Directing-Group-Free C7-Alkylations of N-Alkylindoles Mediated by Cationic Zirconium Complexes: Role of Br?nsted Acid for Catalytic Manifold

Article abstract of DOI:10.1002/chem.201901268

Highly position selective alkylations of N-alkylindoles at C7-positions have been enabled by cationic zirconium complexes. The strategy provides a straightforward access to install alkyl groups at C7-positions of indoles without a complex directing group. Mechanistic studies provided support for the importance of Br?nsted acids in the catalytic manifold.

Full text of DOI:10.1002/chem.201901268

A Journal of
Accepted Article
Title: Directing Group-free C7-alkylations of N-alkylindols Mediated
by Cationic Zirconium Complexes: Role of Brønsted Acid for
Catalytic Manifold
Authors: Ping Chen, Yanhong Hao, Xinxin Wang, Dan Yuan, Yingming
Yao, 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: Chem. Eur. J. 10.1002/chem.201901268
Link to VoR: http://dx.doi.org/10.1002/chem.201901268
Supported by

10.1002/chem.201901268
Chemistry - A European Journal
COMMUNICATION
Directing Group-free C7-alkylations of N-alkylindols Mediated by
Cationic Zirconium Complexes: Role of Brønsted Acid for Catalytic
Manifold
Ping Chen,[a] Yanhong Hao,[a] Xinxin Wang,[a] Dan Yuan,[a],* Yingming Yao,[a],* and Lutz Ackermann[b],*
Abstract:
alkylindole at C7-positions have been enabled by cationic
zirconium complexes. The strategy provides
Highly position-selective alkylations of N-
Limitation of this indirect method are obviously represented by
low step economy, and restriction to oxidant-compatible
substrates.
a
straightforward access to install alkyl groups at C7-positions
of indoles without complex directing group. Mechanistic
studies provided support for the importance of Brønsted
acids in the catalytic manifold.
Early transition metal complexes have found application in
catalyzing C-H functionalization of for instance pyridine,[13]
anisole,[14] and aniline[15] derivatives, which showed different
activity, chemo- and regio-selectivity, and functional group
compatibility with those of late transition metal catalysts.[16]
However, although C2- and C3-alkylation of indoles catalyzed by
group 3 and 4 metal complexes have been established,[17] there
is no precedent of early transition metal catalyzed C7-alkylation.
Indoles are privileged structural motifs, which have found wide
application as biologically and pharmaceutically-active
substances. They are ubiquitously found in natural organisms,
and are also used as raw materials for spices, dyes, fragrances,
and pesticides.[1] The construction of indole derivatives has thus
attracted continued interests and efforts.[2] Particularly, the direct
functionalization of C-H bonds of indoles provides
a
straightforward and highly atom-economic approach to
[3,4,2b]
synthesize substituted indoles.
Conventional electrophilic substitutions of indoles occur
preferentially at C3-position. To achieve functionalization at
other positions, suitable catalysts and/or directing groups are
required. C2-alkylations have been accomplished by introducing
directing groups (e.g., pyridyl, pyrimidinyl, Ac, and CONHOEt)
on the indole nitrogen atom,[5] while C4-, C5- and C6-
functionalizations were realized through introducing pivaloyl,
P(O)tBu2, trifluoroacetyl, CO2Me and CHO directing groups.[6]
Typical catalysts are thus far based on nickel,[5b,7] cobalt,[5c,e]
palladium,[6a,c]
copper,[6b]
iridium,[5a,6d,e,i]
manganese,[5g]
ruthenium[5h,i,6h,j,k] and iron [8] complexes.
To achieve selective functionalization at the C7-position of
indoles,[9] directing groups such as Ac,[9k,10] P(O)tBu2,[9j,11]
Scheme 1. Regioselective synthesis of C7-alkylation of indoles.
pyrimidinyl,[9f] and SiEt2
have been developed.[3] In this
[9n]
context, Tan and Ma reported rhodium-catalyzed site-selective
C7-alkylations and alkenylations of indoles using N-pivaloyl
directing group (Scheme 1a).[9g] Shi developed rhodium-
catalyzed C7-alkylation of N-PtBu2-indole with olefins (Scheme
1b),[9l] while very recently, C7-methylation with acetic anhydride
were realized.[9o] These are the only examples of direct C7-
alkylation of indoles. Another approach to prepare C7-
functionalized indoles is to react electrophiles with indoline,
which can be converted to indoles through oxidation.[12]
Our group has reported cationic zirconium complexes as
catalysts in direct C-H bond alkylation of pyridine derivatives,
giving rise to pyridine alkylation at either C(sp2)-H or C(sp3)-H
bonds.[18] Amine-bridged bis(phenolato) ligands are found to
significantly influence the site-selectivity. In contrast, we herein
disclose the unprecedented alkylation of N-alkylindoles in the
presence of cationic zirconium complexes. Highly regio-selective
C7-alkylation of alkylindoles was achieved without introducing
complex directing group (Scheme 1c). Mechanistic studies
unravelled the key relevance of a Brønsted acids within the
catalytic regime.
Zirconium dibenzyl complexes 1-4 (Figure 1) were prepared
by metathesis reactions of ZrBn4 and bis(phenol) bridged by
different amines. Complexes 1 and 2 are stabilized by tridentate
ligands, while complexes 3 and 4 carry tetradentate ligands.
Cationic complexes were formed in situ from zirconium dibenzyl
complex and [Ph3C][B(C6F5)4](TB),[18a] and their performance
was probed in the C-H alkylation of N-methylindole with styrene
(Table 1).
[a]
[b]
P. Chen, Y. Hao, X. Wang, Prof. Dr. D. Yuan and Prof. Dr. Y. Yao
Key Laboratory of Organic Synthesis of Jiangsu Province, College
of Chemistry, Chemical Engineering and Materials Science
Soochow University
Suzhou 215123, P. R. China
E-mail: yuandan@suda.edu.cn (D. Y.); yaoym@suda.edu.cn (Y. Y.)
Prof. Dr. Lutz Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universiät Götingen
Tammannstraße 2, 37077 Götingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/
In a preliminary study, reaction of N-methylindole and styrene
catalyzed by complex 1 and TB generated alkylation product in
67% yield (Table 1, entry 3). It is noteworthy that two isomers,
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/chem.201901268
Chemistry - A European Journal
COMMUNICATION
i.e., C7-alkylated product 3aa and C3-alkylated 4aa were
detected in 10:1 ratio. The connectivity of the unusual product
3aa was unambiguously verified by single crystal X-ray
diffraction analysis (Table 2).[19]
after 24 h reaction, and the ratio of the C7-product 3aa to the
C3-product 4aa reached 10: 1 (Table 1, entry 7). Pure C7-
alkylated compound 3aa was isolated in 76% yield. This is an
unprecedented example of early transition metal-mediated direct
C7-alkylation of indoles. Moreover, no complex directing group
is required, adding to the synthetic utility of this method.
Figure 1. Complexes 1-4.
Since [Ph3C][B(C6F5)4] (TB) was active in catalyzing Friedel-
Crafts alkylation of indoline and styrene,[20] its performance in
catalyzing the reaction of N-methylindole and styrene was also
studied. A low yield of 50% and poor regioselectivity (3aa: 4aa =
1: 1) was observed (Table 1, entry 1). In addition, neutral
complex 1 failed to catalyze the reaction (Table 1, entry 2).
Apparently, the cationic zirconium complex showed significantly
improved catalytic activity, possibly owing to enhanced Lewis
acidity, and larger space for substrate binding, which is
consistent with previous reports.[18] Complexes 2-4 and TB
revealed poor catalytic activities and/or regioselectivity (Table 1,
entry 4-6). It is noteworthy that complex 2 bearing an n-butyl
amine-bridged tridentate ligand gave reversed regioselectivity,
suggesting that ligand structures largely influence not only the
catalytic activities, but also the position-selectivities (Table 1,
entry 4).
Under the optimal reaction conditions, the scope of the
method was investigated, and the results are summarized in
Table 2. Reactions of N-methylindole with para-halide-
substituted styrenes generated C7-alkylation products 3ab, 3ac,
and 3ad in good yields of 80-84%. In each case, C3-alkylated
products formed in <10% yield. Alkylation reaction was
obviously influenced by steric properties of styrenes, as yields
dropped in the sequence of para-, meta- and ortho-substitution
(i.e., 3ac, 3ae and 3af). Reaction of N-methylindole and 4-alkyl
With the optimized complex 1 in hand, different reaction
conditions, including catalyst loadings, substrate ratios, reaction
temperatures, reaction time and solvents, were screened
(Supporting Information, Table S1). The best overall yield of
88% (3aa and 4aa) was obtained from the reaction of N-
methylindole with 3 equivalents of styrene at 130 °C in PhCl
This article is protected by copyright. All rights reserved.

10.1002/chem.201901268
Chemistry - A European Journal
COMMUNICATION
styrene formed non-separable mixtures of C7- and C3-alkylation
products (3+4)ag and (3+4)ah in 70% and 56% overall yield,
respectively. Regioselectivity was determined to be in 5:1 and
3:1 ratio, respectively. No product was detected in reactions of
with styrene (Scheme 2b, Supporting Information, Figure S3),
implying that C-H bond cleavage is not a rate-determining
step.[21] This finding is consistent with that of deuterium labelling
reaction (a), further corroborating that C-H scission is a
reversible process.[5e,7,9j,l]
4-methoxystyrene
or
N,N-dimethyl-4-vinylaniline.
1,1-
disubstituted alkene reacted with N-methylindole and generated
2,7-dialkylated product 3aj in 51% yield.
Furthermore, reactions of styrene derivatives with 4,N-dimeth-
ylindole and 5,N-dimethylindole produced C7-alkylated products
3ba-3cd in 82-90% yields. Electron-deficient 3,4-dichlorostyrene
reacted with 5,N-dimethylindole, and generated 3ci in a lower
yield of 50%. In comparison, 6-substituted N-methylindole
reacted with styrene and formed exclusively C3-alkylation
product 4da in 70% yield, resulting from increased steric
hindrance. No reaction occurred to bulkier styrene derivatives or
aliphatic alkenes.
Indoles of different N-substituents were also studied (Table 3).
C7-alkylation product 3ea from N-ethylindole was isolated in
70% yield, as evidenced by its solid state structure.[19] In
comparison, reaction of N-isopropylindole formed C3-alkylation
product 4fb as the major product (C7-product: C3-product = 1:
4). Increased steric hindrance of the N-substituent may account
for the different site-selectivity. Reaction of 1-(pyridin-2-yl)-1H-
indole also generated C3-alkylated product 4ga in 51% yield.
This finding deserves further comments, as 2-pyridyl and 2-
pyrimidinyl substituents have been reported to be directing
group for C7 and/or C2-functionalization of indole[5e,f,g,9f,m] and
indoline[12a,b,m] catalyzed by late-transition metal complexes of
rhodium, iridium, ruthenium and palladium. This catalytic system
was also applicable to alkylation of indoline, which gave ortho-
and para-alkylated product 3ha in 92% yield.
Scheme 2. Deuterium labeling experiments.
The reaction of 3,N-dimethylindole with styrene under the
standard conditions gave no desired product, suggesting that
the C3-H bond played a crucial role (Scheme 3a). Thus, to
further elucidate the mode of action, the alkylation was
conducted in the presence of the sterically hindered base 2,6-di-
tert-butylpyridine (Scheme 3b).[22] Thereby, the C7-alkylation
was suppressed, while minor amounts of the C3-alkylation
product were detected. Similarly, the addition of 2,6-di-tert-
butylpyridine likewise led to a suppression of the alkylation in the
presence of [Ph3C][B(C6F5)4] (condition in Table 1, entry 1). Our
findings hence indicate the importance of acids towards the
catalytic alkylation manifold.
Scheme 3. Control experiments.
A plausible mechanism is depicted in Figure 3. Metalation of N-
methylindole with cationic complex A generated intermediate B
with C3 bound to zirconium center. The original C3-H was
trapped by styrene to form a benzylic cation. The subsequent
direct alkylation took solely place at C7-position. This position
selectivity is mainly due to steric influence of the bulky ancillary
bis(phenolato) ligand. Rearomatization leads to intermediate D,
along with formation of a benzylic cation. Reaction of D with N-
methylindole liberated C7-alkylation product, regenerating B for
the next catalytic cycle. The minor route includes 1,2-insertion of
styrene into Zr-C bond of B, followed by hydrolysis with N-
methylindole to generate C3-alkylation product. This is
To gain insights into the catalyst mode of action, C7-D1-N-
methylindole was treated with styrene under standard conditions,
1
which gave C7-alkylation product in 78% yield (Scheme 2a). H
NMR spectrum shows deuterium distribution in alkylation
product as follows: 46% at the methyl group, 33% at the C2-
position, and 21% at the C3-position (Figure S2). It is thus
presumed that C-H bond activation occurred reversibly at C7-,
C3- and C2- positions. KIE was determined to be 1.1 through
parallel reaction of N-methylindole and C7-D1-N-methylindole
conventional
early
transition
metal-catalyzed
C-H
functionalization mode,[16a] which becomes predominant when
This article is protected by copyright. All rights reserved.

10.1002/chem.201901268
Chemistry - A European Journal
COMMUNICATION
provides a straightforward and highly practical strategy to
introduce alkyl groups at C7-position of indole derivatives.
Mechanistic studies revealed the key importance of acids within
the catalytic manifold. Further studies on early transition metal
complexes-catalyzed C-H functionalizations are currently on-
going in our laboratory and will be reported in due course.
the C7-position is sterically congested (e.g., in the case of 4da
and 4fb).
In conclusion, direct C7-alkylation of N-alkylindoles
mediated by cationic zirconium complexes has been developed.
Our strategy does not require complex directing groups, or
blocking the C-2, C-3 position or other reactive site, which
-
Figure 3. Plausible mechanism. Anions ([B(C6F5)4]- and PhCH2 ) are omitted.
[2] a) M. Bandini, A. Eichholzer, Angew. Chem. Int. Ed. 2009, 48, 9608; b) J. A.
Leitch, Y. Bhonoah, C. G. Frost, ACS Catal. 2017, 7, 5618; c) S. Cacchi, G.
Fabrizi, Chem. Rev. 2005, 105, 2873; d) S. Cacchi, G. Fabrizi, Chem. Rev.
2011, 111, PR215; e) L. Ping, D. S. Chung, J. Bouffard, S.-g. Lee, Chem.
Soc. Rev. 2017, 46, 4299; f) L. Ackermann, Synlett 2007, 507-526.
[3] T. A. Shah, P. B. De, S. Pradhan, T. Punniyamurthy, Chem. Commun.
2019, 55, 572.
Acknowledgements
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Grant 21871198), the
Project of Scientific and Technologic Infrastructure of Suzhou
(SZS201708), and PAPD.
[4] a) A. H. Sandtorv, Adv. Synth. Catal. 2015, 357, 2403; b) Y. Yang, Z. Shi,
Chem. Commun. 2018, 54, 1676; c) J. Kalepu, P. Gandeepan, L.
Ackermann, L. T. Pilarski, Chem. Sci. 2018, 9, 4203; d) V. K. Tiwari, M.
Kapur, Org. Biomol. Chem. 2019, 17, 1007.
[5] a) S. Pan, N. Ryu, T. Shibata, J. Am. Chem. Soc. 2012, 134, 17474; b) Y.
Nakao, N. Kashihara, K. S. Kanyiva, T. Hiyama, Angew. Chem. Int. Ed.
2010, 49, 4451; c) P.-S. Lee, N. Yoshikai, Org. Lett. 2015, 17, 22; d) X. Wu,
H. Ji, Org. Lett. 2018, 20, 2224; e) D. Zell, Q. Bu, M. Feldt, L. Ackermann,
Angew. Chem. Int. Ed. 2016, 55, 7408; f) L. Wang, Z. Li, X. Qu, W.-M.
Peng, S.-Q. Hu, H.-B. Wang, Tetrahedron Lett. 2015, 56, 6214; g) C. Wang;
B. Maity, L. Cavallo, M. Rueping, Org. Lett. 2018, 20, 3105; h) V. K. Tiwari,
N. Kamal, M. Kapur, Org. Lett. 2015, 17, 1766; i) G. S. Kumar, M. Kapur,
Org. Lett. 2016, 18, 1112.
Conflict of interest
The authors declare no conflict of interest.
Keywords: C-H activation • C7-alkylation • N-alkylindole •
zirconium catalyst
References:
[6] a) Y. Yang, P. Gao, Y. Zhao, Z. Shi, Angew. Chem. Int. Ed. 2017, 56, 3966;
b) Y. Yang, R. Li, Y. Zhao, D. Zhao, Z. Shi, J. Am. Chem. Soc. 2016, 138,
8734; c) X.-H. Liu, H. Park, J.-H. Hu, Y. Hu, Q.-L. Zhang, B.-L. Wang, B.
Sun, K.-S. Yeung, F.-L. Zhang, J.-Q. Yu, J. Am. Chem. Soc. 2017, 139,
888; d) V. Lanke, K. R. Prabhu, Chem. Commun. 2017, 53, 5117; e) S.
[1] a) G. W. Gribble, J. Chem. Soc., Perkin Trans. 2000, 1, 1045; b) N. K. Garg,
R. Sarpong, B. M. Stoltz, J. Am. Chem. Soc. 2002, 124, 13179; c) J. Tois,
R. Franzen, A. Koskinen, Tetrahedron 2003, 59, 5395; d) F.-E. Chen; J.
Huang, Chem. Rev. 2005, 105, 4671.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901268
Chemistry - A European Journal
COMMUNICATION
Chen, B. Feng, X. Zheng, J. Yin, S. Yang, J. You, Org. Lett. 2017, 19, 2502;
f) J. A. Leitch, C. L. McMullin, M. F. Mahon, Y. Bhonoah, C. G. Frost, ACS
Catal. 2017, 7, 2616; g) M. Simonetti, D. M. Cannas, A. Panigrahi, S.
Kujawa, M. Kryjewski, P. Xie, I. Larrosa, Chem. – Eur. J. 2017, 23, 549; h)
V. Lanke, K. R. Bettadapur, K. R. Prabhu, Org. Lett. 2016, 18, 5496; i) V.
Lanke, K. R. Prabhu, Chem. Commun. 2017, 53, 5117; j) V. Lanke, K. R.
Prabhu, Org. Lett. 2013, 15, 6262; k) L. Ackermann, A. V. Lygin, Org. Lett.
2011, 13, 3332.
2018, 54, 12543; c) H. Tsurugi, K. Yamamoto, H. Nagae, H. Kaneko, K.
Mashima, Dalton Trans. 2014, 43, 2331; d) P. L. Arnold, M. W. McMullon,
J. Rieb, F. E. Kühn, Angew. Chem. Int. Ed. 2015, 54, 82; e) M. Nishiura,
F. Guo, Z. Hou, Acc. Chem. Res. 2015, 48, 2209; f) Z. Dong, Z. Ren, S.
J. Thompson, Y. Xu, G. Dong, Chem. Rev. 2017, 117, 9333.
[17] a) G. Blay, I. Fernndez, J. R. Pedro, C. Vila, Org. Lett. 2007, 9, 2601; b)
G. Blay, I. Fernndez, J. R. Pedro, C. Vila, Tetrahedron Lett. 2007, 48,
6731; c) C. Ogawa, N. Wang, M. Boudou, S. Azoulay, K. Manabe, S.
Kobayashi, Heterocycles 2007, 72, 589; d) Y. L. Hu, H. Jiang, M. Lu,
Green Chem. 2011, 13, 3079; e) P. E. Harrington, M. A. Kerr, Synlett
1996, 1047; f) D. A. Evans, K. A. Scheidt, K. R. Fandrick, H. W. Lam, J.
Wu, J. Am. Chem. Soc. 2003, 125, 10780; g) D. A. Evans, K. R. Fandrick,
H.-J. Song, K. A. Scheidt, R. Xu, J. Am. Chem. Soc. 2007, 129, 10029; h)
P. Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz, L. Ackermann,
Chem. Rev. 2019, 119, 2192.
[7] Y. Schramm, M. Takeuchi, K. Semba, Y. Nakao, J. F. Hartwig, J. Am. Chem.
Soc. 2015, 137, 12215.
[8] a) K. Liang, T. Wu, C. Xia, Org. Biomol. Chem. 2016, 14, 4690; b) M. Y.
Wong, T. Yamakawa, N. Yoshikai, Org. Lett. 2015, 17, 442.
[9] a) C. G. Hartung, A. Fecher, B. Chapell, V. Snieckus, Org. Lett. 2003, 5,
1899; b) S. Paul, G. A. Chotana, D. Holmes, R. C. Reichle, R. E.
Maleczka, M. R. Smith, J. Am. Chem. Soc. 2006, 128, 15552; c) D. W.
Robbins, T. A. Boebel, J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, 4068;
d) R. P. Loach, O. S. Fenton, K. Amaike, D. S. Siegel, E. Ozkal, M.
Movassaghi, J. Org. Chem. 2014, 79, 11254; e) A. K. Pitts, F. OÏHara, R.
H. Snell, M. J. Gaunt, Angew. Chem. Int. Ed. 2015, 54, 5451; f) G. Kumar,
G. Sekar, RSC Adv. 2015, 5, 28292; (g) L. Xu, C. Zhang, Y. He, L. Tan, D.
Ma, Angew. Chem. Int. Ed. 2016, 55, 321; h) Z. Songa, A. P. Antonchick,
Org. Biomol. Chem. 2016, 14, 4804; i) Y. Kim, J. Park, S. Chang, Org.
Lett. 2016, 18, 1892; j) Y. Yang, X. Qiu, Y. Zhao, Y. Mu, Z. Shi, J. Am.
Chem. Soc. 2016, 138, 495; k) Y. Kim, Y. Park, S. Chang, ACS Cent. Sci.
2018, 4, 768; l) A. J. Borah, Z. Shi, J. Am. Chem. Soc. 2018, 140, 6062; m)
T. Okada, K. Nobushige, T. Satosh, M. Miura, Org. Lett. 2016, 18, 1150; n)
D. W. Robbins, T. A. Boebel, J. F. Hartwig, J. Am. Chem. Soc. 2010, 132,
4068; o) X. Qiu, P. Wang, D. Wang, M. Wang, Y. Yuan, Z. Shi, Angew.
Chem. Int. Ed. 2019, 58, 1504.
[18] a) Q. Sun, P. Xie, D. Yuan, Y. Xia, Y. Yao, Chem. Commun. 2017, 53,
7401; b) Q. Sun, P. Chen, Y. Wang, Y. Luo, D. Yuan, Y. Yao, Inorg.
Chem. 2018, 57, 11788.
[19] CCDC 1864802 (3aa) and 1873587 (3ea) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
[20] W. Zhu, Q. Sun, Y. Wang, D. Yuan, Y. Yao, Org. Lett. 2018, 20, 3101.
[21] E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51, 3066.
[22] a) J. Chen, S. K. Goforth, B. A. McKeown, T. B. Gunnoe, Dalton Trans.
2017, 46, 2884. b) L. Ackermann, A. Althammer, Synlett 2008, 995. c) L.
Ackermann, L. T. Kaspar, A. Althammer, Org. Biomol. Chem. 2007, 5,
1975.
[10] D. Kalyani, N. R. Deprez, L. V. Desai, M. S. Sanford, J. Am. Chem. Soc.
2005, 127, 7330.
[11] C. G. Hartung, A. Fecher, B. Chapell, V. Snieckus, Org. Lett. 2003, 5,
1899.
[12] a) W. Ai, X. Yang, Y. Wu, X. Wang, Y. Li, Y. Yang, B. Zhou, Chem. – Eur. J.
2014, 20, 17653; b) C. Premi, A. Dixit, N. Jain, Org. Lett. 2015, 17, 2598;
c) X. Zhou, S. Yu, Z. Qi, L. Kong, X. Li, J. Org. Chem. 2016, 81, 4869; d)
C. Pan, Y. Wang, C. Wu, J.-T. Yu, Org. Biomol. Chem. 2018, 16, 693; e) S.
H. Han., M. Choi, T. Jeong, S. Sharma, N. K. Mishra, J. Park, J. S. Oh, W.
J. Kim, J. S. Lee, I. S. Kim, J. Org. Chem. 2015, 80, 11092; f) H. Oh, J.
Park, S. H. Han, N. K. Mishra, S. H. Lee, Y. Oh, M. Jeon, G.-J. Seong, K.
Y. Chung, I. S. Kim, Tetrahedron 2017, 73, 4739; g) S. Pan, N. Ryu, T.
Shibata, Adv. Synth. Catal. 2014, 356, 929; h) L.-Y. Jiao, M. Oestreich,
Chem. – Eur. J. 2013, 19, 10845; i) L. Zhang, C. Chen, J. Han, Z.-B.
Huang, Y. Zhao, Org. Chem. Front. 2016, 3, 1271; j) M. Kim, N. K. Mishra,
J. Park, S. Han, Y. Shin, S. Sharma, Y. Lee, E.-K. Lee, J. H. Kwak, I. S.
Kim, Chem. Commun. 2014, 50, 14249; k) J. Park, N. K. Mishra, S.
Sharma, S. Han, Y. Shin, T. Jeong, J. S. Oh, J. H. Kwak, Y. H. Jung, I. S.
Kim, J. Org. Chem. 2015, 80, 1818; l) D. Yang, S. Mao, Y.-R. Gao, D.-D.
Guo, S.-H. Guo, B. Li, Y.-Q. Wang, RSC Adv. 2015, 5, 23727; m) X.-F.
Yang, X.-H. Hu, C. Feng, T.-P. Loh, Chem. Commun. 2015, 51, 2532; n) N.
Jin, C. Pan, H. Zhang, P. Xu, Y. Cheng, C. Zhu, Adv. Synth. Catal. 2015,
357, 1149; o) Z. Song, R. Samanta, A. P. Antonchick, Org. Lett. 2013, 15,
5662; p) Z. Shi, B. Li, X. Wan, J. Cheng, Z. Fang, B. Cao, C. Qin, Y. Wang,
Angew. Chem. Int. Ed. 2007, 46, 5554; q) P. Gandeepan, J. Koeller, L.
Ackermann, ACS Catal. 2017, 7, 1030.
[13] a) H. Tsurugi, K. Yamamoto, K. Mashima, J. Am. Chem. Soc. 2011, 133,
732; b) H. Kaneko, H. Nagae, H. Tsurugi, K. Mashima, J. Am. Chem. Soc.
2011, 133, 19626; c) G. Song, B. Wang, M. Nishiura, Z. Hou, Chem. Eur.
J. 2015, 21, 8394; d) B.-T. Guan, Z. Hou, J. Am. Chem. Soc. 2011, 133,
18086; e) G. Song, W. N. O. O, Z. Hou, J. Am. Chem. Soc. 2014, 136,
12209; f) G. Luo, Y. Luo, J. Qu, Z. Hou, Organometallics 2012, 31, 3930;
g) Y. Chen, D. Song, J. Li, X. Hu, X. Bi, T. Jiang, Z. Hou, ChemCatChem
2018, 10, 159; h) B.-J. Deelman, W. M. Stevels, J. H. Teuben, M. T. Lakin,
A. L. Spek, Organometallics 1994, 13, 3881; i) S. Rodewald, R. F. Jordan,
J. Am. Chem. Soc. 1994, 116, 4491.
[14] a) J. Oyamada, Z. Hou, Angew. Chem. Int. Ed. 2011, 50, 10720; b) X. Shi,
M. Nishiura, Z. Hou, J. Am. Chem. Soc. 2016, 138, 6147; c) J. Oyamada,
Z. Hou, Angew. Chem. Int. Ed. 2012, 51, 12828.
[15] G. Song, G. Luo, J. Oyamada, Y. Luo, Z. Hou, Chem. Sci. 2016, 7, 5265.
[16] a) H. Nagae, A. Kundu, M. Inoue, H. Tsurugi, K. Mashima, Asian J. Org.
Chem. 2018, 7, 1256; b) P. M. Edwards, L. L. Schafer, Chem. Commun.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901268
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Highly regioselective alkylation of N-
alkylindole at C7-positions mediated
by cationic zirconium complexes
has been developed. This method
provides a straightforward strategy
to install alkyl groups at C7-
Ping Chen, Yanhong Hao, Xinxin Wang,
Dan Yuan,* Yingming Yao,* and Lutz
Ackermann*
Page No. – Page No.
Directing Group-free C7-alkylations of
N-alkylindols Mediated by Cationic
Zirconium Complexes: Role of
positions of indoles, without
introducing complex directing group.
Mechanistic studies revealed the
key importance of acids within the
catalytic manifold.
Brønsted Acid for Catalytic Manifold
This article is protected by copyright. All rights reserved.