Ruthenium-Catalyzed para-Selective C?H Alkylation of Aniline Derivatives

Article abstract of DOI:10.1002/anie.201708961

The para-selective C?H alkylation of aniline derivatives furnished with a pyrimidine auxiliary is herein reported. This reaction is proposed to take place via an N?H-activated cyclometalate formed in situ. Experimental and DFT mechanistic studies elucidate a dual role of the ruthenium catalyst. Here the ruthenium catalyst can undergo cyclometalation by N?H metalation (as opposed to C?H metalation in meta-selective processes) and form a redox active ruthenium species, to enable site-selective radical addition at the para position.

Full text of DOI:10.1002/anie.201708961

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Ruthenium-Catalyzed para-Selective C-H Alkylation of Aniline
Derivatives
Authors: Christopher Frost, Jamie Leitch, Claire McMullin, Andrew
Paterson, Mary Mahon, and Yunas Bhonoah
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.201708961
Angew. Chem. 10.1002/ange.201708961
Link to VoR: http://dx.doi.org/10.1002/anie.201708961
http://dx.doi.org/10.1002/ange.201708961

10.1002/anie.201708961
Angewandte Chemie International Edition
COMMUNICATION
Ruthenium-Catalyzed para-Selective C-H Alkylation of Aniline
Derivatives
Jamie A. Leitch,[a] Claire L. McMullin,[a] Andrew J. Paterson,[a] Mary F. Mahon,[a] Yunas Bhonoah,[b] and
Christopher G. Frost.*[a]
Abstract: The para-selective C-H alkylation of aniline derivatives
furnished with a pyrimidine auxiliary is herein reported. This is
proposed to take place via a N-H activated cyclometalate formed in
situ. Experimental and DFT mechanistic studies elucidate a dual role
ruthenium catalyst. Here the ruthenium catalyst can undergo
cyclometalation via N-H metalation (as opposed to C-H metalation in
meta-selective processes) and form a redox active ruthenium species,
to enable site selective radical addition at the para position.
Transition-metal catalyzed C-H functionalization has evolved into
a widespread and effective technique to derivate (hetero)arenes
and especially biologically relevant motifs.[1] The innate hurdle in
C-H functionalization is the differentiation of electronically and
sterically similar C-H bonds in an organic structure. To overcome
this, a directing group strategy is often employed to enable
selective ortho-C-H functionalization via chelation assistance with
respect to the directing group.[2] Recent developments have
allowed carefully tailored catalytic systems to permit meta-
selective C-H functionalization.[3] These methods utilize three
primary techniques; templated directing group design,[4] the use
of a transient mediator,[5] and σ-activation by a metal center.[6]
Accessing complementary para-selective methodologies typically
takes advantage of electronic effects to permit C-H
functionalization at the para position of an electron rich arene, with
pioneering reports from Gaunt,[7] Nicewicz,[8] and Ritter[9]
Scheme 1. Previous Reports on Site Selective Catalytic C-H Functionalization
(Scheme 1a). There have been examples of the use of extended
in the Context of this Work.
templates by Maiti,[10] and the careful manipulation of steric effects
by Itami[11] and Nakao.[12] [13]
.
In a recent report Weng and Lu
described the use of 5-membered aminopyridine-based bidentate
cyclometalates in the para-C-H functionalization of
aminonaphthalene derivatives.[14],[15]
We were intrigued to investigate whether complementary Ru-N
cyclometalation of anilines (as opposed to Ru-C in in meta-
selective sigma activation strategies), could lead to an active
catalyst which may permit complementary para-C-H
functionalization (Scheme 1c). Anilines have been widely used as
templates for C-H functionalization development,[16] due to their
ubiquity in active pharmaceuticals[17] and agrochemicals.[18] This
concept was initially investigated by submitting aniline to slightly
modified conditions from our previous work on meta-alkylation
methodology (Scheme 2).[6c]
Herein, we demonstrate that certain aniline derivatives can
undergo para-selective C-H alkylation reactions catalyzed by
ruthenium complexes. σ-Activation focuses on the use of strongly
bound ruthenacycles which can activate remote positions via
electronic effects.[6] Ackermann applied this concept to aniline
derivatives furnished with a pyrimidine directing groups to enable
meta-selective alkylations (Scheme 1b).
[a]
[b]
Mr. Jamie A. Leitch, Dr. Claire L. McMullin, Dr. Andrew J. Paterson,
Dr. Mary F. Mahon, Prof. Christopher G. Frost
Department of Chemistry
University of Bath
Claverton Down, Somerset, BA2 7AY, United Kingdom
E-mail:
Dr. Yunas Bhonoah
Scheme 2. Ruthenium Catalysed para-C-H Alkylation of Aniline
Syngenta
Jealott’s Hill International Research Centre
Bracknell, Berkshire, RG42 6EY, United Kingdom
This led to primarily the ortho/para-substituted aniline (3a),
whereby an in situ lactamization can take place on at the ortho
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201708961
Angewandte Chemie International Edition
COMMUNICATION
position, amongst multiple other products. No C-H alkylation
products were observed in the absence of ruthenium catalyst or
in the presence of radical scavenger TEMPO. This suggests a
redox catalyst is formed in situ enabling radical arene
functionalization. Encouraged by this, we endeavored to promote
a solely para-selective transformation by using a bespoke N-
substituted auxiliary (Table 1).
Despite its use in other meta-alkylation methodologies a
pyrimidine auxiliary (1b) gave the para-substituted structure in
modest conversions (entry 1).[6d],[19] No meta-functionalization was
observed, however competing di-C-H alkylation occurred on the
auxiliary (4b), albeit in low amounts. It is worth noting throughout
the auxiliary optimization, there was no observation of the
ortho/para-disubstituted structure. Pleasingly the use of 5-
chloropyrimidine as the auxiliary (1c) led to completely selective
para-functionalization (entry 2). Pyridyl (1e) and Acetanilide (1f)
did not lead to any C-H functionalized products (entries 4-5), and
pyridoyl derivative (1g) was also unsuccessful (entry 6). A screen
of solvents identified TBME (tert-butyl methyl ether) as the optimal
reaction medium (entries 6-8). A ligand screen manifested that
removal of the ligand entirely was of benefit to the reaction
(entries 10-13), and could be due to a reduction in undesired
ortho-cyclometalation. Unfortunately, isolated yields in this
methodology were found to be substantially lower than NMR
yields, primarily due to polymeric byproducts formed which were
indistinguishable via proton NMR (see ESI, Scheme S3).
Interestingly on increasing the temperature to 140 °C, we
observed formation of competing meta-selectivity (entry 13), and
importantly no reactivity was observed in the absence of the
ruthenium catalyst (entry 16).
Table 1. Ruthenium-Catalyzed para-C-H Alkylation of Aniline Derivatives
With suitable conditions in hand to access para-substituted
structures, we applied this methodology to a range of coupling
partners and substituted arenes (Scheme 3).[20]
Entry
Aux
Ligand
Solvent
3 %[b]
4 %[b]
5 %[b]
[a]
1
1b
1c
1d
1e
1f
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
MesCO2H
Piv-Val-OH
DMEDA
-
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
PhMe
35
39
16
-
6[c]
-
-
-
-
-
-
-
-
-
-
-
-
-
-
2
3
10[c]
-
4
5
-
-
-
-
-
-
-
-
-
-
6
1g
1c
1c
1c
1c
1c
1c
1c
-
7
56
56
81
77
70
85
8
DCE
9
TBME
10
11
12
13
TBME
TBME
TBME
TBME
86
(55)[d]
14[e]
15[f]
16[g]
1c
1c
1c
-
-
-
TBME
TBME
TBME
55
71
-
-
-
38
-
Aux = auxiliary [a] Standard Conditions: aniline derivative (0.25 mmol), methyl
α-bromoisobutyrate (0.75 mmol), [RuCl2(p-cymene)]2 (0.0125 mmol), ligand
(0.075 mmol), K2CO3 (0.5 mmol), solvent (1 mL) under a N2 atmosphere. [b]
1H NMR yield. [c] * denotes position of di-functionalization. [d] isolated yield.
[e] at 140 °C. [f] under an air atmosphere. [g] no ruthenium catalyst.
Scheme 3. Scope of Ruthenium-Catalyzed para-Selective C-H Alkylation of
Aniline Derivatives
This article is protected by copyright. All rights reserved.

10.1002/anie.201708961
Angewandte Chemie International Edition
COMMUNICATION
This scope showed that a variety of tertiary alkyl esters could be
applied in modest yields (3c-3ce). A cyclohexyl derivative was
also shown to be amenable to the reaction (3cf), and must be
noted that all of these examples proceeded with absolute
selectivity for the para position. On varying the ring electronics, it
was found that 3-substitution was tolerated well (3h-m) and that
the none of the electronic influences of these substituents
overrode the selectivity dictated by the N-substitution pattern. The
quinazoline heterocycle was also shown to be applicable to this
methodology, again in modest yields (3na-3nd).
deuterium scrambling in their report.[6f] It must be noted there was
no substantial hydrogen incorporation at either meta or para
positions in either investigation, which demonstrates there is no
reversible direct C-H metalation responsible for the selectivity
observed.
We anticipated that under certain conditions, the regioselectivity
of functionalization could be switched to a meta-selective protocol
using identical an starting material and coupling partner (Scheme
4).[21] With carboxylate assistance as well as a change of solvent
from 1,4-dioxane to DME, the meta-selective reaction was
strongly favored and led to corresponding meta-C-H alkylated
product with very high selectivity (99:1 m/p) (Scheme 4). It must
be noted removal of the AcOH still favors meta-selectivity,
however this is less pronounced. This suggests that in a proposed
equilibrium between N-H and C-H cyclometalated complexes, the
use of
a carbonate base (K2CO3) could favor an N-H
cyclometalation to form para-substituted products, whereas
acetate bases (KOAc) could favor an ortho-C-H cyclometalation
to form meta-substituted products.
Scheme 5. Mechanistic Studies on para Alkylation Methodology
Scheme 4. Ruthenium-Catalyzed meta-C-H Alkylation of Aniline Derivative
Acetanilide was chosen as a model comparison for a crossover
study due to similar electronic influence on the ring, pKa of the N-
H, and that it contains a metal coordinating group (Scheme 5b). If
the pyrimidine is only generating a redox active species capable
of forming the tertiary radicals, which can then interact with an
electron rich organic structure, one would expect to see a mixture
of para-C-H alkylated pyrimidine (3c) and acetanilide (3f). No
presence of 3f was observed and 3c was isolated in equable
yields. This strongly suggests that the C-H functionalization taking
place at the para position is directly influenced by electronic
effects of a coordinated ruthenium species. This result along with
the previous insights suggest a σ-activation/redox pathway
analogous to previous meta-selective methodology,[6] however in
this case unlocking the complementary para-selective chemistry.
As we were observing a definitive shift in selectivity from meta to
para, it was of interest to perform experimental and computational
mechanistic studies to provide rationale to a proposed Ru-N
cyclometalation/activation pathway. Initially we carried out radical
scavenger studies using TEMPO where the use of stoichiometric
amounts led to complete suppression of reactivity. The isolation
of polymeric byproducts, and the unique reactivity of α-
halocarbonyls are also indicative of a radical mechanism.
The proposed mechanism for the remote para C-H alkylation does
not involve cyclometalation on the aromatic ring via ortho-C-H
cyclometalation. In order to explore this an isotopically labelled
derivative 1c-d5 was submitted to the reaction conditions
(Scheme 5a). This showed that under the para conditions there
was negligible H/D scrambling (~2%) in either the unreacted
starting material or the product. This suggests readily reversible
ortho-C-H cyclometalation is not possible. The complementary
meta-selective conditions did however give rise to substantial
scrambling in both recovered starting material and meta-alkylated
product. Despite this, Huang and co-workers did not observe
Density Functional Theory (DFT) calculations of the competing N-
H and C-H activation of 1c have been computed for acetate or
carbonate as the base (see Figure 1 and ESI for discussion).[22]
A
change in preferred activation and hence mechanism occurs, with
acetate favoring C-H activation and hence a meta-selective
mechanism, whilst carbonate has a lower barrier to N-H activation
and a para-selective product.
This article is protected by copyright. All rights reserved.

10.1002/anie.201708961
Angewandte Chemie International Edition
COMMUNICATION
M. E. Farmer, J.-Q. Yu, J. Am. Chem. Soc. 2016, 138, 14876. e) Q.-L.
Zhang, B.-L. Wan, B. Sun, S. Yeung, F.-L. Zhang, J.-Q. Yu. J. Am. Chem.
Soc., 2017, 139, 888.
[6] For selected contributions see: a) O. Saidi, J. Marafie, A. E. W. Ledger,
P. M. Liu, M. F. Mahon, G. Kociok-Köhn, M. K. Whittlesey, C. G. Frost, J.
Am. Chem. Soc., 2011, 133, 19298. b) N. Hofmann, L. Ackermann, J. Am.
Chem. Soc., 2013, 135, 5877. c) A. J. Paterson, S. St John Campbell, M. F.
Mahon, N. J. Press, C. G. Frost, Chem. Commun., 2015, 51, 12807. d) J. Li,
S. Warratz, D. Zell, S. De Sarkar, E. E. Ishikawa, L. Ackermann, J. Am.
Chem. Soc., 2015, 137, 13894. e) C. J. Teskey, Y. W. Lui, M. F. Greaney,
Angew. Chem. Int. Ed., 2015, 54, 11677. f) Q. Yu, L. Hu, Y. Wang, S.
Zheng, J. Huang, Angew. Chem. Int. Ed., 2015, 54, 15284. g) Z. Fan, J. Ni, A.
Zhang, J. Am. Chem. Soc., 2016, 138, 8470. h) Z. Ruan, S.-K. Zhang, C. Zhu,
P. N. Ruth, D. Stalke, L. Ackermann, Angew. Chem. Int. Ed., 2017, 129, 2077.
i) J. A. Leitch, C. L. McMullin, M. F. Mahon, Y. Bhonoah, C. G. Frost, ACS
Catal. 2017, 7, 2616. j) J. Li, K. Korvorapun, S. De Sarkar, T. Rogge, D. J.
Burns, S. Warratz, L. Ackermann, Nat. Commun., 2017, 8, 15430. k) A. J.
Paterson, C. J. Heron, C. L. McMullin, M. F. Mahon, N. J. Press, C. G. Frost,
Org. Biomol. Chem., 2017, 15, 5993.
Figure 1: Summary of DFT calculated free energies (kcal mol-1) relative to the
most stable intermediate, for the competing C-H and N-H activations of 1c at
[Ru(p-cymene)(O2CR)]+ in dioxane, when
R = Me (acetate) or OH
(carbonate).[22]
[7]
Angew. Chem. Int. Ed., 2011, 50, 458.
[8] N. A. Romero, K. A. Margery, N. E. Tay, D. A. Nicewicz, Science, 2015,
349, 1326.
C.-L. Ciana, R. J. Phipps, J. R.; Brandt, F.-M.; Meyer, M. J. Gaunt,
In summary, we have reported the selective para-C-H alkylation
of aniline derivatives, making use of pyrimidine and quinazoline
auxiliaries. Experimental and computational mechanistic studies
suggest that the addition takes place via a radical process to a
ruthenium species cyclometalated at N-H rather than C-H
(previously seen). This positional cyclometalation has been
proposed to dictate the selectivity, which permits functionalization
para to the metal center which in this case is para to the N-
substituted auxiliary.
[9]
G. B. Boursalian, W. S. Ham, A. R. Mazzotti, T. Ritter, Nat. Chem.,
2016, 8, 810.
[10] a) S. Bag, T. Patra, A. Modak, A. Deb, S. Maity, U. Dutta, A. Dey, R.
Kancherla, A. Maji, A. Hazra, M. Bera, D. Maiti, J. Am. Chem. Soc., 2015, 137,
11888. b) T. Patra, S. Bag, R. Kancherla, A. Mondal, A. Dey, S. Pimparka, S.
Agasti, A. Modak, D. Maiti, Angew. Chem. Int. Ed., 2016, 55, 7751. c) M. E.
Hoque, R. Bisht, C. Haldar, B. Chattopadhyay, J. Am. Chem. Soc., 2017, 139,
7745.
[11] a) Y. Saito, Y. Segawa, K. Itami, J. Am. Chem. Soc., 2015, 137, 5193.
b) B. E. Haines, Y. Saito, Y. Segawa, K. Itami, D. G. Musaev, ACS Catal.,
2016, 6, 7536.
[12] a) S. Okumura, S. Tang, T. Saito, K. Semba, S. Sakaki, Y. Nakao, J.
Am. Chem. Soc., 2016, 138, 14699. b) S. Okumura, Y. Nakao, Org. Lett.,
2017, 19, 584. c) L. Yang, K. Semba, Y. Nakao, Angew. Chem. Int. Ed., 2017,
56, 4853.
Acknowledgements
[13] For selected contribution on remote aminoquinoline functionalization
see: H. Qiao, S. Sun, F. Yang, Y. Zhu, W. Zhu, Y. Dong, Y. Wu, X. Kong, L.
Jiang, Y. Wu, Org. Lett., 2015, 17, 6086.
J. A. L. would like to thank the University of Bath and Syngenta
for funding. This research made use of the Balena High
Performance Computing (HPC) Service at the University of Bath.
[14] a) J.-M. Li, Y.-H. Wang, Y. Yu, R.-B. Weng, G. Lu, ACS Catal., 2017, 7,
2661. b) S. Liang, M. Bolte, G. Manolikakes, Chem. Eur. J., 2017, 23, 96.
[15] Other examples of para-selective C-H functionalisation include: a) W.
Liu, L. Ackermann, Org. Lett., 2013, 15, 3484. b) X. Wang, D. Leow, J.-Q. Yu,
J. Am. Chem. Soc., 2011, 133, 13864. c) B. Ma, Z. Chu, B. Huang, Z. Liu, L.
Liu, J. Zhang, Angew. Chem. Int. Ed., 2017, 56, 2749. d) Y. X. Luan, T. Zhang,
W.-W. Yao, K. Lu, L.-Y. Kong, Y.-T. Lin, M. Ye, J. Am. Chem. Soc., 2017, 139,
1786. e) B. Berzina, I. Sokolovs, E. Suna, ACS Catal., 2015, 5, 7008. f) L. T.
Ball, G. C. Lloyd-Jones, C. A. Russell, Science, 2012, 337, 1644.
[16] For selected contributions see: a) Z. Ruan, S. Lackner, L. Ackermann,
Angew. Cem. Int. Ed., 2016, 55, 3153. b) C. E. Houlden, M. Hutchby, C. D.
Bailey, J. G. Ford, S. Tyler, M. Gagné, G. C. Lloyd-Jones, Angew. Chem. Int.
Ed., 2009, 48, 1830. c) S. P. Midya, M. K. Sahoo, V. G. Landge, P. P.
Rajamohanan, E. Balaraman, Nat. Commun., 2015, 6, 8591.
[17] a) E. Weisberg, P. Manley, J. Mestan, S. Cowan-Jacob, A. Ray, J. D.
B. Griffin, Cancer, 2006, 94, 1765. b) M. Baccarani, J. Cortes, F. Pane, D.
Niederwieser, G. Saglio, J. Apperley, F. Cervantes, M. Deininger, A. Gratwohl,
F. Guilhot, A. Hochhaus, M. Horowitz, T. Hughes, H. Kantarjian, R. Larson, J.
Radich, B. Simonsson, R. T. Silver, J. Goldman, R. Hehlmann, J. Clin. Oncol.,
2009, 27, 6041.
Keywords: Ruthenium • para-Selective • Homogeneous
Catalysis • C-H Functionalization • Aniline
[1]
For reading on transition metal catalyzed C-H functionalization see: a)
L. Ackermann, Chem. Rev. 2011, 111, 1315. b) P.B. Arockiam, C. Bruneau, P.
Dixneuf, P. Chem. Rev. 2012, 112, 5879. c) X. Chen, K. M. Engle, D.-H.
Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094. d) K. M. Engle, T.-S.
Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788. e) H. M. L. Davies,
D. Morton, J. Org. Chem., 2016, 81, 343. f) S. De Sarakar, W. Liu, S. I.
Kozhushkov, L. Ackermann, Adv. Synth. Catal. 2014, 356, 1461. g) J. A.
Leitch, Y. Bhonoah, C. G. Frost, ACS Catal., 2017, 7, 5618-5627. For reading
on the modification of biologically active molecules see: h) J. A. Leitch, P. B.
Wilson, C. L. McMullin, M. F. Mahon, Y. Bhonoah, I. H. Williams, C. G. Frost,
ACS Catal., 2016, 6, 5520. i) W. Ma, H. Dong, D. Wang, L. Ackermann, Adv.
Synth. Catal., 2017, 359, 966.
[2]
a) J.-Q. Yu, Adv. Synth. Catal., 2014, 356, 1393. b) M. Zhing, Y. Zahng,
[18] Rappoport, Z. The Chemistry of Anilines; Wiley: New York, 2007
[19] Crystallographic data for 3b. Crystal Data
for C15H17N3O2 (3b): M =271.32 g mol–1, triclinic,
X. Jie, H. Zhao, G. Li, W. Su, Org. Chem. Front., 2014, 1, 843. c) T. W. Lyons,
M. S. Sanford, Chem. Rev., 2010, 110, 1147. d) W. Ma, P. Gandeepan, J. Li,
L. Ackermann, Org. Chem. Front., 2017, 4, 1435. e) L. Ping, D. S. Chung, J.
Bouffard, S.-G. Lee, Chem. Soc. Rev., 2017, 46, 4299. f) Z. Chen, B. Wang, J
Zhang, W. Yu, Y. Zhang, Org. Chem. Front, , 2015, 2, 1107.
space group P-1 (no. 2), a = 6.0353(3), b =
7.4947(3), c = 16.2821(8) Å, α = 98.032(4), β =
90.419(4), γ = 111.856(4)°, U = 675.43(6) Å3, Z =
2, T = 150 K, μ(CuKα) = 0.736 mm–1, Dcalc = 1.334
[3]
a) J.-Y. Cho, M. K. Tse, D. Holmes, R. E. Maleczka, M. R. Smith,
Science, 2002, 295, 305. b) D. W. Robbins, J. F. Hartwig, Angew. Chem. Int.
Ed., 2013, 52, 933. c) Y.-H. Zhang, B-F. Shi, J.-Q. Yu, J. Am. Chem. Soc.,
2009, 131, 5072. d) J. Yang, Org. Biomol. Chem., 2015, 13, 1930. e) R. J.
Phipps, M. J. Gaunt, Science, 2009, 323, 1593.
g cm–3, 5703 reflections measured (10.998° ≤ 2ϴ ≤ 146.772°), 2713 unique
(Rint = 0.0251 which were used in all calculations. The final R1 was 0.0389 (I >
2σ(I)) and wR2 was 0.1047 (all data). Crystallographic data for 3 have been
deposited with Cambridge Crystallographic Data Centre: Deposition number
CCDC 1555867. Copies of these data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge, CB2 1EZ, UK;
Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
[20] Unreactive and low yielding coupling partners are given in the ESI..
[21] Under Ackermann’s conditions from references 6b or 6d only para-
substituted products were formed.
[4]
For selected contributions see: a) D. Leow, G. Li, T.S. Mei, J.-Q. Yu,
Nature, 2012, 486, 518. b) R.-Y. Tang, G. Li, J.-Q. Yu, Nature, 2014, 507, 215.
c) A. Dey, S. Agasti, D. Maiti, Org. Biomol. Chem., 2016, 14, 5440. d) Y.
Kuninobu, H. Ida, M. Nishi, M. Kanai, Nat. Chem. 2015, 7, 712. e) H. J. Davis,
M. T. Mihai, R. J. Phipps, J. Am. Chem. Soc., 2016, 138, 12759. f) Z. Zhang,
K. Tanaka, J.-Q. Yu, Nature, 2017, 543, 538.
[5]
For selected contributions see: a) J. Luo, S. Preciado, I. Larrosa, J. Am.
Chem. Soc., 2014, 136, 4109. b) X.-C. Wang, W. Gong, L.-Z. Fang, R.-Y. Zhu,
S. Li, K. M. Engle, J.-Q. Yu, Nature, 2015, 519, 334. c) Z. Dong, J. Wang, G.
Dong, J. Am. Chem. Soc., 2015, 137, 5887. d) H. S. Shi, P. Wang, S. Suzuki,
[22] Full details and references for computational methods can be found in
the ESI.
This article is protected by copyright. All rights reserved.

10.1002/anie.201708961
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here))
Layout 2:
COMMUNICATION
Jamie A. Leitch, Claire L. McMullin,
Andrew J. Paterson, Mary F. Mahon,
Yunas Bhonoah, and Christopher G.
Frost*
1-4.
Ruthenium-Catalyzed para-Selective
C-H Alkylation of Aniline Derivatives
Para-normal activity: The para-selective C-H alkylation of aniline derivatives is
reported. The methodology is proposed to proceed via a dual role ruthenium process:
cycloruthenation at N-H, and redox radical generation. This strategy proved to access
para-selective alkylations using pyrimidine and quinazoline auxiliaries.
This article is protected by copyright. All rights reserved.