Access to Atropisomerically En-riched Biaryls by the Coupling of Aryllithiums with Arynes under Control by Homochiral Oxazolines

Article abstract of DOI:10.1002/ejoc.201501503

We report the preparation of axially stereoenriched biphenyls by the coupling of in situ generated aryllithiums and arynes using chiral oxazoline auxiliaries. The design of the aryne precursors, the choice of oxazoline and the reaction conditions were key to accessing the desired, highly substituted, atropisomerically enriched biarylic products. In one case, the two atropo-diastereomers could be obtained in isomerically pure form by column chromatographic separation and their absolute configurations established by X-ray crystallography. The stereoselectivity of the reaction seems to be governed by subtle parameters.

Full text of DOI:10.1002/ejoc.201501503

DOI: 10.1002/ejoc.201501503
Full Paper
Stereoenriched Biphenyls
Access to Atropisomerically Enriched Biaryls by the Coupling of
Aryllithiums with Arynes under Control by Homochiral
Oxazolines
Boubacar Yalcouye,[a] Anaïs Berthelot-Bréhier,[a] David Augros,[a] Armen Panossian,*[a]
Sabine Choppin,[b] Matthieu Chessé,[a,b] Françoise Colobert,[b] and Frédéric R. Leroux*[a]
Abstract: We report the preparation of axially stereoenriched ropo-diastereomers could be obtained in isomerically pure form
biphenyls by the coupling of in situ generated aryllithiums and
arynes using chiral oxazoline auxiliaries. The design of the aryne
precursors, the choice of oxazoline and the reaction conditions
were key to accessing the desired, highly substituted, atropiso-
merically enriched biarylic products. In one case, the two at-
by column chromatographic separation and their absolute con-
figurations established by X-ray crystallography. The stereo-
selectivity of the reaction seems to be governed by subtle pa-
rameters.
Introduction
culty of transforming the tert-butylsulfinyl group. In this paper
we describe the use of 2-oxazolines as chiral auxiliaries in an
alternative atropo-diastereoselective aryne coupling reaction.
These chiral substituents ensure a central-to-axial chirality trans-
fer combined with the separation of atropisomers. Additionally,
in comparison with tert-butyl sulfoxides, oxazolines allow a
more versatile functionalization of the resulting biaryl by hy-
drolysis or reduction of the carbon-based auxiliary.[5]
Owing to their importance in organic synthesis, catalysis, natu-
ral products and medicinal chemistry among others, biaryls and
especially atropisomerically enriched biaryls have been the fo-
cus of constant attention and synthetic efforts.[1] In the toolbox
of methods for constructing the biaryl motif, the sequential hal-
ogen/lithium-exchange-mediated reaction of ortho-dihalo-
arenes with aryllithiums, which produces transient arynes, has
proved valuable to access biaryls with various substitution pat-
terns.[2,3] Indeed, polyhalogenated biaryls can be easily ob-
tained by this so-called “aryne coupling” reaction,[2c,2g–2i,3a]
whereas transition-metal-mediated reactions towards the same
products would suffer regioselectivity issues. The method has
allowed the synthesis of C1-symmetric biarylic mono- or diphos-
phine ligands as well as dibenzophosphole moie-
ties.[2e,2f,2I,2k,2m,3,4] Additionally, we have shown that the desired
biaryls could be obtained in highly atropo-enriched form by
using chiral sulfoxide auxiliaries through a post-aryne coupling
desymmetrization or deracemization strategy.[3a] Moreover, we
reported very recently on a more direct strategy, an atropose-
lective biaryl-producing aryl–aryne coupling reaction in which
stereoinduction is provided by a tert-butylsulfinyl group located
on the aryllithium nucleophile.[3b] However, this method
showed limited scope due, in part, to disparate reactivity, the
difficult separation of atropisomers in some cases, and the diffi-
Results and Discussion
Similarly to our work on aryl sulfoxides,[3b] we imagined that 2-
aryloxazolines could serve as pro-nucleophiles in the atropo-dia-
stereoselective aryne coupling reaction (Scheme 1). This choice
of chiral auxiliary was motivated by the good ortho-directing
ability of oxazolines as well as their efficient stereoinduction in
the trapping of polar alkyl- or arylmetal species with electro-
philes[5a,5b] and their successful use in a parent reaction, atropo-
diastereoselective biaryl-producing nucleophilic aromatic sub-
stitution (the “Meyers reaction”).[5b,6] Additionally, Meyers and
co-workers actually reported the addition of (achiral) aryloxa-
zolines onto arynes as an undesired side reaction.[7] In our case,
we were expecting the central chirality of the oxazoline to con-
trol the axial chirality of the biaryl product (G in Scheme 1)
by coordination to the lithium atom in intermediate B[8] and a
presumed stereoselective attack on the in situ generated aryne
[a] CNRS - Université de Strasbourg (ECPM), UMR 7509, COHA,
25 Rue Becquerel, 67087 Strasbourg, France
E-mail: armen.panossian@unistra.fr
E. We therefore prepared 5-aryloxazolines 1a–e from
L-valinol
and -tert-leucinol following an established procedure
L
(Scheme 2).[9] Compounds 1a–c,e were then submitted to the
aryne coupling reaction with 1-bromo-2-iodobenzene. In all
cases, the expected biaryl coupling products were isolated in
moderate yields of 31–56 % (Table 1). Interestingly, biaryls 2a–
d displayed atropo-diastereoenrichment, in ratios of around 2:1,
irrespective of the nature of substituents R1 and R2. Unfortu-
frederic.leroux@unistra.fr
www.coha-lab.org
[b] CNRS - Université de Strasbourg (ECPM), UMR 7509, SynCat,
25 Rue Becquerel, 67087 Strasbourg, France
Supporting information and ORCID(s) from the author(s) for this article
are available on the WWW under http://dx.doi.org/10.1002/
ejoc.201501503.
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Scheme 1. Proposed mechanism for the atropo-diastereoselective aryne coupling reaction (Ox* = chiral oxazoline). For the sake of simplicity, aryllithium
species are represented as monomers.[8]
nately, the mixtures of diastereomers, obtained as oils in all
cases, could not be separated by column chromatography nor
by crystallization. Moreover, as observed in related reac-
tions,[7a,7c,10] a cyclized product was also isolated in each case
after aqueous work-up and purification, namely the corre-
sponding fluorenone 3a–c, issuing from the attack of the inter-
mediate biarylyllithium on the oxazoline auxiliary (reaction path
IV in Scheme 1). Consequently, the total aryl–aryl coupling
yields were higher than 31–56 %; however, as axial chirality was
lost in the fluorenones, their formation in large amounts was a
drawback of the method.
Table 1. Atropo-diastereoselective aryne coupling reaction of enantiopure
aryloxazolines with benzyne.
Entry S. M.
R1
R2
X
Biaryl
Yield
[%][a]
dr[b]
Fluorenone
1
2
3
4
1a
1b
1c
1e
Me
Cl
Cl
iPr
iPr
tBu
iPr
Br
H
H
I
2a
2b
2c
2d
31
53
56
46
71:29
66:34
69:31
66:34
3a
3b
3b
3c
Br
[a] Combined yield of both atropo-diastereomers. [b] Diastereomeric ratio
measured by 1H-NMR analysis of the isolated mixture of atropo-diastereo-
mers using aromatic signals (see the Supporting Information for details).
rings during the formation of the flat fluorene moiety (Figure 1,
a). To achieve this goal, the aryne precursor should bear a bulky
substituent RL at one of the ortho positions relative to the triple
bond. Nevertheless, as we previously described,[2j] when steric
effects are preponderant, the aryne coupling reaction between
an aryllithium and an ortho-substituted benzyne affords the
product resulting from attack on the less hindered carbon (Fig-
ure 1, b). This would lead to the biaryl product in which RL is
not located ortho to the aryl–aryl bond as desired, but in the
Scheme 2. Synthesis of the starting 2-aryloxazoline pro-nucleophiles.
To circumvent the drop in biaryl yield due to the formation meta position. The simplest way of overcoming this problem is
of the cyclized byproduct, we reasoned that the biphenylyllith- to use a symmetrical aryne precursor bearing the RL group at
ium intermediate should be substituted in all positions ortho to both ortho positions (Figure 1, c). As a bulky substituent, we
the aryl–aryl bond so as to hamper rotation around the biaryl chose the trimethylsilyl group, for three reasons: 1) it can be
axis and, consequently, coplanarization of the two aromatic easily introduced by metallation and trapping with chlorotri-
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methylsilane, 2) it is generally tolerant to organolithium bases
and 3) it is easily transformed by a variety of methods, for exam-
ple, proto-, carbo-, halo- or borodesilylation, Hiyama coupling
and Tamao–Fleming oxidation.[11]
Scheme 3. Synthesis of bis(trimethylsilyl)-substituted benzodioxole-based ar-
yne precursors and their use in a model aryne coupling reaction.
Figure 1. Assumed structural requirements for preventing the cyclization to
yield compounds 3.
using a different Suzuki–Miyaura coupling-based strategy.[13]
When 8 was treated first with tBuLi, then with the dibrominated
aryne precursor 5a, the expected biaryl 9a was formed in a
very modest 12 % yield, with the corresponding undesired
fluorenone 10 obtained in 4 % yield, despite the presence of
the TMS groups. We then evaluated compound 5b in the same
reaction. In this case, no side-product 10 was observed, and
biaryl 9b (see the X-ray diffraction structure in Figure 2)[14] was
isolated in a rather high 67 % yield considering the bulkiness
of the four ortho substituents around the aryl–aryl bond
(Scheme 4). It appears therefore that the trapping of the
carbanion by the oxazoline substituent (step IV in Scheme 1)
in the biarylyllithium intermediate (F in Scheme 1) is almost as
Thus, we focused our attention on 5,6-dihalo-4,7-bis(trimeth-
ylsilyl)benzo-1,3-dioxoles 5a,b (Scheme 3, a). Indeed, they could
be easily prepared from 5-bromobenzodioxole by regioselective
halogenation, followed by double lithiation and in situ trapping
with TMSCl.[12] The dibromo compound 5a was then treated
with 2,6-dimethoxyphenyllithium as a model nucleophile in the
aryne coupling reaction (Scheme 3, b). Owing to the bulkiness
of the aryne precursor, the reaction temperature had to be
–35 °C prior to the addition of 5a, to ensure the efficient forma-
tion of the aryne, and then allowed to rise further to 25 °C over
15 h. Under these conditions, the expected biaryl product 6
was obtained in a very gratifying 82 % yield, given the high
degree of steric congestion around the biaryl bond.
Then, as a model oxazoline-containing pro-nucleophile, we fast as the bromine/lithium exchange with the aryne precursor
turned our attention towards the trimethoxy-substituted com- (step III in Scheme 1). This trapping is, however, much slower
pound 8 (Scheme 4). Indeed, the long-term aim here was to than the iodine/lithium exchange (X2 = I in precursor C of
evaluate the synthetic utility of the atropo-diastereoselective Scheme 1) when combined with the presence of bulky TMS
aryne coupling reaction by accessing the biaryl core of (–)-steg- groups on the aryne. Interestingly, when 1.1 equiv. of N,N,N′,N′-
anacin, the formal synthesis of which we recently described by tetramethylethylenediamine (TMEDA) was added to the reac-
Scheme 4. Synthesis of a model 2-bromoaryloxazoline and its use in aryne coupling reactions with 5a and 5b.
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tion mixture to investigate the role of de-aggregation in inter- with inseparable unidentified impurities, presumably arising
mediate B[8] (step II in Scheme 1), a more complex mixture was from competitive lithiation at the benzylic position of the ox-
obtained, with a lower yield of 38 % of the coupling product azoline moiety and subsequent reaction(s). In all other cases
9b. This may indicate an increased reactivity of aryllithium inter- (12a–c), the atropo-diastereomers of the coupling products
mediates leading to more side-products, or a competitive addi- could be separated cleanly by simple silica gel column chroma-
tion of the amine ligand onto the transient aryne.[15]
tography. The trend in diastereoselectivity shows an increase in
the dr with increasing size of the substituent at the stereocenter
in the Me-iPr-tBu series (Table 2, entries 1–3) with the large
but flat phenyl substituent giving a slightly higher 65:35 dr.
Gratifyingly, the slightly major atropo-diastereomer of 12b
could be recrystallized and its absolute configuration was deter-
mined to be (S,aR) by X-ray diffraction (Figure 3).[14] It is interest-
Table 2. Atropo-diastereoselective aryne coupling reactions of a bis-silylated
aryne with enantiopure aryloxazolines bearing a stereocenter α to the nitro-
gen.
Figure 2. ORTEP drawing of biaryl 9b obtained by X-ray diffraction crystallog-
raphy (hydrogen atoms have been omitted for clarity).[14]
Having efficient coupling conditions in hand, we assessed
the diastereoselective variant of the reaction starting from en-
antiopure oxazolines 11a–d, prepared by the previous proce-
dures starting from the corresponding natural amino alcohols
bearing a single stereocenter α to the nitrogen (Scheme 5). In
all cases, the expected biaryl was obtained without the forma-
tion of the fluorenone byproduct (Table 2). With oxazolines
11a–c bearing an alkyl substituent, yields of 51–67 % of the
biaryl were achieved (Table 2, entries 1–3). These yields are
higher than the yields of biaryls 2a–d (Table 1), thereby con-
firming the suppression of the formation of the fluorenone. The
phenyl-substituted oxazoline 11d led to complex mixtures
when the bromine/lithium exchange with tBuLi was performed
at –78 °C (entry 4). We suspected a mediocre nucleophilic ver-
sus basic selectivity of the lithium base at that temperature.
Decreasing the temperature to –100 °C (entry 5) did not show
any improvement in terms of side-product formation, and the
conversion was affected negatively. The diastereomeric ratios
Entry
S. M.
R
Product
Yield [%][a]
dr[b]
1
2
3
11a
11b
11c
11d
11d
Me
iPr
tBu
Ph
12a
12b
12c
12d
12d
51
52:48
56:44
61:39
65:35
65:35
67[c]
52
4
65[d]
27[d]
5[e]
Ph
[a] Combined yield of both atropo-diastereomers. [b] Diastereomeric ratio
determined by 1H NMR analysis of the crude mixture (see the Supporting
Information for details). [c] Isolated yield of each atropo-diastereoisomer:
33 %. [d] Approximate yield; the biaryl could not be completely isolated from
inseparable impurities. [e] The initial bromine/lithium exchange was per-
formed at –100 °C instead of –78 °C.
1
were determined by H NMR analysis of the crude mixtures. In
both entries 4 and 5, the atropisomers of the desired product
12d could be separated but were systemically contaminated
Figure 3. ORTEP drawing of the slightly major atropo-diastereomer (S,aR) of
12b obtained by X-ray diffraction crystallography (hydrogen atoms have
been omitted for clarity, except for the hydrogen substituent on the stereo-
genic carbon), and structure of (–)-steganacin.[14]
Scheme 5. Synthesis of enantiopure 2-(2-bromo-3,4,5-trimethoxyphenyl)ox-
azoline pro-nucleophiles bearing a stereocenter α to the nitrogen.
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ing to note that this compound, prepared from natural L-valine,
shows an identical axial configuration to natural (–)-steganacin
(Figure 3). Additionally, as in the case of 9b, the presence of
TMEDA (1.1 equiv.) in the reaction of 11b and 5b led to a drop
in yield (from 67 to 38 %) without variation of the diastereo-
meric ratio (56:44).
To better understand the diastereoselectivity of the reaction,
we also prepared three parent oxazolines 13a–c, in which the
stereocenter is α to the oxygen rather than to the nitrogen, and
oxazoline 13d bearing two stereogenic carbon atoms α to both
the nitrogen and oxygen with one a coordinating methoxy
group (Scheme 6). When submitted to the aryne coupling reac-
tion with 5b under the previously determined standard condi-
tions, only compound 13a led to the expected biaryl 14a in
45 % yield and 52:48 dr (Table 3, entry 1). All the other ana-
logues, 13b–d, afforded the corresponding proto-debromin-
ated starting oxazolines (entries 2–4). With 13c, 0.2 equiv. of
BuLi were added to the mixture after the introduction of the
aryne precursor to trigger the chain reaction, as we did for un-
reactive ortho-lithioaryl sulfoxides (analogues of intermediate B
in Scheme 1).[3b] Biaryl 14c was then obtained with a low 56:44
dr (entry 5), but, as in the case of its isomer 12d, could not be
isolated from inseparable unidentified impurities. The remark-
ably low reactivity of oxazolines 13b–d under the standard con-
ditions (entries 2–4) in comparison with 11a–d might be attrib-
uted to a modified aggregation state of the aryllithium, possibly
blocked as a dimer or oligomer;[8] this aggregation state could
be facilitated either by the absence of substituents α to the
nitrogen (13b,c), removing steric bulk from around the bridging
lithium atoms, or by the presence of an additional coordinating
substituent at that position (13d). In the case of 13c, the posi-
tive effect of the addition of 0.2 equiv. of BuLi (entry 5), as-
sumed to promote the generation of the aryne, could also arise
from disrupting an unproductive aggregation state. However,
the difference in reactivity of compounds 13b,c compared with
oxazoline 13a to afford the desired biaryl (entry 1) remains puz-
zling.
Scheme 6. Synthesis of enantiopure 2-(2-bromo-3,4,5-trimethoxyphenyl)oxa-
zoline pro-nucleophiles bearing a stereocenter α to oxygen or two stereocen-
ters (Ar = 2-bromo-3,4,5-trimethoxyphenyl).
Table 3. Atropo-diastereoselective aryne coupling reactions of a bis-silylated
aryne with enantiopure aryloxazolines bearing a stereocenter α to the oxy-
gen or two stereocenters.
To account for the trend in diastereoselectivity of the reac-
tions in Table 2, we propose the following tentative rationale
(Scheme 7). The 2-(2-lithiophenyl)oxazoline is assumed to exist
in THF as a metallacycle in which the nitrogen is coordinated
to lithium, and as an equilibrium between the monomer, which
is presumably more reactive, and dimer forms, following the
findings of Reich and co-workers.[8a] The approach to the nu-
cleophile by the aryne from either face of the phenyl ring is
assumed to take place perpendicularly to diminish steric con-
straints and to align as much as possible the C–Li bond with
one “sp2” lobe of the aryne π anti-bonding orbital for an effi-
cient overlap. In the anti approach with regard to the R substit-
uent of the stereocenter, the aryne approaches the unhindered
face of the aryloxazoline. However, the carbon–lithium bond
is pushed upwards, which causes a clockwise rotation of the
oxazoline, and, consequently, of the R group, which thus occu-
pies the same region in space as the TMS group of the aryne
in the transition state. Conversely, in the syn attack, the aryne
Entry
S. M.
Biaryl
Yield [%][a]
dr[b]
1
2
3
13a
13b
13c
13d
13c
14a
14b
14c
14d
14c
45
0
0
52:48
–
–
4
0
–
5[c]
40[d]
56:44
[a] Combined yield of both atropo-diastereomers. [b] Diastereomeric ratio
determined by 1H NMR analysis of the crude mixture (see the Supporting
Information for details). [c] BuLi (0.2 equiv.) was added after the introduction
of 5b. [d] Approximate yield; the biaryl could not be completely isolated from
inseparable impurities.
clockwise, thereby turning the bulky R group away from the
approaches the hindered face of the aryloxazoline, the C–Li TMS in the transition state. Consequently, the competition be-
bond is pushed downwards and the oxazoline rotates counter- tween the steric hindrance during the approach of the aryne
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and the nucleophile, and the steric hindrance between the TMS uration of the major atropo-diastereomer of 12b, it seems that
and R groups in the transition state would explain the moderate repulsion of R and TMS in the transition state slightly over-
diastereoselectivity recorded in these coupling reactions with comes the repulsion in the approach to the pre-transition state.
the bis-trimethylsilylated aryne derived from 5b. As X-ray dif- On the other hand, when simple benzyne undergoes the cou-
fraction crystallography unambiguously established the config- pling reaction (Table 1), no TMS group is present to destabilize
Scheme 7. Rationale for the atropo-selectivity of the aryne coupling reaction of a bis-ortho-silylated aryne with enantiopure aryloxazolines 11a–d bearing a
single stereocenter α to the nitrogen. For the sake of simplicity, aryllithium species are represented as monomers.[8]
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the anti transition state, which should then favour sensibly the ian government for a doctoral grant. A. B. B. thanks the French
anti pathway. This is coherent with the higher dr values ob- Ministère de l'Education Nationale et de la Recherche for an
served in Table 1 compared with those in Table 2.
MENRT Ph. D. grant. D. A., A. P. and F. L. thank the French
Agence Nationale pour la Recherche (ANR) (grant number ANR-
14-CE06-0003-01, ChirNoCat) for financial support.
Conclusions
Keywords: Biaryls · Arynes · Cross coupling · Lithium ·
Chirality · Atropisomerism
We recently published the first example of the atropo-selective
coupling of an aryne and an aromatic nucleophile in the ab-
sence of transition metals using a chiral tert-butylsulfinyl auxil-
iary.[3b] Although limited in terms of scope due the lack of ver-
satility of the tert-butylsulfinyl group, the method paved the
way to the development of atropo-selective aryl-aryne coupling
reactions. In this present report, we have described the devel-
opment of the chiral oxazoline-based coupling reaction, with
the expected axially stereoenriched biphenyls being obtained
with up to 71:29 dr. Depending on the aryne precursor, both
atropisomers could be isolated in diastereopure form after col-
umn chromatography and highly congested tetra-ortho-substi-
tuted, atropisomerically enriched biphenyls could be obtained.
In these reactions, the relative rates of the halogen/lithium ex-
changes and of the self-immolative attack of the biarylyllithium
onto the auxiliary appeared critical to obtaining decent yields
of the desired biphenyls. We succeeded in resolving this prob-
lem by using a 1-bromo-2-iodoarene as the aryne precursor,
moreover bearing two bulky trimethylsilyl groups ortho to the
two ends of the triple bond of the aryne. We have proposed a
tentative rationale for the stereoselectivity of the reactions,
which may be governed by delicate steric constraints. In partic-
ular, it seems that the presence of the TMS groups on the aryne,
although minimizing the formation of the undesired fluorenone
side-product, tends to counterbalance the stereoinduction pro-
vided by the chiral oxazoline. Further studies are underway to
overcome this issue. The application of this new method to
the formal synthesis of (–)-steganacin as well as to asymmetric
catalysis, in which chiral oxazolines are widely used as li-
gands,[16] is also underway and will be reported in due course.
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M in pentanes) was added
dropwise to a solution of (2-bromoaryl)oxazoline 11 or 13 (1 equiv.)
in dry THF (2.5 mL/mmol) under argon at –78 °C. The mixture was
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–35 °C. A room-temperature solution of the aryne precursor 5b
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organic layers were dried with Na2SO4 and concentrated under re-
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Acknowledgments
This work was supported by the French Centre National de la
Recherche Scientifique (CNRS). B. Y. is very grateful to the Mal-
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Full Paper
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Received: November 30, 2015
Published Online: December 23, 2015
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