazolium I, II, V7 and triazolium VII, VIII8
salts as NHC precursors (Scheme 1) from amino acids. A few
preliminary asymmetric test reactions were also conducted. We
have now prepared the additional imidazolium salts III, IV and
VI. The NHC precursors III and VI were synthesized from
ine9,10a,b and -phenylglycine12,13, respectively, in accordance with
literature procedures. The NHC precursor IV was synthesized from
D-ser-
L
and
a
-arylations, Cu- and Rh-catalysed conjugate additions, cata-
D-valinol via coupling of (R)-2-(chloromethyl)-4-isopropyl-4,5-
lytic hydrogenations in the presence of Ir or Rh, desymmetrization
by Ru-based ring closing metathesis (RCM) or hydrosilylation
reactions with Rh- or Ru-catalysts. Recent investigations have also
demonstrated the advantages of using NHCs as new organocata-
lysts, for instance in aldehyde activation in so-called ‘umpolung’
reactions.4 The NHC organocatalytic reactions have been further
extended to include asymmetric organocatalytic transformations
performed with chiral NHCs.5a,b In particular, asymmetric NHC
catalysed reactions generating acyl anion equivalents from
aldehyde substrates by polarity-reversal, have been applied in a
series of reactions.6
dihydrooxazole14a,b and 1-(2,6-diisopropylphenyl)-4,5-dihydro-
1H-imidazole10a by using known procedures.10b
The synthesis design was based on a combination of different
strategies11 to obtain chiral NHCs with the potential to induce chi-
rality, such as sterically bulky N-substituents, restricted rotation
and proximity of the stereogenic centre to the carbene centre.
Our aim herein was to apply the new NHC precatalysts and study
their potential to afford chiral induction as ligands in asymmetric
organometallic catalysis and as organocatalysts in enantioselective
reactions. Our results are presented below.
In order to allow a greater variety of enantioselective metal cat-
alysed transformations, as well as to broaden the application of
2. Results and discussion
With the aim of identifying the potential of new chiral NHCs to
induce chiral induction, we applied some model reactions:
⇑
Corresponding author. Tel.: +47 735 940 94.
E-mail address: Anne.Fiksdahl@chem.ntnu.no (A. Fiksdahl).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.09.004

R. B. Strand et al. / Tetrahedron: Asymmetry 23 (2012) 1350–1359
1351
MeO
OMe
OMe
N
N
N
N
N
N+
N
N
N+
-
PF6
O
-
-
N
PF6
II
PF6
I
III
-
-
Va:
X = Cl , R = H
Vb: X-= PF6 , R = H
-
N
N
-
-
N
N
X-
Ph
OR
Vc:
X = PF6 ,R = Ms
O
-
Vd: X-= PF6-,R = Ac
PF6
-
-
N
Ve:
X = PF6 ,R = Pivaloyl
Vf: X-= PF6-,R = Bz
IV
V
Vg: X-= PF6-,R = TBDMS
R
N
N+
N
N
Ph
Ph
N
N
N
N
Cl-
VI
X-
ClO4 Ph
VIII
OH
OBn
VIIa; R = Me, X- = Cl-
VIIb; R = H, X- = ClO4
-
Scheme 1. Structures of NHC precursors.
- Cu-NHC catalysed conjugate addition (Table 1)13,15,18
- Au(I)-NHC catalysed cyclopropanation (Table 2)16a–c and
- NHC-organocatalysed cross-annulation (Table 3).5a,17,19
groups in compound I with the achiral less substituted phenyl
group in compound II, afforded a large drop in enantioselectivity
(from 57% to 11% ee). A remarkable decrease in enantioselectivity
was observed going from the oxazole-based NHC-ligand IV (25%
ee) to III (3% ee). In NHCs IV and III, the oxazole group is con-
nected to the imidazole framework through the 2-position, leav-
ing the stereogenic centre in the oxazole side-chain, and
through the chiral 4-position. This is in contrast to the general
idea that enantioselectivity would increase with the proximity
of the chiral centre to the carbene centre. The favoured formation
of the (R)-2 enantiomer with NHC precursors Vb-Vg is in accor-
dance with other studies13 with related chiral N-phenylpropyl-
based NHCs. It is noteworthy that the inverse configuration of ad-
duct 2 was induced by the introduction of a triazolium 3-methyl-
group VIIb-VIIa.
In order to enable comparison with similar results by others,
standardized reaction conditions15 were applied in our studies
and no product isolation or attempts at optimization were made.
As shown by others,22 optimization of this reaction, for example
on solvent effects, allowed an increase in enantioselectivity from
15% ee (in CH2Cl2) and 25% ee (in diethyl ether) to 70% ee (in
DMA). As a result, the optimization of the reaction conditions
was supposed to increase the enantiomeric purity obtained by
our NHCs. Higher enantioselectivities would also be expected for
other less challenging substrates and different alkylzincs.21,22
2.1. Enantioselective Cu-NHC catalysed conjugate additions
Conjugate addition reactions involving organocopper interme-
diates can be performed in an enantioselective manner by using
chiral ligands. By using various chiral phosphine ligands, the cop-
per-catalysed conjugate addition of diethylzinc to cyclohex-2-en-
one 1 to afford the (2R)- and (2S)-ethyl-adducts 2 (Table 1), has
been studied extensively. The reaction has been used as a test reac-
tion for many chiral catalytic systems, including Cu-NHCs, mostly
with moderate enantioselectivities.13,15,18 The highest ee reported
so far20 [92% ee (R)], has not been improved upon by recent studies
for the optimization of chiral Cu-NHC systems, derived from amino
acids.21,22 Up to 82% and 70% ee of, respectively, (S)- and (R)-ad-
ducts 2 were obtained by studying the solvent effect as well as
the influence of catalyst loading, the Cu:NHC ratio and the Cu salt.
However, asymmetric conjugate additions with other modified
reactants were more straightforward and excellent ees could
be obtained by allowing selected enones, such as substituted
cyclohexenones or smaller/larger cycloenones, to react with differ-
ent alkylzinc reagents.
The presently tested new Cu-NHCs, based on both the imidazo-
lium and the triazolium systems, afforded high catalytic activity, as
shown by the high, and mainly quantitative, conversion of cyclo-
hexenone 1 into the corresponding adduct 2 by diethylzinc conju-
gate addition (Table 1).
All of our NHC-ligands tested afforded chiral induction in the
reaction. The highest enantioselectivity obtained, 57% ee (R),
was achieved with the symmetrically substituted imidazolium
salt I and was comparable to results obtained with the commer-
cial triazolium salt IX (55% ee) and other reports.13,15,18 In gen-
eral, lower enantioselectivity was obtained (<25% ee) for both
types of systems, including the previously known imidazolium
salt X.18 Replacing one of the two chiral bulky phenylpyrrolidine
2.2. Enantioselective Au-NHC catalysis
Research on designing new catalytic systems has been one of
the most challenging fields in modern organic chemistry. Thus,
after being neglected by organic chemists for a long time, the use
of gold(I)–phosphine or –NHC2a,23 complexes as catalysts for
organic transformations has become a rapidly expanding field over
the past decade. The electrophilic ‘soft’ Lewis acid carbophilic
properties and unique reactivity of gold(I) have lead to the
development of a number of useful carbon–carbon and carbon–
heteroatom bond-forming processes, in particular based on the
nucleophilic attack on gold activated alkynes.

1352
R. B. Strand et al. / Tetrahedron: Asymmetry 23 (2012) 1350–1359
Table 1
Cu-NHC catalysed conjugate addition13,15
O
O
NHC (3 mol%)
Cu(OTf)2 (2 mol%)
nBuLi (8 mol%)
ZnEt2 (1.5 equiv)
Et2O, rt
Et
1
2
Ligand
Conv.a (%)
ee%b
MeO
OMe
N
N
N+
PF6
N
>99
57 (R)
-
I
OMe
N
N+
N
>99
11 (R)
-
PF6
II
N
N
-
98
3
PF6
O
N
III
N
N
O
>99
25 (R)
-
PF6
N
IV
>99
90
>99
75
90
77
9 (R)
23 (R)
14 (R)
13 (R)
12 (R)
8 (R)
Vb:
R=H
Vc: Ms
N
N
Vd:
Ve:
Vf:
Ac
Piv
Bz
RO
Vg: TBDMS
V
PF6
N
N
N
Ph
>99c
12 (S)
Cl-
VIIa
OBn
N
Ph
N
N
88c
11 (R)
14 (S)
-
ClO4
OBn
VIIb
N
N
N
56c
-
ClO4
VIII
Ph
O
N
N
N
>99c
55 (R)
BF4
IX
Ph

R. B. Strand et al. / Tetrahedron: Asymmetry 23 (2012) 1350–1359
1353
Table 1 (continued)
Ligand
Conv.a (%)
ee%b
N
N
87
24 (S)
-
BF4
X
a
Determined by GLC.
Determined by chiral GLC (Lipodex E).
Reaction time 30 min.
b
c
Table 2
Au-NHC catalysed olefin cyclopropanation16a
OAc
OAc
OAc
5% Au-NHC-Cl, 5% AgNTf2
DCM, rt, 2 h
OAc
OAc
OAc
3
4
5-trans
5-
cis
Au–NHC complex
Conv.a (%)
Ratioa (cis:trans)
ee%b (cis)
ee%b (trans)
80
60:40
65:35
63:37
12
21
17
13
28
22
14d
45e
N
N
Au
Cl
OH
Au-Va
Ph
N
N
N
93
59:41
3
0
Au
Cl
OH
Ph
Au-VI
N
N
>49c
59:41
8
6
OBn
Au
Cl
Au-VIIa
a
b
c
Determined by GLC.
Determined by chiral GLC (Varian CP-Chirasil-Dex CB).
Reaction time 30 min.
d
e
The reaction was performed at ꢀ40 °C in 3 h.
The reaction was performed at ꢀ40 °C in 3 + 24 h at rt.
However, the literature overview points out the early stage of
atropoisomeric P-based bidentate gold-ligands has recently been
reviewed.26
the development, with the field of enantioselective gold(I)-cata-
lysed transformations being more rare.24 This fact may be due to
the linear coordination mode of gold(I) complexes, locating the po-
tential reacting centre distant from the chiral information carried
by the ligand. Thus, gold-catalysed asymmetric transformations
are still challenging, and are characterized by limited mechanistic
understanding and restricted knowledge of the active chiral gold
complexes. However, new approaches and strategies have recently
enabled the development of a number of effective gold(I)-catalysed
enantioselective transformations. With few exceptions, the ligands
applied in such reactions have been restricted to enantiomerically
pure axially chiral bisphosphine complexes, typically shown by the
promising results obtained for the enantioselective synthesis of
proline derivatives by 1,3-dipolar cycloadditions in the presence
of chiral binap-AuTFA complexes.25 The recent development of
Although NHCs represent
a growing class of ligands in
transition metal catalysis, there have only been few reports on
asymmetric gold catalysis applying chiral gold–NHC complexes.
Cycloisomerization of 1,6-enynes and both atropoisomeric and
other C2-symmetric NHC ligand systems have been reported on.
However, only modest to moderate enantioselectivity (<60% ee)
has been obtained.27–29 Similar results were obtained in asymmet-
ric intramolecular hydroaminations with axially chiral Au(I)–NHC
complexes.30 To the best of our knowledge, there is only one report
on the application of more conventional NHC ligands, which
applies bis(NHC) connected through a chiral dioxolane backbone,
as ligands for gold(I) complexes. Such systems induced good to
excellent enantioselectivity in the hydrogenation of prochiral
alkenes.31

1354
R. B. Strand et al. / Tetrahedron: Asymmetry 23 (2012) 1350–1359
These results demonstrate that chiral NHCs based on regular
the trans-c
-lactones in 23% yield in up to 66% ee.5b High enantiose-
NHC structures may be as promising as the axially chiral concept
for the design of new chiral NHC–gold complexes, despite the high
enantioselectivities successfully obtained with atropoisomeric bis-
phosphine–gold complexes. Hence, there is a potential for new chi-
ral NHCs in asymmetric synthesis based on gold catalysis. The
identification of new NHC ligands may also lead to the develop-
ment of new gold catalysed enantioselective transformations.
We have recently investigated gold(I)-catalysed olefin cyclo-
propanations from different propargylic substrates.16a Good to
excellent ees have previously been obtained in the enantioselective
gold(I) catalysed cyclopropanations of propargyl esters with chiral
atropoisomeric bisphosphinegold(I)-complexes.32 A highly enan-
tioselective rearrangement (95–99% ee) of propargyl substrates
into cyclic structures, catalysed by chiral acyclic diaminocar-
bene–gold(I) complexes, has also been reported.33
With this in mind, we wanted to study our new chiral NHCs as
gold(I) ligands to identify their potential in asymmetric cycloprop-
anation. Hence, we replaced our originally used gold(I)phosphine-
catalyst16a with the chiral gold(I)–NHC catalytic systems Au-Va,
Au-VI and Au-VIIa (Table 2).16 These new chiral Au(I)NHC-Cl com-
plexes were prepared in high yields (>80%) from the NHC-Cl pre-
cursors by carbene transfer reactions via the respective silver(I)–
carbene complexes.30,34 NHCAg-Cl are useful carbene transfer
agents, since the NHC ligands are readily transferred from silver
to gold, due to the labile silver(I)–carbene bond and the higher
NHC affinity for gold. The one-pot (i) Ag2O and (ii) AuCl(Me2S) pro-
tocol provides the [NHC-Cl]—[NHCAg-Cl]—[NHCAu-Cl] reaction se-
quence and represents a convenient method for the preparation of
gold–NHC complexes. However, successful carbene transfer takes
place by the formation of Ag-halide by-products and, thus, this
method is limited to accessible NHC-halide substrates.
Mostly, the catalytic activities of gold complexes Au-Va, Au-VI
and Au-VIIa were high (Table 2), while the chiral induction of the
un-optimized reactions were poor (<13% ee). The lower NHC cata-
lytic activity (80% conv.) of imidazolium complex Au-Va with a
benzylic side chain, permitted higher enantioselectivity (12–13%
ee) relative to the similar phenyl-substituted imidazolium complex
Au-VI (0–3% ee at 93% conv.). Some optimization studies were car-
ried out, applying the most promising catalyst Au-Va. The chiral
induction was unaffected and the conversion became poorer by
replacing DCM with THF or acetonitrile as a solvent. However, a
doubling of the enantioselectivity, up to 28% ee, was seen by low-
ering the reaction temperature in DCM to ꢀ40 °C. A threefold con-
version (14–45%) was obtained by leaving the reaction at ambient
temperature for 24 h.
lectivity (69–94% ee) but even lower yields (9–21%) were obtained
by chiral cyclophane-type NHCs.5a The importance of bulky N-sub-
stituents, the solvent effect as well as the large increase of enanti-
oselectivity by increasing the temperature was observed.
We initially performed an optimization of some general reac-
tion conditions with imidazolium salt Vb in order to study both
conversion/yield and enantioselectivity. The first studies on suit-
able bases revealed that DBU, applied at room temperature, more
efficiently promoted the reaction and was more convenient to
use than KHMDS (added at ꢀ78 °C) giving complex product mix-
tures. No effect was observed by halving the catalyst loading
(40–20 mol % NHC), or varying the substrate concentration. The ef-
fects of varying some reaction parameters are shown in Table 3.
Reduction in the amount of base from 40 to 20 mol % (entries
1,2), increasing the temperature (entries 3 and 4) or varying the
solvent systems (THF, DMF MeCN, entries 1–6) did not have any
significant effect, since enantioselectivity only varied from 0% to
39% ee. However, the highest chiral induction was afforded in tol-
uene or DCM, in particular, for the trans-isomer (42–55% ee, entries
7–13). Further reduction of the amount of base to 10 or 5 mol %
(entries 12 and 13) gave a significant drop in catalytic activity, as
shown by the much lower conversion degree (25% conv., entries
12 and 13). The reaction in toluene at room temperature afforded
more promising ees for both diastereomers (50/19% ee; entry 9)
and higher conversion (69% conv.) than in DCM (55/4% ee; 27%
conv. entry 7). Since less formation of the self-condensation by-
products was observed in toluene, even at elevated temperatures
(> 99% conv. at 55–110 °C, entries 10 and 11), we decided to apply
20 mol % of DBU in toluene at room temperature and 24 h reaction
time, as the standard cross annulation reaction conditions for the
following enantioselectivity studies with NHC precatalysts III–X
(20 mol %, Table 4).
We wanted to make sure that the reported conversions in Ta-
bles 3 and 4, obtained by GLC analysis with an internal standard,
were in accordance with realistic isolated product yields. Indeed,
the isolation of a total yield of 71% of the target trans and cis c-lac-
tone products 8 from the organocatalysed reaction with precata-
lyst Vb at 70 °C in THF, was approximately in agreement with
the quantitative substrate conversion shown by GLC (entry 4). In
general, GLC and NMR of the crude product mixtures from the fol-
lowing studies (Table 4) confirmed that % conversion corresponded
well with the amount of target products formed.
The chiral induction afforded by our tested NHCs generated from
precatalysts III–X varied considerably (Table 4). The oxazole-based
NHC-ligands IV and III behaved significantly differently, since high-
er ees were obtained for IV (20–24% ee) than III (5–4% ee). The
unexpected decrease in enantioselectivity by the decreased dis-
tance between the stereogenic centre and the carbene centre is also
in accordance with results for the Cu-NHC catalysed conjugate
addition (Table 1). The lower catalytic activity of the NHC obtained
from precatalyst IV (30% conv.) apparently allows higher selectiv-
ity. The closely related benzyl-Va and phenyl-VI substituted
imidazolium salt precatalysts afforded comparable enantioselectiv-
ities in the cross-annulation studies (26–35% ee of 8-trans). How-
ever, the NHC catalytic activity dropped going from Va (Bn; 89%
conv.) to IV (Ph; 25% conv.). The imidazolium salt Vb, used for opti-
mization studies, induced higher enantioselectivity (50% ee) than
the related imidazolium derivatives Vd–g (24–43% ee). The highest
ee for the 8-cis product (41% ee) was, however, afforded by the sym-
metrically substituted imidazolium salt X, in accordance with pre-
vious cross-annulation studies.5a However, in addition to low
conversion (57%), the major product in this case was the cinnamal-
dehyde self-condensation product, as reported by others.5a
The low enantioselectivity obtained by the gold complexes Au-
Va, Au-VI and Au-VIIa may be explained by the general linear coor-
dination mode of ligand–Au-substrate complexes. The presently
used NHC ligands may be too small or flexible and thus too distant
from the reactive substrate to afford effective chiral induction.
2.3. Organocatalytic transformations
Organocatalytic transformations performed with chiral NHCs
include, in particular, asymmetric NHC catalysed reactions of acyl
anion equivalents generated by polarity-reversal of aldehyde sub-
strates.6 One application is the stereoselective cross-annulation
lactone synthesis from the cinnamaldehyde enal 6 and trifluoro-
acetophenone 7 (Table 2). The target c-butyrolactone 8 is formed
as mixtures of trans- and cis-diastereomers by an organocatalysed
condensation reaction. The crucial step is the formation of an acti-
vated homoenolate intermediate, obtained from a chiral NHC and
the a
,b-unsaturated aldehyde by a ‘umpolung’ process.17,19,35–38
Asymmetric condensation reactions have been performed with
bridged chiral imidazole-NHCs based on aminoalcohols, affording
The NHC catalysts generated from the new triazolium salts VIIb,
VIII and the commercial IX were highly efficient (> 99% conv. in

R. B. Strand et al. / Tetrahedron: Asymmetry 23 (2012) 1350–1359
1355
Table 3
NHC-organocatalysed cross-annulation; optimization of reaction conditions with NHC precatalyst Vb
Ph
N
N
O
O
O
O
-
PF6
OH
Vb
O
O
H
Ph
CF3
Ph
CF3
Ph
CF3
Ph
Ph
8-trans
Ph
NHC 20 mol%
DBU
6
7
8-cis
Entry
DBU mol %
Temp (°C)
Solvent
Time (h)
Conv.a (%)
trans:cisb
ee%c (trans)
ee%c (cis)
1
2
3
4
40
20
20
20
rt
rt
50
70
THF
THF
THF
THF
18
24
2
72
54
46
>99
71d
51
46
27
71
69
72:28
76:24
73:27
71:29
24
31
35
35
16
11
4
24
5
5
6
7
8
20
20
20
20
20
20
20
10
5
rt
rt
rt
35
rt
55
110
rt
DMF
MeCN
DCM
DCM
Toluene
Toluene
Toluene
Toluene
Toluene
24
24
24
24
24
18
2
72:28
83:17
81:19
81:19
77:23
73:27
71:29
75:25
72:28
17
39
55
51
50
50
51
48
42
3
0
4
3
19
9
5
33
36
9
10
11
12
13
>99
>99
25
24
44
rt
25
a
b
c
Determined by GLC using an internal standard.
Determined by GLC.
Determined by chiral GLC (Varian CP-Chirasil-Dex CB).
Isolated yield.
d
Table 4
NHC-organocatalysed cross-annulation8,25
O
O
O
O
NHC 20 mol%
DBU 20 mol%
O
O
H
Ph
CF3
Ph
Ph
CF3
toluene, rt, 24 h
Ph
CF3
Ph
Ph
6
7
8-cis
8-trans
Precatalyst
Conv.a (%)
Ratio trans:cisb
ee%c (trans)
ee%c (cis)
N
N
87
30
89
48:52
5
4
-
O
PF6
N
III
N
N
O
-
46:54
20
24
PF6
N
IV
N
N
Cl-
66:34
26
15
OH
Va
(continued on next page)

1356
R. B. Strand et al. / Tetrahedron: Asymmetry 23 (2012) 1350–1359
Table 4 (continued)
Precatalyst
Conv.a (%)
Ratio trans:cisb
ee%c (trans)
ee%c (cis)
69
29
77:23
63:37
50
4
19
22
82
47
78
91
49:51
48:52
53:47
53:47
25
24
43
30
18
31
31
28
Vb: R=H
Vc: Ms
N
N
Vd
:
Ac
Ve: Piv
-
PF6
Vf:
Bz
OR
OH
Vg:
TBDMS
V
N
N
25
68:32
59:41
35
0
Cl-
VI
N
N
Ph
N
83d
10d
19d
Cl-
OBn
VIIa
N
Ph
N
N
>99
>99
57:43
55:45
0
0
3
-
ClO4
OBn
VIIb
N
N
N
10
-
ClO4
VIII
Ph
O
N
N
N
>99e
54:46
73:27
3
7
-
Ph
BF4
IX
57f
20
41
N
N
-
BF4
X
a
b
c
d
e
f
Determined by GLC using an internal standard.
Determined by GLC.
Determined by chiral GLC (Varian CP-Chirasil-Dex CB).
The reaction was performed with 40 mol % DBU in THF.
Reaction time 6 h.
Crude product mixture contained only 40% of 8-cis/trans products, as shown by 1H NMR.
6–24 h) in promoting the cross-annulation of enal 6 and ketone 7.
However, only minor enantioselectivity (0–10% ee) was obtained
by these NHC precursors, when applying the standardized reaction
conditions. However, application of triazolium salt VIIa by modi-
fied reaction conditions (40 mol % DBU and THF as solvent) al-
lowed an increase in enantioselectivity; 10% ee for 8-trans and
19% ee for 8-cis were obtained.
of diethylzinc to cyclohexenone 1. These results are in accordance
with most previous unoptimized studies.13,15,18
Even if the chiral induction in the gold(I)–NHC catalysed cyclo-
propanation reactions was low (<28% ee), this result represents the
first chiral gold(I)–NHC catalysed olefin cyclopropanation and may
nevertheless indicate a potential for chiral Au(I)–NHC catalytic sys-
tems in future optimized asymmetric cyclopropanations.
Through optimization of the reaction conditions for NHC-
organocatalysed cross-annulation of cinnamaldehyde 6 and triflu-
3. Conclusion
oroacetophenone 7, up to 50% ee of the trans-8
c-lactone was
reached by applying DBU (20 mol %) and imidazolium-NHC Vb
(20 mol %) in toluene at room temperature. Even if a lower enanti-
oselectivity (50% ee) was induced studies relative to previous stud-
ies5a,b (66–94% ee), more effective product formation was obtained
(69% conv.) compared to previous reports (9–21% yield).
The results from the application of new NHCs as ligands in
asymmetric organometallic catalysis and as organocatalysts in
enantioselective reactions are reported.
Moderate enantioselectivities (55–57% ee) were obtained in
unoptimized asymmetric Cu-NHC catalysed conjugated additions

R. B. Strand et al. / Tetrahedron: Asymmetry 23 (2012) 1350–1359
1357
In general, we have herein demonstrated the importance of
optimizing the reaction conditions for each particular reaction,
even within a group of structurally similar NHCs. Specific NHC
characteristics are vital to afford chiral induction, and seem to vary
considerably with each reaction studied, since one particular chiral
NHC could be promising for one enantioselective reaction, may be
less successful for a different transformation. Consequently, unpre-
dictable outcomes may be challenging when designing chiral NHCs
with general abilities to induce asymmetry in a broader range of
reactions.
4.2.1.2. (S)-(2-Isopropyl-4,5-dihydrooxazol-4-yl)methanol.
This
compound was prepared from (R)-methyl 2-isopropyl-4,5-dihydroox-
azole-4-carboxylate (3.00 g, 17.5 mmol) and NaBH4 (2.65 g, 70.1
mmol) in EtOH (70 mL) in accordance with the literature.9a,b After
1 h at reflux and 15 h at room temperature, brine (75 mL) was added
and the suspension was extracted with DCM (2 ꢁ 100 mL). The com-
bined organic layers were washed with brine, dried (Na2SO4) and the
solvents evaporated. Purification by flash chromatography (EtOAc)
on silica yielded pure (S)-(2-isopropyl-4,5-dihydrooxazol-4-yl)metha-
nol (1.57 g, 63%) as a colourless liquid. 1H NMR (400 MHz, CDCl3) d
4.30 (1H, dd, J 7.8, 9.7 Hz, CHaHbO), 4.24–4.16 (1H, m, CHCH2), 4.11–
4.07 (1H, m, CHaHbO), 3.77 (1H, ddd, J 2.8, 3.9, 11.4 Hz, CHaHbOH),
3.56 (1H, ddd, J 2.0, 4.6, 11.4 Hz, CHaHbOH), 3.19 (1H, s (br), OH),
2.59 (1H, sept, J 6.8 Hz, CH(CH3)2), 1.20 (6H, d, J 6.8 Hz, CH(CH3)2);
HRMS (ESI): MNa+, 166.0840. C7H13NNaO2 requires 166.0839.
4. Experimental
4.1. General
Dry THF, Et2O and DCM were collected from a MB SPS–800 sol-
vent purification system. Unless otherwise stated, all reactions
were performed under a nitrogen atmosphere in predried glass-
ware. Flash chromatography was performed with Merck silica gel
4.2.1.3. (R)-(2-Isopropyl-4,5-dihydrooxazol-4-yl)methyl 4-methyl-
benzenesulfonate.
This compound was prepared from (S)-(2-
isopropyl-4,5-dihydrooxazol-4-yl)methanol (1.00 g, 6.98 mmol), p-
TsCl (1.46 g, 7.66 mmol) and NEt3 (3.90 mL, 28.0 mmol) in DCM
(18 mL) with catalytic amounts of 4-DMAP (25.5 mg, 0.209 mmol)
in accordance with the literature.9c Purification by flash chromatogra-
phy (50% EtOAc/n-hexane) yielded (R)-(2-isopropyl-4,5-dihydrooxa-
zol-4-yl)methyl 4-methylbenzenesulfonate (1.90 g, 92%) as an
orange oil. Rf 0.25 (50% EtOAc/hexane). 1H NMR (400 MHz, CDCl3) d
7.78 (2H, d, J 8.3 Hz, Harom), 7.35 (2H, d, J 8.0 Hz, Harom) 4.32–4.22
(2H, m, CHCH2, CHaHbO), 4.17–4.10 (2H, m, CHaHbO, CHCHaHbOTs),
3.95–3.89 (1H, m, CHCHaHbOTs), 2.53 (1H, sept, J 6.8 Hz, CH(CH3)2),
2.45 (3H, s, CH3), 1.15 (3H, d, J 6.8 Hz, CH(CH3)2), 1.14 (3H, d, J
6.8 Hz, CH(CH3)2); HRMS (ESI): MH+, 298.1113. C14H20N2SO4 requires
298.1108.
(SDS, 60 Å, 40–63 lm) or with a Supelco Versa Flash system with
commercially prepacked Versa Flash cartridges. 1H and 13C NMR
spectra were recorded on a Bruker Avance DPX 400 MHz spectrom-
eter. Chemical shifts (d) are reported in parts per million (ppm) rel-
ative to TMS as the internal standard or by calibration on the
solvent resonance peak. Coupling constants (J) are reported in
Hertz (Hz). The attributions of the chemical shifts were determined
by means of COSY, HSQC, HMQS, HMBC and NOESY experiments.
High resolution mass spectra (HRMS) were determined with an
Agilent 6520 QTOF MS (ESI) or with a Finnigan MAT 95 XL MS
(EI). Optical rotations were measured on a Perkin–Elmer Model
341 Polarimeter. IR spectra were obtained with a Nicolet 20SXF
FT-IR spectrometer, recorded on a Smart Endurance reflexion cell.
Melting points were recorded on a Stuart SMP3 apparatus.
4.2.1.4. (S)-3-(2,6-Diisopropylphenyl)-1-((2-isopropyl-4,5-dihydro-
oxazol-4-yl)methyl)-4,5-dihydro-1H-imidazol-3-ium hexafluoro-
phosphate III.
The title compound was prepared from (R)-(2-
4.2. Chiral NHC salts
isopropyl-4,5-dihydrooxazol-4-yl)methyl 4-methylbenzenesulfonate
(258 mg, 0.868 mmol) and 1-(2,6-diisopropylphenyl)-4,5-dihydro-
1H-imidazole10a (200 mg, 0.868 mmol) in DMF (0.20 mL) in accor-
dance with the literature.10b After 20 h at 80 °C, the solvent was evap-
orated and left a dark brown oil. The crude was dissolved in DCM
(3.5 mL) and KPF6 (320 mg, 1.74 mmol) was added. Stirring for 2 h
at room temperature gave a brown suspension that was purified di-
rectly by flash chromatography (2% EtOH/DCM). Subsequent tritur-
ation with ether and washing of the precipitate with additional
ether provided the desired imidazolium salt III (261 mg, 60%) as a
The preparation of NHC precursors I, II, V, VII and VIII and ethyl
2-(2,6-diisopropylphenylamino)-2-oxoacetate have previously
been published.7,8 Imidazolium salt X18 and 1-(2,6-diisopropyl-
phenyl)-4,5-dihydro-1H-imidazole10a were prepared according to
the literature. Commercially available (Sigma–Aldrich) triazolium
salt IX was used.
4.2.1. Preparation of NHC precursor III from
4.2.1.1. (R)-Methyl 2-isopropyl-4,5-dihydrooxazole-4-carboxyl-
ate. At first, SOCl2 (7.60 mL, 104.2 mmol) was added to -ser-
D-serine
white solid. Mp 92 °C. ½a D20
ꢂ
¼ ꢀ21:7 (c 1.01, DCM); mmax (neat)
2967 (br), 2872 (br), 1641, 1459, 1270, 1199, 1057, 832 cmꢀ1
;
1H
D
ine (10.0 g, 95.1 mmol) in MeOH and allowed to react at room
NMR (400 MHz, CDCl3) d 8.04 (1H, s, NCHN), 7.45 (1H, t, J 7.8 Hz, Har-
om), 7.25 (2H, d, J 7.8 Hz, Harom), 4.53–4.33 (4H, m, NCH2CH2N,
NCHCHaHbO), 4.25–4.11 (2H, m, NCH2CH2N), 3.93–3.84 (2H, m,
NCHaHbCH, NCHCHaHbO), 3.55–3.44 (1H, m, NCHaHbCH), 3.02–2.90
(2H, m, ArCH(CH3)2), 2.54 (1H, sept, J 6.8 Hz, oxazol-CH(CH3)2), 1.29
(6H, d, J 6.8 Hz, ArCH(CH3)2), 1.23 (6H, d, J 6.8 Hz, ArCH(CH3)2), 1.15
(6H, d, J 6.8 Hz, oxazol-CH(CH3)2); 13C NMR (100 MHz, CDCl3) d
174.2 (NCO), 158.0 (NCHN), 146.9 (Carom), 146.8 (Carom), 131.2 (CHar-
om), 129.8 (Carom), 124.9 (CHarom), 124.8 (CHarom), 69.6 (NCHCH2O),
64.1 (NCHCH2O), 53.3 (NCH2CH2N), 52.4 (NCH2CH), 50.2 (NCH2CH2N),
28.6 (ArCH(CH3)2), 28.5 (ArCH(CH3)2), 28.1 (oxazol-CH(CH3)2), 24.8
(ArCH(CH3)2), 24.7 (ArCH(CH3)2), 24.1 (ArCH(CH3)2), 24.0
(ArCH(CH3)2), 19.6 (oxazol-CH(CH3)2); HRMS (ESI): imidazolium-M+,
356.2701. C22H34N3O requires 356.2696.
temperature for 24 h.9a Removal of the solvents left a white solid
that upon washing with n-hexane (3 ꢁ 25 mL) provided the
D-ser-
ine methylester HCl salt (14.4 g, 97%) as a colourless solid. 1H NMR
(300 MHz, D2O) d 4.32–4.28 (1H, m, CH), 4.12 (1H, dd, J 4.2,
12.5 Hz, CHaHbOH), 4.02 (1H, dd, J 3.4, 12.5 Hz, CHaHbOH), 3.88
(3H, s, CH3).
Next, Et3OBF4 (6.54 g, 34.4 mmol) was dissolved in DCM (80 mL),
after which 2-methylpropionamide (3.00 g, 34.4 mmol) was added
and the colourless solution stirred at room temperature for 24 h.
The opaque solution was cooled to 0 °C and NEt3 (6.01 mL,
43.1 mmol) and D-serine methylester HCl (5.36 g, 34.4 mmol) were
subsequently added. After stirring for 2 days at ambient tempera-
ture, the suspension was filtered and the solid residue washed with
DCM (100 mL). The combined organic layers were washed with
NH4Cl (50 mL), dried (Na2SO4) and evaporated in vacuo. Purification
by flash chromatography (50% EtOAc/n-hexane) yielded (R)-methyl
2-isopropyl-4,5-dihydrooxazole-4-carboxylate (3.98 g, 67%) as a
pale yellow liquid. 1H NMR was in accordance with literature.40
4.2.2. Preparation of NHC precursor IV from D-valinol
4.2.2.1.
ole.
(R)-2-(Chloromethyl)-4-isopropyl-4,5-dihydrooxaz-
Chloroacetonitrile (1.68 mL, 26.5 mmol) and EtOH
(1.70 mL, 29.1 mmol) in Et2O (20 mL) was cooled to 0 °C and HCl

1358
R. B. Strand et al. / Tetrahedron: Asymmetry 23 (2012) 1350–1359
was bubbled through for 30 min in accordance with the litera-
ture.14a The mixture was cooled to ꢀ25 °C and a white precipitate
was formed. Filtration and washing of the precipitate with Et2O
(10 mL) yielded ethyl 2-chloroacetimidate hydrochloride (3.62 g,
86%) as a white solid. Mp 88 °C (lit.14a 89 °C). The imidate hydro-
chloride was used without further purification.
(6H, d, J 6.8 Hz, CH(CH3)2); HRMS (EI): M+, 368.2096. C22H28N2O3
requires 368.2094.
4.2.3.3. (S)-2-(2-(2,6-Diisopropylphenylamino)ethylamino)-2-phen-
yl ethanol.
This compound was prepared in accordance with the
literature from (S)-N1-(2,6-diisopropylphenyl)-N2-(2-hydroxy-1-phen-
ylethyl)oxalamide (0.170 g, 0.461 mmol) and LiAlH4 (0.130 g,
3.43 mmol) in THF (4 mL).13 The work-up was performed as described
above for (S)-2-amino-2-phenylethanol, to yield the bisamine (0.15 g,
96%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) d 7.41–7.27 (5H,
m), 7.11–7.03 (3H, m, Harom), 3.83 (1H, dd, J 4.4, 8.3 Hz), 3.76 (1H,
dd, J 4.4, 10.6 Hz), 3.61 (1H, dd, J 8.4, 10.6 Hz), 3.27 (2H, sept, J
6.8 Hz), 3.03–2.91 (2H, m), 2.85–2.71 (2H, m), 1.88–1.83 (1H, m),
1.23 (6H, d, J 6.8 Hz), 1.22 (6H, d, J 6.8 Hz); HRMS (EI): (MꢀH2O)+,
322.2409. C22H30N2 requires 322.2404.
Next, NEt3 (0.871 mL, 6.25 mmol) was added to a suspension of
ethyl 2-chloroacetimidate hydrochloride (1.00 g, 6.33 mmol) and
D
-valinol (0.645 g, 6.25 mmol) in DCM (21 mL) at 0 °C in accor-
dance with the literature.14b Purification by flash chromatography
(14% n-hexane/EtOAc, 3% NEt3) provided the pure desired oxazole
product (723 mg, 72%) as a colourless liquid. The 1H NMR was in
accordance with literature.14b
4.2.2.2. (R)-3-(2,6-Diisopropylphenyl)-1-((4-isopropyl-4,5-dihy-
drooxazol-2-yl)methyl)-4,5-dihydro-1H-imidazol-3-ium hexa-
fluorophosphate IV.
(R)-2-(chloromethyl)-4-isopropyl-4,5-dihydrooxazole
The title compound was prepared from
(140 mg,
4.2.3.4. (S)-3-(2,6-Diisopropylphenyl)-1-(2-hydroxy-1-phenyl-
ethyl)-4,5-dihydro-1H-imidazol-3-ium chloride VI.
The ti-
0.866 mmol) and 1-(2,6-diisopropylphenyl)-4,5-dihydro-1H-imid-
azole (200 mg, 0.868 mmol) in DMF (0.20 mL) according to the lit-
erature.10b After 22 h, the solvent was removed and the black oily
residue was dissolved in DCM (3.5 mL) and KPF6 (320 mg,
1.74 mmol) was added. The suspension was stirred for 20 h at
room temperature before it was purified directly by flash chroma-
tography (2% EtOH/DCM). Washing the oily product with ether
provided the pure imidazolium salt IV (237 mg, 54%) as a white so-
tle compound was prepared in accordance with the literature
from (S)-2-(2-(2,6-diisopropylphenylamino)ethylamino)-2-phen-
ylethanol (0.150 g, 0.441 mmol), anhydrous HCl/MeOH (2 M,
0.22 mL, 0.440 mmol) and HC(OMe)3 (0.24 mL, 0.233 g, 2.20 mmol)
in toluene (1.5 mL).13 Stirring the crude solid with ether (2 mL) for
30 min and subsequent filtration provided the desired imidazoli-
um salt VI (0.126 g, 74%) as a beige solid. Mp 197 °C (decomp.);
½
a 2D0
ꢂ
¼ þ39:5 (c 0.75, DCM); mmax (neat) 3172 (br), 2961, 2868,
lid. Mp 168 °C. ½a D20
ꢂ
¼ þ0:2 (c 1.0, DCM); mmax (neat) 2964 (br),
1632, 1455, 1259, 1075, 706 cmꢀ1 1H NMR (400 MHz, CDCl3) d
;
1682, 1649, 1467, 1276, 1191, 1100, 1057, 975, 833 cmꢀ1
;
1H
9.16 (1H, s, NCHN), 7.48–7.36 (6H, m, Harom), 7.29–7.22 (2H, m, Har-
om), 5.72–5.63 (1H, m, CH), 4.42–4.31 (1H, m, NCHaHbCH2N), 4.27–
4.18 (2H, m, NCH2CHaHbN, CHaHbOH), 4.17–4.07 (2H, m,
NCH2CHaHbN, CHaHbOH), 4.06–3.95 (1H, m, NCHaHbCH2N), 3.12
(1H, sept, J 6.6 Hz, CH(CH3)2), 2.90 (1H, sept, J 6.6 Hz, CH(CH3)2),
1.32–1.24 (12H, m, 2 ꢁ CH(CH3)2); 13C NMR (100 MHz, CDCl3) d
159.5 (NCHN), 147.1 (Carom), 146.4 (Carom), 133.4 (Carom), 131.2
(CHarom), 129.9 (Carom), 129.5 (CHarom), 129.4 (2 ꢁ CHarom), 127.8
(2 ꢁ CHarom), 125.1 (CHarom), 124.8 (CHarom), 63.6 (CH), 59.8
(CH2OH), 53.1 (NCH2CH2N), 46.4 (NCH2CH2N), 28.8 (CH(CH3)2),
28.7 (CH(CH3)2), 25.2 (CH(CH3)2), 25.0 (CH(CH3)2), 24.1 (CH(CH3)2),
24.0 (CH(CH3)2); HRMS (ESI): imidazolium-M+, 351.2430.
NMR (400 MHz, CDCl3) d 8.05 (1H, s, NCHN), 7.45 (1H, t, J 7.5 Hz,
arom), 7.25 (2H, d, J 7.5 Hz, Harom), 4.47 (2H, s, NCH2CN), 4.46–
H
4.31 (3H, m, NCH2CH2N, NCHCHaHbO), 4.28–4.15 (2H, m,
NCH2CH2N), 4.09–4.03 (1H, m, NCHCHaHbO), 3.95–3.86 (1H, m,
NCHCHaHbO), 3.08–2.92 (2H, m, ArCH(CH3)2), 1.72 (1H, sept, J
6.6 Hz, oxazol-CH(CH3)2), 1.28 (6H, d, J 6.7 Hz, ArCH(CH3)2), 1.23
(6H, d, J 5.8 Hz, ArCH(CH3)2), 0.97 (3H, d, J 6.6 Hz, oxazol-
CH(CH3)2), 0.89 (3H, d, J 6.6 Hz, oxazol-CH(CH3)2); 13C NMR
(100 MHz, CDCl3) d 160.6 (NCO), 159.4 (NCHN), 146.8 (Carom),
146.7 (Carom), 131.2 (CHarom), 129.6 (Carom), 124.9 (CHarom), 124.8
(CHarom), 72.1 (NCHCH2O), 71.8 (NCHCH2O), 53.7 (NCH2CH2N),
49.8 (NCH2CH2N), 44.3 (NCH2CN), 32.6 (oxazol-CH(CH3)2), 28.5
(ArCH(CH3)2), 28.4 (ArCH(CH3)2), 24.7 (ArCH(CH3)2), 24.6
(ArCH(CH3)2), 24.1 (ArCH(CH3)2), 24.0 (ArCH(CH3)2), 18.7 (oxazol-
CH(CH3)2), 18.4 (oxazol-CH(CH3)2); HRMS (ESI): imidazolium-M+,
356.2698. C22H34N3O requires 356.2696.
C23H31N2O requires 351.2431.
4.3. Chiral NHC-gold catalysts
4.3.1. General procedure for the preparation of NHC-AuCl
catalysts Au-V, Au-VI, Au-VIIa34
4.2.3. Preparation of NHC precursor VI from
4.2.3.1. (S)-2-Amino-2-phenylethanol39
was prepared from
LiAlH4 (0.311 g, 8.19 mmol) in THF (10 mL) according to the litera-
ture.12 The work-up was performed by adding NaSO4 (1 M, 11 mL),
extraction with ether (3 ꢁ 9 mL) and the organic layers were
washed with brine, dried over MgSO4 and evaporated in vacuo to
provide (S)-2-amino-2-phenylethanol (0.244 g, 54%) as an orange
solid. The 1H NMR was in accordance with the literature.
L
-phenylglycine
This compound
The azolium salt (1 equiv) and Ag2O (0.5 equiv) were stirred in
DCM overnight at room temperature before AuCl(Me2S) (1 equiv)
was added. After 4–5 h at room temperature, the purple suspen-
sion was filtered through a Celite pad and the solution was evapo-
rated until 2–3 mL was left. The gold complex precipitated upon
the addition of n-pentane or hexane. Washing the precipitate with
n-pentane provided the desired NHC–AuCl complexes in good
yields.
.
L
-phenylglycine (0.496 g, 3.28 mmol) and
4.3.2. (S)-(1-(2,6-Diisopropylphenyl)-3-(1-hydroxy-3-phenylpro
pan-2-yl)imidazolidin-2-ylidene)gold(I) chloride Au-Va
4.2.3.2. (S)-N1-(2,6-Diisopropylphenyl)-N2-(2-hydroxy-1-phen-
ylethyl)oxalamide.
This compound was prepared in accor-
This compound was prepared as described above from NHC-
salt Va (112 mg, 0.279 mmol), Ag2O (34.0 mg, 0.147 mmol),
AuCl(Me2S) (86.0 mg, 0.292 mmol) in DCM (5 mL). This yielded
the desired NHC-AuCl Au-Va (140 mg, 84%) as a pale brown so-
dance with the literature from (S)-2-amino-2-phenylethanol
(0.160 g, 1.17 mmol) and ethyl 2-(2,6-diisopropylphenylamino)-
2-oxoacetate (0.410 g, 1.48 mmol) in DCM (3 mL).13 Purification
by flash chromatography (25% EtOAc/n-pentane) provided the pure
oxalamide (0.19 g, 43%) as a colourless oil. Rf 0.17 (25% EtOAc/n-
pentane); 1H NMR (300 MHz, CDCl3) d 8.72 (1H, s, NH), 8.15 (1H,
d, J 7.1 Hz, NHCH), 7.45–7.30 (6H, m, Harom), 7.21–7.17 (2H, m, Har-
om), 5.15–5.08 (1H, m, CH), 4.00–3.95 (2H, m, CH2OH), 2.99 (2H,
sept, J 6.8 Hz, 2 ꢁ CH(CH3)2), 1.20 (6H, d, J 6.8 Hz, CH(CH3)2), 1.19
lid. Mp 80 °C (decomp.); ½a D20
¼ ꢀ17:8 (c 0.55, MeOH); mmax
ꢂ
(neat) 3473 (br), 2960, 2924, 2826, 1498, 1455, 1272, 1053,
;
747, 700 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.39–7.28 (6H, m,
Harom), 7.16–7.10 (2H, m, Harom), 5.11–5.02 (1H, m, CH), 4.04–
3.89 (2H, m, CH2OH), 3.87–3.79 (1H, m, NCHaHbCH2N), 3.78–
3.66 (2H, m, NCHaHbCH2N, NCH2CHaHbN), 3.59–3.49 (1H, m,

R. B. Strand et al. / Tetrahedron: Asymmetry 23 (2012) 1350–1359
1359
NCH2CHaHbN), 3.09 (1H, dd, J 5.4, 14.4 Hz, CHaHbPh), 2.99 (1H,
References
dd, J 10.5, 14.3 Hz, CHaHbPh), 2.90 (1H, sept, J 6.8 Hz, CH(CH3)2),
2.32 (1H, sept, J 6.8 Hz, CH(CH3)2), 1.89 (1H, s (br), OH), 1.31
(3H, d, J 6.6 Hz, CH(CH3)2), 1.21 (3H, d, J 6.9 Hz, CH(CH3)2),
1.18 (3H, d, J 6.8 Hz, CH(CH3)2), 1.07 (3H, d, J 6.8 Hz, CH(CH3)2);
13C NMR (100 MHz, CDCl3) d 194.2 (C@Au), 146.7 (Carom), 146.6
(Carom), 136.3 (Carom), 134.3 (Carom), 129.7 (CHarom), 129.1
(2 ꢁ CHarom), 128.8 (2 ꢁ CHarom), 127.0 (CHarom), 124.6 (CHarom),
124.4 (CHarom), 63.4 (CH2OH), 62.1 (CH), 52.9 (NCH2CH2N), 45.3
(NCH2CH2N), 35.1 (CH2Ph), 28.4 (CH(CH3)2), 28.1 (CH(CH3)2),
25.1 (CH(CH3)2), 25.0 (CH(CH3)2), 24.4 (CH(CH3)2), 24.1
(CH(CH3)2); HRMS (ESI): [(M+ꢀH+)+NH4+]+, 578.2430. C24H35Au-
N3O requires 578.2440.
1. (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290; (b) Würtz, S.; Glorius,
F. Acc. Chem. Res. 2008, 41, 1523.
2. (a) Diez-Gonzalez, S.; Marion, N.; Nolan, S. P. Chem. Rev. 2009, 109, 3612; (b)
Strassner, T. Top. Organomet. Chem. 2007, 22, 125; (c) Someya, H.; Ohmiya, H.;
Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 1565; (d) Zinn, F. K.; Viciu, M. S.;
Nolan, S. P. Annu. Rep. Prog. Chem. Sect. B 2004, 100, 231.
3. Wang, F.; Liu, L.-j.; Wang, W.; Li, S.; Shi, M. Coord. Chem. Rev. 2012, 256, 804.
4. Marion, N.; Díez-González, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988.
5. (a) Matsuoka, Y.; Ishida, Y.; Sasaki, D.; Saigo, K. Chem. Eur. J. 2008, 14, 9215; (b)
Matsuoka, Y.; Ishida, Y.; Saigo, K. Tetrahedron Lett. 2008, 49, 2985.
6. Vora, H. U.; Rovis, T. Aldrichim. Acta 2011, 44, 3–11.
7. Strand, R. B.; Helgerud, T.; Solvang, T.; Sperger, C. A.; Fiksdahl, A. Tetrahedron:
Asymmetry 2011, 22, 1994.
8. Strand, R. B.; Solvang, T.; Sperger, C. A. Fiksdahl A. Tetrahedron: Asymmetry
2012, 23, 838.
9. (a) Yoon, C. H.; Flanigan, D. L.; Yoo, K. S.; Jung, K. W. Eur. J. Org. Chem. 2007, 37;
(b) Einsiedel, J.; Schoerner, C.; Gmeiner, P. Tetrahedron 2003, 59, 3403; c Braga,
A. L.; Lüdtke, D. S.; Sehnem, J. A.; Alberto, E. E. Tetrahedron 2005, 61, 11664.
10. (a) Paczal, A.; Bényei, A. C.; Kotschy, A. J. Org. Chem. 2006, 71, 5969; (b)
Nanchen, S.; Pfaltz, A. Chem. Eur. J. 2006, 12, 4550.
11. (a) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347; (b) O‘Toole, S. E.;
Connon, S. J. Org. Biomol. Chem. 2009, 7, 3584; (c) Clavier, H.; Boulanger, L.;
Audic, N.; Toupet, L.; Mauduit, M.; Guillemin, J.-C. Chem. Commun. 2004, 10,
1224; (d) Gischig, S.; Togni, A. Organometallics 2004, 23, 2479; (e) Van
Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem. Soc.
2002, 124, 4954; (f) Zhu, S.; Wang, C.; Chen, L.; Liang, R.; Yu, Y.; Jiang, H. Org.
Lett. 2011, 13, 1146.
4.3.3. (S)-(1-(2,6-Diisopropylphenyl)-3-(2-hydroxy-1-phenylethyl)
imidazolidin-2-ylidene)gold(I) chloride Au-VI
This compound was prepared as described above from imidazo-
lium salt VI (39.0 mg, 0.101 mmol), Ag2O (12.0 mg, 0.0518 mmol)
and AuCl(Me2S) (30.7 mg, 0.104 mmol) in DCM (5 mL). An addi-
tional filtration and washing with more pentane were needed
due to the presence of silver salts. This yielded the desired NHC-
AuCl Au-VI (48 mg, 81%) as a pale yellow solid. Mp 201 °C (de-
comp.); ½a 2D0
ꢂ
¼ þ47:7 (c 0.72, DCM); mmax (neat) 3464 (br), 2960,
12. Granander, J.; Scott, R.; Hilmersson, G. Tetrahedron 2002, 58, 4717.
13. Clavier, H.; Coutable, L.; Toupet, L.; Guillemin, J.-C.; Mauduit, M. J. Organomet.
Chem. 2005, 690, 5237.
2865, 1497, 1454, 1269, 1054, 699 cmꢀ1
;
1H NMR (400 MHz,
CDCl3) d 7.45–7.36 (6H, m, Harom), 7.22–7.18 (2H, m, Harom), 5.97
(1H, dd, J 5.6, 8.7 Hz, CH), 4.35–4.23 (2H, m, CH2OH), 3.97–3.89
(1H, m, NCHaHbCH2N), 3.87–3.79 (1H, m, NCH2CHaHbN), 3.78–
3.69 (1H, m, NCH2CHaHbN), 3.59–3.51 (1H, m, NCHaHbCH2N),
3.00 (1H, sept, J 6.8 Hz, CH(CH3)2), 2.84 (1H, sept, J 6.8 Hz,
CH(CH3)2), 1.99 (1H, s (br), OH), 1.38 (6H, d, J 6.8 Hz, CH(CH3)2),
1.25 (3H, d, J 6.8 Hz, CH(CH3)2), 1.21 (3H, d, J 6.8 Hz, CH(CH3)2);
13C NMR (100 MHz, CDCl3) d 194.7 (C@Au), 146.9 (Carom), 146.5
(Carom), 135.1 (Carom), 134.3 (Carom), 129.9 (CHarom), 129.2
(2 ꢁ CHarom), 128.8 (CHarom), 127.4 (2 ꢁ CHarom), 124.7 (CHarom),
124.6 (CHarom), 64.0 (CH), 61.0 (CH2OH), 53.2 (NCH2CH2N), 44.7
(NCH2CH2N), 28.6 (CH(CH3)2), 28.5 (CH(CH3)2), 25.1 (CH(CH3)2),
24.4 (CH(CH3)2), 24.2 (CH(CH3)2); HRMS (ESI): [(M+ꢀH+)+NH4+]+,
564.2275. C23H33AuN3O requires 564.2284.
14. (a) Stillings, M. R.; Welbourn, A. P.; Walter, D. S. J. Med. Chem. 1986, 29, 2280;
(b) Ye, M.-C.; Li, B.; Zhou, J.; Sun, X.-L.; Tang, Y. J. Org. Chem. 2005, 70, 6108.
15. Clavier, H.; Guillemin, J.-C.; Maudiut, M. Chirality 2007, 19, 471.
16. (a) Sperger, C. A.; Tungen, J. E.; Fiksdahl, A. Eur. J. Org. Chem. 2011, 3719; (b)
Nieto-Oberhuber, C.; Muñoz, M. P.; López, S.; Jiménez-Núñez, E.; Nevado, C.;
Herrero-Gómez, E.; Raducan, M.; Echavarren, A. M. Chem. Eur. J. 2006, 12, 1677;
(c) Sperger, C. A.; Fiksdahl, A. Unpublished results.
17. Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205.
18. Winn, C. L.; Guillen, F.; Pytkowicz, J.; Roland, S.; Mangeney, P.; Alexakis, A. J.
Organomet. Chem. 2005, 690, 5672.
19. Burstein, C.; Tschan, S.; Xie, X.; Glorius, F. Synthesis 2006, 2418.
20. Rix, D.; Labat, S.; Toupet, L.; Crévisy, C.; Mauduit, M. Eur. J. Inorg. Chem. 1989,
2009.
21. Yoshimura, M.; Shibata, N.; Kawakami, M.; Sakaguchi, S. Tetrahedron 2012, 68,
3512.
22. Harano, A.; Sakaguchi, S. J. Organomet. Chem. 2010, 696, 61.
23. Marion, N.; Nolan, S. P. Chem. Soc. Rev. 2008, 37, 1776.
24. Widenhoefer, R. A. Chem. Eur. J. 2008, 14, 5382.
25. Nájera, C.; Sansano, J. M. Monatsh. Chem. 2011, 142, 659.
26. Pradal, A.; Toullec, P. Y.; Michelet, V. Synthesis 2011, 1501.
27. Wang, W.; Yang, J.; Wang, F.; Shi, M. Organometallics 2011, 30, 3859.
28. Matsumoto, Y.; Selim, K. B.; Nakanishi, H.; Yamada, K.-I.; Yamamoto, Y.;
Tomioka, K. Tetrahedron Lett. 2010, 51, 404.
29. Yamada, K.-I.; Matsumoto, Y.; Selim, K. B.; Yamamoto, Y.; Tomioka, K.
Tetrahedron 2012, 68, 4159.
30. Liu, L.-J.; Wang, F.; Wang, W.; Zhao, M.-X.; Shi, M. Beilstein J. Org. Chem. 2011, 7,
555.
31. Arnanz, A.; Gonzalez-Arellano, C.; Juan, A.; Villaverde, G.; Corma, A.; Iglesias,
M.; Sanchez, F. Chem. Commun. 2010, 46, 3001.
32. Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 18002.
33. Wang, Yi-M.; Kuzniewski, C. N.; Rauniyar, V.; Hoong, C.; Toste, F. D. J. Am. Chem.
Soc. 2011, 133, 12972.
34. (a) Wang, H. M. J.; Lin, I. J. B. Organometallics 1998, 17, 972; (b) Lemke, J.; Pinto,
A.; Niehoff, P.; Vasylyeva, V.; Metzler-Nolte, N. Dalton Trans. 2009, 7063; (c) de
Frémont, P.; Scott, N. M.; Stevens, E. D.; Nolan, S. P. Organometallics 2005, 24,
2411.
4.3.4. (S)-(4-(1-(Benzyloxy)-3-phenylpropan-2-yl)-3-methyl-1-
phenyl-1H-1,2,4-triazol-5(4H)-ylidene)gold(I) chloride Au-VIIa
This compound was prepared as described above from triazo-
lium salt VIIa (50.0 mg, 0.119 mmol), Ag2O (18.0 mg,
0.0777 mmol), AuCl(Me2S) (35.0 mg, 0.119 mmol) in DCM
(7.5 mL). This yielded the desired NHC-AuCl Au-VIIa (60 mg,
82%) as a pale brown solid. Mp 62 °C (decomp.); ½a D20
¼ ꢀ65 (c
ꢂ
1.0, DCM); mmax (neat) 3100–3000 (w), 3000–2850 (w), 1596,
1495, 1113, 1071, 747, 697 cmꢀ1 1H NMR (400 MHz, CDCl3) d
;
7.93–7.89 (2H, m, Harom), 7.52–7.44 (3H, m, Harom), 7.33–7.10
(10H, m, Harom), 4.71–4.62 (1H, m, CHCHaHbO), 4.64–4.52 (1H,
m, CH), 4.54 (1H, d, J 12.0 Hz, OCHaHbPh), 4.48 (1H, d, J 12.0 Hz,
OCHaHbPh), 4.12–4.07 (1H, m, CHCHaHbO), 3.91–3.84 (1H, m,
CHCHaHbPh), 3.34 (1H, dd, J 4.4, 14.0 Hz, CHCHaHbPh), 2.11 (3H,
s, CH3); 13C NMR (100 MHz, CDCl3)
d 170.6 (C@Au), 153.1
35. Glorius, F.; Hirano, K. Ernst, Schering Foundation Symposium Proceedings, (2007–
02, Organocatalysis), 2008, pp 159–181.
36. Schrader, W.; Handayani, P. P.; Burstein, C.; Glorius, F. Chem. Commun. 2007,
716.
(CCH3), 139.3 (Carom), 137.2 (Carom), 136.0 (Carom), 129.4 (CHarom),
129.3 (2 ꢁ CHarom), 129.0 (2 ꢁ CHarom), 128.9 (2 ꢁ CHarom), 128.6
(2 ꢁ CHarom), 128.1 (CHarom), 127.8 (2 ꢁ CHarom), 127.4 (CHarom),
123.7 (2 ꢁ CHarom), 73.5 (OCH2Ph), 71.8 (CHCH2O), 61.6 (CH),
38.1 (CHCH2Ph), 10.6 (CH3); HRMS (ESI): [M+NH4]+, 633.1684.
C25H29AuClN4O requires 633.1690.
37. He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131.
38. Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370.
39. Hsiao, Y.; Hegedus, L. S. J. Org. Chem. 1997, 62, 3586.
40. Glorius, F.; Neuburger, M.; Pfaltz, A. Helv. Chim. Acta 2001, 84, 3178.
Acknowledgment
The Research Council of Norway is acknowledged for their
financial support.