The Winding Road towards an Atropo-enantioselective ‘ARYNE Coupling’

Article abstract of DOI:10.1002/ejoc.202100087

For the first time, the challenging atropo-enantioselective coupling of in-situ generated arynes and aryllithiums in the presence of a chiral ligand of lithium was investigated. This preliminary study demonstrates the feasibility of this concept, by affording enantioenriched axially chiral biaryls even in the case of products showing a high degree of steric congestion around the newly created aryl?aryl bond.

Full text of DOI:10.1002/ejoc.202100087

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Very Important Paper
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The Winding Road towards an Atropo-enantioselective
‘
ARYNE Coupling’
[a]
[b]
[b]
[a]
[a]
David Augros, Corinne Comoy, Yves Fort, Frédéric R. Leroux,* and Armen Panossian*
For the first time, the challenging atropo-enantioselective
coupling of in-situ generated arynes and aryllithiums in the
presence of a chiral ligand of lithium was investigated. This
preliminary study demonstrates the feasibility of this concept,
by affording enantioenriched axially chiral biaryls even in the
case of products showing a high degree of steric congestion
around the newly created arylÀ aryl bond.
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Introduction
lithium exchange, a chain process that was termed the ‘ARYNE
[
6]
coupling’, which is in fact a specific case of carbolithiation. We
were particularly interested in the development of atroposelec-
tive versions of this coupling, in order to access axially chiral
biaryls; so far, we have explored the post-coupling deracemiza-
In contrast to the well-studied and successful enantioselective
trapping of organolithiums with various activated electrophiles,
[1]
enantioselective carbolithiations have been less studied. In
the latter reactions, the electrophilic partner is a non-activated
prochiral olefin and the nucleophilic one is most often an
alkyllithium. Yet, aryllithium nucleophiles have also been
studied in this reaction, leading to a broad range of
enantioselectivity, usually with sparteine employed as the chiral
[7]
tion or desymmetrization or the atropo-diastereoselective
[8]
coupling (Scheme 2). In the present paper, we will describe
our preliminary attempts towards the atropo-enantioselective
version of the reaction (Scheme 2), which is highly challenging
on several aspects: 1) As mentioned above, enantioselective
carbolithiations have not been studied intensely, in particular
on alkynes as electrophiles, and are unknown for arynes and 2)
The control of selectivity would be more difficult with arynes
than with alkenes or linear alkynes, as stated earlier; 3)
[2]
ligand for lithium. Concerning the electrophile, however, apart
from olefins, there are only a few reports on alkynes as reaction
partners for enantio-retentive carbolithiations, although some
of the latter involve an enantioselective lithiation as the first
[3]
[9]
step, rendering the whole sequence enantioselective.
Enantioselective reactions of arynes are scarce; 4) Atropo-
enantioselective creation of a biaryl bond from an aryllithium as
precursor has also been scarcely reported.
[4]
Formally, ortho-arynes could be seen as a peculiar case of
reaction partner for carbolithiation, with the π system of the
transient arynes being much more reactive than in standard
inactivated alkenes or alkynes. However, unlike alkenes whose
π system is orthogonal to the atomic plane, thus allowing re/si
face differentiation, the electrophilic π system of an ortho-aryne
is coplanar with the arene ring. Hence, steric distinction in the
course of the enantioselective carbolithiation step would be
much more challenging with arynes, especially since the triple
bond is strongly bent, thus moving away substituents from the
incoming nucleophile (Scheme 1).
[10]
For some years now, we have been interested in the access
[
5]
to biaryls from ortho-arynes, more exactly in the reaction of
aryllithiums and ortho-arynes generated in situ upon halogen/
[
a] Dr. D. Augros, Dr. F. R. Leroux, Dr. A. Panossian
Université de Strasbourg, Université de Haute-Alsace, CNRS, LIMA, UMR
7
042,
67000 Strasbourg, France
E-mail: frederic.leroux@unistra.fr
armen.panossian@unistra.fr
http://lima.unistra.fr/
http://coha.unistra.fr/
[
b] Dr. C. Comoy, Prof. Dr. Y. Fort
Université de Lorraine, CNRS, L2CM UMR 7053,
B.P. 70239, 54506 Vandœuvre-lès-Nancy, France
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100087
Scheme 1. Schematic comparison of the carbolithiation of arynes with
aryllithiums, of alkynes and of alkenes.
Part of the “YourJOC Talents” Special Collection.
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[
11]
Results and Discussion
ferrocene.
(
In this case, when targeting the biaryl core of
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-)-steganacin, we gratifyingly obtained both a high yield (86%)
In our previous efforts for the development of an atropo-
stereoselective ARYNE coupling by means of chiral sulfoxides,
oxazolines or diether auxiliaries attached to the aryllithium
nucleophile, we were unable to achieve concomitantly high
and an optimal atroposelectivity, with only one detectable
atropo-diastereomer; furthermore, the product could be ana-
lyzed by X-ray diffraction crystallography, allowing determina-
tion of the configuration of the newly created chiral axis and
[8]
[12]
yields and high diastereoselectivities. The most efficient
approach appeared to be the use of a chiral oxazoline as chiral
auxiliary, leading to moderate diastereoselectivity but satisfying
yield, and allowing efficient separation of atropodiastereomers
as well as post-functionalization of the biaryl moiety, as
demonstrated in the formal synthesis of each enantiomer of
proposition of a stereochemical rationale (Scheme 3).
Un-
fortunately, all our attempts to remove efficiently the chiral
auxiliary by quaternarization, oxidation or coordination of
nitrogen followed by benzylic substitution or oxidation proved
fruitless.
Considering the additional steps required for installation
and transformation of a covalently bound chiral auxiliary and
the difficulties we encountered, an enantioselective process
involving a chiral ligand of lithium seemed much more
appealing. Towards this end, a few solvents were assessed as a
replacement for THF, which is usually employed in this reaction.
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[8b–d]
natural product steganacin with high enantiopurity.
As a
new attempt for stereocontrol of the organolithium species, we
decided to assess the L-proline-derived (S)-[(2-methoxymethyl)
pyrrolidine-1-yl]methyl auxiliary (SMP-methyl), which had suc-
cessfully been used in the diastereoselective derivation of
David Augros was born in Châteauroux
(Li, Na) and transition metal (Ni, Pd …)
organometallic chemistry directed towards
organic synthesis and new nanomaterials for
catalysis or electronics.
(France) in 1993. He obtained a Master degree
in Molecular and Supramolecular Chemistry at
the University of Strasbourg (France), where
he also graduated from the European School
of Chemistry, Polymers and Materials Science
with a specialisation in organic chemistry. He
obtained his Ph.D. in 2018 under the super-
vision of Dr. Frédéric R. Leroux and Dr. Armen
Panossian, working on the “aryne coupling”
reaction to access atropisomerically enriched
biaryls and on the synthesis of biphenylenes.
He is now working as a radiochemist at Selcia
in Ongar (United Kingdom).
Frederic Leroux obtained a Ph.D. from the
University of Konstanz (Germany) in 1997.
After a postdoctoral stay with Prof. M. Schloss-
er at the University of Lausanne (Switzerland)
he became Assistant Professor in 1998. In
2
001 he moved then to the Swiss Federal
Institute of Technology in Lausanne (EPFL). He
joined in 2003 the CNRS as Research Associate
and was promoted CNRS Research Director in
2009. The philosophy of his research is based
on a fruitful interplay of several objectives (a)
the synthesis of biologically relevant mole-
cules, (b) asymmetric methodologies using
organic and organometallic chemistry, (c)
organofluorine chemistry and (d) application
of the objectives to industrial problems, which
led to strong industrial collaborations.
Corinne Comoy studied chemistry at the
University of Orléans (France), where she
received her Ph.D in Organic and Bioorganic
Chemistry in 1996. After postdoctoral research
positions at the University of Göttingen
(Germany, 1996–1997) with Professor A. de
Meijere and then with Professor François Huet
at the University of Le Mans (France, 1997–
Armen Panossian carried out his PhD studies
under the supervision of Dr. Angela Marinetti
at the ICSN (Gif-sur-Yvette, France). In 2009,
he moved to the ICIQ (Tarragona, Spain) for a
postdoctoral position in the group of Dr.
Anton Vidal-Ferran. After one year as tempo-
rary assistant professor at the Université Pierre
et Marie Curie (Paris, France), he became in
1
998), she has been appointed as assistant
professor at University of Lorraine in 1998. Her
research fields include organic synthesis, polar
and transition metal organometallic chemistry
as well as heterocyclic chemistry. Since 2003,
she has joined the research group of Professor
Yves Fort, where her current research interests
concern the development of new method-
ologies for the regio- and stereoselective
functionalization of heterocycles and for cas-
cade reactions.
2
011 CNRS Research Associate (Chargé de
Recherche). He obtained his habilitation in
2019. His research interests focus on the
control of chirality, heavy metal-free methods,
the organic chemistry of heteroelements of
the main group.
Yves Fort received his Ph.D. in 1983 under the
supervision of Prof. J.-P. Pete (Reims Univer-
sity). He successively held a postdoctoral and
a CNRS researcher positions in Nancy (France),
where he obtained his Doctorat d’Etat des
sciences physiques in 1987 under the super-
vision of Prof. P. Caubère. In 1998, he has
been appointed as Professor at Nancy. His
current research interests are focused on polar
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Scheme 2. The ARYNE coupling and its atroposelective versions.
The aim was to use a less coordinating solvent, to favor
complexation of lithium by the potentially chiral ligand. As
reaction partners, we selected 1a as aryne precursor and achiral
2
-aryloxazoline 4a as pronucleophile so as to mimic the
conditions of a working atropo-diastereoselective ARYNE cou-
pling. As a slight difference, the pronucleophile was iodinated
to ensure efficient formation of the aryllithium in other solvents
than THF, by iodine/lithium exchange instead of bromine/
lithium exchange or direct lithiation. With these partners in
hand, the coupling promoted by butyllithium was shown to
proceed in all solvents tested, namely THF, toluene, diethyl
ether and even dichloromethane, although with modest yields
in the latter two solvents. Interestingly, toluene afforded
formation of the product in a very good 91% yield, which is in
Scheme 3. Atropo-diastereoselective coupling with the SMP-methyl auxiliary
and comparison with previous work with oxazolines.
[8c,6f,g]
line with our previous studies,
and even in higher yield
than in THF in this case. When tert-BuLi was used in place of
BuLi in toluene, a much lower 34% conversion was observed by
1
H NMR (Table 1).
diamine similarly furnished a low yield of 5a under either
substoichiometric or stoichiometric conditions (entries 4–5). The
BINAM-derived analogue L3 unfortunately proved insoluble
under the reaction conditions. We were hopeful concerning the
We then evaluated a small series of bidentate ligands,
achiral or chiral, nitrogen- or oxygen-based (Table 2). It was
shown indeed in our previous work on the coupling of 3-
thienyllithium and 1,2-benzyne that some ligands could have a
[13]
well-known ligand sparteine,
which proved efficient in
[6f,g]
[2]
dramatic accelerating effect in toluene as solvent.
The ligand
enantioselective carbolithiations by aryllithiums. Disappoint-
ingly, its (+)-enantiomer L4 also led to a complex mixture and
only traces of 5a. Moving to oxygen-based ligands, we assessed
the lithium salt of (S)-BINOL L5, obtained by reaction of 2 equiv.
of BuLi with (S)-BINOL. Similarly to the case of L3, we
encountered solubility issues and had to add some THF during
the formation of L5; this allowed us to obtain the coupling
product 5a with 71% yield, albeit in racemic form. Tomioka’s
diether ligand L6, which was successful in other strategies to
was added to the reaction mixture after the full formation of
the aryllithium nucleophile, the resulting mixture was stirred for
5
minutes and the aryne precursor 1a was finally introduced.
While in the absence of ligand, 91% yield of the coupling
product 5a were achieved, employing 0.2 equiv. of TMEDA (L1)
led to 76% yield, and a full equivalent of L1 afforded a complex
mixture, in which only traces of 5a were detected (entries 1–3).
The racemic analogue L2 based on trans-cyclohexane-1,2-
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[10a,b,14,10c]
access axially chiral biaryls via organolithiums,
racemic product under substoichiometric
gave a
Table 1. Assessment of solvents in a model ARYNE coupling.
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conditions
(0.2 equiv.), but, gratifyingly, 11% ee of 5a under stoichiometric
conditions with an honorable 60% yield, thus proving the
concept of the atropo-enantioselective ARYNE coupling medi-
ated by a chiral external ligand of lithium (entries 9–10). The
[10c,2k]
structurally related ligand L7,
which is also a diether
analogue of L2, afforded a much lower yield of 5a, which was
contaminated with an unidentified side-product in small
amounts preventing accurate determination of the enantiomer-
ic excess, although the latter remains low (�19%, entry 11).
Following this first hit in terms of enantioselectivity, we
tackled the variation of reaction conditions for the atropo-
enantioselective coupling. We had to target coupling partners
leading to biaryls that would be at least trisubstituted in ortho
positions of the biaryl junction, in order to ensure, as much as
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[
a]
Entry
Solvent
THF
Et O
2
DCM
Toluene
Toluene
Toluene
AlkLi (nb equiv.)
Yield or (conversion)
1
2
3
4
5
6
BuLi (1 equiv.)
BuLi (1 equiv.)
BuLi (1 equiv.)
BuLi (1 equiv.)
tBuLi (2 equiv.)[
59%
34%
36%
91%
(34%)
b]
[c]
tBuLi (2 equiv.)
Traces
[15,16]
1
possible, their configurational stability.
Initially, we selected
[a] Isolated yield, or conversion into the product estimated by H NMR
given in parentheses. [b] Pronucleophile 4a was added onto a À 78°C
sesamol-derived pronucleophile 4b, displaying two different
oxygen-based substituents, inert towards organolithiums, in
ortho positions of the masked carbanion, which would stabilize
solution of tBuLi in toluene. [c] Degradation of the reaction mixture.
[
17]
the latter without internal coordination of the lithium cation,
Table 2. Evaluation of ligands in the ARYNE coupling.
but could allow intermolecular coordination. Considering the
unknown degree of aggregation of the chiral aryllithium, we
wished indeed to depart from the case of the coordinating
oxazolinyl group, presumably leading to smaller and more rigid
aggregates, which would have a different impact on enantiose-
lectivity. As reaction partners, we chose 1c–d, which were
shown to be the most efficient benzyne precursors for ARYNE
[6g]
couplings taking place in toluene as solvent (Table 3). In this
series of experiments, the time required for full formation of the
aryllithium nucleophile had been ascertained by separate tests.
In the absence of added ligand, the coupling showed low
efficiency, with at best 26% conversion into the desired biaryl
5
b (entries 1–3). The main products observed were 4b and 4b’,
resulting respectively from re-iodination (by iodine/lithium
exchange on 1c–d) and hydrolysis (either by the n- or sec-butyl
iodide generated in the first stage of the reaction or during the
final aqueous quench) of the aryllithium. We then assessed a
few chiral ligands in this reaction, namely (+)-sparteine L4,
Tomioka’s diether L6 and bis-oxazoline L8. In all cases, the yield
of 5b remained quite low due to the formation of side-products
4b and 4b’ mentioned above, as well as of the rather
unexpected 1,2-diiodobenzene 1c’, which we never observed in
coupling experiments carried out in THF as solvent. Disappoint-
ingly, L4 repeatedly afforded a racemic product (entries 4–7),
whereas, on the contrary, L6 repeatedly gave 10% ee (entries
9–13). Ligand L8, which had not been tested yet, was unable to
produce the biaryl (entry 8). These modest yields and low
enantioselectivities could not be improved by changing the
nature of the alkyllithium base (entries 4–5 and 9, 12–13), the
order of addition of reactants for the formation of the chiral
aryllithium (entries 5–7), the nature of the benzyne precursor
and the length of the mixing time in the presence of the ligand
[a]
[b]
Entry
Ligand
x equiv.
Yield or (conversion)
ee
1
2
3
4
5
6
7
8
9
–
–
0.2
1
0.2
1
0.2
1
0.2
0.2
1
91%
76%
(Traces)
–
–
–
–
–
–
–
L1
L1
L2
L2
L3
L4
L5
L6
L6
L7
[
[
c]
c]
24%
18%
[d]
n.d.
(Traces)
71%
67%
60%
12%
[e]
0%
0%
1
1
0
1
11%
�19%
[
f]
1
1
[a] Isolated yield, or conversion into the product estimated by H NMR
given in parentheses. [b] Enantiomeric excess determined by chiral phase
HPLC. [c] Complex mixture. [d] The ligand proved insoluble under the
reaction conditions. [e] THF (0.125 mL /mL toluene) was added to help
solubilize L5. [f] The product could not be perfectly purified from traces of
an unidentified side-product. (n.d.=not determined).
(entries 10–11). Note that, upon addition of a ligand, the yield
of 5b tends to increase, as well as those of iodinated side-
products 4b and 1c’, whereas the yield of the protonated
nucleophile 4b’ tends to decrease.
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Table 3. Variation of parameters in the atropo-enantioselective ARYNE coupling of 4b with benzyne.
1
2
3
4
5
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7
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9
0
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2
3
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0
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0
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0
1
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9
0
1
2
3
4
5
6
7
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
[
a]
[b]
[a]
Entry
1
AlkLi (nb. equiv.)
t
1
[min]
t
2
[min]
Ligand
Yield or (conv.)
ee
Side-products/ Yields or (conv.)
1
2
3
4
5
1c
1c
1c
1c
1c
BuLi (1)
sBuLi (1)
tBuLi (2)
BuLi (1)
tBuLi (2)
30
60
15
30
15
–
–
–
60
60
–
–
–
L4
(26%)
(18%)
(11%)
2%
-
–
–
4b/(11%), 4b’/(56%)
4b/(13%), 4b’/(64%)
4b’/(89%)
4b/(32%), 4b’/(52%)
4b/(12%), 4b’/(51%),
n.d.
0%
L4
27%
1
c’/19%
4b/(21%), 4b’/(28%),
c’/18%
4b/(18%), 4b’/(34%),
c’/20%
4b/(13%), 4b’/(79%),
c’/36%
4b/13%, 4b’/59%,
c’/50%
4b/(34%), 4b’/(23%),
c’/42%
4b/(43%), 4b’/(22%),
c’/40%
4b/(14%), 4b’/(33%),
c’/3%
4b/(24%), 4b’/(23%),
c’/14%
[
[
c]
6
7
8
9
1c
1c
1c
1c
1d
1d
1c
1c
tBuLi (2)
tBuLi (2)
tBuLi (2)
tBuLi (2)
tBuLi (2)
tBuLi (2)
BuLi (1)
sBuLi (1)
60
60
15
15
15
L4
L4
L8
L6
L6
L6
L6
L6
32%
28%
(Traces)
11%
30%
14%
32%
36%
0%
1
d]
0%
1
60
60
0%
1
10%
10%
10%
10%
10%
1
[
e]
1
0
1
[
e]
11
120
30
1
1
2
60
60
1
13
60
1
1
[a] Isolated yield, or conversion into the product estimated by H NMR given in parentheses. [b] Enantiomeric excess determined by chiral phase HPLC. [c]
tBuLi was added to a mixture of 4b and L4. [d] 4b was added to a mixture of tBuLi and L4. [e] tBuLi was added to a mixture of 4b and L6. (n.d.=not
determined.)
The formation of product 1c’ from benzyne had already
side of the masked carbanion a small methoxy group and a
large and spherical trifluoromethyl substituent, would allow a
better differentiation in the stereoselective course of the
nucleophilic attack onto the aryne. Additionally, the presence of
been documented under different reaction conditions, either
[18]
via a postulated radical mechanism or by attack of iodide on
benzyne followed by trapping of the 2-iodoaryl carbanion by an
[19]
electrophilic iodine source (I or IF). In our case, we presume
the bulky CF group would impede a dynamic interconversion
2
3
that a mechanism similar to the latter one accounts for the
formation of 1c’, with the nucleophilic iodide being lithium
iodide, generated upon iodine/lithium exchange on 4b by tBuLi
or protonation of the aryllithium with n- or sBuI; and the
electrophilic iodine source being 1c–d or the re-iodinated 4b.
The fact that 1c’ is formed only in the presence of a ligand
would then be explained by the complexation of LiI or of the
resulting 2-iodophenyllithium, respectively solubilizing the
former in toluene and stabilizing the latter, overall favoring
their availability for further reactions (Scheme 4). Interestingly,
an additional experiment involving 4b, BuLi and 1c in the
absence of ligand but in the presence of added lithium iodide
of atropo-diastereomeric biaryllithium/chiral ligand complexes
by axial epimerization, leading to dynamic thermodynamic or
kinetic resolutions as potential alternative scenarii for the
enantioselection of the process. Thus, 4c was opposed to aryne
precursors 1c and 1a (Table 4). Interestingly, although the
aryllithium resulting from bromine/lithium exchange on 4c was
not fully soluble in toluene, the reaction in absence of ligand
still managed to produce the desired biaryls 5c and 5d
(entries 1 and 4 respectively). The yield was moderate for 5c,
the main side-product being 3-trifluoromethylanisole formed by
protonation of the aryllithium derived from 4c. Some other
side-products were detected in small amounts in F NMR with
chemical shifts close to the one of the desired biaryl 5c,
suggesting the formation of isomers arising from equilibration
of the 2-lithio-2’-methoxy-6’-trifluoromethylbiphenyl intermedi-
ate towards more stable biphenyllithium isomers – with lithium
1
9
(1 equiv.) gave 31% of 5b but no diiodo compound 1c’.
The low enantioselectivities obtained in the coupling of 4b
and 1c–d led us to reconsider the structure of the aryllithium
nucleophile. Whereas 4b shows little steric distinction between
the methoxy group and the dioxole ring, the latter being
moreover quite flat, we were hoping that 4c, bearing on either
ortho to OMe or CF – caused by a too long residence time
before trapping by iodine from 1c. On the other hand, biaryl
3
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
Figure 1. Structure of side-product 6 and X-ray diffraction crystallographic
picture (ellipsoids at the 50% probability level).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
employed instead of one (entry 7), the ee remained sensibly the
same, but the yield was twice lower, presumably due to the
enhancement of the nucleophilicity or basicity of lithium-based
intermediates upon coordination, leading to side-reactions as in
the formation of 1c’ (vide supra). We also varied the temper-
ature in the complexation stage of the aryllithium nucleophile
with L6 and observed a small decrease in ee when their mixing
temperature was lowered (entries 6, 8–9), possibly implying a
less efficient complexation; indeed, the reaction proceeds
already well in the absence of ligand (entry 4). Finally, employ-
ing diether L7 gave almost identical results, in terms of yield
and ee of 5d, to experiments using the structurally related L6
(entries 10 vs 6). One would thus favor the use of L6 since it is
much more easily accessible and is moreover UV-active,
allowing a better tracking and recovery of the ligand at the end
of the reaction.
Considering the specific increments for ortho substituents
[
16]
MeO, F C and TMS (respectively 4.6, 9.5 and 9.4 kcal/mol) one
3
could estimate, by coarse but erroneous additivity, a rotational
barrier of at least 23.5 kcal/mol for the key biaryllithium
intermediate leading to 5d. The actual value, which should be
even higher, would render axial epimerization extremely slow
in the temperature range of the reaction. Hence, a dynamic
resolution as mentioned earlier seems improbable. Accordingly,
the enantioselectivity of the reaction would either arise from a
selective attack of the aryllithium/chiral ligand complex onto
the aryne, or by a non-selective attack onto the aryne followed
by a non-dynamic kinetic resolution in the trapping of the
biaryllithium/chiral ligand complex by an iodine atom provided
by the aryne precursor. Finally, a combination of both scenarii,
operating at the same time, is also possible.
Scheme 4. Tentative rationale for the formation of 4b’ and 1c’.
5
d was obtained in a very good 89% yield (entry 4), especially
when considering the very high steric congestion around the
aryl-aryl bond due to the bulky iodo, trifluoromethyl and
[16]
trimethylsilyl ortho substituents.
Chiral ligands were then Conclusion
assessed in these reactions. (+)-Sparteine L4 failed to afford the
expected coupling products (entries 2 and 5). Tomioka’s diether
L6 proved more successful, with similar 59% and 55% yields of
In summary, we have engaged in the development of an
atropo-enantioselective version of the so-called ARYNE cou-
pling, which would lead to axially chiral biaryls starting from
haloarenes, halogenated ortho-aryne precursors, alkyllithiums
and chiral ligands for lithium. This targeted process was
expected to be highly challenging due to the lack of precedents
in enantioselective carbolithiations of alkynes in general, and of
arynes in particular, and to the very little number of reports on
enantioselective reactions of arynes and on the atropo-
enantioselective construction of a biaryl bond from an
5
c and 5d (entries 3 and 6 respectively). In the reaction of
entry 3, 5c was formed in very low ee, while side-product 6,
whose structure was confirmed by X-ray diffraction crystallog-
raphy (Figure 1), was isolated in 13% yield and presumably
formed by an unexpected homocoupling of 4c upon loss of
À
[20]
CF3 to generate an aryne.
This side-product was not
detected when using 1a, which gratifyingly led to 17% ee of
d when using ligand L6 (entry 6). When 2 equiv. of L6 were
5
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Table 4. Variation of parameters in the atropo-enantioselective ARYNE coupling of 4c.
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
[
a]
[b]
Entry
Aryne precursor
Ligand
T [°C]
t [min]
Product
Yield or (conv.)
ee
–
1
2
3
4
5
6
7
8
9
1c
1c
1c
1a
1a
1a
1a
1a
1a
1a
–
–
–
5c
5c
5c
5d
5d
5d
5d
5d
5d
5d
46%
n.d. (traces)
59%
89%
n.d. (traces)
55%
26%
32%
68%
L4
L6
–
À 78
60
30
–
60
60
60
60
60
60
n.d.
<5%
–
0
–
0
0
0
L4
n.d.
L6[
17%
14%
13%
10%
16%
c]
L6
[d]
L6
L6
L7
0/À 78
[
e]
À 78
1
0
0
54%
1
[a] Isolated yield, or conversion into the product estimated by H NMR given in parentheses. [b] Enantiomeric excess determined by chiral phase HPLC. [c] 2
equivalents of L6 were used. [d] The temperature of the reaction medium was decreased from 0°C to À 78°C as soon as the ligand had been added to the
mixture, which was then stirred for 60 min at À 78°C before addition of 1a. [e] The temperature of the reaction medium was decreased from 0°C to À 78°C
prior to the addition of the ligand, and only then the resulting mixture was stirred for 60 min at À 78°C before addition of 1a. (n.d.=not determined).
aryllithium. And indeed, the task proved difficult. Gratifyingly, Acknowledgements
we were able to obtain a proof of concept, with a handful of
reactions affording the desired atropo-enantioenriched prod-
ucts with up to 17% ee. Among the few ligands screened,
Tomioka’s diether based on a hydrobenzoin core offered the
best compromise in terms of synthetic access, enantioselectiv-
ity, efficiency and practicality. Yet, the scope of the reaction and
enantioselectivity remain to be improved, and the mechanism
for enantioselectivity remains to be elucidated. Corresponding
efforts are underway in our laboratories.
We gratefully acknowledge the French Agence Nationale de la
Recherche (ANR) (grant number ANR-14-CE06-0003-01, ChirNo-
Cat), the CNRS, the Université de Strasbourg, the Université de
Haute-Alsace and the Université de Lorraine for financial support.
We also acknowledge Sandrine Adach of the SynBioN synthesis
platform of the L2CM UMR 7053, Université de Lorraine, for the
preparation of batches of aryne precursors 1a–b. We are thankful
to the analytical services of the Université de Strasbourg for
elemental analysis, high resolution mass spectroscopy analysis
and X-ray diffraction crystallography.
Experimental Section
General procedure for the ARYNE coupling
Conflict of Interest
BuLi (1 equiv.) or tert-BuLi (2 equiv.) was added dropwise to a
stirred solution of the pronucleophile 4a, 4b or 4c (1 equiv.) in the
desired anhydrous solvent (0.25 M) at the specified temperature.
The mixture was stirred for a known time and was then cooled
down to À 78°C. A precooled À 78°C solution of the aryne precursor
The authors declare no conflict of interest.
Keywords: Aryllithiums · Arynes · Axial chirality · Biaryls ·
Ligand effects
1
a, 1c or 1d (1 equiv.) in the same solvent (0.25 M) was then
cannulated into the first one. The mixture was stirred overnight (ca.
1
5 h) from À 78°C to r.t. and then quenched with water and
extracted thrice with Et O. The combined organic layers were dried
over Na SO , filtered and evaporated to dryness to give the crude
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© 2021 Wiley-VCH GmbH