Indolizy Carbene Ligand. Evaluation of Electronic Properties and Applications in Asymmetric Gold(I) Catalysis

Article abstract of DOI:10.1002/anie.202106142

We report herein a new family of carbene ligands based on an indolizine-ylidene (Indolizy) moiety. The corresponding gold(I) complexes are easily obtained from the gold(I)-promoted cyclization of allenylpyridine precursors. Evaluation of the electronic pr

Full text of DOI:10.1002/anie.202106142

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Asymmetric Catalysis
Indolizy Carbene Ligand. Evaluation of Electronic Properties and
Applications in Asymmetric Gold(I) Catalysis
Thibaut Martinez, Avassaya Vanitcha, Claire Troufflard, Nicolas Vanthuyne, Jꢀrꢀmy Fortꢀ,
Geoffrey Gontard, Gilles Lemiꢁre,* Virginie Mouriꢁs-Mansuy,* and Louis Fensterbank*
Dedicated to Prof. Christian Bruneau for his outstanding contribution to catalysis
Abstract: We report herein a new family of carbene ligands
based on an indolizine-ylidene (Indolizy) moiety. The corres-
ponding gold(I) complexes are easily obtained from the
gold(I)-promoted cyclization of allenylpyridine precursors.
Evaluation of the electronic properties by experimental
methods and also by DFT calculations confirms strong s-
donating and p-accepting properties of these ligands. Cationi-
zation of the gold(I) complexes generates catalytic species that
trigger diverse reactions of (poly)unsaturated precursors.
When armed with a methylene phosphine oxide moiety on
the stereogenic center adjacent to the nitrogen atom, the
corresponding bifunctional carbene ligands give rise to highly
enantioselective heterocyclizations. DFT calculations brought
some rationalization and highlighted the critical roles played
by the phosphine oxide group and the tosylate anion in the
asymmetric cyclization of g-allenols.
such as N-heterocyclic carbenes (NHCs A)[5] have exhibited
high potential. More accessible than a lot of phosphine
ligands that are tedious to prepare and prone to oxidation,
they have the ability to form stable complexes thanks to
strong s-bonding with the gold metallic center while p-
backbonding to the carbene will be highly dependent from its
structural features, the interplay of both effects leading to
specific reactivities.[6] In 2005, the group of Bertrand[7]
developed a new class of carbenes, the cyclic (alkyl)-
(amino)carbenes (CAACs B) in which a nitrogen of a classical
NHC diaminocarbene was replaced by a carbon atom. Those
are more s-donating and p-accepting than the parent NHCs.[8]
The corresponding gold complexes[9] have led to the first
examples of hydroamination of alkynes and allenes using
ammonia or hydrazine.[10] The replacement of the alkyl
substituent of CAACs by an aryl leads to the formation of
new cyclic (amino)(aryl)carbenes (CAArCs C),[11] that still
feature high nucleophilicity but also enhanced electrophilicity
resulting in a smaller single-triplet gap than for CAACs.
The implementation of asymmetric gold-catalyzed pro-
cesses relying on monodentate C-ligands has initially con-
sisted in the introduction of stereogenic centers on the
imidazolium backbone or on the N-ligated substituents.[12,13]
Tomioka and coll.[14] synthesized the first chiral C2-symmetric
dihydroimidazol-2-ylidene gold(I) complexes and applied
them in a moderately enantioselective methoxycyclization
of 1,6-enynes (up to 59% ee). Improved enantioselectivities
(above 70%) for similar reactions were observed using C2-
symmetric NHC complexes bearing bulky stereogenic N-
substituents.[15,16] Still, these systems suffer from the fact that
the nitrogen substituents are too remote from the gold center
to fix an adequate steric environment and several strategies
for the introduction of higher performance elements of chiral
discrimination have been proposed to render carbenes the
ligands of choice for asymmetric gold-catalyzed transforma-
tions.[17,18] Notably, NHC-type ligands based on an imidazo-
[1,5-a]pyridine-3-ylidene (ImPy D) skeleton, initially dis-
closed by the groups of Lassaletta and Glorius have allowed
the synthesis of new families of carbene ligands by the
introduction of substituents at the C5 position. The latter are
in close proximity to the metal-center and can be designed to
convey properties to the gold complexes.[21] For instance, the
p-acceptor properties of ImPy ligands were enhanced by the
introduction of a cyclophane scaffold and found applications
in the catalysis of the cycloisomerization of ene-allenes.[19]
The substitution at the C5 position constitutes also an
opportunity to provide axially chiral complexes.[22] Zhang
Introduction
The last decades have witnessed a strong expansion in
homogeneous gold catalysis promoting a broad range of
organic transformations.[1] The high p-Lewis acidity of
cationic gold(I) complexes allow them to activate various
unsaturations such as alkynes, allenes and also alkenes
towards intra- or intermolecular nucleophilic addition.[2]
During the process, the ligands carried by the gold(I) center
play a major role in terms of stability, allowing low catalyst
loadings, modulation of activity, and selectivity.[3] Further-
more, the linear coordination of gold(I) complexes that
positions the ancillary ligand opposite to the substrate and
thus to the outer-sphere attack of the nucleophile renders
asymmetric gold catalysis a challenging goal.[4] The role of the
chiral ligand is therefore crucial notably by constraining the
degrees of freedom of the system. In this context, C-ligands
[*] Dr. T. Martinez, Dr. A. Vanitcha, C. Troufflard, J. Fortꢀ, G. Gontard,
Dr. G. Lemiꢁre, Dr. V. Mouriꢁs-Mansuy, Prof. L. Fensterbank
Institut Parisien de Chimie Molꢀculaire, Sorbonne Universitꢀ, CNRS
4 Place Jussieu, CC 229, 75252 Paris Cedex 05 (France)
E-mail: gilles.lemiere@sorbonne-universite.fr
virginie-mansuy@sorbonne-universite.fr
louis.fensterbank@sorbonne-universite.fr
Dr. N. Vanthuyne
Aix Marseille Univ, CNRS, Centrale Marseille, iSm2
13397 Marseille Cedex 20 (France)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202106142.
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1 that we previously worked out.[31,32] Two resonance forms
can be written for complexes of type 2, vinylgold vs. carbene,
[33]
À
but the very short Au C bond distance (1.993(4) ꢀ) on 2a,
reminiscent of other gold carbenes,[34] suggested a carbenic
character favorable for catalytic applications. Overall, the
ligands E connected to the gold center of complexes 2 could
be considered as the first examples of vinylogous CAACs[7]
that also include chiral congeners.
Prompted by a recent report from the MuÇoz group on
a related use of bis-pyridyl allenes 1 (R1 = Me, R2 = 2-
methylpyridine) as precursors of gold carbenes and their
preliminary catalytic activity,[35] we herein extend the family
of gold(I) complexes 2, evaluate the electronic properties
conferred by ligands E and study their catalytic applications
notably in enantioselective gold(I) catalysis.
Results and Discussion
Preparation of a Family of Gold(I) Complexes 2
We synthesized a wide range of gold(I) complexes 2
including achiral complex 2b and chiral complexes 2a and
2c–k. As depicted in Scheme 1, they were obtained in two
steps from propargyl acetates 3 and 3’. SN2’ reactions on the
latter provided various pyridyl-allenes 1 that were engaged in
the previously mentioned cyclization reaction using 1 equiv of
Me2SAuCl to smoothly deliver complexes 2.[31] Through this
route, we could control strategic positions on chiral com-
plexes (Æ)-2: i) the nature of the stereogenic center, either
devoid of an additional coordinating group (2c) or flanked
with a b-phosphorus group (phosphine oxide for 2a and 2d–g
featuring an increasing steric demand, phosphine sulfide for
2h and phosphonate for 2i), ii) the vinyl position close to the
gold(I) center by varying the aryl scaffold through the
introduction of a 4,6-dimethylphenyl moiety (complexes 2d
and 2 f). The obtained cyclization yields for complexes 2, from
quantitative for 2a–c to 34% for 2 f were relatively consistent
with the steric bulk imposed by the substituents of the allene
moieties and gave sufficient material for catalytic trials. X-ray
diffraction (XRD) analyses were obtained for complexes 2c–
Figure 1. Milestones in the development of AuI-carbene complexes
and presentation of the work.
further refined this approach by providing chiral bifunctional
NHC ligands flanked with a tetrahydroisoquinoline moiety at
the C5 position.[23] The corresponding gold complexes proved
to be competent in a series of asymmetric transformations
(Figure 1).
Regarding CAACs, the presence of a quaternary carbon
center adjacent to the ylidene carbon is a good lever to
introduce stereogenicity close to the active site. Bertrand and
coll. initially prepared an enantiopure (À)-menthol derived
CAAC ligand[7a] but no asymmetric catalysis in a copper-
catalyzed asymmetric conjugated borylation reaction was
recorded,[24] this being certainly due to a conformational
inversion of the menthyl group. In contrast, a more rigid
CAAC with extended chirality derived from a 5a-cholestan-3-
one steroid backbone was recently synthesized and the
corresponding copper complex CholestCAACCuCl, promoted
encouraging enantioselectivity (55% ee) in the same boryla-
tion reaction.[24,25] It should also be noted that racemic chiral
CAACAuCl complexes have been prepared by Kumar and
Waldmann via a Me2SAuCl-promoted cyclization-rearrange-
ment sequence of 1,7-enynes and two examples of catalysis
were given.[26]
As part of our ongoing interest in the design of new chiral
ligands for gold complexes[27–29] we have devised the new
family of Indolizy C-ligands E, possibly bifunctional[30] (Fig-
ure 1). While direct isolation of these ligands has not been
accomplished so far, we found more convenient to directly
access to the corresponding gold complexes 2 through an
efficient gold-promoted cyclization of allenepyridines of type
2 f.[33] The Au C bond lengths lie in the same range from
À
1.990(6) ꢀ for 2d to 2.002(1) ꢀ for 2 f. As shown also on
Scheme 1, for complexes 2 bearing a phosphine oxide,
a stabilising dipole-dipole interaction between the oxygen of
the phosphine oxide and the nitrogen atom of the N-
containing 6-membered ring seems to operate with an
average O-N distance of 2.95 ꢀ.
To obtain enantiomerically pure complexes 2, we relied on
a total chirality transfer in the gold-promoted cyclization.[31]
This could be accomplished from allene (À)-1a to give
precatalyst catalyst (À)-(S)-2a whose absolute configuration
was determined by XRD.[36] Nevertheless, we found more
convenient to obtain each enantiomer of complexes 2a and
2c–i by preparative chiral HPLC.[37] It should be noted that
thiophosphine complex 2h could not be resolved and proved
unstable in the HPLC conditions. We were also able to
directly obtain enantiopure indolizy-gold(I) complexes 2j and
2k using inexpensive (À)-menthone from the chiral pool.[7] In
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Scheme 1. Indolizy AuI precatalysts 2.
three steps including initially the addition of ethynylmagne-
sium bromide onto (À)-menthone,[38] a mixture of two
separable diastereoisomeric propargylic acetates 3j and 3k
was obtained. Subsequent cuprate addition led to the
formation of tetrasubstituted allenes as single diastereomers
in an excellent yield of 97% for both (aS)-1j and (aR)-1k.
Finally, the corresponding chiral gold(I) complexes 2j and 2k
were obtained in, respectively 52% and 99% yield, by
stereospecific reaction with Me2SAuCl. The structure of 2k
was confirmed by XRD analysis (see SI).[39]
2-one-4-ylidene carbene.[42] Nevertheless, p-acceptor capabil-
ities correlate with the energies of the relevant p*-orbitals
and not necessarily the LUMO so that the sole consideration
of the LUMO energy can be misleading.[43] Visualization of
the shape of the frontier orbitals allows for a qualitative
estimation of their geometrical appropriateness for a possible
overlap with the metals d-orbitals. While the HOMO of
Indolizy-b is mainly located on the ylidene carbon, the
LUMO is rather opposite to this site and mainly delocalized
over the N-containing 6-membered ring (Figure 2b). Inter-
estingly, the LUMO + 1 that lies slightly higher than the one
Evaluation of the Electronic Properties
The modification of the NHC backbones
can dramatically change their electronic
features.[40] Based on this fact, we have first
determined the geometries and energies of
the frontier orbitals for the free ligand
Indolizy-b of complex 2b (see also Figure 2)
by means of DFT calculations at the B3LYP/
def2-TZVP level of theory. It was found that
the HOMO of Indolizy-b (À4.97 eV) lies
considerably higher than those calculated for
relevant CAACs considered as very good s-
donor ligands. This data highlights the ten-
dency of the ylidene carbon to increase its
electron-donating ability when decreasing
the number of electronegative nitrogen
atoms connected to it.[41]
Intriguingly, Indolizy-b exhibits a LUMO
Figure 2. a) Relevant HOMOs and LUMOs (present on the ylidene carbon) energy levels
and singlet-triplet transition energy of a series of relevant NHC including Indolizy-b
calculated at the B3LYP/def2-TZVP level of theory b) Vizualisation of the frontier orbitals
of Indolizy-b plotted with Gaussview at an isosurface value of 0.05 au.
lying at a very low energy level that is at first
glance suggestive of an exceptional p-acidity
for this ligand, comparable to the coumaraz-
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calculated for a highly p-acidic CAArC[11] (À1.30 vs. À1.47), is
much present on the ylidene carbon and therefore can also
account for the overall p-acidity of the ligand. Finally,
Indolizy-b presents a very small singlet-triplet gap (24.3 kcal
molÀ1) smaller than the one calculated for the coumaraz-2-
one-4-ylidene carbene (26.7 kcalmolÀ1), which presages good
bonding abilities.[44]
Scheme 3. Synthesis of Indolizy selenide derivative 6.
To experimentally corroborate these calculations, we first
gauged the donating ability of the Indolizy ligand following
the Huynh Electronic Parameter (HEP). This method,
initially based on the 13C NMR spectroscopy analysis of
trans-[PdBr2(iPr2-bimy)L] (iPr2-bimy = 1,3-diisopropylbenzi-
midazolin-2-ylidene) complexes on which L is a NHC ligand,
has also been transposed to [Au(iPr2-bimy)L] gold(I) com-
plexes.[45,46] While the HEP method has never been used for
the evaluation of the s-donation of CAACs or analogues, we
nevertheless synthesized the [Au(iPr2-bimy)(Indolizy-b)]BF4
complex 5 in good yield (84%) through a one-pot reaction by
selenium derivative 6,[48,49] prepared in 85% yield by mixing
in acetonitrile elemental selenium with allene 1b at 1308C in
a sealed tube for 22 h (Scheme 3).[50] The structure was
ascertained by a single crystal XRD analysis.[51]
With a d 77Se NMR value of 566.7 ppm in [D6]acetone and
528.1 ppm in CDCl3, Indolizy ligand appears far more p-
accepting than IPr (d 77Se: 87.0 ppm in [D6]acetone)[48] but
slightly less p-accepting than the CAArC of Figure 2 (d 77Se:
601 ppm).[11] Interestingly this last finding is also consistent
with the above-presented DFT study.
À
mixing iPr2-bimyH+BF4 (4) in the presence of K2CO3 and
We also examined the impact of the electronic properties
of the Indolizy ligand by using the gold(I) precatalyst 2a in
a diagnostic reaction consisting in the cycloisomerization of
allene-diene 7 (Scheme 4). It was shown that in this trans-
gold complex 2b (Scheme 2). The structure of 5 was secured
Scheme 4. Diagnostic reaction using the allenediene precursor 7.
formation the p-activation of the allene by a cationic gold(I)
catalyst triggers the generation of a cationic intermediate 8.
The latter can evolve following two pathways depending on
the influence of the ancillary ligand: an alkyl shift or a 1,2-
hydride shift giving, respectively the [4+2] cycloadduct 9 or
the [4+3] cycloadduct 10.[52] Bicyclic product 10 is a marker of
a strong donor ligand which favors a carbene reactivity of
intermediate 8. For instance IPr or IMes ligand will provide
almost exclusively 10.[52] In contrast, hydrindane product 9
suggests a cationic pathway because of the reduced donation
of the ancillary ligand. This is what happens when using p-
accepting cyclophane-NHCs which yields a 72:28 ratio of 9 vs.
10.[21] In the presence of AgSbF6 and 2a, a 74:26 mixture of
cycloadducts 9 and 10 was obtained in 67% yield. While this
type of ratio has to be taken cautiously since steric effects can
also be at play,[52e] the convergence between the 77Se NMR
value and this experiment suggests significant p-acidic
properties of the Indolizy ligand.
Scheme 2. Synthesis of complex 5 and its XRD structure (hydrogen
atoms are omitted for clarity). Selected bond lengths [ꢃ] and angle
[deg]: Au1–C27 2.035(3), Au1–C1 2.033(3), C1-Au1-C27 174.5(1)8.
by XRD analysis.[47] As expected, a linear coordination
pattern in which the central gold(I) atom is both coordinated
to the iPr2-bimy and Indolizy-b ligands was observed. The
1
À
isopropyl C H protons of complex 5 appeared by H NMR as
a multiplet at 5.05 ppm, falling in the range of the expected
values for this type of complexes, and which indicated a free
rotation around the Au-Ccarbene bonds.[45] Moreover, the
13C NMR spectrum of 5 exhibited two carbene resonances
at 193.1 ppm, presumably for the iPr2-bimy carbene and more
downfield at 204.5 ppm for the Indolizy ligand. A two
dimensional HMBC NMR analysis confirmed these assign-
ments (see SI). Based on the linear correlation between the
13
C
(iPr2-bimy) values for the PdII and AuI complexes,
carbene
a HEP value of 184.7 ppm, corresponding to the highest HEP
value ever found for a carbene ligand, and much higher than
the HEP of IPr (177.5 ppm), was determined for the Indolizy
ligand. It therefore appears that Indolizy ligand features
strong s-donating properties which fits with the DFT
calculations.
Applications in Asymmetric Catalysis
Besides the cyloisomerization of 7, we checked the
reactivity of precatalyst 2a in a few diagnostic reactions (see
SI). Consistent results with literature were obtained. We also
checked the configurational stability of (À)-(S)-2d in thermal
conditions (808C for 24 h, see SI). All these positive data
Next, the p-acceptor character of the Indolizy ligand was
assessed by measuring the 77Se NMR chemical shift of the
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Table 1: Methoxycyclization reaction.
that do not bear a phosphine oxide moiety, the yields were
excellent but quasi-racemic mixtures were obtained (en-
tries 9–11). In contrast, for complex (+)-(R)-2d bearing
a phosphine oxide moiety, enantioselectivity was restored
(e.r. = 27:73, entry 12). This slight improvement compared to
(À)-(S)-2a could be ascribed to the larger steric hindrance in
vicinity of the gold(I) center brought by the 3,5-dimethyl-
phenyl group on the vinyl carbon. The introduction of 3,5-
dimethylphenyl groups on the phosphorus atom as for (À)-
(R)-2e significantly increased the enantiomeric ratio to 12:88
(entry 13). As previously shown, the decrease or increase in
temperature did not improve the enantioselectivities (en-
tries 14 and 15). Gratifyingly, combining both previous steric
constrains by using (À)-(R)-2 f yielded the best e.r. value of
8:92 (entry 16). This also corresponds to the best e.r. obtained
on 14a with a carbene gold complex.[17,56] Using gold(I)
complex (R)-2g bearing two 3,5-di-tert-butylphenyl groups
on the phosphorus atom led however to a lower enantiose-
lectivity (entry 17), suggesting that the steric hindrance
around the phosphorus atom does not seem to be the sole
factor to influence the enantioinduction. Finally, substitution
of the phosphine oxide moiety by a phosphonate ((À)-2i)
moiety proved to be highly detrimental to the enantioselec-
tivity (entry 18) giving a e.r. of 57:43. Allenol 13b gave similar
Entry
[Au]
Yield of 12 [%]
e.r.[a] (R:S)[b]
1
2
3
4
5
(À)-(S)-2a
(+)-2c
(À)-(S)-2d
(À)-(R)-2e
(+)-(S)-2 f
92[c]
97[c]
76
76
95
59:41
50:50
54:46
38:62
64:36
[a] Enantiomeric ratios were determined by chiral HPLC; [b] The config-
urations were assigned by comparison with literature [29]; [c] NMR
yields with trimethoxybenzene as internal standard.
drove us to test asymmetric catalysis with Indolizy-Au
complexes 2 (except 2h)[53] We first studied the methoxycyc-
lization of enyne 11 that has served as benchmark reaction in
numerous studies.[29] Using typical conditions (AgSbF6 as
cationizing agent in MeOH at rt), low enantioselectivities
were recorded, the best result of 28% ee being obtained with
complex (+)-(S)-2 f (Table 1, entry 5). Interestingly, a preca-
talyst bearing a gem-dialkyl group ((+)-2c) with no
additional functionality provided a racemic mixture
Table 2: Intramolecular hydroalkoxylation.
(entry 2) while the other complexes bearing a phos-
phine oxide substituted arm allowed some tangible
enantiomeric discrimination.
Based on these promising findings, we examined
the purely intramolecular gold-catalyzed hydroal-
koxylation of 4,5-hexadien-1-ols 13a and 13b and
the results are summarized in Table 2. Precatalysts 2
were first activated with a silver salt before the
addition of substrates 13. We started our studies
with gold(I) complex (À)-(S)-2a and initially
checked the influence of the silver salt as cationizing
agent on the enantioselectivity of the reaction. At
258C with AgSbF6 in toluene (entry 1), low yield of
14a (16%) was obtained with almost no enantiose-
lectivity (e.r. = 45:55). Increasing the temperature
to 508C (entry 2) resulted in a yield increase (52%)
but a decrease of enantioselectivity. Keeping this
temperature with other silver salts (entries 3,4), low
yields of 14a in racemic form were observed.
Entry
[Au]
[Ag]
T [8C]
t [h]
Yield of 14a [%]
e.r.[a]
(S:R)[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
(À)-(S)-2a
(+)-(R)-2a
(À)-(S)-2a
(+)-(R)-2a
(À)-(S)-2a
(À)-(S)-2a
(À)-(S)-2a
(+)-(R)-2a
2j
AgSbF6
AgSbF6
AgOTf
AgNTf2
AgOTs
AgOTs
AgOTs
AgOTs
AgOTs
AgOTs
AgOTs
AgOTs
AgOTs
AgOTs
AgOTs
AgOTs
AgOTs
AgOTs
25
50
50
50
25
À20
0
10
25
25
25
25
25
À20
50
25
25
25
30
16
16
26
5
19
5
7
2
2
2
3.5
2.5
5 d
1.5
1.5
1.5
22
16
52
28
28
quant.
–
45:55
49:51
51:49
50:50
70:30
–
–
34
–
41:59
50:50
51:49
52:48
27:73
12:88
24:76
13:87
8:92
quant.
quant.
quant.
quant.
quant.
quant.
quant.
quant.
quant.
quant.
2k
(+)-2c
(+)-(R)-2d
(À)-(R)-2e
(À)-(R)-2e
(À)-(R)-2e
(À)-(R)-2 f
(R)-2g
Interestingly, with AgOTs at 258C,[54] tetrahy-
drofuran 14a was obtained quantitatively with
a promising enantiomeric ratio of 70:30 (entry 5).
The absolute configuration of the (S)-major enan-
tiomer was assigned by comparison with previous
chiral HPLC data and optical rotation.[55] From
a second set of experiments with AgOTs, we showed
that the reaction does not work at temperatures
below 108C and that no enantioselectivity was
observed (entries 6–8). From all these experiments,
we converged to catalytic reactions at 258C with
AgOTs as chloride scavenger as in entry 5. Screen-
ing of the gold complexes brought intriguing find-
ings. We confirmed that for complexes 2k, 2j and 2c
27:73
57:43
(À)-2i
[Au]
Entry
[Ag]
T [8C]
t [h]
Yield of 14b [%]
e.r.[a]
19[c]
20
21
22
23
(À)-(S)-2a
(+)-(R)-2a
(+)-(R)-2d
(À)-(R)-2e
(+)-(S)-2 f
AgSbF6
AgOTs
AgOTs
AgOTs
AgOTs
25
25
25
25
25
16
16
1.5
1.5
1.5
81%
49:51
60:40
58:42
74:26
23:77
quant.
quant.
quant.
quant.
[a] Enantiomeric ratios were determined by chiral HPLC. [b] The configurations were
assigned by comparison with literature [55]. [c] The reaction was run in DCM.
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Table 3: Intramolecular hydroamination.
phosphine oxide group could change its conformation to set
the coordination to a cationic gold center.
DFT calculations were also performed to get insight into
the mechanism of the cyclisation of a g-allenol in order to
figure out the crucial role of the phosphine oxide moiety and
of the tosylate anion in the cycloisomerization process.
Indeed, it appeared that the enantioselective induction was
rather effective only in the case where a phosphine oxide was
present on the carbene ligand in combination with a tosylate
as counterion pointing out a possible participation of these
two polar functional groups (see Table 2).
Although an inner-sphere mechanism was initially pro-
posed by Telles in 1998 to describe the gold(I)-catalyzed
addition of methanol onto alkynes,[60] the outer-sphere
mechanism for the addition of an O- or N-nucleophile to
Entry
[Au]
Yield of 16 [%]
e.r.[a]
1
2
3
4
5
6
(+)-(R)-2a
(+)-(R)-2d
(À)-(R)-2e
(À)-(R)-2 f
(S)-2g
71
74
66
66
66
48
28:72
25:75
15:85
17:83
70:30
55:45
(À)-2i
[a] Enantiomeric ratios were determined by chiral HPLC.
À
a gold-coordinated C C multiple bond complex has received
results with each catalyst 2, the highest enantioselectivity
being recorded with (+)-(S)-2 f (entry 23).
much more experimental and theoretical supports.[54,61] Nev-
ertheless, gold complexes with ligands bearing a judiciously
positioned pendant donor function, such as a phosphine
oxide[62] or an amine,[63] may favour a syn-addition through an
inner-sphere mechanism. The polar function might also play
an active role in the proton transfer steps thanks to its
hydrogen-bond acceptor capability.[62] Concerning transfor-
mations involving allenes, an inner-sphere mechanism sup-
ported by calculations has already been put forward for the
intramolecular cyclisation of g-amino allenes when a bis-gold
phosphine complex was used.[64]
The asymmetric intramolecular hydroamination of sulfo-
namide 15 was next examined. As shown in Table 3,
pyrrolidine derivative 16 was obtained in moderate to good
yields in 24 h hours at 508C (Table 2, entries 1–6). The
enantiomeric ratios followed the same trend as described for
g-allenols 13 with the same catalysts. As for 13b, the use of
precatalysts (À)-(R)-2e and (À)-(R)-2 f did not make real
difference in terms of enantioselectivity (entries 3 and 4).
In the following DFT study, we considered the inner- and
outer-sphere mechanisms for the cycloisomerization of a g-
allenol yielding to a respective syn- and anti-addition of the
hydroxy group onto the gold-activated allene.[65] As men-
tioned earlier, the presence of the tosylate anion is crucial and
therefore its involvement has been taken into consideration.
Calculations were performed with the complex (R)-2a·OTs.
Hexa-4,5-dien-1-ol 18 was used as a model to compute the
formation of the (R)-vinyltetrahydrofuran product (Fig-
ure 3a). As non-polar solvents gave the best results in terms
of reactivity and enantioselectivity, it can be assumed that the
tosylate anion stays rather close to the gold complex during
the whole substrate transformation. Thereby, we considered
two starting gold-allene h2 complexes I and I’ with the tosylate
anion interacting either with the metal or with the hetero-
cyclic ring, respectively. In the latter complex I’, which is
slightly less stable than I by 1.5 kcalmolÀ1, the electron-rich
oxygen of the phosphine oxide is pointing towards the
electrophilic metal (d Au-O = 3.62 ꢀ) and therefore is located
in a suitable position to adopt an appropriate conformation
for interactions with the coordinated substrate. A transition
state for the inner-sphere mechanism involving unambiguous
hydrogen bonding between the phosphine oxide and the
hydroxyl group could be computed (blue pathway, Figure 3a).
The optimised structure (S)-TSSYN’ displays an activation
barrier of 14.0 kcalmolÀ1 as a consequence of a beneficial
template effect. The nucleophilicity of the hydroxyl group is
enhanced by the proximity of the hydrogen-bond acceptor
which also accounts for the lower energy barrier observed.
The cyclization is endergonic by 9.8 kcalmolÀ1 from I’ and
lead to the intermediate (R)-II’ where the protonated
tetrahydrofuran is intramolecularly stabilised by the phos-
Mechanistic Aspects
As discussed above, analysis of the XRD structures of
most of the neutral chlorinated gold complexes 2 revealed
that the privileged conformation is the one where the
phosphine oxide moiety is directly pointing towards the N-
containing heterocyclic ring (Scheme 1). However, the gold
catalysts are effective under their cationic form after abstrac-
tion of the chloride ligand. We attempted to crystallize the
cationic form of the gold complex (Æ)-2a (as a racemic
mixture) after anion metathesis using a stoichiometric
amount of silver triflimidate.[57] The expected cationic com-
plex (Æ)-17 was formed and its XRD structure[58] revealed
a dimeric complex with a Au-Au distance of 3.0255(4) ꢀ,
which is characteristic of an aurophilic interaction
(Scheme 5).[59] An intermolecular interaction between the
phosphine oxide group of one monomer and the gold cationic
center of the other one was observed, featuring a distance of
2.091(1) ꢀ between the Au and O atoms. Thus, this XRD
structure confirmed that the pending arm bearing the
Scheme 5. Synthesis of the cationic catalyst Æ-17 and XRD structure.
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Figure 3. a) Gibbs energy profile for the enantioselective cycloisomerization of g-allenol 18 in the presence of (R)-2a·OTs at the M06/def2-
QZVP(Au)-6–311+G(2d,p)//B3LYP-D3/SDD(Au)-6-31G(d,p) level of theory (CPCM solvent=toluene). (R)-TSANTI is obtained from an isoenergetic
isomer of I with the metal complexed to the other face of the double bond. b) Visualization of the transition states for the cylization and
protodeauration steps.
phine oxide. Reversibility in the cyclization of g-allenols due
to ring constraints has already been evidenced experimentally
by the groups of Gagnꢁ and Widenhoefer.[61c] The next
elementary step to form the desired product is the proto-
deauration. This step usually requires the assistance of an
exogenous molecule playing the role of a proton shuttle.[61b,66]
Once again, the phosphine oxide group is ideally placed to act
this way and operates similarly to a molecular crane by first
picking up the proton to deliver it to the reactive C-Au bond.
This promotes the protodeauration and furnishes the gold(I)-
complexed product (R)-III’.
coordinated to the gold center, stabilizes the cyclization
transition state through hydrogen bonding. The resulting
vinylgold intermediate (R)-II is more stable than (R)-II’ by
14.5 kcalmolÀ1 and the cyclization becomes exergonic. The
anti-addition without the assistance of the tosylate anion was
also computed with a corresponding transition state (R)-
TSANTI lying about 9 kcalmolÀ1 above the syn-addition. The
protodeauration step can also be assisted by the tosylate. The
transient p-toluenesulfonic acid delivers the proton to the C-
Au bond through (R)-TSII-III with an activation barrier of only
8.1 kcalmolÀ1 from (R)-II to lead to the final intermediate
(R)-III. Interestingly, in this pathway with the tosylate
coordinated to the gold center, the oxygen of the phosphine
oxide prefers to point towards the electron-deficient N-
containing heterocyclic ring (d O-N = 2.96 ꢀ in structure I).
The favored interaction brings some rigidity to the system and
forces the phosphine oxide moiety to display its two aromatic
substituents nearby the chiral active catalytic site, which
rationalizes the influence of the aromatic rings substitution on
the enantioinduction. In this pathway, the cyclization is the
stereochemically-determining step. Gratifyingly, the forma-
tion of the (S)-vinyltetrahydrofuran product could be com-
puted as well and the transition state corresponding to the
cyclization step is higher than the one calculated for the (R)-
product by 1.3 kcalmolÀ1 (see SI). Although this DFT study
has been carried out with a simpler model, the results are
consistent with the finding that allenol 13a is converted into
(R)-14a using (R)-2a and analogues as precatalysts.
The transition state (R)-TSII’-III’ is located 18.3 kcalmolÀ1
above the starting intermediate I’. The overall cycloisomeri-
zation process is highly exergonic with an associated energy
gain of about 20 kcalmolÀ1 that totally drives the reaction
despite the first endergonic step. In such a case, the tosylate
does not play an active role in the transformation. This
pathway is very similar to the one calculated with the cationic
complex of (R)-2a (not taking the anion into consideration,
see SI). Even though the stereogenic center is installed during
the cyclisation, this internal addition is presumably reversible
and the small energy barrier to go backwards (about
4 kcalmolÀ1) implies a fast equilibrium. Therefore, the final
and irreversible protodeauration step would be the actual
stereochemically determining event.[67]
However, the tosylate anion is not a weakly coordinating
anion and therefore can be involved in the cyclization and the
protodeauration steps (black pathway, Figure 3a). Indeed, the
activation barrier to reach (R)-TSSYN from the starting
intermediate I is only 9.1 kcalmolÀ1. The tosylate, which is
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Research Articles
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The authors thank Sorbonne Universitꢁ (PhD grant to TM),
the Franco Thai Scholarship Program administered by
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The authors declare no conflict of interest.
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www.angewandte.org
ꢂ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 2 – 12
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Zuccaccia, F. Tarantelli, P. Belanzoni, ACS Catal. 2015, 5, 803 –
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814.
Manuscript received: May 6, 2021
Revised manuscript received: June 21, 2021
Accepted manuscript online: July 9, 2021
Version of record online: && &&
,
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Angew. Chem. Int. Ed. 2021, 60, 2 – 12
ꢂ 2021 Wiley-VCH GmbH
www.angewandte.org
&&&&
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Research Articles
Asymmetric Catalysis
AuI complexes coordinated to the Indolizy
ligand, a new carbene ligand that results
from the gold-promoted cyclization of
a pyridyl-allene were investigated. The
electronic properties of the Indolizy
ligand were analysed. The introduction of
a stereogenic center in a-position to the
carbene center coupled to the intro-
duction of a pending phosphine oxide
group affords highly efficient and enan-
tioselective AuI catalysts.
T. Martinez, A. Vanitcha, C. Troufflard,
N. Vanthuyne, J. Fortꢀ, G. Gontard,
G. Lemiꢁre,* V. Mouriꢁs-Mansuy,*
L. Fensterbank*
&&&& — &&&&
Indolizy Carbene Ligand. Evaluation of
Electronic Properties and Applications in
Asymmetric Gold(I) Catalysis
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www.angewandte.org
ꢂ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 2 – 12
These are not the final page numbers!