Stereoselective Sulfinyl Aniline-Promoted Pd-Catalyzed C?H Arylation and Acetoxylation of Aliphatic Amides

Article abstract of DOI:10.1002/chem.201703274

Stereoselective functionalization of aliphatic C?H bonds presents a great challenge. Following this target, we disclose herein an original strategy towards direct arylation of aliphatic chains at ?-methylene position based on a use of amide-sulfoxide bicoordinating directing group. Although moderate to high chiral induction (up to 9:1 d.r.) is achieved, diastereomerically pure compounds may be afforded by simple separation of diastereomeric products by silica gel chromatography. Accordingly, this reaction allows preparation of a large scope of high-value scaffolds in synthetically useful yields while recyclable character of our chiral auxiliary brings an additional benefit. A potential of this methodology to build up original molecules by sequential diarylation and expedient (two step) synthesis of a biologically active compound are further disclosed. Finally a first example of stereoselective direct acetoxylation of aliphatic chains is reported.

Full text of DOI:10.1002/chem.201703274

DOI: 10.1002/chem.201703274
Communication
&
CÀH Aactivation |Hot Paper|
Stereoselective Sulfinyl Aniline-Promoted Pd-Catalyzed CÀH
Arylation and Acetoxylation of Aliphatic Amides
Soufyan Jerhaoui,[a] Jean-Pierre Djukic,[b] Joanna Wencel-Delord,*[a] and
FranÅoise Colobert*[a]
motifs on a single methylene carbon center. Noteworthy, regio-
Abstract: Stereoselective functionalization of aliphatic CÀ
selective activation of ß-methylene CÀH bonds presents al-
H bonds presents a great challenge. Following this target,
ready a great challenge, due to the steric encumbrance at
we disclose herein an original strategy towards direct ary-
such a non-activated position.[4] Only recently, Houk and Yu,[5]
lation of aliphatic chains at ß-methylene position based
Duan,[6] He and Chen[7] reported independently pioneering
on a use of amide-sulfoxide bicoordinating directing
work on enantioselective direct arylation of linear aliphatic car-
group. Although moderate to high chiral induction (up to
boxylic acid derivatives using aminoethylquinoline or axially
9:1 d.r.) is achieved, diastereomerically pure compounds
chiral phosphoric amide ligands. However, designing alterna-
may be afforded by simple separation of diastereomeric
tive catalytic systems, allowing implementation of the C(sp3)ÀH
products by silica gel chromatography. Accordingly, this
activation logic to build up high-value-added scaffolds with ap-
reaction allows preparation of a large scope of high-value
pealing biological applications is tempting.
scaffolds in synthetically useful yields while recyclable
Pyrethroids, molecular scaffolds containing dimethylcyclo-
character of our chiral auxiliary brings an additional bene-
propane carboxylic acid motifs, such as permethrin and alleth-
fit. A potential of this methodology to build up original
rin, constitute the majority of commercial household insecti-
molecules by sequential diarylation and expedient (two
cides (Figure 1).[8] Recently, due to the extensive use of these
step) synthesis of a biologically active compound are fur-
insecticides, alarming upsurge of resistance has been wit-
ther disclosed. Finally a first example of stereoselective
nessed and thus the parent molecular scaffolds with compara-
direct acetoxylation of aliphatic chains is reported.
ble or improved biological activities are urgently requested.
Following such a goal, linear analogues of pyrethroids were re-
cently proposed and their promising biological activities were
disclosed.[9] However, an asymmetric synthesis of these scaf-
Over the last years CÀH activation field allowing direct func-
tionalization of otherwise inert CÀH bonds has established
folds is rather complex, clearly hampering their large screen-
itself as a valuable and modern tool for the synthesis of com-
plex and appealing molecular scaffolds for pharmaceutical and
agrochemical industry, as well as advanced materials sci-
ence.[1,2] Despite the great importance of chiral molecules, ste-
reocontrolled CÀH couplings have remained an underdevel-
oped field for many years.[3] In particular, asymmetric directed
functionalization of aliphatic chains has been elusive till 2015,
due to several intrinsic difficulties of such reactions such as
low reactivity of alkane CÀH bonds, conformational freedom
and challenging differentiation between two prochiral CÀH
ing. Likewise, 2-cyanopropionic acid derivatives have demon-
strated a promising activity as estrogen receptor inhibitors
with potential applications in the treatment for rheumatoid ar-
thritis.[10] Retrosynthetic analysis of both types of skeletons re-
veals that an implementation of a direct arylation step would
[a] S. Jerhaoui, Dr. J. Wencel-Delord, Prof. Dr. F. Colobert
SynCat, Laboratoire de Chimie Moleculaire (UMR CNRS 7509)
Universite de Strasbourg, ECPM
25 Rue Becquerel
67087 Strasbourg (France)
E-mail: francoise.colobert@unistra.fr
wenceldelord@unistra.fr
[b] Dr. J.-P. Djukic
LCSOM, Institut de Chimie de Strasbourg (UMR 7177)
Universite de Strasbourg
4 Rue Blaise Pascal
67070 Strasbourg Cedex (France)
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under https://doi.org/10.1002/
chem.201703274.
Figure 1. New approach to chiral biologically active molecules through ste-
reoselective activation of aliphatic CÀH bonds.
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greatly facilitate and speed up their preparation. In addition, if
a differentiation of the two prochiral methylene CÀH bonds is
possible, optically enriched products could be directly ac-
cessed. Moreover, as for the bioassay evaluations the reactivity
of both enantiomers needs to be determined, a design of dia-
stereoselective transformations delivering both requested dia-
stereomers in a single transformation seems particularly ap-
pealing. In such a context, we recently demonstrated that a
stereogenic sulfinyl aniline ((S)-2-(p-tolylsulfinyl)aniline, APS)
moiety can be efficiently employed as a recyclable chiral auxili-
ary for stereoselective functionalization of small cycloalkanes,
yet enabling construction of unprecedented chiral scaf-
folds.[11,12] Based on this pioneering work and targeting a new
asymmetric approach towards direct functionalization of linear
alkanes, we report herein a diastereoselective CÀH arylation of
aliphatic substrates using (S)-2-(p-tolylsulfinyl)aniline (APS) as a
chiral auxiliary and precursor of a bicoordinating directing
group. During the preparation of this manuscript, a closely re-
lated bicoordinating DG has been employed for direct aryla-
tion of aliphatic substrates, however, the stereoselective out-
come of such transformation was just mentioned in one exam-
ple.[13]
(Table 1, entry 2–3). Significantly higher conversion was
reached in toluene while heating the reaction mixture at
1008C but both diastereoisomers of the product were generat-
ed in an equal rate (Table 1, entry 4). Some stereocontrol could
however be achieved while employing toluene/hexafluoroiso-
propanol (HFIP) mixture (Table 1, entry 5). A comparable result
was also obtained in a mixture toluene/trifluoroacetic acid
(Table 1, entry 6) but surprisingly, no product formation was
observed using Pd(TFA)2 catalyst in combination with AgTFA
(Table 1, entry 8). Prolonged reaction time (36 h) allowed high
conversion of the starting material into the desired product,
even when using 5 mol% of the Pd-catalyst (Table 1, entry 7).
Regrettably, replacement of the silver salt by potassium or
cesium carbonate resulted in an inhibition of the reaction
(Table 1, entries 9, 10). Likewise, significantly inferior results in
terms of either efficiency or stereoselectivity were obtained
using pivalic acid or potassium fluoride additives, respectively
(Table 1, entries 11, 12), reaction conditions inspired from the
recent work of Chen and He.[13] Although this aim of this opti-
mization study was to establish a protocol allowing high reac-
tivity for such a challenging C(sp3)ÀH activation at methylene
position, it also clearly shows that regardless of the conditions
used, only modest diastereoselectivity (typically 3:2) could be
achieved. However, as the diastereomeric products are often
easily separable by silica gel column, this strategy remains a
useful tool for the preparation of optically pure compounds.
Noteworthy, no direct coupling was achieved when using the
aliphatic substrate with a sterically more demanding chiral aux-
iliary (SOpTol moiety replaced by SOtBu group) (Table 1,
entry 13).
At the outset of our study, we selected valeric acid derivative
1a, bearing the APS auxiliary (prepared in one-pot procedure
in 80% yield and ee>98%),[14] as a test substrate and 4-iodoni-
trobenzene 2A as a coupling partner. Deceivingly, under reac-
tion conditions previously developed for the functionalization
of cycloalkanes, the desired product was not obtained (Table 1,
entry 1). However, removal of water from the reaction mixture
allowed conversion of 1a into the expected arylation product
3aA in 30% yield and low diastereoselectivity of 3:2, regard-
less the presence of NaTFA (TFA=trifluoroacetate) additive
With the optimized reaction conditions in hand we explored
the scope of this transformation regarding both, the influence
of the aliphatic substituent of the CÀH substrate and the
nature of the iodoarenes (Scheme 1). The direct arylation of 1a
occurred smoothly using both electron rich and electron poor
ArÀI. Indeed, iodoarene substrates bearing substituents such
as nitro-, methoxy, acetyl and methyl ester or 3-iodonaphta-
lene could be used with success affording products 3aA–aF
and 3bF respectively in 67–88 total yield. Remarkably, even a
sterically demanding 2-acetyl-iodobenzene 2E underwent the
coupling smoothly delivering 3aE in 67% total yield. Deceiv-
ingly, regardless the nature of ArÀI used, the diastereoselectiv-
ity of the transformation remained a 3:2 ratio. Nevertheless, as
in most of the cases, the diastereomeric products can be easily
separated, this reaction delivering both enantiomers in a single
step and reasonable yield (45–67%) is synthetically highly ap-
pealing. Furthermore, good reactivity was retained while modi-
fying the length of the aliphatic chain of the CÀH substrate. A
significantly improved chiral induction was achieved when
using a synthetically valuable but challenging coupling partner,
2-bromoiodobenzene 2G. Under the standard reaction condi-
tions 1b coupled easily, yielding 3bG in a diastereomeric ratio
of 7:3, yet affording optically pure (S)-3bG in high 57% yield.
Increased chain length of the aliphatic substrates (1c and 1d)
had a minor impact on the transformation, and yet CÀC bond
formations with both electron-rich and electron-poor iodoar-
enes occurred diastereomerically, and enantiomerically pure
Table 1. Optimization study.
Entry
Base
Solvent
Temp. [8C]
Conv. [%][a]
d.r.[a]
1[b]
2[b]
3
4
5
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgTFA
K2CO3
Cs2CO3
AgOAc
Ag2CO3
AgOAc
HFIP/H2O (4:1)
HFIP
HFIP
80
80
80
0
–
30
30
60
65
50
85
0
0
0
20
65
5
3:2
3:2
1:1
3:2
3:2
3:2
–
–
–
3:2
1:1
nd
PhMe
100
100
100
110
100
110
110
110
110
110
PhMe/HFIP (4:1)
PhMe/TFA (4:1)
PhMe/HFIP (4:1)
PhMe/HFIP (4:1)
PhMe/HFIP (4:1)
PhMe/HFIP (4:1)
PhMe/HFIP (4:1)
HFIP
6
7[c]
8[d]
9
10
11[e]
12[f]
13[g]
PhMe/HFIP (4:1)
[a] Determined on crude 1H NMR. [b] NaTFA (50 mol%). [c] 5 mol% of
Pd(OAc)2 was used with 36 h reaction time. [d] Pd(TFA)2 was used as cata-
lyst. [e] PivOH (1 equiv) was used as additive. [f] KF (3 equiv) was used as
additive. [g] Substrate bearing SOtBu moiety as the chiral auxiliary.
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Scheme 1. Substrates scope for direct arylation of aliphatic substrates (1a–k).
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scaffolds were readily obtained after standard silica-gel column
purification. Additionally, total ß-selectivity was achieved while
using substrate 1e, which could potentially undergo a func-
tionalization at more acidic, benzylic position. Both enantio-
pure diastereomers of 3eI were thus obtained in yields of 55
and 36%.
compounds was attributed by analogy. As expected a chlorine
or CF3 in the para and meta positions of the substrate did not
modify the reactivity and 3mC, 3nI, and 3nF were obtained in
comparable diastereoselectivity and good to excellent yield.
Regarding the high reactivity of our catalytic system and ef-
ficient chiral induction at the benzylic position (substrate 1l–n)
we hypothesized that if a propane carboxylic acid substrate
1o is used, a sequential functionalization could be performed,
yet delivering complex chiral molecular scaffolds from a very
simple precursor (Scheme 3). Such a two-step CÀH activation
would be particularly appealing as it allows in situ construction
of a variety of 3-arylpropionic acid derived substrates. In partic-
ular, use of the ortho-substituted iodoarenes in the first step
seems challenging as ortho-substituted iodoarenes have only
rarely been used with success in the context of direct aryla-
tion.[13,16] However, a targeted coupling between 1o and ortho-
substituted iodoarenes would deliver straightforwardly a new
class of non-commercially available saturated cinnamic acid de-
rivatives. Accordingly, at the outset of this work two sets of
preliminary studies were conducted: 1) biarylation of 1o, using
an excess of an aryl iodide and 2) direct arylation of 1o with
several ortho-substituted iodoarenes. As foreseen, the double
CÀH activation occurred readily in presence of 2.5 equivalents
of 2B or 2D, delivering coupling products 3oBB and 3oDD in,
respectively 62 and 88% yield (Scheme 3a).
Subsequently, we focused our attention on more sterically
demanding aliphatic substrates, very challenging compounds
for CÀH functionalization. As expected, an increased steric bulk
in proximity of the pro-stereogenic CÀH bonds to be activated
directly impacts both, chirality induction and efficiency of the
overall transformation. Indeed, coupling between the cyclohex-
ane substituted 1 f and 2I delivered 3 fI in significantly im-
proved d.r. of 4:1, but only 55% conversion was achieved
under the standard protocol. Likewise, substrate 1g bearing
tBu-moiety was almost totally ineffective. Introduction of a
sterically less demanding cyclopentane core at the ß-position
(1h) resulted in high reactivity, as illustrated by the coupling
with 2I, which delivered 3hI in 80% yield with an improved
diastereoselectivity of 7:3. Besides, similar results in terms of re-
activity and chiral induction were obtained while using
branched substrate 1i and thus the direct coupling with both
electron-rich and electron-poor aryliodides could be per-
formed, delivering, after purification, the optically pure scaf-
folds. The presence of an ester moiety on an aliphatic sub-
strate was well tolerated, since 1j was converted into 3jD in a
total yield of 85% and no ester-directed CÀH activation was
evidenced. Likewise, the presence of a nitrogen atom did not
alter the reactivity as illustrated by the coupling of a phthali-
mide-protected substrate 1k giving products 3kK and 3kH in
75 and 92% total yield, respectively with isolation of (S)-3kH
and (R)-3kH in 53 and 39% yields.
Likewise, the arylation of 1o under unchanged reaction con-
ditions turned out to be tolerant towards sterically bulky iodo-
benzenes, as three different couplings with aromatics bearing
COMe, Br or NO2 substituents in the ortho-position were re-
markably high yielding (3oE, 3oG and 3oP delivered in 90, 91,
and 89% yield, respectively) (Scheme 3b). Noteworthy is that
double arylation could be efficiently suppressed while using
almost equimolar quantities of both coupling partners. Regard-
ing the efficiency of these transformations, one-pot, two-step
difunctionalization of 1o was thus explored (Scheme 3c). Re-
wardingly, after initial total conversion of 1o into 1oP, an addi-
tion of a second coupling partner, 3-iodoanisole 2C together
with an additional portion of the silver salt, allowed isolation
of the desired coupling product 3oPC in high yield of 78%
and 3:1 diastereomeric ratio.
In order to further delimitate the potential of our catalytic
system, we subsequently focused on a direct functionalization
at the benzylic position (Scheme 2). Encouragingly, when react-
ing 1l and 2A under standard protocol, albeit at a decreased
temperature (808C), the desired coupling occurred with an im-
proved stereoinduction of 3:1 and high overall efficiency (total
yield of 80%), delivering (S)-3lA in 50% yield.
Further screening of different iodoarenes revealed that re-
gardless of both steric and electronic properties, the reaction
is high yielding. In clear contrast, the nature of the coupling
partner has a major impact on the stereoselectivity of the over-
all transformation. Indeed, while the same crude diasteroselec-
tivity (3:1) was observed using 3-nitro-substituted iodobenzene
2I, 4:1 ratio between the two diastereomeric products was
measured when employing meta-substituted electron-poor io-
dobenzenes, such as 3-fluoroiodobenzene 2L and 1-iodo-3-(tri-
fluoromethyl)benzene 2M. Further diastereoselectivity en-
hancement up to 5.7:1 was shown when employing 4-iodoto-
luene 2J. The presence of a methoxy or bromo substituent on
the coupling partner improves the chiral induction up to 9:1
and 3lO, 3lC and 3lM were isolated in 84, 78, and 92% yields,
respectively. Noteworthy, recrystallization of 3lO delivered dia-
stereomerically pure crystals suitable for X-ray analysis.[15] The
absolute configuration of the major diastereomer of 3lO was
determined as (R,Ss) and the absolute configuration of all other
In order to showcase the synthetic value of our transforma-
tion, we next focused on a cleavage of the chiral auxiliary APS
(Scheme 4). Initially, inspired by the literature,[13] a hydrolysis of
3iH under acidic conditions was tested. Deceivingly, using a
rather harsh protocol (1m HCl in EtOH at 1008C; 12 h), a deg-
radation of the auxiliary was observed, yet preventing its re-
covery and reuse. In contrast, deprotection under basic condi-
tions is clearly more appealing as not only the desired aliphatic
chiral esters 4iH and 4lI were afforded in 82 and 96% yield,
but also the APS moiety was straightforwardly recovered
(93%) with an unchanged optical purity.
Subsequently, a scale-up of this direct arylation was targeted
in order to illustrate the potential of this methodology for the
expedient two-step synthesis of a biologically active bioisoster
of permethrin 5 (Scheme 5).[9] Accordingly, the direct function-
alization of 1i was conducted at 0.5 g scale with no significant
alteration of the reaction outcome delivering 3iK in 91% yield
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Scheme 2. Substrates scope for direct arylation at benzylic position (1l–n).
and high diastereoselectivity of 9:1. A subsequent removal of
the chiral auxiliary under basic conditions and esterification
step delivered the desired insecticide skeleton 5 in remarkable
83% overall yield and high optical purity (e.r. of 9:1). Accord-
ingly, the herein described methodology can be considered as
a promising synthetic tool for a rapid preparation of an array
of biologically active skeletons.
Finally, in order to extend the potential of the APS-directed
diastereoselective activation of aliphatic CÀH bonds, we endea-
vored on developing
a
related direct CÀO coupling
(Scheme 6).[17] Importantly, asymmetric CÀO bond formation by
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Scheme 3. Difunctionalization of 1o.
means of CÀH activation remains elusive.[18] Encouragingly,
while reacting substrate 1l with (diacetoxyiodo)benzene (PIDA;
used as OAc source), in a presence of a Pd-catalyst, the desired
product 6 was formed very efficiently (91% yield). Noteworthy
is that, although with low stereocontrol (7:3 d.r.), this reaction
can be considered as a proof of concept work showcasing that
the direct CÀH acetoxylation may also be applied to stereose-
lectively construct a CÀO bond.
In conclusion, a diastereoselective C(sp3)ÀH activation of ali-
phatic substrates is reported. This Pd-catalyzed asymmetric
transformation implies use of a stereogenic directing group
bearing a recyclable and easy to recover APS auxiliary. High re-
activity of the catalytic system makes it tolerant towards a
large scope of coupling partners and hence a direct functional-
Scheme 4. Cleavage of the chiral auxiliary.
Scheme 5. Synthesis of insecticide derivative 5.
Scheme 6. APS-directed stereoselective acetoxylation.
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context of direct arylation, ortho-substituted iodoarenes turned
out to be efficient partners under our protocol. In addition, a
sequential double functionalization of propane carboxylic acid
derivative was conducted yet revealing the potential of our
strategy to build up structural diversity from very simple start-
ing material. This protocol establishes also itself as an appeal-
ing synthetic tool for expedient synthesis of biologically active
scaffolds. Finally, a stereoselective direct acetoxylation, yet un-
achievable transformation, was conducted efficiently, delivering
the desired CÀO coupling product in high yield.
[3] For recent reviews on asymmetric CÀH activation see: a) J. Wencel-
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Chem. Soc. 2017, 139, 8514.
Experimental Section
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[12] Previous examples concerning use of stereogenic sulfoxide DG for
direct CÀH activation: a) Q. Dherbassy, G. Schwertz, M. Chessꢂ, C. K.
Hazra, J. Wencel-Delord, F. Colobert, Chem. Eur. J. 2016, 22, 1735; b) Q.
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[13] During the preparation of this manuscript a related article describing
non-stereoselective functionalization of aliphatic substrates has been
published: D. Mu, F. Gao, G. Chen, G. He, ACS Catal. 2017, 7, 1880.
[14] For detailed description of the synthesis of APS auxiliary see SI.
[15] CCDC 1550280 contains the supplementary crystallographic data for
this paper and for the major diastereomer of 3IO. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre. Due to the difficulty in obtention of monocrystals, 3IO was pre-
pared as a racemic mixture and the major diastereomer was isolated
and recrystalized. Accordingly, the relative configuration could be de-
termined yet allowing determination of the absolute configuration of
the enantiomerically pure compounds herein reported.
General procedure for the arylation of aliphatic chains
To a pressure tube were added the appropriate substrate (1 equiv),
coupling partner (2–3 equiv), silver acetate (2.2 equiv) and palladiu-
m(II) acetate (5 mol%). The mixture was then dissolved in a 0.1m
of a 4:1 mixture of toluene and HFIP. The mixture was then stirred
10 min at room temperature, then at 80–1108C during 16–36 h.
After cooling down to room temperature, the mixture was diluted
with DCM, filtered through PTFE 45 mm filter with a syringe and
evaporated under reduced pressure. The crude product was puri-
fied by column chromatography on silica gel using cyclohexane/
EtOAc (typically 9:1 to 7:3) as eluent.
Acknowledgements
We thank the CNRS (Centre National de la Recherche Scientifi-
que), the “Ministere de l’Education Nationale et de la Recher-
che”, and ANR (Agence Nationale de la Recherche) France for
financial support. S.J. is very grateful to the ANR (Agence Na-
tionale de la Recherche), France for a doctoral grant. We are
also very greatful to Dr. Lydia Karmazin and Dr. Corinne Bailly
for single crystal X-ray diffraction analysis..
Conflict of interest
The authors declare no conflict of interest.
[16] For selected publications describing Pd-catalyzed arylation of aliphatic
CÀH bonds using ortho-substituted ArÀI see: a) M. Wasa, K. M. Engle, J.-
Q. Yu, J. Am. Chem. Soc. 2009, 131, 9886; b) J. He, S. Li, Y. Deng, H. Fu,
B. N. Laforteza, J. E. Spangler, A. Homs, J.-Q. Yu, Science 2014, 343, 1216;
c) K. Chen, S.-Q. Zhang, J.-W. Xu, F. Hu, B.-F. Shi, Chem. Commun. 2014,
50, 13924; d) J. Liu, Y. Xie, W. Zeng, D. Lin, Y. Deng, X. Lu, J. Org. Chem.
2015, 80, 4618.
Keywords: aliphatic substrates · bixoordinating DG · CÀH
activation · direct arylation · sulfoxide
[1] For selected recent reviews on CÀH activation see: a) J. F. Hartwig, J.
Am. Chem. Soc. 2016, 138, 2; b) T. Gensch, M. N. Hopkinson, F. Glorius, J.
Wencel-Delord, Chem. Soc. Rev. 2016, 45, 2900; c) C. Liu, J. Yuan, M.
Gao, S. Tang, W. Li, R. Shi, A. Lei, Chem. Rev. 2015, 115, 12138; d) B. V.
Varun, J. Dhineshkumar, K. R. Bettadapur, Y. Siddaraju, K. Alagiri, K. R.
Prabhu, Tetrahedron Lett. 2017, 58, 803; e) H. Sun, Y. Huang, Synlett
2015, 26, 2751; f) X.-S. Xue, P. Ji, B. Zhou, J.-P. Cheng, Chem. Rev. 2017,
117, 8622–8648; g) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu, Y. Zhang,
Org. Chem. Front. 2015, 2, 1107; h) H. M. L. Davies, D. Morton, J. Org.
Chem. 2016, 81, 343.
[17] For a review on direct CÀO bond formation see: S. Moghimi, M. Mahda-
vi, A. Shafiee, A. Foroumadi, Eur. J. Org. Chem. 2016, 3282.
[18] For rare example see: intermolecular C(sp2)ÀH/CÀO coupling: a) X.-F.
Cheng, Y. Li, Y.-M. Su, F. Yin, J.-Y. Wang, J. Sheng, H. U. Vora, X.-S. Wang,
J.-Q. Yu, J. Am. Chem. Soc. 2013, 135, 1236; for diastereoselctive acetox-
ylation of methane CÀH bonds see: b) 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.
[2] For selected reviews on application of CÀH activation for the synthesis
of complex molecular scaffolds see: a) E. J. E. Caro-Diaz, M. Urbano, D. J.
Buzard, R. M. Jones, Bioorg. Med. Chem. Lett. 2016, 26, 5378; b) J.
Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5, 369; c) D. Y.-K. Chen, S. W.
Manuscript received: July 14, 2017
Version of record online: && &&, 0000
Chem. Eur. J. 2017, 23, 1 – 8
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
CÀH Aactivation
S. Jerhaoui, J.-P. Djukic, J. Wencel-Delord,*
F. Colobert*
&& – &&
Stereoselective Sulfinyl Aniline-
Promoted Pd-Catalyzed CÀH Arylation
and Acetoxylation of Aliphatic Amides
Aliphatic stereogenic chains can now
be obtained through C(sp3)ÀH activa-
tion using the recyclable chiral auxiliary
p-tolylsulfinylaniline.
&
&
Chem. Eur. J. 2017, 23, 1 – 8
www.chemeurj.org
8
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!