Synthesis of axially chiral biaryls through sulfoxide-directed asymmetric mild C-H activation and dynamic kinetic resolution

Article abstract of DOI:10.1002/anie.201407865

A mild and robust direct C-H functionalization strategy has been applied to the synthesis of axially chiral biaryls. Such an efficient and stereoselective transformation occurs through an original dynamic kinetic resolution pathway enabling the conversion of diastereomeric mixtures of non-prefunctionalized substrates into atropisomerically pure, highly substituted biaryl scaffolds. The main feature of this transformation is the use of an enantiopure sulfoxide as both chiral auxiliary and traceless directing group. The potential of newly synthesized biaryls as valuable building blocks is further illustrated.

Full text of DOI:10.1002/anie.201407865

Angewandte
Chemie
DOI: 10.1002/anie.201407865
ꢀ
C H Activation
Synthesis of Axially Chiral Biaryls through Sulfoxide-Directed
ꢀ
Asymmetric Mild C H Activation and Dynamic Kinetic Resolution**
Chinmoy Kumar Hazra, Quentin Dherbassy, Joanna Wencel-Delord,* and FranÅoise Colobert*
ꢀ
Abstract: A mild and robust direct C H functionalization
strategy has been applied to the synthesis of axially chiral
biaryls. Such an efficient and stereoselective transformation
occurs through an original dynamic kinetic resolution pathway
enabling the conversion of diastereomeric mixtures of non-
prefunctionalized substrates into atropisomerically pure,
highly substituted biaryl scaffolds. The main feature of this
transformation is the use of an enantiopure sulfoxide as both
chiral auxiliary and traceless directing group. The potential of
newly synthesized biaryls as valuable building blocks is further
illustrated.
a configurationally stable racemic biaryl substrate bearing
a judiciously chosen coordinating group (directing group,
ꢀ
DG) could undergo direct C H cleavage, generating a metal-
lacyclic intermediate. The formation of such a small-ring-size
metal-bridged moiety should enable to lower the rotational
barrier thus facilitating an isomerization step.[8] A DKR could
hence be feasible and the formation of desired functionalized
ꢀ
Ar Ar scaffolds in an atroposelective manner might be
expected. Additionally, if a “traceless” DG[9] is employed, the
newly generated chiral biaryl could be further used as
building block for the synthesis of high-value-added enantio-
pure scaffolds. The success of such an appealing transforma-
tion, however, depends on a few key points: 1) the selection of
an efficient DG, 2) the choice of a chiral source prompt to
efficiently induce axial stereocontrol, and 3) the use of mild
reaction conditions under which the axial chirality of the
biaryl substrate is uncontrolled and the isomerization will
occur as the reaction proceeds.
A
xially chiral biaryls are intriguing molecular scaffolds with
significant applications as biologically active compounds
(vancomycin, korupensamin, steganacin, etc.), privileged
ligands, and promising materials (e.g., liquid crystals).[1]
Despite their key importance, general, efficient, and stereo-
selective synthetic routes to access such atropisomeric
moieties are still scarce. Recently, significant advances have
been achieved in asymmetric Suzuki–Miyaura couplings.[2,3]
However, the difficulty of such transformations frequently
lies in the antagonism between its efficiency and its selectivity,
and thus the substrate scope remains limited.
In 2010, Miller developed an original approach toward
axially chiral biaryls using the dynamic kinetic resolution
(DKR) strategy occurring during the peptide-catalyzed
bromination of racemic substrates.[4] In 2013, the group of
Fernꢀndez and Lassaletta[5] and the group of Stoltz and
Virgil[6] discovered simultaneously but independently that
racemic mixtures of prefunctionalized (naphthyl)quinoline
derivatives underwent Pd0-catalyzed couplings and DKR
affording atropisomerically pure scaffolds in synthetically
useful yields (Scheme 1A). The key racemization step is
Recently, our group focused on the use of chiral sulfoxides
[10]
ꢀ
as DG in the context of diastereoselective C H activation.
We discovered that biarylsulfoxides undergo Pd-catalyzed
asymmetric Fujiwara–Moritani (dehydrogenative Heck)
reaction affording chiral biaryls with moderate diastereose-
lectivity. As such olefination requires rather harsh reaction
conditions (808C; sealed tube), the biaryl substrates are
configurationally unstable under the reaction conditions and
the rotation around the biaryl axis is possibly enhancing the
formation of functionalized products in an atropoenriched
manner. However, this preliminary work made us confident
about the potential of sulfoxides as stereogenic DGs.[11]
Herein, we report the stereoselective, sulfoxide-directed
acetoxylation and iodination of biaryls occurring through
ꢀ
a mild C H activation/DKR sequence (Scheme 1C). Notably,
ꢀ
ꢀ
believed to occur after the oxidative addition of the C X
this report is a rare example of the application of direct C H
bond to Pd0. Inspired by these seminal works we hypothesized
functionalization to access atropisomeric scaffolds.[12,13] Note-
worthy, several elegant examples of diastereo-[14] and enan-
that a related DKR-type transformation could be developed
using a C H activation strategy (Scheme 1B). Indeed,
[7]
tioselective[15] direct C O and C I couplings enabling the
formation of carbon stereogenic centers have been reported.
ꢀ
ꢀ
ꢀ
ꢀ
Our endeavor toward a mild C H activation/DKR
[*] Dr. C. K. Hazra, Q. Dherbassy, Dr. J. Wencel-Delord, Prof. F. Colobert
Laboratoire de Chimie Molꢀculaire (UMR CNRS 7509)
Universitꢀ de Strasbourg, ECPM
ꢀ
reaction began by investigating the C O coupling reaction
(Table 1). Firstly, a standard substrate 1a,[16] used as a 1:1.1
mixture of two diastereomers, was reacted with Pd(OAc)2 and
PhI(OAc)2 (used as both acetoxylating agent and oxidant).
Although the desired product 2a could be isolated in
encouraging yield (up to 50%) and excellent diastereoselec-
tivity (> 98%), a high reaction temperature was required
(808C, Table 1, entry 1). Rewardingly, the replacement of
PhI(OAc)2 by acetic acid and persulfate oxidant drastically
25 Rue Becquerel, 67087, Strasbourg (France)
E-mail: wenceldelord@unistra.fr
francoise.colobert@unistra.fr
[**] We thank the CNRS (Centre National de la Recherche Scientifique)
and the “Ministere de l’Education Nationale et de la Recherche”
(France) for financial support. C.K.H. is very grateful to CiRFC of
Strasbourg for a postdoctoral grant. We also thank Dr. Lydia Brelot
for single-crystal X-ray diffraction analysis.
ꢀ
improved the efficiency of this C O coupling (entry 2) and
the reaction proceeded smoothly even at room temperature
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407865.
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diastereoselectivity for 2b was prob-
ably due to the less sterically
demanding OMe group. Recrystal-
lization of 2b, however, enabled to
isolate the atropisomerically pure
product in 78% yield. Our catalytic
system is also compatible with elec-
tron-poor substrates (1d–f). When
1 f, bearing two possible coordinat-
ing groups, i.e., sulfoxide and ester,
was submitted to the reaction con-
ꢀ
ditions, the sulfoxide-directed C H
activation occurred selectively at the
expected 6’-position. Subsequently,
6-substituted biaryls have been
tested; such proaxially chiral 1g–1i
underwent highly diastereoselective
ꢀ
C O coupling and no diacetoxyla-
tion occurred. Finally, our attention
turned towards ortho-trisubstituted
substrates. 1j, bearing less bulky
OMe and F substituents afforded
2j in excellent yield and stereose-
lectivity. In contrast, a decreased
chiral induction was observed in the
case of the more hindered 1k and 1l.
Surprisingly, when trisubstituted
biaryls bearing a rather bulky Cl
Scheme 1. Synthesis of chiral biaryls throug DKR/transition metal-catalyzed cross couplings.
Table 1: Optimization of the acetoxylation reaction.
substituent at the 6-position and F or Me groups at the 2’-
position (1m,n) were submitted to the reaction conditions, the
corresponding acetoxylated products 2m and 2n were
isolated in atropisomerically pure form but in lower yields.
Notably, the remaining 1m,n were recovered as sole diaste-
reomers in 40 and 41% yields, respectively.
Regarding the scope of the reaction, two key trends
emerge. Firstly, the diastereomeric mixture of substrates
bearing substituents at either 6- or 2’-positions or weakly
hindering substituents at both 6- and 2’-positions are con-
verted into atropisomerically pure products (2a–2j) in
excellent yields. These results clearly suggest an expected
“OAc” (x equiv), Oxidant Solvent T [8C]/t [h] Yield [%][a] d.r.[b]
1
2
3
PhI(OAc)2 (2.4)
AcOH (46), K2S2O8
HFIP
HFIP
80/16
80/24
25/14
25/14
25/16
41
89
88
93
86
>98:2
90:10
96:4
98:2
83:17
AcOH (46), (NH4)2S2O8 HFIP
4[c] AcOH (46), (NH4)2S2O8 HFIP
ꢀ
5
AcOH (46), (NH4)2S2O8 H2O
C H activation/DKR pathway (Scheme 3). As the axial
1
chirality of the substrates is uncontrolled at 258C, we
assume that the rotation around the biaryl axis might occur
when the Pd-bridged metallacycle is formed.[5,20] The mech-
anistic scenario in which 1) both diastereomers of 1 undergo
[a] Yield of the isolated product. [b] Determined by crude H NMR
spectroscopy. [c] Reaction was conducted with 2 equiv of H2O and under
air.
ꢀ
(entry 3). The catalytic system was also robust as no
precaution toward air and moisture were required. A small
amount of water was even beneficial and 2a was isolated in
93% yield and 98:2 d.r. (entry 4).[17] The transformation was
still efficient in aqueous medium (entry 5). Notable, no
acetoxylation of 1a occurred in the absence of the Pd-
catalyst. The structure of 2a was confirmed by X-ray
diffraction analysis and the absolute (SaR) configuration
was attributed.[18]
With the optimized reaction conditions in hand, the scope
of this reaction was explored using diastereomeric mixtures of
differently substituted biphenyl substrates (Scheme 2).[19]
The reaction proceeded smoothly for an array of 2’-
substituted biaryls (Scheme 2, 2a–f). A slight decrease in the
rapid C H activation, followed by 2) a reductive elimination
from Int-B and an isomerization of Int-A into a presumably
more stable Int-B is proposed.[21] The key feature of this
transformation is that the reductive elimination from Int-A
seems to be unfavored and sufficiently slow to enable
isomerization. Such hypothesis is consistent with the litera-
ꢀ
ꢀ
ture as C O and C N bond forming reductive eliminations
are reputed to be energetically difficult.[22]
In contrast, the acetoxylation of the biaryls bearing
sterically more demanding substituents (1m,n) leads to the
formation of the atropisomerically pure product but full
conversion is not achieved. The functionalized products are
isolated in moderate yields and remaining starting materials
are recovered as sole diastereomers. In such a case, a simple
2
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kinetic resolution operates and we believe that the function-
alization on one diastereomer of the substrate (1-A) is
unfavored due to steric reasons.
ꢀ
To get insight on this original C H activation/DKR
transformation, several mechanistic studies were undertaken.
First, an intermolecular kinetic isotope effect of 1.09 was
measured when 1j and 6’-D-1j[23] were submitted to the
ꢀ
acetoxylation reaction conditions [Eq. (1)]. Moreover, the C
H activation step is reversible. When 6’-D-1j was reacted with
Pd(OAc)2 in HFIP/AcOH mixture, significant D/H scram-
bling was observed [Eq. (2)]. These results indicate that direct
metalation is rather rapid, not rate-determining, and coherent
with the hypothesis that the overall outcome of this trans-
formation is probably controlled by the kinetics of reductive
elimination and isomerization.
Subsequently, to provide experimental evidence for the
(dynamic) kinetic resolution pathway, the kinetics of the
acetoxylation reactions of 1e, 1j, and 1m (used as diastereo-
meric mixtures (approximately 1:1.5 d.r.)) were followed
using 19F NMR (Figure 1).[24] For each substrate, the change of
Scheme 2. Substrate scope of the asymmetric direct acetoxylation
occurring through (dynamic) kinetic resolution. Standard reaction
conditions: 1 (0.2–0.3 mmol); Pd(OAc)2 (10 mol%); (NH4)2S2O8
(2 equiv), H2O (2 equiv), HFIP/AcOH 1/1 v/v, air, 258C; yields of
isolated products; d.r. determined by 1H NMR analysis of the crude
mixture. [a] At 1.5 mmol scale. [b] At 108C. [c] Yield and d.r. after re-
crystallization. [d] d.r. in brackets is that of the product after silica gel
column chromatography. HFIP=1,1,1,3,3,3-hexafluoroisopropan-2-ol.
Figure 1. Variation of the diastereomeric excess of 1e, 1j, and 1m as
a function of conversion.
the diastereomeric excess was measured during the reaction
and plotted as a function of conversion. When 1e was
submitted to the reaction conditions, its diastereomeric ratio
remains constant which might suggest that both diastereo-
ꢀ
mers of 1e undergo rapid C H activation. However, as (SaR)-
2e is isolated in 79% yield and 95:5 d.r., reductive elimination
from Int-A seems to be significantly slower than the rotation
ꢀ
around the Ar Ar axis. In contrast, during the reaction of 1j,
the d.e. changes significantly indicating a faster conversion of
Scheme 3. Proposed mechanistic scenario.
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A
B
one diastereomer (k1 ¼ k1 ). However, the isolation of (SaS)-
2j in atropomerically pure form and in 88% yield clearly
indicates a DKR mechanism and unfavored reductive elim-
ination from Int-A. Finally, the acetoxylation of the mixture
of two diastereomers of 1m led to full conversion of (SaR)-
1m (i.e., 1-B Scheme 3)[25] and the transformation literally
stops when reaching 65% conversion (total consumption of
the major diastereomer). The increased steric hindrance
around the biaryl axis of 1m might prevent the DKR pathway
and simple kinetic resolution (KR) occurs.
Encouraged by the efficiency of this diastereoselective
acetoxylation reaction, we subsequently focused on proving
ꢀ
a more general character of such an original asymmetric C H
activation reaction. Aiming at the construction of syntheti-
cally useful axially chiral scaffolds, we turned our attention
toward an iodination reaction. Rapidly, we discovered that
a simple replacement of the (NH4)2S2O8 oxidant by N-
iodosuccinimide (NIS; 1.3 equiv) led to a complete switch in
the reactivity of our catalytic system enabling smooth, mild,
ꢀ
and highly diastereoselective C I coupling (Scheme 4). The
standard substrate 1a could thus be converted to atropiso-
merically pure 3a in excellent 98% yield.[26]
The study of the reaction scope showed that quite similar
ꢀ
DKR occurs for this C I coupling. However, slightly lowered
diastereoselectivities were observed and longer reaction
times were required to achieve full conversions (Scheme 4).
Yet, disubstituted biaryls could be converted at room temper-
ature and in good yields to iodinated products with diaste-
reoselectivities ranging from 91:9 to > 98:2 (3a–3i). The
ꢀ
efficiency of this C I coupling for ortho-trisubstituted mol-
Scheme 4. Substrate scope of the asymmetric direct iodination occur-
ing through (dynamic) kinetic resolution. Standard reaction condi-
tions: 1 (0.3–0.2 mmol); Pd(OAc)2 (5 mol%); NIS (1.3 equiv), HFIP/
AcOH 1/1 v/v, air, 258C; yields of isolated products; d.r. determined
by 1H NMR analysis of the crude mixture. [a] DCE as solvent at 408C,
10 mol% of Pd(OAc)2. [b] d.r. after column chromatography. [c] Yield
and d.r. after recrystallization. [d] 10 mol% of Pd(OAc)2. [e] Conversion
and d.r. measured on crude mixture. [f] NBS was used and the
reaction was performed at 408C. DCE=dichloroethane; NBS=N-
bromosuccinimide.
ecules strongly depends on the steric hindrance generated by
the 6- and 2’-substituents. Comparable to the acetoxylation
reaction, an excellent atroposelectivity was achieved for 3j
bearing less bulky substituents. A progressive increase of the
ꢀ
steric demand around the Ar Ar axis, firstly, led to a lower
level of diastereoselectivity (3k, 3l). Finally, the highly
congested substrate 3n underwent iodination under
a simple kinetic resolution scenario. Besides, in the presence
of NBS, 1a could also be converted into the expected
brominated 4a; however, a slight decrease in stereocontrol
was found (d.r. of 93:7).
ꢀ
In conclusion, an original atroposelective mild C H
The additional key advantage of the herein presented
strategy relies on the traceless character of the chiral
sulfoxide DG, which paves the way toward a general appli-
cation of our transformation. This DG can be readily removed
from the chiral products with retention of axial stereoenrich-
ment by a sulfoxide/lithium exchange followed by electro-
philic trapping (various electrophiles are compatible).[27] As
a representative example (Figure 2), chiral 2a (prepared at
1.5 mmol scale in 96% yield and d.r.
activation occurring through dynamic kinetic resolution is
reported. The isomerization of the diastereomeric mixture of
biaryl substrates is believed to occur when bridging pallada-
cyclic intermediates with decreased configurational stability
are generated. Such an original transformation paves the way
toward the synthesis of acetoxylated and iodinated atrop-
ꢀ
isomeric biaryls and is a rare example of C H activation-
based asymmetric strategy enabling axial stereocontrol.
> 98:2) was first converted to the
protected alcohol 6 (in 89% yield).
Subsequently,
low-temperature
exchange with lithium and electro-
philic trapping using dry ice afforded
chiral carboxylic acid 7 in non-opti-
mized 57% yield and ee higher than
98%.
Figure 2. Representative example of the transformation of the sulfoxide DG.
4
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Chemie
[10] T. Wesch, F. R. Leroux, F. Colobert, Adv. Synth. Catal. 2013, 355,
Moreover, as sulfoxides are easily transformable into
a myriad of functionalities, the herein presented strategy
offers general access toward a plethora of highly valuable
chiral biaryl building blocks.
2139.
[11] Use of racemic sulfoxides as DG: a) R. Samanta, A. P. Anton-
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2741.
Received: August 1, 2014
Revised: August 23, 2014
Published online: && &&, &&&&
Keywords: asymmetric synthesis · atroposelectivity ·
.
ꢀ
C H activation · dynamic kinetic resolution · sulfoxides
ꢀ
[13] For recent reviews on asymmetric C H activation, see: a) C.
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Supporting Information.
[17] We hypothesize that a small amount of water may improve the
solubility of (NH4)2S2O8 in the reaction mixture.
[18] CCDC-1015458 ((SaR)-2a), 1015459 ((SaR)-2e), 1015460
((SaS)-2j), 1015461 ((SaR)-3 f), and 1015462 ((SaR)-3j) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[6] V. Bhat, S. Wang, B. M. Stoltz, S. C. Virgil, J. Am. Chem. Soc.
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[19] Diastereomeric ratios of substrates range from 1:1 to 1:2; two
diastereomers are clearly distinguishable by NMR at room
temperature and a coalescence temperature superior to 1008C
for 1e, 1j, and 1m was determined by variable temperature
1H NMR spectroscopy. In the case of 1b the coalescence
temperature is significantly lower (608C).
[20] Coordination of Pd with S atom is proposed based on the
literature (for representative example see: 11a,c) and the
observed regioselectivity.
[21] As the absolute SaR configuration of the products was deter-
mined by X-ray analysis, it is assumed that reductive elimination
from Int-B is favored.
[22] See for example: M. S. Driver, J. F. Hartwig, J. Am. Chem. Soc.
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46, 1936.
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Principles and Applications (Ed.: C. Wolf), The Royal Society of
Chemistry, London, 2008, pp. 84 – 135.
[23] 6’-D-1j was prepared from 1j via 6’-H/D exchange; for details
see the Supporting Information.
[24] For details and plots of the conversion of 1e,j,m as function of
time see the Supporting Information.
[25] Confirmed by X-ray analysis of (SaR)-1m.
[26] No iodinated product was detected in the absence of Pd-catalyst.
[27] F. R. Leroux, A. Berthelot, L. Bonnafoux, A. Panossian, F.
Colobert, Chem. Eur. J. 2012, 18, 14232, and references herein.
[9] F. Zhang, D. R. Spring, Chem. Soc. Rev. 2014, 43, 6906.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
ꢀ
C H Activation
C. K. Hazra, Q. Dherbassy,
J. Wencel-Delord,*
F. Colobert*
&&&& — &&&&
Synthesis of Axially Chiral Biaryls through
ꢀ
Sulfoxide-Directed Asymmetric Mild C H
Activation and Dynamic Kinetic
Resolution
ꢀ
Pd makes it rotate: A C H activation/
occur via a palladacyclic intermediate.
Chiral induction is achieved using the
sulfoxide motif as both “traceless”
directing group and chiral source.
dynamic kinetic resolution protocol is
developed to access axially chiral biaryls.
The isomerization step is believed to
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!