Enantioselective Aluminum-Free Alkene Hydroarylations through C?H Activation by a Chiral Nickel/JoSPOphos Manifold

Article abstract of DOI:10.1002/anie.201813191

Highly enantioselective nickel-catalyzed alkene endo-hydroarylations were accomplished with full selectivity by organometallic C?H activation. The asymmetric assembly of chiral six-membered scaffolds proved viable in the absence of pyrophoric organoaluminum reagents within an unprecedented nickel/JoSPOphos manifold.

Full text of DOI:10.1002/anie.201813191

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Enantioselective Aluminum-Free Alkene Hydroarylations via C–H
Activation by a Chiral Nickel/JoSPOphos Manifold
Authors: Joachim Loup, Valentin Müller, Debasish Ghorai, and Lutz
Ackermann
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: Angew. Chem. Int. Ed. 10.1002/anie.201813191
Angew. Chem. 10.1002/ange.201813191
Link to VoR: http://dx.doi.org/10.1002/anie.201813191
http://dx.doi.org/10.1002/ange.201813191

10.1002/anie.201813191
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Aluminum-Free Alkene Hydroarylations via C–H
Activation by a Chiral Nickel/JoSPOphos Manifold
Joachim Loup,+ Valentin Müller,+ Debasish Ghorai, and Lutz Ackermann*
Abstract: Highly enantioselective nickel-catalyzed alkene endo-
hydroarylations were accomplished with full selectivity via
organometallic C–H activation. The asymmetric assembly of chiral
six-membered scaffolds proved viable in the absence of pyrophoric
organoaluminum
reagents
within
an
unprecedented
nickel/JoSPOphos manifold.
The selective modification of omnipresent C–H bonds has been
recognized as a transformative tool in molecular syntheses.[1]
While major progress was realized with the aid of noble 4d and
5d transition metals, recent focus has shifted towards Earth-
abundant and less toxic 3d metals.[2] Despite significant
advances in organometallic catalysis, full selectivity control
towards enantioselective C–H functionalizations continues to
heavily rely on precious 4d transition metals, prominently
featuring palladium and rhodium complexes.[3] In sharp contrast,
enantioselective C–H activations with inexpensive 3d base
metals continue to be scarce.[4] Based on the elegant studies by
Bergman and Ellman, undirected cyclizations of azoles have
Scheme 1. Asymmetric hydroarylations via nickel-catalyzed C–H activation.
We initiated our studies by testing a wealth of chiral ligands for
the envisioned asymmetric alkene hydroarylation (Table 1 and
Table S-1).[13] The desired product was obtained with moderate
performance
using
preligand
L1.[4e]
Monodentate
phosphoramidite L2 provided product 2a with poor yield and
enantio-induction. In contrast, the prototypical secondary
phosphine oxide (SPO)[14] L3 led to ligand acceleration, but poor
enantioselectivity. We, thus, probed further HASPO preligands,
with derivative L4 furnishing promising results. Unfortunately, all
(pre)ligands required the pyrophoric AlMe3 as additive.
Thereafter, we tested JoSPOphos-type ligands due to their
documented efficacy in rhodium(I)-catalyzed asymmetric
hydrofunctionalization reactions.[15] To our delight, JoSPOphos
L9 afforded the desired product 2a in excellent yield and
enantioselectivity, while the related ligand L10 gave moderate
enantioselectivity. It is noteworthy that this transformation
represents a proof of concept in that it constitutes the first use of
been dominated by rhodium(I) catalysts,[5] with
a single
enantioselective transformation being reported thus far.[6] In
recent years, nickel-catalyzed[7] cyclizations via C–H activation[8]
have emerged as a viable tool for molecular syntheses,
predominantly delivering the exo-products.[8a,8c-e] However,
enantioselective endo-cyclizations via C–H activation have
proven elusive, with
a
notable exception featuring
pyridones.[8b,8c] Despite major progress, this approach was
limited to strongly activated azolium salts,[8e] and/or pyrophoric
organoaluminum reagents as Lewis-acidic additives. In contrast,
within our program on nickel-catalysis[9] with secondary
phosphine oxide (SPO) pre-ligands,[10] we have devised the
a
JoSPOphos ligand with a transition metal other than
unprecedented
nickel-catalyzed
enantioselective
endo-
rhodium(I). Poor results were obtained with the corresponding
JosiPhos phosphine ligand L11, highlighting the superiority of
the phosphine oxide moiety. Interestingly, the C–H activation
efficiently occurred with catalyst loadings as low as 1.0 mol %
(entries 1 and 2), while the JoSPOphos-enabled hydroarylation
proceeded even in the absence pyrophoric AlMe3 (entries 3-5).
Given the prospect for functional group tolerance, we further
focused on the AlMe3-free conditions (Table S-2).[13] Here,
variations of the ligand-to-metal ratio improved the
enantioselectivity slightly (entries 6-9), with an excess of the
ligand L9 providing inferior results, which is likely due to the
formation of less selective bis-ligated nickel species (entries 6
and 7).
cyclization of imidazoles with alkenes. Notable features of our
strategy include 1) the use of Earth-abundant nickel catalysts for
synthetically meaningful alkene hydroarylation, 2) asymmetric
secondary
C–H
alkylations
of
biologically
relevant
(benz)imidazoles[11] and purines,[12] 3) first nickel-catalyzed
endo-selective cyclizations of azoles, 4) unactivated alkenes, 5)
organoaluminum-free conditions with unmatched functional
group tolerance, and 6) detailed mechanistic insights on a novel
nickel/JoSPOphos design (Scheme 1).
[*]
J. Loup,[+] V. Müller,[+] Dr. D. Ghorai, Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de
Dr. D. Ghorai, Prof. Dr. L. Ackermann
Department of Chemistry, University of Pavia
Viale Taramelli, 10, 27100 Pavia (Italy)
[+]
These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/anie.201813191
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of the enantioselective C–H alkylations.[a]
high selectivity control (Scheme 2c). Thereby, biologically
relevant morpholines and pyrene fluorophores proved to be
compatible within the nickel/SPO regime. The AlMe3-free
reaction conditions translated into sensitive functional groups,
such as amino, chloro and ester, being fully tolerated.
Entry
[Ni(cod)2]/
mol %
[L9]/
mol %
[AlMe3]/
mol %
Yield/%
e.r.
1
2
3
4
5
6
7
8
9
2.5
1.0
10
10
-
2.5
1.0
10
10
95
97
91
n.r.
n.r.
98
38
96
31
>99:1
>99:1
97:3
-
4.0
-
-
-
-
-
-
-
-
10
-
5.0
5.0
5.0
5.0
5.0
10
89:11
77:23
96:4
94:6
2.5
1.25
Scheme 2. Enantioselective C–H alkylations with alkenes and late-stage
diversification. [a] With Ni(cod)2 (10 mol %) and L9 (5.0 mol %).
[a] Reaction conditions: 1a (0.50 mmol), Ni(cod)2 (10 mol %), L (10 mol %),
AlMe3 (40 mol %), PhMe (2.0 mL), 95 °C, 16 h. Isolated yields.
Enantioselectivities determined by chiral HPLC. [b] At 130 °C. [c] NaOtBu
(20 mol %) was added. [d] Using Ni(cod)2 (2.5 mol %), L9 (2.5 mol %) and
AlMe3 (10 mol %) in PhMe (1.0 mL). [e] In PhMe (1.0 mL). n.r. = no reaction.
Moreover, a variety of highly functionalized tethered prochiral
alkenes 1 was well accepted, providing the desired products 2 in
high yields and excellent levels of enantiocontrol (Scheme 3).[13]
Additional double bonds in the tethered alkene were fully
accommodated, with the distal olefins remaining entirely
untouched, as exemplified with N-γ-geranyl- 1x, N-γ-farnesyl-
benzimidazole 1y and 1z.
With the optimized reaction conditions in hand, we next studied
the versatility of the asymmetric C–H transformation. The
desired products
2 were obtained with high levels of
enantiocontrol. Various substituted benzimidazoles 1 were thus
identified as viable substrates (Scheme 2a).[16] The absolute
configurations of product 2e as well as the products of late-stage
modification 3 and 4 were unambiguously assigned by X-ray
diffraction analysis (Scheme 2b).[17] The scope of the
enantioselective C–H alkylation was not limited to
benzimidazoles. Indeed, imidazole 1n and
a variety of
pharmaceutically relevant heterocycles, including bioactive
purines and theophylline motifs 1, were efficiently converted with
This article is protected by copyright. All rights reserved.

10.1002/anie.201813191
Angewandte Chemie International Edition
COMMUNICATION
and preligand L9, which was unambiguously characterized by X-
ray crystallographic diffraction analysis (Scheme 6a).[17]
Complex 5 was shown to be competent in both stoichiometric
and catalytic settings (Scheme 6b,c). Finally, the absence of a
non-linear effect (NLE) was indicative of a mono-ligated nickel
catalyst being operative in the enantioselective C–H
alkylation.[13,19]
[a]
Scheme 3. Enantioselective C–H alkylations of substituted alkenes.
Ni(cod)2 (10 mol %) and L9 (5.0 mol %).
With
Given the unique features of the asymmetric aluminum-free
nickel-catalyzed C–H alkylation, we became attracted to unravel
its mode of action. To this end, C–H activations with deuterium-
labeled benzimidazole [D]1-1a revealed H/D scrambling at the
methyl group and positions of the original olefin (Scheme 4).
This observation can be rationalized with a facile C–H scission
step. Furthermore, C–H activation performed with isotopically
labeled compound [D]1-1a showed a kinetic isotope effect (KIE)
of kH/kD ≈ 1.1.[13]
Scheme 6. Synthesis and use of complex 5. [a] With Ni(cod)2 (5.0 mol %).
Based on our mechanistic studies,[20] we propose the
asymmetric C–H alkylation to be initiated by the formation of the
nickel(II) complex 5 (Scheme 7), which is then coordinated by
substrate 1 to form the active catalyst A. Intermediate A next
undergoes a fast migratory insertion to deliver the cyclized
compound B. After a kinetically relevant coordination of a
second molecule 1a (C), being reflected in its first order kinetics,
a facile C–H activation event takes place, which is proposed to
occur by a ligand-to-ligand hydrogen transfer (LLHT) manifold
(D).[20a,21] The observed H/D scrambling (Scheme 4) is likely due
to off-cycle π-allyl nickel intermediates.
Scheme 4. Reaction with isotopically labeled substrate [D]1-1a.
Subsequently, detailed kinetic studies of the enantioselective C–
H
alkylation unraveled a first-order dependence on the
concentration of the substrate 1a, the ligand L9 and the nickel
precursor (Scheme 5), in the latter case with an inhibition at
higher nickel concentrations.[13] Further, the addition of free
cyclooctadiene (cod) resulted in a deceleration of catalysis.[13,18]
Scheme 5. Kinetic analysis of the nickel-catalyzed C−H activation.
Next, we independently prepared the novel well-defined
organometallic nickel(II)-JoSPOphos complex 5 from Ni(cod)2
This article is protected by copyright. All rights reserved.

10.1002/anie.201813191
Angewandte Chemie International Edition
COMMUNICATION
Int. Ed. 2009, 48, 9792–9826; l) R. G. Bergman, Nature 2007, 446,
391–393.
[2]
a) P. Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz, L.
Ackermann,
Chem.
Rev.
2019,
119,
DOI:
10.1021/acs.chemrev.8b00507; b) Y. Hu, B. Zhou, C. Wang, Acc.
Chem. Res. 2018, 51, 816–827; c) T. Yoshino, S. Matsunaga, Adv.
Synth. Catal. 2017, 359, 1245–1262; d) D. Wei, X. Zhu, J.-L. Niu,
M.-P. Song, ChemCatChem 2016, 8, 1242–1263; e) W. Liu, L.
Ackermann, ACS Catal. 2016, 6, 3743–3752; f) H. Koji, M. Miura,
Chem. Lett. 2015, 44, 868–873; g) K. Gao, N. Yoshikai, Acc.
Chem. Res. 2014, 47, 1208–1219; h) A. A. Kulkarni, O. Daugulis,
Synthesis 2009, 4087–4109.
[3]
[4]
a) C. G. Newton, S.-G. Wang, C. C. Oliveira, N. Cramer, Chem.
Rev. 2017, 117, 8908–8976; b) K. Liao, T. C. Pickel, V. Boyarskikh,
J. Bacsa, D. G. Musaev, H. M. L. Davies, Nature 2017, 551, 609–
613; c) D.-W. Gao, Q. Gu, C. Zheng, S.-L. You, Acc. Chem. Res.
2017, 50, 351–365; d) S. Motevalli, Y. Sokeirik, A. Ghanem, Eur. J.
Org. Chem. 2016, 1459–1475; e) C. Zheng, S.-L. You, RSC
Advances 2014, 4, 6173–6214; f) H. M. L. Davies, J. R. Manning,
Nature 2008, 451, 417–424.
For cobalt(III)-catalyzed C–H activation, see: a) F. Pesciaioli, U.
Dhawa, R. Yin, J. C. A. Oliveira, M. John, L. Ackermann, Angew.
Chem. Int. Ed. 2018, 57, 15425–15429. For low-valent cobalt-
catalyzed C–H activation, see: b) J. Yang, A. Rérat, Y. J. Lim, C.
Gosmini, N. Yoshikai, Angew. Chem. Int. Ed. 2017, 56, 2449–
2453; c) P.-S. Lee, N. Yoshikai, Org. Lett. 2015, 17, 22–25; d) J.
Yang, N. Yoshikai, J. Am. Chem. Soc. 2014, 136, 16748–16751.
For iron-catalyzed C–H activation, see: e) J. Loup, D. Zell, J. C. A.
Oliveira, H. Keil, D. Stalke, L. Ackermann, Angew. Chem. Int. Ed.
2017, 56, 14197–14201.
[5]
a) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem. Rev. 2010,
110, 624–655; b) J. C. Lewis, R. G. Bergman, J. A. Ellman, Acc.
Chem. Res. 2008, 41, 1013–1025; c) J. C. Rech, M. Yato, D.
Duckett, B. Ember, P. V. LoGrasso, R. G. Bergman, J. A. Ellman, J.
Am. Chem. Soc. 2007, 129, 490–491; d) K. L. Tan, A. Vasudevan,
R. G. Bergman, J. A. Ellman, A. J. Souers, Org. Lett. 2003, 5,
2131–2134; e) K. L. Tan, R. G. Bergman, J. A. Ellman, J. Am.
Chem. Soc. 2002, 124, 3202–3203; f) K. L. Tan, R. G. Bergman, J.
A. Ellman, J. Am. Chem. Soc. 2001, 123, 2685–2686.
Scheme 7. Plausible catalytic cycle.
[6]
[7]
A. S. Tsai, R. M. Wilson, H. Harada, R. G. Bergman, J. A. Ellman,
Chem. Commun. 2009, 3910–3912.
In conclusion, we have reported on the first nickel-catalyzed
enantioselective endo-alkene-hydroarylation via organometallic
aluminum-free C–H activation. Thus, a novel nickel/JoSPOphos
manifold enabled C–H activation with high efficacy and
outstanding levels of enantiocontrol. The Earth-abundant nickel
catalysis did not require pyrophoric organoaluminum additives,
and detailed mechanistic studies provided strong support for a
facile LLHT C–H activation with first order kinetics.
Representative examples: a) Y. Schramm, M. Takeuchi, K. Semba,
Y. Nakao, J. F. Hartwig, J. Am. Chem. Soc. 2015, 137, 12215–
12218; b) W.-C. Lee, C.-H. Chen, C.-Y. Liu, M.-S. Yu, Y.-H. Lin, T.-
G. Ong, Chem. Commun. 2015, 51, 17104–17107; c) R. Tamura,
Y. Yamada, Y. Nakao, T. Hiyama, Angew. Chem. Int. Ed. 2012, 51,
5679–5682; d) Y. Nakao, N. Kashihara, K. S. Kanyiva, T. Hiyama,
Angew. Chem. Int. Ed. 2010, 49, 4451–4454; e) C.-C. Tsai, W.-C.
Shih, C.-H. Fang, C.-Y. Li, T.-G. Ong, G. P. A. Yap, J. Am. Chem.
Soc. 2010, 132, 11887–11889; f) Y. Nakao, H. Idei, K. S. Kanyiva,
T. Hiyama, J. Am. Chem. Soc. 2009, 131, 15996–15997. Selected
reviews in: g) L. Ackermann, T. B. Gunnoe, L. G. Habgood,
Catalytic Hydroarylation of Carbon-Carbon Multiple Bonds, Wiley-
VCH, Weinheim, Germany, 2018; h) Y. Nakao, Chem. Rec. 2011,
11, 242–251.
Acknowledgements
[8]
[9]
a) Y.-X. Wang, S.-L. Qi, Y.-X. Luan, X.-W. Han, S. Wang, H. Chen,
M. Ye, J. Am. Chem. Soc. 2018, 140, 5360–5364; b) J. Diesel, A.
M. Finogenova, N. Cramer, J. Am. Chem. Soc. 2018, 140, 4489–
4493; c) P. A. Donets, N. Cramer, Angew. Chem. Int. Ed. 2015, 54,
633–637; d) P. A. Donets, N. Cramer, J. Am. Chem. Soc. 2013,
135, 11772–11775; e) A. T. Normand, S. K. Yen, H. V. Huynh, T.
S. A. Hor, K. J. Cavell, Organometallics 2008, 27, 3153–3160.
For selected recent examples, see: a) S.-K. Zhang, R. C. Samanta,
N. Sauermann, L. Ackermann, Chem. Eur. J. 2018, 24,
DOI:10.1002/chem.201805441; b) Z. Ruan, S.-K. Zhang, C. Zhu, P.
N. Ruth, D. Stalke, L. Ackermann, Angew. Chem. Int. Ed. 2017, 56,
2045–2049; c) S. Nakanowatari, T. Müller, J. C. A. Oliveira, L.
Ackermann, Angew. Chem. Int. Ed. 2017, 56, 15891–15895; d) Z.
Ruan, S. Lackner, L. Ackermann, Angew. Chem. Int. Ed. 2016, 55,
3153–3157; e) Z. Ruan, S. Lackner, L. Ackermann, ACS Catal.
2016, 6, 4690–4693; f) W. Song, S. Lackner, L. Ackermann,
Angew. Chem. Int. Ed. 2014, 53, 2477–2480.
For selected examples, see: a) D. Zell, S. Warratz, D. Gelman, S.
J. Garden, L. Ackermann, Chem. Eur. J. 2016, 22, 1248–1252; b)
L. Ackermann, A. Althammer, R. Born, Angew. Chem. Int. Ed.
2006, 45, 2619–2622; c) L. Ackermann, Org. Lett. 2005, 7, 3123–
3125.
D. Song, S. Ma, ChemMedChem 2016, 11, 646–659.
M. Hocek, Eur. J. Org. Chem. 2003, 245–254.
For detailed information, see the Supporting Information.
L. Ackermann, Synthesis 2006, 1557–1571.
Generous support by the DFG (SPP 1807 and Gottfried-
Wilhelm-Leibniz award) is gratefully acknowledged. We thank Dr.
Christopher Golz (University Göttingen) for assistance with the
X-ray diffraction analysis, and Karsten Rauch (University
Göttingen) for the synthesis of L4 and L5.
Keywords: asymmetric catalysis • nickel • C−H activation •
SPOs • aluminum-free
[1]
a) Y. Xu, G. Dong, Chem. Sci. 2018, 9, 1424–1432; b) W. Wang,
M. M. Lorion, J. Shah, A. R. Kapdi, L. Ackermann, Angew. Chem.
Int. Ed. 2018, 57, 14700–14717; c) T. Piou, T. Rovis, Acc. Chem.
Res. 2018, 51, 170–180; d) P. Gandeepan, L. Ackermann, Chem
2018, 4, 199–222; e) Y. Park, Y. Kim, S. Chang, Chem. Rev. 2017,
117, 9247–9301; f) J. He, M. Wasa, K. S. L. Chan, Q. Shao, J.-Q.
Yu, Chem. Rev. 2017, 117, 8754–8786; g) B. Ye, N. Cramer, Acc.
Chem. Res. 2015, 48, 1308–1318; h) G. Rouquet, N. Chatani,
Angew. Chem. Int. Ed. 2013, 52, 11726–11743; i) D. A. Colby, A.
S. Tsai, R. G. Bergman, J. A. Ellman, Acc. Chem. Res. 2012, 45,
814–825; j) T. Satoh, M. Miura, Chem. Eur. J. 2010, 16, 11212–
11222; k) L. Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem.
[10]
[11]
[12]
[13]
[14]
This article is protected by copyright. All rights reserved.

10.1002/anie.201813191
Angewandte Chemie International Edition
COMMUNICATION
[15]
Selected examples: a) D. Berthold, B. Breit, Org. Lett. 2018, 20,
598–601; b) X. Wu, Z. Chen, Y.-B. Bai, V. M. Dong, J. Am. Chem.
Soc. 2016, 138, 12013–12016; c) A. M. Haydl, L. J. Hilpert, B.
Breit, Chem. Eur. J. 2016, 22, 6547–6551; d) A. M. Haydl, K. Xu, B.
Breit, Angew. Chem. Int. Ed. 2015, 54, 7149–7153; e) K. Xu, N.
Thieme, B. Breit, Angew. Chem. Int. Ed. 2014, 53, 7268–7271; f) H.
Landert, F. Spindler, A. Wyss, H.-U. Blaser, B. Pugin, Y.
Ribourduoille, B. Gschwend, B. Ramalingam, A. Pfaltz, Angew.
Chem. Int. Ed. 2010, 49, 6873–6876; g) L. Ackermann, in Trivalent
Phosphorus Compounds in Asymmetric Catalysis, Sythesis and
Applications (Ed.: A. Börner), Wiley-VCH, Weinheim, 2008, pp.
831–847.
[16]
[17]
5-Membered rings could be formed with high levels of enantio-
control as well, yet lower conversions were observed here (Table
S-3 in the Supporting Information). Substrates 1 bearing aryl
substituents gave thus far less satisfactory results.
CCDC 1871583, 1871584, 1871585 and 1871582 for compounds
2e, 3,
4 and 5, respectively, contain the supplementary
crystallographic data for this contribution. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
[18]
a) A. J. Nett, J. Montgomery, P. M. Zimmerman, ACS Catal. 2017,
7, 7352–7362; b) A. J. Nett, W. Zhao, P. M. Zimmerman, J.
Montgomery, J. Am. Chem. Soc. 2015, 137, 7636–7639.
T. Satyanarayana, S. Abraham, H. B. Kagan, Angew. Chem. Int.
Ed. 2009, 48, 456–494.
a) S. Tang, O. Eisenstein, Y. Nakao, S. Sakaki, Organometallics
2017, 36, 2761–2771; b) V. Singh, Y. Nakao, S. Sakaki, M. M.
Deshmukh, J. Org. Chem. 2017, 82, 289–301; c) Y. Gao, K. N.
Houk, C.-Y. Ho, X. Hong, Org. Biomol. Chem. 2017, 15, 7131–
7139; d) X. Hong, J. Wang, Y.-F. Yang, L. He, C.-Y. Ho, K. N.
Houk, ACS Catal. 2015, 5, 5545–5555; e) Y.-Y. Jiang, Z. Li, J. Shi,
Organometallics 2012, 31, 4356–4366.
[19]
[20]
[21]
For the discussion on mechanistic aspects, see: a) D. Zell, M.
Bursch, V. Müller, S. Grimme, L. Ackermann, Angew. Chem. Int.
Ed. 2017, 56, 10378–10382; b) O. Eisenstein, J. Milani, R. N.
Perutz, Chem. Rev. 2017, 117, 8710–8753; c) L.-J. Xiao, X.-N. Fu,
M.-J. Zhou, J.-H. Xie, L.-X. Wang, X.-F. Xu, Q.-L. Zhou, J. Am.
Chem. Soc. 2016, 138, 2957–2960; d) J. S. Bair, Y. Schramm, A.
G. Sergeev, E. Clot, O. Eisenstein, J. F. Hartwig, J. Am. Chem.
Soc. 2014, 136, 13098–13101; e) J. Guihaumé, S. Halbert, O.
Eisenstein, R. N. Perutz, Organometallics 2012, 31, 1300–1314; f)
L. Ackermann, Chem. Rev. 2011, 111, 1315–1345.
This article is protected by copyright. All rights reserved.

10.1002/anie.201813191
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
J. Loup,+ V. Müller,+ D. Ghorai, and L.
Ackermann*
Page No. – Page No.
Enantioselective Aluminum-Free
Alkene Hydroarylations via C–H
Activation by a Chiral
Text for Table of Contents
Nickel/JoSPOphos Manifold
SPO rules: A chiral Ni/SPO regime enabled outstanding levels of enantio-control in asymmetric C–H alkylations
with unactivated alkenes.
This article is protected by copyright. All rights reserved.