1,1,1,3,3,3-Hexafluoroisopropanol as a Remarkable Medium for Atroposelective Sulfoxide-Directed Fujiwara-Moritani Reaction with Acrylates and Styrenes

Article abstract of DOI:10.1002/chem.201503650

Axially chiral biaryls are ubiquitous structural motifs of biologically active molecules and privileged ligands for asymmetric catalysis. Their properties are due to their configurationally stable axis, and therefore, the control of their absolute configuration is essential. Efficient access to atropo-enantioenriched biaryl moieties through asymmetric direct C-H activation, by using enantiopure sulfoxide as both the directing group (DG) and chiral auxiliary, is reported. The stereoselective oxidative Heck reactions are performed in high yields and with excellent atropo-stereoselectivities. The pivotal role of 1,1,1,3,3,3-hexafluoropropanol (HFIP) solvent, which enables a drastic increase in yield and stereoselectivity of this transformation, is evidenced and investigated. Finally, the synthetic usefulness of the herein disclosed transformation is showcased because the traceless character of the sulfoxide DG allows straightforward conversions of the newly accessed, atropopure sulfoxide-biaryls into several differently substituted axially chiral scaffolds.

Full text of DOI:10.1002/chem.201503650

DOI: 10.1002/chem.201503650
Full Paper
&
Asymmetric Synthesis
1,1,1,3,3,3-Hexafluoroisopropanol as a Remarkable Medium for
Atroposelective Sulfoxide-Directed Fujiwara–Moritani Reaction
with Acrylates and Styrenes
Quentin Dherbassy, Geoffrey Schwertz, Matthieu ChessØ, Chinmoy Kumar Hazra,
Joanna Wencel-Delord,* and FranÅoise Colobert*[a]
Abstract: Axially chiral biaryls are ubiquitous structural
motifs of biologically active molecules and privileged ligands
for asymmetric catalysis. Their properties are due to their
configurationally stable axis, and therefore, the control of
their absolute configuration is essential. Efficient access to
atropo-enantioenriched biaryl moieties through asymmetric
direct CÀH activation, by using enantiopure sulfoxide as
both the directing group (DG) and chiral auxiliary, is report-
ed. The stereoselective oxidative Heck reactions are per-
formed in high yields and with excellent atropo-stereoselec-
tivities. The pivotal role of 1,1,1,3,3,3-hexafluoropropanol
(HFIP) solvent, which enables a drastic increase in yield and
stereoselectivity of this transformation, is evidenced and in-
vestigated. Finally, the synthetic usefulness of the herein dis-
closed transformation is showcased because the traceless
character of the sulfoxide DG allows straightforward conver-
sions of the newly accessed, atropopure sulfoxide-biaryls
into several differently substituted axially chiral scaffolds.
Introduction
be performed with simple starting materials, but also unprece-
dented retrosynthetic disconnections that allow the rapid con-
struction of complex molecular scaffolds can be envisioned.[7]
In contrast, asymmetric CÀH activation reactions remain rather
rare and are mainly limited to the synthesis of compounds
with central chirality.[8] Indeed, the application of direct func-
tionalization to access axially chiral skeletons has remained,
until recently, a barely explored field. An early example was
disclosed by Murai in 2000 and concerned a rhodium-catalyzed
atroposelective CÀH activation/alkylation of 2-(1-naphthyl)-3-
methylpyridine (Figure 1A). Disappointingly, only moderate
enantioselectivity (49%) and efficiency (37% yield) were ach-
ieved with a chiral ferrocenyl phosphine ligand.[9] A further
major advance in this field was reported by You and concerned
an oxidative Heck reaction between 1-(naphthalen-1-yl)benzo-
(h)isoquinoline derivatives and styrenes (Figure 1B).[10] In paral-
lel, a stereoselective construction of the ArÀAr axis by means
of a direct arylation was disclosed, but only a rather moderate
level of chiral induction (72% ee) could be achieved when cou-
Sterically hindered biaryls with at least two bulky substituents
in ortho positions of the biaryl axis are intriguing chiral skele-
tons. During the past two decades, increasing interest has
been given to such atropisomeric compounds because of their
prominent biological properties,[1] but also their unique apti-
tude to induce stereoselectivity in asymmetric homogenous
catalysis.[2] Accordingly, multiple synthetic routes towards these
important skeletons have been devised,[3] among which the
asymmetric transition metal-catalyzed cross-coupling reaction
between two aryl units is arguably the most general one.[4] Al-
though the potential of the stereoselective Suzuki–Miyaura
coupling is undeniable, this approach generally fails if the con-
struction of highly sterically congested biaryls containing four
substituents around the biaryl linkage is targeted.[5]
Over the last decade organic synthetic chemistry has been
witnessing an incredible expansion of the transition-metal-cat-
alyzed CÀH activation field[6] and a variety of catalytic systems
based on metals, such as Pd, Rh, Ru, Cu, Ni, and Co have been
discovered. Consequently, not only more step- and waste-eco-
nomic versions of classical cross-coupling reactions can now
pling
a thiophene with a hindered boronic acid (Fig-
ure 1C).[11,12]
Although the development of enantioselective transforma-
tions is particularly appealing because only a catalytic amount
of a chiral source is required, the design of a chiral ligand com-
patible with CÀH activation reactions is far from trivial. Indeed,
in the key metallacyclic intermediates, at least two coordina-
tion sites are occupied by the CÀH activation substrate (one
MÀC bond and at least one DGÀM bond), and thus, coordina-
tion with an additional chiral inductor may be disfavored. An
alternative solution to perform stereoselective CÀH activation
is to introduce the chiral information onto a DG.[13] To guaran-
[a] Q. Dherbassy, G. Schwertz, M. ChessØ, Dr. C. K. Hazra, Dr. J. Wencel-Delord,
Prof. F. Colobert
Laboratoire de Chimie MolØculaire (UMR CNRS 7509)
UniversitØ de Strasbourg, ECPM, 25 Rue Becquerel
67087, Strasbourg (France)
E-mail: wenceldelord@unistra.fr
francoise.colobert@unistra.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503650.
Chem. Eur. J. 2016, 22, 1735 – 1743
1735
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Figure 1. CÀH activation based strategies towards the synthesis of axially chiral compounds. DG=directing group, ee=enantiomeric excess, biox*=2,2’-bis(2-
oxazoline, de=diastereomeric excess, Tol =tolyl.
tee the synthetic utility of such an approach, a chiral DG needs
to be straightforwardly accessible from cheap precursors and
easily removable after the CÀH functionalization step. Because
these requirements are fulfilled by enantiomerically pure sulf-
oxide moieties, previously employed in the palladium-cata-
lyzed asymmetric Suzuki–Miyaura reaction,[14] we have recently
endeavored to develop diastereoselective sulfoxide-directed
CÀH activation reactions.[15] In our pioneering work concerning
a palladium-catalyzed direct olefination of a biaryl–sulfoxide,
we demonstrated that this moiety could be efficiently used as
the stereogenic DG to enable the formation of the axially
chiral skeletons (Figure 1D). Deceivingly, rather modest results
in terms of stereodiscrimination and efficiency were ob-
tained.[16] Moreover, quite a high reaction temperature (808C),
a large excess of silver-based oxidant (6 equiv of AgOAc), and
strongly activated coupling partners were crucial. A major ad-
vance was achieved a few months later, when we discovered
that the same substrates might undergo direct CÀO and CÀX
bond formations.[17] Intriguingly, these new couplings could be
performed with excellent atroposelection and almost quantita-
tive yields, which showcased the underestimated potential of
chiral sulfoxides in the CÀH activation field. Notably, related
direct acetoxylation and iodination reactions, which delivered
axially chiral compounds, by using a stereogenic phosphate as
the DG*, were recently reported by Yang et al.[18]
Encouraged by our results concerning carbon–heteroatom
bond formation, we decided to revisit our pioneering work on
oxidative olefination. Herein, we report our discoveries on the
unique and intriguing role of 1,1,1,3,3,3-hexafluoropropanol
(HFIP) solvent in atropo-diastereoselective, sulfoxide-directed
CÀC coupling. Notably, this polyfluorinated alcohol stood out
recently as an optimal solvent for several challenging CÀH acti-
vation reactions,[19] but its particular role has remained ambig-
uous. The mechanistic studies presented above indicate that
the key feature of our catalytic system was the formation of
hydrogen-bonded complex between the substrate and solvent
facilitating the CÀH activation step and improving the stereo-
chemical outcome of this transformation. Importantly, such hy-
drogen-bonding-induced substrate activation could also ac-
count for the reactivity enhancement of other CÀH activation
reactions conducted in HFIP medium.
Results and Discussion
Fluorinated alcohols have attracted increasing attention from
organic chemists as unusual media within which to perform
Chem. Eur. J. 2016, 22, 1735 – 1743
www.chemeurj.org
1736
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
various transformations, including both transition-metal and
organocatalyzed reactions.[20] It has been observed that due to
With the reoptimized reaction conditions in hand, we ex-
plored the scope of this transformation (Scheme 1). We were
pleased to observe that the beneficial effect of HFIP in this ste-
reoselective CÀC coupling was general because now the reac-
tion proceeded in quantitative yield with excellent atropo-dia-
stereoselectivity for an array of 2’-substituted biaryl sulfoxides
(Scheme 1; Cond A: previously reported conditions, Cond B:
the newly reoptimized catalytic system). Substrates containing
both electron-donating (Scheme 1, 1a–b) and -withdrawing
(Scheme 1, 1d–g) substituents could be functionalized
smoothly to deliver the desired atropopure scaffolds. Notably,
under the newly optimized reaction conditions, the CF3-sub-
stitued 1d substrate could be efficiently functionalized to de-
liver atropopure 2d in 80% yield, whereas the reaction con-
ducted in DCE was extremely sluggish (30% yield and 74:26
d.r.). When 1g, which contained two possible coordinating
groups, namely, sulfoxide and ester, was submitted to the reac-
tion conditions, the sulfoxide-directed CÀH activation occurred
selectively at the anticipated 6’-position. Furthermore, the reac-
tion outcome for a proaxially chiral 6-substituted biaryl was in-
vestigated; the expected 2h product was obtained as a single
atropisomer in quantitative yield; this highlighted that double
alkenylation was strongly disfavored. Finally, our attention
turned towards ortho-trisubstituted substrates 1i–n. Substrates
1i–j, which bear small F-substituent at 2’-position, afforded 2i–
j in excellent yield and good diastereoselectivity. These results
are of particular importance because the asymmetric synthesis
of tetrasubstituted axially chiral scaffolds is a great synthetic
challenge.[3a] Unfortunately, increased steric demand around
the biaryl linkage has a detrimental effect on atroposelectivity;
a modest diastereoselectivity was observed in the case of
more hindered products 2k–n. An increase in the reaction
temperature to 808C generally does not enable improved
chiral induction as products 2l and 2n were obtained with the
same d.r. values. Only in the case of 2i was the stereocontrol
slightly enhanced to reach 95:5 d.r. when performing the reac-
tion under refluxing conditions.
their unique properties,[20a] such as extreme polarity (1.068 EN ),
T
high acidity (pKa =9.3), excellent hydrogen-bond-donor abili-
ties (a=1.96), and low nucleophilicity (N=À4.23), these sol-
vents may exert an unexpected effect on an reaction outcome,
modifying not only the reactivity of a catalytic system, but also
its regio- and stereoselectivity. Accordingly, commercially avail-
able HFIP has recently been employed in several CÀH activa-
tion reactions and clearly outcompeted other organic sol-
vents.[19] Intrigued by the unique features of HFIP, we per-
formed our previously developed sulfoxide-directed oxidative
olefination in this polyfluorinated alcohol. Gratifyingly, the use
of HFIP instead of 1,2-dichloroethane (DCE), when keeping
other reaction parameters constant, enabled smooth function-
alization of our standard substrate 1a to deliver 2a in 82%
yield and, remarkably, as a single atropisomer (Table 1, entry 2).
Table 1. Optimization of the oxidative olefination of 1a.
Entry
Solvent
AgOAc [equiv]
T [8C]
Yield [%][a]
d.r. [%][b]
1
2
3
4
5
6
7[c]
8[d]
DCE
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
6
6
4
2
1
–
2
2
80
80
80
80
80
80
80
RT
87
82
88
93
60
8
82:18
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
77
98
[a] Yield of product isolated. [b] The diastereomeric ratio (d.r.) of the crude
mixture was determined by 1H NMR spectroscopy analysis. [c] 5 mol% of
Pd(OAc)2. [d] 30 h.
The structure of 2c was confirmed by XRD analysis and the
absolute (SaR) configuration was assigned (Figure 2).[21] This
configuration of 2c is coherent with the presumed favored pal-
Encouraged by this solvent-improved chiral induction, we pur-
sued optimization of the reaction conditions. Surprisingly, re-
duction of excess of silver oxidant allowed further enhance-
ment of the efficiency of this transformation, while conserving
the total diastereoselectivity. An optimal yield of 93% of 2a
was obtained with only 2 equivalents of AgOAc (Table 1,
entry 4); merely a trace amount of 2a was generated in ab-
sence of this terminal oxidant (Table 1, entry 6). Additionally,
a lower catalyst loading (5 mol% of Pd(OAc)2) resulted in
a slightly decreased reaction yield (77%; Table 1, entry 7). Im-
portantly, this modified catalytic system turned out to be effi-
cient under significantly milder reaction conditions; the cou-
pling could be performed at room temperature, but a longer
reaction time was needed to complete this transformation. Fi-
nally, product 2a was obtained in almost quantitative yield
with total atroposelection when using HFIP as the solvent and
10 mol% of the Pd(OAc)2 catalyst, in combination with 2 equiv-
alents of AgOAc, at room temperature and after 30 h of reac-
tion (Table 1, entry 8).
Figure 2. X-ray structure of (SaR)-2c and the proposed favored and unfa-
vored metallacyclic intermediates.
Chem. Eur. J. 2016, 22, 1735 – 1743
www.chemeurj.org
1737
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
position of the aromatic ring boosted the reactivity
and the corresponding products 3b–d were afforded
in a completely atroposelective manner. The best
yield of 80% and d.r. superior to 98:2 were obtained
with 2,3,4,5,6-pentafluorostyrene (3e). Unfortunately,
the reactivity was completely shut down when using
electron-rich styrene derivatives, such as 4-methoxys-
tyrene. Notably, this reaction tolerated different sub-
stitution patterns of the biaryl substrate well, since
3 f and proaxially chiral 3g were isolated in compara-
ble yields with excellent diastereoselectivity.
Moreover, we were pleased to find that an atropo-
pure biaryl product containing a 1,1-disubstituted
olefin moiety could also be synthesized (Scheme 3).
Indeed, when diethyl 2-(ethoxymethyl)malonate was
used as a precursor of diethyl 2-methylenemalonate,
the reaction proceeded smoothly and the desired
product 4a was generated in 89% yield and d.r. of
97:3.
The results obtained for this oxidative Heck reac-
tion clearly show the intriguing superiority of the cat-
alytic system with the HFIP medium. Indeed, not only
reactivity, but even more surprisingly, atroposelectivi-
ty could be drastically improved by using this ex-
tremely polar, fluorinated solvent. We therefore en-
gaged experimental efforts to shed some light on
this particular feature of our catalytic system.
First, to prove the unique reactivity of HFIP solvent,
the standard olefination reaction of 1a with methyl
acrylate was conducted in several other media
(Table 2). Small-scale solvent screening revealed that
any coupling occurred when the non-fluorinated
HFIP-congener, that is, iPrOH, was used as a solvent,
which suggested that higher polarity and/or stronger
acidity induced by the presence of the fluorine atom
in HFIP were crucial (Table 2, entry 1). AcOH, DCE,
and CHCl3 were also totally inefficient in this reaction
(Table 2, entries 2–4). Solvent mixtures were also
tested. No desired product was obtained when HFIP
was added as a cosolvent to iPrOH (9:1 v/v mixture)
or in a mixture of DCE/AcOH (Table 2, entries 5 and 7,
respectively). Finally, reactivity could be restored in
a 9:1 mixture of DCE/HFIP, although a longer reaction
Scheme 1. Scope of biphenylsulfoxide partners with acrylate derivatives.; Yield of isolat-
ed product; d.r. determined by 1H NMR spectroscopy. [a] After recrystallization.
ladacylic intermediate, in which steric hindrance generated by
the pTol substituent of the sulfoxide and the Pd atom is mini-
mized.
time was required to complete this transformation (Table 2,
entry 6). A comparable reactivity between a mixture of DCE/
HFIP and HFIP alone was observed when using at least
20 equivalents of HFIP relative to 1a (approximately 1.4:1 v/v
mixture of DCE/HFIP). This study clearly highlights the unique
properties of HFIP solvent that cannot be attributed directly to
its acidic character or strong polarity.
Encouraged by excellent results in term of both yield and
atroposelectivity when using our reoptimized reaction condi-
tions, obtained with methyl acrylate, we then focused on ap-
plying other, less activated coupling partners (Scheme 2). We
were pleased to find that 1a, when reacted with styrene at
808C, afforded desired 3a as a single atropisomer, but in sig-
nificantly decreased yield (41%). The structure of 3a was con-
firmed by XRD analysis and its SaR configuration was evi-
denced. Subsequently, the scope of this transformation with
regard to the styrene coupling partner was examined. The in-
troduction of an electron-withdrawing substituent on the para
Having demonstrated that HFIP was an exceptional solvent
for our catalytic system, we focused on the origin of the re-
markable stereoselectivity improvement. First, the influence of
temperature was studied. Indeed, because the olefination with
acrylate occurs smoothly in HFIP at room temperature, this de-
crease in the reaction temperature, compared with 808C in
DCE, could account for the superior chiral induction. We there-
Chem. Eur. J. 2016, 22, 1735 – 1743
www.chemeurj.org
1738
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 2. Scope of biphenylsulfoxide partners with styrenes; yield of product isolated; d.r. determined by 1H NMR spectroscopy.
fore performed the coupling of biaryls 1a–d with methyl acry-
late in HFIP at 808C (Figure 3). The corresponding products
2a–d were isolated after only 6 h in 93, 98, 85, and 96% yield,
respectively. Importantly, this direct functionalization at 808C
occurred with no significant erosion of the atroposelection;
thus proving that the reaction temperature had only a minor
impact on chiral induction.
Subsequently, because HFIP is an excellent hydrogen-bond
donor,[22] we surmised that this acidic fluorinated molecule
might be involved in hydrogen bonding with the sulfoxide
moiety. Indeed, it is well known in the literature that the sulf-
oxide group promptly undergoes hydrogen bonding with vari-
ous solvents, such as alcohols, water, acetonitrile, and carboxyl-
ic acids.[23] Such weak bonding results in lengthening of the S=
O bond, and hence, it can be reasonably expected that the co-
ordinating properties of our DG would be altered, which
would directly impact on the reactivity of the substrate to-
wards the CÀH activation step. Consequently, 1H NMR spectros-
copy studies were undertaken (for details, see the Supporting
Information). A very strong downfield shift (Dd=2.473 ppm) of
the alcoholic proton was observed when a substoichiometric
amount of HFIP (0.4 equiv) was added to a solution of 1a in
CDCl3. In parallel, when HFIP was present in excess relative to
1a, a significant upfield shift of the signal of the proton ortho
to the sulfoxide by Dd=0.975 ppm (2 signals corresponding
to each atropisomers of 1a) was evidenced, which suggested
that the electron-withdrawing character of the sulfoxide
moiety decreased upon hydrogen bonding.
Scheme 3. Synthesis of an atropopure biaryl containing a 1,1-disubstituted
olefin moiety.
Table 2. Screening of solvents for the oxidative olefination of 1a.
Entry
Solvent
Time [days]
Conversion [%][a]
1
2
3
4
5
6
7
iPrOH
AcOH
DCE
CHCl3
iPrOH/HFIP (9:1 v/v)
DCE/HFIP (9:1 v/v)
DCE/AcOH (9:1 v/v)
3
3
2
3
3
5
2
0
0
0
<5
0
98
0
1
[a] Conversion determined by H NMR spectroscopy.
Chem. Eur. J. 2016, 22, 1735 – 1743
www.chemeurj.org
1739
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Figure 3. Influence of the reaction temperature on the diastereoselectivity of the olefination reaction with HFIP as a solvent.
1
Furthermore, the equilibrium constant for the formation of
the hydrogen-bonded adduct between 1a and HFIP was calcu-
lated by processing the NMR spectroscopy data.[24,25] Equilibri-
um constants, Keg, of (18.5Æ4.7) and (23.5Æ9.8)mÀ1 for the
major and minor atropodiastereomers of 1a were determined,
which clearly indicated a strong interaction between hydro-
gen-bond-donating HFIP and the hydrogen-bond-accepting
sulfoxide. These values are of the same order of magnitude as
those reported in related studies on hydrogen-bond com-
plexes of various sulfoxides with alcohols.[26,27]
Accordingly, both H NMR and IR spectroscopy studies cor-
roborate the formation of a hydrogen bond between our
chiral DG and HFIP. Hence, it can be reasonably surmised that
such substrate–solvent complexation has two major impacts
on the outcome of the studied transformation. First, because
this hydrogen bond results in a weakening of the SÀO bond,
the electronic properties of this coordinating group are modi-
fied and can directly influence the rate of the CÀH activation
step. Moreover, if the metalation step is rate determining, the
kinetics of the overall transformation are therefore altered. In
parallel, the involvement of the sulfoxide group in the hydro-
gen bond can reasonably influence the geometry of the pre-
transition state and/or the key palladacyclic intermediate;
hence enhancing efficient stereoinduction.
In addition, the expected complexation between HFIP and
the sulfoxide moiety was investigated by IR spectroscopy anal-
ysis (for details, see the Supporting Information).[27] Initially, the
hydrogenic stretching of the free OH group of HFIP absorbs IR
radiation sharply at n˜ =3542.8 cmÀ1, whereas, upon addition of
2c, the absorption is shifted to lower wavenumbers and flat-
tened to give a broad bond, which is characteristic for an OH
group involved in hydrogen bonding. Additionally, the SO
moiety of 2c, characterized by a stretching bond at n˜ =
1038.6 cmÀ1, when complexed with HFIP, shows two absorp-
tion maxima at n˜ =1022.7 and 1011.1 cmÀ1. The multiplicity of
the SÀO stretching frequency could be attributed either to the
presence of two possible conformers (rotational isomerism
about the SÀC bond) or to Fermi resonance (an overtone of
some other vibration that occurs near one-half of the SÀO vi-
bration frequency).[28]
To examine the influence of HFIP on the rate of this oxida-
tive olefination, kinetic isotope effect (KIE) studies were under-
taken (Scheme 4).[29] Two sets of experiments were conducted.
In the first one, a KIE of 2.2 from the two parallel reactions
with 1d and 6’-1d under our original reaction conditions
(10 mol% of Pd(OAc)2, 6 equiv of AgOAc, DCE, 808C) was de-
termined. In the second one, with HFIP as a solvent, 2 equiva-
lents of AgOAc, and conducting the reaction at room tempera-
ture, a much stronger KIE of 5.9 was measured. These results
indicate that in both cases the rate-determining step involves
breaking of a CÀH bond. Moreover, the much stronger KIE in
HFIP could suggest that the precise mechanism of this metala-
Scheme 4. KIE studies in DCE and HFIP.
Chem. Eur. J. 2016, 22, 1735 – 1743
www.chemeurj.org
1740
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
tion is different in both solvents and distinct transition states
in both cases could be expected.[30] The modified value of the
KIE effect could also result from the geometry change of 1d
and the corresponding intermediates upon hydrogen bonding
by HFIP. In addition, the reversibility of this oxidative Heck re-
action was investigated (Scheme 5). Under both reaction con-
ditions, no H/D scrambling was observed on 6’-1d, which indi-
cated the nonreversible character of CÀH cleavage, and hence,
supported its involvement in the rate-determining step.
both the coordination properties and steric features of the
chiral DG. Subsequently, precoordination of Pd(OAc)2, followed
by irreversible, rate-determining CÀH bond cleavage occurs, to
afford atropisomeric palladacyclic intermediates. The stereo-
genic environment of the sulfoxide, further increased by the
involvement of the oxygen atom of the sulfoxide in a hydrogen
bond with HFIP, results in the favorable generation of the inter-
mediate Int AHFIP with decreased steric hindrance. Insertion of
the olefin coupling partner into the CÀPd bond, followed by b-
H elimination, delivers functionalized product 2 as a single
atropisomer. The catalytic cycle is completed by the reoxida-
tion of palladium(0) into palladium(II) by the silver salt.
An additional advantage of the reoptimized catalytic system
involving HFIP as a solvent is that a decreased amount of silver
salt oxidant, two equivalents versus six equivalents previously
used, are sufficient to ensure optimal regeneration of the cata-
lyst. The fluorinated solvents are prompt to reduce the oxida-
tion potential of some organic species,[31] and hence, it could
be possible that the reoxidation of the Pd0 species in HFIP is
facilitated.[32] Additionally, the distinct solubility of AgOAc in
both solvents could also have an impact on this step.
Finally, to illustrate the key advantage of the sulfoxide DG,
that is, its traceless character, postmodifications of 2 were un-
dertaken. Rewardingly, the sulfoxide DG could be efficiently
transformed into several functional groups to give access to
highly substituted atropopure biaryls.
As an example, optically pure atropisomeric 2a (prepared in
98% yield and >98:2 d.r.) was first reduced with diisobutylalu-
minium hydride (DIBAL-H) followed by protection of the corre-
sponding alcohol as a tert-butyldimethylsilyl ether (TBDMS) to
afford 5 in 75% yield (Scheme 6). Subsequently, exchange with
tert-butyllithium at À788C in THF afforded the atropo-enantio-
On the basis of the above-presented mechanistic studies
and literature data, the catalytic cycle presented in Figure 4 is
proposed. Initially, a biarylsulfoxide substrate interacts through
hydrogen bonding with HFIP to generate an “activated sub-
strate”. This substrate–solvent interaction is assumed to modify
Scheme 5. Study of the reversibility of the oxidative Heck reaction.
Figure 4. Proposed catalytic cycle.
Chem. Eur. J. 2016, 22, 1735 – 1743
www.chemeurj.org
1741
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 6. Examples of transformations of the sulfoxide DG.
compounds were removed under reduced pressure. The mixture
was analyzed by H NMR spectroscopy to determine the d.r. value
and the product was purified by column chromatography on silica
gel.
pure biaryllithium species, which was trapped with various
electrophiles to afford the corresponding enantiopure[33] bi-
phenyl alcohol 6 (40% yield), biphenyl carboxylic acid 7[34]
(78% yield), and biphenyl aldehyde 8[33] (48% yield).
1
Acknowledgements
Conclusion
We discovered that a very efficient atropo-diastereoselective
oxidative olefination could now be performed by direct func-
tionalization of biaryls containing a chiral sulfoxide as the DG.
The reaction outcome in terms of both efficiency and stereose-
lectivity was drastically improved with HFIP as the reaction sol-
vent, which enabled the accomplishment of this asymmetric
CÀH activation/CÀC coupling at room temperature. Under
these modified reaction conditions, not only could acrylate be
used as a coupling partner, but also styrenes and 1,1-disubsti-
tuted activated olefin were applied efficiently. Mechanistic
studies were undertaken to elucidate the particular role of
HFIP in this reaction. The hydrogen bond between this solvent
and the oxygen atom of the sulfoxide DG could be evidenced.
The involvement of the sulfoxide in hydrogen bonding was ex-
pected to modify both the coordinating properties of this DG
and its steric requirements; hence allowing an evidently supe-
rior transformation. Finally, the traceless character of this ste-
reogenic DG was evidenced by performing postmodifications
of the atropopure scaffolds. Three parent axially chiral com-
pounds could thus be obtained without loss of optical purity.
We thank the CNRS (Centre National de la Recherche Scientifi-
que), the Ministere de l’Education Nationale et de la Recherche,
and ANR (Agence Nationale de la Recherche), France, for finan-
cial support. Q.D. is very grateful to the Ministere de l’Educa-
tion Nationale et de la Recherche, France, for a doctoral grant,
and C.K.H. acknowledges the CiRFC of Strasbourg for a post-
doctoral grant.
Keywords: asymmetric synthesis · chirality · CÀH activation ·
fluorine · olefination
[1] a) G. Bringmann, D. Menche, Acc. Chem. Res. 2001, 34, 615; b) P. Lloyd-
Williams, E. Giralt, Chem. Soc. Rev. 2001, 30, 145; c) G. Bringmann, T.
Gulder, T. A. M. Gulder, M. Breuning, Chem. Rev. 2011, 111, 563.
[2] a) In Asymmetric Catalysis in Organic Synthesis (Ed.: R. Noyori), Wiley
Europe, Weinheim, 1994; b) In Chiral Auxiliaries and Ligands in Asym-
metric Synthesis (Ed.: J. Seyden-Penne), Wiley, New York, 1995; in New
Frontiers in Asymmetric Catalysis (Ed.: K. Mikami, M. Lautens), Wiley,
2007.
[3] a) J. Wencel-Delord, A. Panossian, F. R. Leroux, F. Colobert, Chem. Soc.
Rev. 2015, 44, 3418; b) G. Ma, M. P. Sibi, Chem. Eur. J. 2015, 21, 11644;
c) G. Bringmann, A. J. Price Mortimer, P. A. Keller, M. J. Gresser, J. Garner,
M. Breuning, Angew. Chem. Int. Ed. 2005, 44, 5384; Angew. Chem. 2005,
117, 5518; d) M. C. Kozlowski, B. J. Morgan, E. C. Linton, Chem. Soc. Rev.
2009, 38, 3193; e) G. Bringmann, J. Hinrichs, T. Pabst, P. Henschel, K.
Peters, E.-M. Peters, Synthesis 2001, 1, 0155.
Experimental Section
General procedure for the atroposelective oxidative Heck re-
action
[4] a) O. Baudoin, Eur. J. Org. Chem. 2005, 4223; b) D. Zhang, Q. Wang,
Coord. Chem. Rev. 2015, 286, 1.
[5] For rare examples of atroposelective synthesis of tetrasubstituted biar-
yls through Suzuki coupling, see: a) M. Genov, A. Almorín, P. Espinet,
Chem. Eur. J. 2006, 12, 9346; b) Y. Uozumi, Y. Matsuura, T. Arakawa,
Y. M. A. Yamada, Angew. Chem. Int. Ed. 2009, 48, 2708; Angew. Chem.
2009, 121, 2746.
[6] For selected reviews, see: a) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu, Y.
Zhang, Org. Chem. Front. 2015, 2, 1107; b) N. Kuhl, N. Schrçder, F. Glo-
rius, Adv. Synth. Catal. 2014, 356, 1443; c) K. M. Engle, J.-Q. Yu, J. Org.
An oven-dried reactor was charged with substrate 1 (0.3 mmol,
1 equiv), AgOAc (0.6 mmol, 2 equiv), and Pd(OAc)2 (10 mol%,
0.03 mmol). HFIP (1.5 mL, 0.2m) and methyl acrylate (0.6 mmol,
2 equiv) were added, the reactor was sealed, and the reaction mix-
ture was stirred at 258C. The reaction was monitored by TLC until
total consumption of the starting material. The crude mixture was
diluted with Et2O, filtered through a plug of Celite, and the volatile
Chem. Eur. J. 2016, 22, 1735 – 1743
www.chemeurj.org
1742
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Chem. 2013, 78, 8927; d) G. Song, F. Wang, X. Li, Chem. Soc. Rev. 2012,
41, 3651; e) D. A. Colby, A. S. Tsai, R. G. Bergman, J. A. Ellman, Acc. Chem.
Res. 2012, 45, 814; f) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glo-
rius, Angew. Chem. Int. Ed. 2012, 51, 10236; Angew. Chem. 2012, 124,
10382; g) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112,
5879; h) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215; i) J.
Wencel-Delord, T. Drçge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40,
4740; j) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147.
[7] For selected reviews, see: a) T. Newhouse, P. S. Baran, Angew. Chem. Int.
Ed. 2011, 50, 3362; Angew. Chem. 2011, 123, 3422; b) L. McMurray, F.
O’Hara, M. J. Gaunt, Chem. Soc. Rev. 2011, 40, 1885; c) J. Yamaguchi,
A. D. Yamaguchi, K. Itami, Angew. Chem. Int. Ed. 2012, 51, 8960; Angew.
Chem. 2012, 124, 9092; d) D. Y.-K. Chen, S. W. Youn, Chem. Eur. J. 2012,
18, 9452; e) J. Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5, 369.
[8] For recent reviews on asymmetric CÀH activation, see: a) C. Zheng, S.-L.
You, RSC Adv. 2014, 4, 6173; b) J. Wencel-Delord, F. Colobert, Chem. Eur.
J. 2013, 19, 14010; c) N. Cramer, Chimia 2012, 66, 869; d) R. Giri, B.-F.
Shi, K. M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc. Rev. 2009, 38, 3242.
[9] F. Kakiuchi, P. Le Gendre, A. Yamada, H. Ohtaki, S. Murai, Tetrahedron:
Asymmetry 2000, 11, 2647.
Am. Chem. Soc. 2013, 135, 18056; e) W. Gong, G. Zhang, T. Liu, R. Giri, J.-
Q. Yu, J. Am. Chem. Soc. 2014, 136, 16940; f) G. Chen, T. Shigenari, P.
Jain, Z. Zhang, Z. Jin, J. He, S. Li, C. Mapelli, M. M. Miller, M. A. Poss, P. M.
Scola, K.-S. Yeung, J.-Q. Yu, J. Am. Chem. Soc. 2015, 137, 3338.
[20] For selected reviews, see: a) J.-P. BØguØ, D. Bonnet-Delpon, B. Crousse,
Synlett 2004, 1, 0018; b) I. A. Shuklov, N. V. Dubrovina, A. Bçrner, Synthe-
sis 2007, 19, 2925; c) T. Sugiishi, M. Matsugi, H. Hamamoto, H. Amii, RSC
Adv. 2015, 5, 17269.
[21] CCDC-1423467 (2c) and 1423468 (3a). These data are provided free of
charge by The Cambridge Crystallographic Data Centre.
[22] a) A. Berkessel, J. A. Adrio, D. Hüttenhain, J. M. Neudçrfl, J. Am. Chem.
Soc. 2006, 128, 8421; b) K. S. Ravikumar, F. Barbier, J.-P. BØguØ, D.
Bonnet-Delpon, J. Fluorine Chem. 1999, 95, 123; c) D. Vuluga, J. Legros,
B. Crousse, A. M. Z. Slawin, C. Laurence, P. Nicolet, D. Bonnet-Delpon, J.
Org. Chem. 2011, 76, 1126.
[23] For examples of hydrogen bonding involving sulfoxides, see: a) J.
Kiefer, K. Noack, B. Kirchner, Curr. Phys. Chem. 2011, 1, 340; b) M. K. D. L.
Belarmino, V. F. Cruz, N. B. D. Lima, J. Mol. Model. 2014, 20, 2477.
[24] For details, see the Supporting Information.
[25] For related examples, see: a) K. F. Wong, S. Ng, Spectrochimica Acta Part
A 1976, 32, 455; b) F. L. Slejko, R. S. Drago, D. G. Brown, J. Am. Chem.
Soc. 1972, 94, 9210.
[10] J. Zheng, S.-L. You, Angew. Chem. Int. Ed. 2014, 53, 13244; Angew. Chem.
2014, 126, 13460.
[11] K. Yamaguchi, J. Yamaguchi, A. Studer, K. Itami, Chem. Sci. 2012, 3, 2165.
[12] K. Yamaguchi, H. Kondo, J. Yamaguchi, K. Itami, Chem. Sci. 2013, 4,
3753.
[26] a) P. Ruostesuo, P. Pirilä-Honkanen, S. Kaartinen, Spectrochimica Acta
Part A 1988, 44, 359; b) P. Ruostesuo, J. Karjalainen, Acta Chem. Scand.
1982, 36, 273.
[13] For examples of diastereoselective CÀH activation, see: a) R. Giri, X.
Chen, J.-Q. Yu, Angew. Chem. Int. Ed. 2005, 44, 2112; Angew. Chem.
2005, 117, 2150; b) R. Giri, X. Chen, X.-S. Hao, J.-J. Li, J. Liang, Z.-P. Fan,
J.-Q. Yu, Tetrahedron: Asymmetry 2005, 16, 3502; c) R. Giri, J. Liang, J.-G.
Lei, J.-J. Li, D.-H. Wang, X. Chen, I. C. Naggar, C. Guo, B. M. Foxman, J.-Q.
Yu, Angew. Chem. Int. Ed. 2005, 44, 7420; Angew. Chem. 2005, 117, 7586;
for a recent review, see: d) J. Wencel-Delord, F. Colobert, Synlett 2015,
26, 2644.
[14] a) P.-E. Broutin, F. Colobert, Org. Lett. 2003, 5, 3281; b) P.-E. Broutin, F.
Colobert, Eur. J. Org. Chem. 2005, 1113; c) P.-E. Broutin, F. Colobert, Org.
Lett. 2005, 7, 3737; d) F. Colobert, V. Valdivia, S. Choppin, F. R. Leroux, I.
Fernµndez, E. lvarez, N. Khiar, Org. Lett. 2009, 11, 5130; e) T. Leermann,
P.-E. Broutin, F. R. Leroux, F. Colobert, Org. Biomol. Chem. 2012, 10, 4095.
[15] For examples of sulfoxide-directed non-asymmetric CÀH activation, see:
a) R. Samanta, A. P. Antonchick, Angew. Chem. Int. Ed. 2011, 50, 5217;
Angew. Chem. 2011, 123, 5323; b) T. Wesch, A. Berthelot-BrØhier, F. R.
Leroux, F. Colobert, Org. Lett. 2013, 15, 2490; c) B. Wang, C. Shen, J. Yao,
H. Yin, Y. Zhang, Org. Lett. 2014, 16, 46; d) K. Nobushige, K. Hirano, T.
Satoh, M. Miura, Org. Lett. 2014, 16, 1188; e) K. Padala, M. Jeganmohan,
Chem. Commun. 2014, 50, 14573.
[27] L. S. Gabrielyan, L. G. Melik-Ohanjanyan, S. A. Markarian, J. Appl. Spec-
trosc. 2013, 80, 135.
[28] a) J. C. Tai, J. Comput. Chem. 1981, 2, 161, and references cited therein;
b) L. Cazaux, J. D. Bastide, G. Chassaing, P. Maroni, Spectrochimica Acta
Part A 1979, 35, 15.
[29] E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51, 3066;
Angew. Chem. 2012, 124, 3120.
[30] M. Gómez-Gallego, M. A. Sierra, Chem. Rev. 2011, 111, 4857.
[31] a) E. Gaster, Y. Vainer, A. Regev, S. Narute, K. Sudheendran, A. Werbeloff,
H. Shalit, D. Pappo, Angew. Chem. Int. Ed. 2015, 54, 4198; Angew. Chem.
2015, 127, 4272; b) B. Elsler, A. Wiebe, D. Schollmeyer, K. M. Dyballa, R.
Franke, S. R. Waldvogel, Chem. Eur. J. 2015, 21, 12321.
[32] For an example of the solvent-dependent potential for the oxidation of
Pd0 species, see: C. Amatore, A. Jutand, M. J. Medeiros, L. Mottier, J.
Electroanal. Chem. 1997, 422, 125.
[33] During all postmodification transformations of the sulfoxide DG pre-
sented herein, a common axially chiral biphenyllithium intermediate
was generated. The synthesis of 7 with 99% ee clearly shows that this
common intermediate is configurationally stable, and therefore, it may
be assumed that compounds 6 and 8 are also generated without epi-
merization.
[16] T. Wesch, F. R. Leroux, F. Colobert, Adv. Synth. Catal. 2013, 355, 2139.
[17] C. K. Hazra, Q. Dherbassy, J. Wencel-Delord, F. Colobert, Angew. Chem.
Int. Ed. 2014, 53, 13871; Angew. Chem. 2014, 126, 14091.
[34] Determined by chiral HPLC by using an AD-H column; for details, see
the Supporting Information.
[18] Y.-N. Ma, H.-Y. Zhang, S.-D. Yang, Org. Lett. 2015, 17, 2034.
[19] For selected examples, see: a) C. Zhang, Y. Rao, Org. Lett. 2015, 17,
4456; b) D. Leow, G. Li, T.-S. Mei, J.-Q. Yu, Nature 2012, 486, 518; c) G. Li,
D. Leow, L. Wan, J.-Q. Yu, Angew. Chem. Int. Ed. 2013, 52, 1245; Angew.
Chem. 2013, 125, 1283; d) L. Wan, N. Dastbaravardeh, G. Li, J.-Q. Yu, J.
Received: September 11, 2015
Published online on December 18, 2015
Chem. Eur. J. 2016, 22, 1735 – 1743
www.chemeurj.org
1743
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim