Enantio- and Diastereoswitchable C?H Arylation of Methylene Groups in Cycloalkanes

Article abstract of DOI:10.1002/chem.201902046

A complementary set of chiral N,N-ligands enables the Pd-catalyzed β-C?H arylation of unbiased internal methylene groups in good yield and with high levels of enantio- and diastereoinduction. Both the dia- and enantioselectivity can be reversed, thus allowing the selective arylation of any of the four β-C?H bonds in cycloalkanecarboxamides of various ring sizes. The method is applicable to a broad range of aryl iodides with electron-withdrawing and -donating substituents in the o-, m-, or p-position.

Full text of DOI:10.1002/chem.201902046

A Journal of
Accepted Article
Title: Enantio- and Diastereoswitchable C-H Arylation of Methylene
Groups in Cycloalkanes
Authors: Michal S Andrä, Lukas Schifferer, Corina Pollok, Christian
Merten, Lukas J Goossen, and Jin-Quan Yu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201902046
Link to VoR: http://dx.doi.org/10.1002/chem.201902046
Supported by

10.1002/chem.201902046
Chemistry - A European Journal
COMMUNICATION
Enantio- and Diastereoswitchable C–H Arylation of Methylene
Groups in Cycloalkanes
Michal S. Andrä,[a,b] Lukas Schifferer,[a] Corina Pollok,[a] Christian Merten,[a] Lukas J. Gooßen,*[a] Jin-
Quan Yu*[b]
Abstract: A complementary set of chiral N,N-ligands enables the Pd-
catalyzed -C–H arylation of unbiased internal methylene groups in
good and with high levels of enantio- and diastereoinduction. Both the
dia- and enantioselectivity can be reversed, thus allowing to
selectively arylate any one of the four -C–H bonds in
cycloalkanecarboxamides of various ring sizes. The method is
applicable to a broad range of aryl iodides with electron-withdrawing
and -donating substituents in o-, m-, or p-position.
heteroatom-substituted methylene C–H bonds.[11,4c,4d] However,
the control of both enantio- and diastereselectivity in -C–H
functionalizations of simple, unbiased methylene groups is still an
unsolved challenge. Especially diastereoinduction by an external
catalyst has not been demonstrated in directed C–H activation.
Recently, an enantioselective -arylation of amides via
asymmetric metal insertion into methylene C–H bonds has been
achieved using chiral bidentate acetyl-protected aminoethyl
quinoline (APAQ) ligands (Scheme 1B).[12] This prototype system
was efficient only for amides with -unbranched, aliphatic carbon
chains. Unfortunately, it gave unsatisfactory results yields and
selectivities when we attempted to apply it to amides with -
branched carbon chains (see Supporting Information). This is
understandable, because the -arylation of -branched
substrates with four similarly accessible C–H groups within reach
of a directing group adds tremendous challenges to controlling
selectivity (Scheme 1C).
The design of catalytic methods that enable the selective
activation of specific C–H bonds within complex molecules is
among the most important goals of modern method development.
This is due to their potential to steeply increase molecular
complexity, bypassing prefunctionalization or deconvolution steps.
However, it is tremendously challenging to achieve the required
selectivity levels, since even small molecules usually contain a
large number of C–H bonds in comparable steric environments
and with near-identical bond strengths.
For symmetrical substrates, monoarylation can now lead to
two diastereomeric pairs of enantiomers. In order to selectively
access any of the four C–H monoarylation products, not only the
enantioselectivity, but also the diastereoselectivity of the
transformation must be fully controlled, ideally by the catalyst-
ligand system alone, overriding substrate effects (Scheme 1C).
Although the past decade has witnessed remarkable progress
in this field, there are still only few reports of intermolecular
enantioselective functionalization of alkane sp3-C–H bonds. Most
of these rely on directing groups (DGs) that facilitate metalation of
specifically one of the nearby C–H bonds.[1] Diastereoselectivity
in C–H activation is usually based on substrate control, e.g. in
directed cis-selective functionalization of small cycloalkane
rings,[2,3] five-membered heterocycles,[4] six-membered hetero-
cycles with certain substitution patterns,[5,4b] in transannular C–H
functionalizations,[6] and for acyclic amino acids.[7] However, this
approach requires substrates with strong diastereoinduction.
Substrates with moderate diastereoinduction usually yield
mixtures of cis/trans-isomers with inconsistent diastereo-
selectivites, e.g. in medium-sized cycloalkanes.[8] Moreover, the
use of strategies based on substrate control for enantioselective
transformations inherently depends on the availability of
enantiopure starting materials (Scheme 1A).[4a,7]
A: diastereoselective sp 3 -CH activation, substrate-controlled
B.V.S. Reddy, L.R. Reddy, E.J. Corey, Org. Lett. 2006, 8, 3391-3394
B: enantioselective sp 3 -CH activation, ligand-controlled
chiral ligand
G. Chen, W. Gong, Z. Zhuang, M.S. Andrä, Y.-Q. Chen, X. Hong,
Y.-F. Yang, T. Liu, K.N. Houk, J.-Q. Yu, Science 2016, 353, 1023-1027
Asymmetric induction via use of chiral ligands is still in its
infancy in sp3-C–H functionalization. Encouraging results have
been achieved for sterically accessible methyl groups[9] and for
methylene groups with electronic bias, including strained
cycloalkyl systems,[3,8a,8b] benzylic positions,[10] and -
C: this work - simultaneous enantio- and diastereocontrol
chiral cis-selective
ligand
[a]
Dr. M. S. Andrä, L. Schifferer, Dr. C. Pollok, Dr. C. Merten, Prof. Dr.
L. J. Gooßen
n
n
n
n
ZEMOS, Fakultät für Chemie und Biochemie,
Ruhr-Universität Bochum
Universitätsstr. 150, 44801 Bochum (Germany)
E-mail: lukas.goossen@rub.de
n
[b]
Dr. M. S. Andrä, Prof. Dr. J.-Q. Yu,
chiral trans-selective
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, California 92037 (USA)
E-mail: yu200@scripps.edu
ligand
Scheme 1. Stereodivergent directed methylene C–H functionalization.
Supporting information for this article and ORCID identification
number(s) for the author(s) is given via a link at the end of the
document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201902046
Chemistry - A European Journal
COMMUNICATION
We set out to address this fascinating problem by establishing
a method for stereoselective arylation of cycloalkylamides. A
stereocontrolled -arylation of cycloalkanes would be
synthetically highly valuable. Alternative asymmetric entries to
1,2-disubstituted cycloalkanes, e.g. conjugate addition across
trisubstituted double bonds, cis-selective hydrogenation, or trans-
selective hydroarylation of olefinic substrates, have significant
limitations.[13] Especially for diversity-oriented synthesis in drug
discovery, a unified and rapid enantioselective entry to all possible
stereoisomers via -arylation of cyclohexanecarboxylic acid
derivatives would be advantageous.
structural parameters on yield, diastereo- and enantioselectivity.
Selected results are shown in Table 1.
The achiral parent ligand L1 promoted the arylation in
moderate yield with an encouraging diastereomeric ratio (dr) of
2:1 in favor of the cis-compound.[14] Creating a stereocenter
proximal to the ligand’s amide group by introduction of a phenyl
substituent in L2 gave a comfortable level of asymmetric induction
in the C–H arylation. The aromatic substituent also increased
diastereoselectivity in favor of the cis product cis-3aa, with the
best results being obtained with the sterically crowded aromatic
3,5-tBu2Ph group. Both optical induction and diastereoinduction
were further enhanced by a second stereocenter in the ligand
backbone. Following upfront screening experiments, we focused
on syn-APAQ ligands in which the two substituents would both
point either up- or downwards in the palladacycle.[12] The relatively
small methyl group in L5 proved to be the optimal residue with
respect to yield, enantiomeric ratio (er) and cis/trans ratio. In the
reaction of these sterically demanding substrates, the key
challenge turned out to be achieving high conversions while
preserving high levels of steric induction. This was finally
achieved by the addition of AgOAc[15,16] to the reaction mixture. A
high yield in combination with a high selectivity for the 1R,2S
configured cis-product were, thus, obtained when arylating
substrate 1a in the presence of a catalyst system generated from
(PdOAc)2 and ligand L5, using a mixture of Ag2CO3 and AgOAc
as the base, in HFIP at 80°C for 36 h in a sealed vial under air in
the dark.
Table 1. Structural optimization of APAQ ligands in cyclohexane arylations.
Intending to increase the steric bulk in the ligand backbone
beyond the 3,5-tBu2Ph group, we designed a new series of APAQ-
ligands L6-L9 with -tertiary alkyl substituents replacing the
planar aryl group. This structural modification was decisive in
reverting the diastereoselectivity from cis- to trans-arylation.
Near-quantitative yields and good selectivities in favor of the
trans-diastereomer were achieved with adamantyl-substituted L9
(99% yield, dr = 24:76, er = 84:16). Introduction of a second
substituent to the backbone of L9 led to a sharp decline in yield
and stereoselectivity (Table S2, Supporting Information), which
might point to steric overcrowding. A rationalization of the
reversed diastereosecletivity can be found in the mechanistic
discussion depicted in Scheme 2.
Ligand
Yield
L1
L2
L3
L4
L5
64%
76%
64%
63%
74%
85% a
dr: cis to trans
er: 1R,2S to 1S,2R
Ligand
67:33
50:50
L6
80:20
78:22
L7
89:11
89:11
L8
8:92
97:3
L9
96:4 a
97:3 a
Next, we turned to exploring the scope of the aryl iodide
coupling partners and found that a wide range of derivatives can
be converted (Table 2). Electron-rich electrophiles gave
consistently higher yields than those bearing electron withdrawing
substituents, but in all cases, diastereo- and enantioselectivity
remained high. Selected ortho-substituted aryl iodides were
smoothly converted, which is remarkable considering Pd-
catalysts’ notorious sensitivity to steric crowding in C–H activation.
Unfortunately, the oily products did not permit an investigation of
their absolute stereochemistry by X-ray diffraction. However,
combined HPLC and VCD investigation revealed the substitution
pattern of the aryl halide to have a strong influence on the
stereochemical outcome (Supporting Information).
Yield
84%
85%
57%
99%
24:76
84:16
dr: cis to trans
er: 1S,2S to 1R,2R
34:66
89:11
31:69
88:12
37:63
87:13
Conditions: 100 mol 1a, 10 mol Pd(OAc)2, 12 mol L1-L9, 175 mol Ag2CO3 ,
250 mol aryl iodide, 1 mL HFIP, 80 °C, air, 36 h, a) additional 30 mol AgOAc.
We chose the model reaction of p-iodotoluene 2a with
cyclohexane 1a bearing our proven perfluorinated tolylamide
directing group in order tackle this long-standing challenge, and
search for ligands that control both dia- and enantioselectivity of
this C–H arylation. We thus evaluated the APAQ ligands reported
in ref. 12 along with several new APAQ ligands bearing different
substituents, and systematically investigated the influence of
In combination with ligand L5, aryl iodides bearing
substituents in para- and in meta-position preferentially gave the
cis-products. In sharp contrast, aryl iodides bearing ortho-
This article is protected by copyright. All rights reserved.

10.1002/chem.201902046
Chemistry - A European Journal
COMMUNICATION
substituents gave the trans-diastereomers. At this stage, we can
only speculate on what causes the remarkable reversal in
diastereoselectivity between ortho- and meta-substituted aryl
iodides, well-illustrated by - and -naphthyl iodides (cis-3a and
trans-3a in Table 2). One might view it to be a consequence of
to lead to a different outcome in the competition of the aryl and
cycloalkane residues for the least hindered space within the
coordination sphere of palladium (see Scheme 2). Moreover, the
chiral induction is opposite in para- than in meta-substituted
products.
the different steric demands of the two aryl scaffolds. This seems
Table 2. Substrate scope with cis-favoring ligand L5.
Conditions: 100 mol 1, 10 mol Pd(OAc)2, 12 mol L5, 175 mol Ag2CO3 , 30 mol AgOAc, 250 mol aryl iodide, 1 mL HFIP, 80 °C, air, 36 h, yields determined
by 1H-NMR, isolated yields even exceeded the analytical ones slightly when reactions were run on a scale of 0.4 mmol, dr determined by GC, er determined for the
main diastereomer.
Application width with regard to the cyclic amides was also
probed. Arylation of five- and seven-membered cycloalkanes with
L5 gave the cis-configured products 3ba and 3ca with high
diastereomeric and enantiomeric induction. Flexible, acyclic
substrates such as 2,2-diethylacetamide gave only low yields and
stereoselectivities (Supporting Information), which can partially be
attributed to their higher degree of rotational freedom. Not only
does this enlarge the pool of potential transition structures, but it
also causes additional steric restrains at the catalyst center,
further reducing its activity.
Other than in 6- and 7-membered cycloalkanes, the required
palladacyclic intermediates en route to a trans-configured 3- to 5-
membered ring product would be much more strained than their
cis-configured counterpart (Supporting Information). It is thus not
surprising that the steric interaction imposed by ligand L9 was
insufficient to enforce a reversal of diastereoselectivity for such
substrates (3ba in Table 3).
A tentative mechanistic sketch of the transformation is
outlined in Scheme 2. Based on preceding work,[16] it is
reasonable to assume that the reaction is initiated by coordination
of the amide substrate 1 to the palladium center, followed by C–
H metalation. Whereas this step has been proposed to be stereo-
determining for unbranched substrates,[12,16] this can be ruled out
here since the substitution pattern of the aryl iodide 2 has a
profound influence on the stereochemistry of the products. Thus,
the stereo-determining step must be either the oxidative addition
of the aryl iodide or the reductive elimination. Oxidative addition
can lead to a number of PdIV isomers, each present in different
quantities and with variable reactivities towards reductive
We next probed whether the use of ligand L9 would
consistently reverse the diastereoselectivity for a broad range of
substrates (Table 3). Indeed, trans-products were obtained for
para- and meta-substituted aryl iodides, while ortho-substitution
resulted in cis-products, which is the opposite of what was
observed for L5. Therefore, both ligands exhibit completely
complementary diastereoinduction.
This article is protected by copyright. All rights reserved.

10.1002/chem.201902046
Chemistry - A European Journal
COMMUNICATION
elimination. One might speculate that ligands L5 and L9 facilitate
the reductive elimination from different PdIV conformers, resulting
in the release of different diastereomers. This would be in
agreement with reports on stereodivergent reaction outcomes
based on reductive elimination from PdIV species.[17,10d]
intermediate, because both substrates and the ligand all affect the
outcome. The remarkable reversal in diastereoselectivity between
ortho- and meta-substituted aryl iodides, well-illustrated by - and
-naphthyl iodides (cis-3a and trans-3a in Table 2), could be a
consequence of different steric demands of the aryl scaffolds.
This seems to lead to a different outcome in the competition of the
aryl moiety and the cycloalkane residue for the least hindered
space within the coordination sphere of palladium.
Table 3. Scope of aryl iodide coupling partners with trans-favoring ligand L9.
In conclusion, we have established the first example of a
catalyst-controlled enantio- and diastereoselective C–H arylation
of two unbiased -methylene groups. The two enantiomers of the
complementary ligands L5 and L9 allow to preferentially
functionalize each of the four accessible -C–H bonds of
cyclohexyl carboxamides providing straightforward access to their
2-arylated derivatives with unprecedented spatial control over two
contiguous stereocenters. Although the ligand influence is not yet
sufficiently strong to override all substrate effects, this is an
important step towards gaining full stereocontrol over C–H
functionalization.
Experimental Section
Typical procedure, medium scale: Amide 1a (137.3 mg, 400 µmol), ligand
L5 (20.0 mg, 48 µmol), Ag2CO3 (193 mg, 700 µmol), Pd(OAc)2 (9.0 mg, 40
µmol), iodo-4-methylbenzene (218 mg, 1.00 mmol) and AgOAc (20 mg,
120 µmol) were weighed in air and placed in a screw cap vial with a
magnetic stirring bar. Hexafluoroisopropanol (4.0 mL) was added, the vial
sealed and the mixture was stirred at room temperature for 10 minutes
before heating at 80 °C in the dark for 36 h. The mixture was allowed to
cool to room temperature, filtered through Celite with CH2Cl2 and
concentrated in vacuo. NMR-analysis implied 85% analytical yield (dr
95:5). Column chromatography (SiO2, PhMe) gave 140 mg cis-3aa (322
μmol, 81%), as yellow oil and a mixture of trans-3aa and starting material
1a (2:1, .31 mg).
Conditions: 100 mol 1, 10 mol Pd(OAc)2, 12 mol L9, 175 mol Ag2CO3, 250
mol aryl iodide, 1 mL HFIP, 80 °C, air, 36 h
Acknowledgements
We acknowledge financial support by the DFG (Forschungs-
stipendium for MSA), The Scripps Research Institute and the NIH
(NIGMS 2R01 GM084019). We thank Lisa Feldmann for MALDI
measurements, and Laura Pasternack for NMR assistance. CP
and CM were funded by the Deutsche Forschungsgemeinschaft
(DFG, German Research Foundation) under Germany’s
Excellence Strategy – EXC-2033 – Projektnummer 390677874.
Keywords: C–H functionalization • methylene activation •
enantioselective • diastereoselective • catalyst-control
[1]
[2]
[3]
a) C. G. Newton, S.-G. Wang, C. C. Oliveira, N. Cramer, Chem. Rev.
2017, 117, 8908–8976; b) T. G. Saint-Denis, R.-Y. Zhu, G. Chen, Q.-F.
Wu, J.-Q. Yu, Science 2018, 359, eaao4798.
a) A. Kubota, M. S. Sanford, Synthesis 2011, 2011, 2579–2589; b) D. S.
Roman, A. B. Charette, Org. Lett. 2013, 15, 4394–4397; c) R. Parella, B.
Gopalakrishnan, S. A. Babu, Org. Lett. 2013, 15, 3238–3241.
Scheme 2. Schematic mechanism, including two representative PdIV isomers.
a) M. Wasa, K. M. Engle, D. W. Lin, E. J. Yoo, J.-Q. Yu, J. Am. Chem.
Soc. 2011, 133, 19598–19601; b) K.-J. Xiao, D. W. Lin, M. Miura, R.-Y.
Zhu, W. Gong, M. Wasa, J.-Q. Yu, J. Am. Chem. Soc. 2014, 136, 8138–
8142; c) K. S. L. Chan, H.-Y. Fu, J.-Q. Yu, J. Am. Chem. Soc. 2015, 137,
2042–2046; d) J. Kim, M. Sim, N. Kim, S. Hong, Chem. Sci. 2015, 6,
3611–3616; e) J. Pedroni, N. Cramer, J. Am. Chem. Soc. 2017, 139,
Irrespective of whether the oxidative addition, reductive
elimination, or a combination of both dictate the stereochemical
outcome, the differentiation must take place within the PdIV
This article is protected by copyright. All rights reserved.

10.1002/chem.201902046
Chemistry - A European Journal
COMMUNICATION
12398–12401; f) Q.-F. Wu, X.-B. Wang, P.-X. Shen, J.-Q. Yu, ACS
catalysis 2018, 8, 2577–2584; g) P.-X. Shen, L. Hu, Q. Shao, K. Hong,
J.-Q. Yu, J. Am. Chem. Soc. 2018, 140, 6545–6549, h) L. Hu, P.-X. Shen,
Q. Shao, K. Hong, J. X. Qiao, J.-Q. Yu, Angew. Chem. Int. Ed. 2019, 58,
2134–2138.
E. Kefalidis, E. Clot, O. Baudoin, Angew. Chem. Int. Ed. 2010, 49, 7261–
7265; d) Q.-F. Wu, P.-X. Shen, J. He, X.-B. Wang, F. Zhang, Q. Shao,
R.-Y. Zhu, C. Mapelli, J. X. Qiao, M. A. Poss, J.-Q. Yu, Science 2017,
355, 499–503; e) A. P. Smalley, J. D. Cuthbertson, M. J. Gaunt, J. Am.
Chem. Soc. 2017, 139, 1412–1415; f) Q. Shao, Q.-F. Wu, J. He, J.-Q.
Yu, J. Am. Chem. Soc. 2018, 140, 5322–5325.
[4]
a) D. P. Affron, O. A. Davis, J. A. Bull, Org. Lett. 2014, 16, 4956–4959; b)
R. Parella, S. A. Babu, J. Org. Chem. 2015, 80, 2339–2355; c) P. Jain, P.
Verma, G. Xia, J.-Q. Yu, Nat. Chem. 2017, 9, 140–144; d) Y.-k. Tahara,
M. Michino, M. Ito, K. S. Kanyiva, T. Shibata, Chem. Commun. 2015, 51,
16660–16663
[10] a) S.-B. Yan, S. Zhang, W.-L. Duan, Org. Lett. 2015, 17, 2458–2461; b)
F.-L. Zhang, K. Hong, T.-J. Li, H. Park, J.-Q. Yu, Science 2016, 351,
252–256; c) H. Wang, H.-R. Tong, G. He, G. Chen, Angew. Chem. Int.
Ed. 2016, 55, 15387–15391; d) H. Park, P. Verma, K. Hong, J.-Q. Yu,
Nat. Chem. 2018, 10, 755–762.
[5]
[6]
S. Ye, W. Yang, T. Coon, D. Fanning, T. Neubert, D. Stamos, J.-Q. Yu,
Chem. Eur. J. 2016, 22, 4748–4752.
[11] a) S. Pan, K. Endo, T. Shibata, Org. Lett. 2011, 13, 4692–4695; b) S.
Pan, Y. Matsuo, K. Endo, T. Shibata, Tetrahedron 2012, 68, 9009–9015;
c) Y.-k. Tahara, M. Michino, M. Ito, K. S. Kanyiva, T. Shibata, Chem.
Commun. 2015, 51, 16660–16663; d) P. Jain, P. Verma, G. Xia, J.-Q. Yu,
Nat. Chem. 2017, 9, 140–144; e) A. T. Tran, J.-Q. Yu, Angew. Chem. Int.
Ed. 2017, 56, 10530–10534.
a) L. V. Desai, K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2004, 126,
9542–9543; b) G. He, G. Chen, Angew. Chem. Int. Ed. 2011, 50, 5192–
5196; c) J. J. Topczewski, P. J. Cabrera, N. I. Saper, M. S. Sanford,
Nature 2016, 531, 220–224; d) P. J. Cabrera, M. Lee, M. S. Sanford, J.
Am. Chem. Soc. 2018, 140, 5599–5606.
[7]
Examples of mehylene C–H activation of amino acid derivates: a) B. V.
S. Reddy, L. R. Reddy, E. J. Corey, Org. Lett. 2006, 8, 3391–3394; b) L.
D. Tran, O. Daugulis, Angew. Chem. Int. Ed. 2012, 51, 5188–5191; c) K.
Chen, B.-F. Shi, Angew. Chem. Int. Ed. 2014, 53, 11950–11954; d) J.
He, S. Li, Y. Deng, H. Fu, B. N. Laforteza, J. E. Spangler, A. Homs, J.-Q.
Yu, Science 2014, 343, 1216–1220; e) R.-Y. Zhu, K. Tanaka, G.-C. Li, J.
He, H.-Y. Fu, S.-H. Li, J.-Q. Yu, J. Am. Chem. Soc. 2015, 137, 7067–
7070; f) G. Liao, X.-S. Yin, K. Chen, Q. Zhang, S.-Q. Zhang, B.-F. Shi,
Nat. Commun. 2016, 7, 12901; g) 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, 3338–3351.
a) J. He, H. Jiang, R. Takise, R.-Y. Zhu, G. Chen, H.-X. Dai, T. G. M.
Dhar, J. Shi, H. Zhang, P. T. W. Cheng, J.-Q. Yu, Angew. Chem. Int. Ed.
2016, 55, 785–789; b) J. He, Q. Shao, Q. Wu, J.-Q. Yu, J. Am. Chem.
Soc. 2017, 139, 3344–3347; c) Z. Ren, F. Mo, G. Dong, J. Am. Chem.
Soc. 2012, 134, 16991–16994; d) M. Wasa, K. S. L. Chan, X.-G. Zhang,
J. He, M. Miura, J.-Q. Yu, J. Am. Chem. Soc. 2012, 134, 18570–18572;
e) S.-Y. Zhang, G. He, W. A. Nack, Y. Zhao, Q. Li, G. Chen, J. Am. Chem.
Soc. 2013, 135, 2124–2127.
[12] a) G. Chen, W. Gong, Z. Zhuang, M. S. Andrä, Y.-Q. Chen, X. Hong, Y.-
F. Yang, T. Liu, K. N. Houk, J.-Q. Yu, Science 2016, 353, 1023–1027; b)
Y. Wang, Z.-J. Shi, Chem 2016, 1, 528–530.
[13] There are only few reports on highly stereoselective functionalization of
nitrocycloalkenes and cycloalkane carbonitriles via asymmetric
conjugate addition: a) T. Hayashi, T. Senda, M. Ogasawara, J. Am.
Chem. Soc. 2000, 122, 10716–10717; b) C. A. Luchaco-Cullis, A. H.
Hoveyda, J. Am. Chem. Soc. 2002, 124, 8192–8193; c) W. J.
Dziechciejewski, R. Weber, O. Sowada, M. M. K. Boysen, Org. Lett. 2015,
17, 4132–4135.
[14] The main diastereomer‘s cis-configuration was unambiguously
confirmed by hydrogenation of its unsaturated analogue (Supporting
Information).
[8]
[15] AgOAc formed in situ from Ag2CO3 and HOAc had previously been
proposed to facilitate C–H arylation.
[16] Y.-F. Yang, G. Chen, X. Hong, J.-Q. Yu, K. N. Houk, J. Am. Chem. Soc.
2017, 139, 8514–8521.
[17] a) K. M. Engle, T.-S. Mei, X. Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2011,
50, 1478–1491; b) N. M. Camasso, M. H. Pérez-Temprano, M. S.
Sanford, J. Am. Chem. Soc. 2014, 136, 12771–12775; c) M. Nappi, C.
He, W. G. Whitehurst, B. G. N. Chappell, M. J. Gaunt, Angew. Chem. Int.
Ed. 2018, 57, 3178–3182.
[9]
a) R. Giri, X. Chen, J.-Q. Yu, Angew. Chem. Int. Ed. 2005, 44, 2112–
2115; b) B.-F. Shi, N. Maugel, Y.-H. Zhang, J.-Q. Yu, Angew. Chem. Int.
Ed. 2008, 47, 4882–4886; c) A. Renaudat, L. Jean-Gérard, R. Jazzar, C.
This article is protected by copyright. All rights reserved.

10.1002/chem.201902046
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
M. S. Andrä, L. Schifferer, C. Pollock, C.
Merten, Lukas J. Gooßen*, Jin-Quan
Yu*
Page No. – Page No.
Enantio- and Diastereoswitchable C–
H-Arylation of Methylene Groups in
Cycloalkanes
Text for Table of Contents
An unprecedentedly selective -C–H arylation of directing group-substituted
cycloalkanes is reported. Known APAQ-ligands give cis-products with high
yields, enantio- and diastereoselectivities. New ligands reversed the
diastereoselectivity in favour of the trans products.
This article is protected by copyright. All rights reserved.