Iridium-Catalyzed Enantioselective Intermolecular Indole C2-Allylation

Article abstract of DOI:10.1002/anie.202001956

The enantioselective intermolecular C2-allylation of 3-substituted indoles is reported for the first time. This directing group-free approach relies on a chiral Ir-(P, olefin) complex and Mg(ClO₄)₂ Lewis acid catalyst system to promote allylic substitution, providing the C2-allylated products in typically high yields (40–99 %) and enantioselectivities (83–99 % ee) with excellent regiocontrol. Experimental studies and DFT calculations suggest that the reaction proceeds via direct C2-allylation, rather than C3-allylation followed by in situ migration. Steric congestion at the indole-C3 position and improved π–π stacking interactions have been identified as major contributors to the C2-selectivity.

Full text of DOI:10.1002/anie.202001956

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Iridium Catalyzed Enantioselective Intermolecular Indole C2-
Allylation
Authors: James A. Rossi-Ashton, Aimee K. Clarke, James R. Donald,
Chao Zheng, Richard J. K. Taylor, William Paul Unsworth,
and Shu-Li You
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.202001956
Angew. Chem. 10.1002/ange.202001956
Link to VoR: http://dx.doi.org/10.1002/anie.202001956
http://dx.doi.org/10.1002/ange.202001956

10.1002/anie.202001956
Angewandte Chemie International Edition
RESEARCH ARTICLE
Iridium Catalyzed Enantioselective Intermolecular Indole C2-
Allylation
James A. Rossi-Ashton,†[a] Aimee K. Clarke,†[a] James R. Donald,[a] Chao Zheng,*[b] Richard J. K.
Taylor,*[a] William P. Unsworth,*[a] Shu-Li You*[b]
[a]
Mr. J. A. Rossi-Ashton, Dr. A. K. Clarke, Dr. J. R. Donald, Prof. R. J. K. Taylor, Dr. W. P. Unsworth
Department of Chemistry, University of York, York, YO10 5DD
E-mail: richard.taylor@york.ac.uk, william.unsworth@york.ac.uk
Prof. C. Zheng, Prof. S.-L. You
[b]
State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, 345 Lingling Lu, Shanghai
200032, China
E-mail: zhengchao@sioc.ac.cn, slyou@sioc.ac.cn
†These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract: The enantioselective intermolecular C2-allylation of 3-
substituted indoles is reported for the first time. This directing group-
free approach relies on a chiral Ir-(P, olefin) complex and Mg(ClO4)2
Lewis acid catalyst system to promote allylic substitution, providing
the C2-allylated products in typically high yields (40–99%) and
enantioselectivities (83–99% ee) with excellent regiocontrol.
Experimental studies and DFT calculations suggest that the reaction
proceeds via direct C2-allylation, rather than C3-allylation followed by
in situ migration. Steric congestion at the indole-C3 position and
improved π-π stacking interactions have been identified as major
contributors to the C2-selectivity.
following this approach.[12] However, these strategies almost
always lead to the formation of annulated C2-allylated indoles. A
search of the literature revealed that the sole exception to this
generalization comes from Tambar et al.[13] who developed an
innovative
intramolecular
route
to
branched,
highly
enantioenriched C2-allylated 3-amino indoles employing an
enantioselective aza-Claisen rearrangement (Scheme 1, c).
Introduction
Indole is a core structural element in many natural and synthetic
organic compounds that possess a wide diversity of important
biological activities.[1] Allylation of the indole core is a fundamental
transformation, integral to numerous synthetic processes.[2]
Consistent with the innate reactivity of indoles, intermolecular
asymmetric allylation of the C3-position of indole is a well-
established process.[3] The analogous N1-allylation is relatively
less well-explored, although there exist various innovative
methods for this recently developed by the groups of Hartwig,[4]
You,[5] Krische[6] and others.[7] To the best of our knowledge, there
are no methods capable of directly allylating indole at the C2-
position in an enantioselective, intermolecular fashion.
Most intermolecular indole C2-allylation strategies involve
either directed lithiation[8] (by lithium-halogen exchange or
deprotonation) of the C2-position (Scheme 1, a), or C-H activation
orchestrated by a directing group (typically attached at the N1-
position) (Scheme 1, b).[9,10] Despite the numerous merits of these
approaches, their dependency on directing groups is an obvious
drawback, requiring additional installation and removal steps.
Furthermore, these strategies typically result in the formation of
achiral, linear allylated products, and the rare examples that form
branched products generally require more forcing reaction
conditions, are often low yielding, and are all racemic.[9c-g]
Scheme 1. Intermolecular indole C2-allylation.
Intramolecular reactions can overcome the regioselectivity
issues associated with intermolecular indole reactivity.[11] Several
asymmetric indole C2-allylation procedures have been developed
In this study, we demonstrate the successful implementation of a
strategy to access enantioenriched C2-allylated 3-substituted[14,15]
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202001956
Angewandte Chemie International Edition
RESEARCH ARTICLE
indoles 3 via the intermolecular allylic substitution of branched
allylic alcohols 1 and readily available indoles 2, catalyzed by a
chiral Ir-(P, olefin) complex[16] and a Lewis acid additive (Scheme
1, d). At the start of this study, gaining effective control over the
regioselectivity of the allyic substitution step with respect to the
indole (especially C2- versus C3-substitution) was expected to be
a key challenge. This motivated our decision to explore the use of
Lewis acidic additives, as we postulated that under these
reactions conditions, allylation of indole 2 at either its C2- or C3-
position[17] would result in the convergent formation of the desired
C2-allylated product 3; either, indole 2 could react with the π-allyl
iridium complex via the less sterically hindered C2-position, to
form allylated product 3 directly, or alternatively, it could react via
the more electron-rich C3-position but then undergo an in situ
stereospecific migration.[18] In this latter scenario, the Lewis acid
(that is essential for the activation of allylic alcohol 1) would also
help to promote the required stereospecific migration.
Mechanistic and computational studies (vide infra) suggest that
direct C2-allylic substitution is the dominant pathway in the cases
tested, but crucially, because both mechanistic pathways
converge to the same product 3, this means that effective C2-
allylation can be achieved even in cases in which C3-allylic
substitution competes.
Table 1. General reaction conditions optimization.
3 /
Entry
1
2 (eq.)
Temp.
1 / %
4 / %
%
99
63
96
69
99
97
ee
98
1
2
3
4
5
6
a
a
a
b
b
a
a (1.1)
b (1.1)
b (1.3)
a (1.1)
a (1.1)
a (1.3)
RT
RT
0
0
0
19
0
99
RT
>99
98
0
RT
29
0
0
40 °C
40 °C
96
0
97
0
0
Substituents were tolerated at all positions around the phenyl ring
of the allylic alcohol partner (Scheme 2) including electron-
deficient (di-nitro 3j) and electron-rich (trimethoxy 3k) aromatics.
Enantioselectivity was universally high and the branched isomer
product was formed exclusively in all of these examples. It was
also possible to use heteroaryl allylic alcohols (3m–3o), although
there was some erosion of the linear:branched regioselectivity
when using indole allylic alcohol (3o).
Results and Discussion
Our investigation started with the identification of suitable reaction
conditions (see Supporting Information for full details), including
finding a Lewis acid capable of performing up to three key roles
within the allylation-migration cascade: 1) to activate the allylic
alcohol towards formation of the Ir-π-allyl complex, 2) to facilitate
the enantioselective C2- or C3-allylation whilst avoiding
competing N1-allylation, and 3) to facilitate the stereospecific
migration of the allyl group from the C3- to the C2-position of
indole if needed.
Remarkably, inexpensive Mg(ClO4)2 (which has never
previously been used in iridium-catalyzed allylic substitution) was
identified as the best Lewis acid for the reaction between phenyl
allylic alcohol 1a and 3-methyl indole 2a, enabling the formation
of C2-allylated indole 3a in 99% yield and 98% ee (Table 1, entry
1) when used in combination with [Ir(cod)Cl]2 and the (S)-Carreira
ligand (L1 - see Scheme 2 for its structure).[19] When exploring the
generality of this reaction we recognized that increasing the bulk
at the C3-position of the indole reaction partner (e.g. 2b) resulted
in a lower yield due to the formation of a ketone side-product 4
(entry 2), however, this problem was easily rectified by a minor
increase in the indole equivalents (1.1→1.3 eq, entry 3). We also
found that in some cases, a small increase in the reaction
temperature to 40 °C was needed to ensure complete conversion
into the allylated products (entries 4 and 5), and for consistency,
these conditions (entry 6) were taken forward into the substrate
scoping phase of the work,[20] which is summarized in Scheme 2.
A wide variety of substituents were well tolerated at the C3-
position of indole including alkyl, aryl, benzyl and allyl as well as
halide functionality[21] at the C3-, C5- and C6-positions of indole,
all providing their corresponding C2-allylated products in excellent
yields and enantioselectivities. The lower yield obtained for 3-
phenyl-substituted allylated product 3p was due to the
competitive formation of propiophenone side-product 4; the extent
of side-product formation was reduced as steric bulk decreased
at the C3-position (phenyl → benzyl → allyl) and could also be
suppressed by using increased indole equivalents (see earlier
optimization). Alkyl tethers incorporating a free alcohol (3w), a
protected alcohol (3x) and amine functionality (3y–3aa) at the C3-
position of indole were all well tolerated. N-Methyl indole was a
suitable substrate, furnishing C2-allylated product (3ab) in 72%
yield and 84% ee. Indole 3ac was also formed from a
trimethoxybenzene-based allylic alcohol in good yield and
excellent enantioselectivity; its structural assignment is supported
by X-ray crystallographic data, from which the absolute
stereochemistry of all other substrates was assigned by
analogy.[19] It should be noted that when carbonyl groups were
directly attached to the C3-position of indole, C2-allylation was
unsuccessful,[22] which is not altogether surprising, given that the
nucleophilicity of indole is significantly reduced upon substitution
with such electron-withdrawing groups.
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202001956
Angewandte Chemie International Edition
RESEARCH ARTICLE
[a]Yields of isolated products after column chromatography are reported. Enantiomeric excess (ee) values were determined by HPLC analysis with a chiral stationary
phase. The concentration 0.5 M is with respect to the allylic alcohol. [b]Branched:linear product ratio determined by analysis of 1H NMR spectrum of the crude reaction
mixture. [c]As a 13:1 mixture of rotamers.
Scheme 2. Allylic alcohol and indole substrate scope for C2-allylation procedure.[a]
Predictably, a C3-substituent is required on the indole to achieve
selective C2-allylation, and in the absence of this substituent,
allylation takes places exclusively at the C3-position; for example,
the formation of products 5a–h from indole 4 (Scheme 3). Notably,
these products were all formed in good to excellent yields and
excellent enantioselectivities,[23,24] reflecting the mild nature of our
reaction conditions relative to previous methods.[3a-c] Indeed, this
represents the most enantioselective method for the synthesis of
these fundamental scaffolds to date.
[a]Yields of isolated products reported. Enantiomeric excess (ee) values were
determined by HPLC analysis with a chiral stationary phase. [b]0.25 eq Zn(OTf)2
used instead of Mg(ClO4)2 and reaction performed at RT.
Scheme 3. Substrate scope for C3-allylation.[a]
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202001956
Angewandte Chemie International Edition
RESEARCH ARTICLE
Mechanistic Studies
Next, a series of control reactions were conducted to help
elucidate the roles of each reaction component (Table 2). Product
3a was not formed in the absence of Lewis acid (entry 2), clearly
demonstrating its necessity for reactivity. Furthermore, the nature
of the Lewis acid, both the cation and anion, plays a key role in
C2- vs N1-selectivity, as well as the enantioselectivity of the
reaction (see Lewis acid optimization screen in SI). In the absence
of the iridium catalyst (entry 3) or the ligand (entry 4) a minor
amount of product was formed, most probably via Lewis acidic
activation of the allylic alcohol, as no asymmetric induction was
observed.
Table 2. Control experiments.
Deviation from standard
Entry
Yield / %
ee / %
conditions
1
2
3
4
none
97
0
97
-
no Mg(ClO4)2
no [Ir(cod)Cl]2
no L1
18
18
0
[a]Reaction conditions: 5a or 9 (0.52 mmol), 1a, 1e or 1r (0.40 mmol), [Ir(cod)Cl]2
(4 mol%), L1 (16 mol%), Mg(ClO4)2 (0.10 mmol) in CH2Cl2 (2.0 mL) at 40 °C, 20
h. [b]1H NMR yields of products reported based on a trimethoxybenzene internal
standard. Enantiomeric excess (ee) values were determined by HPLC analysis
with a chiral stationary phase.
0
Next, to help understand whether the reaction proceeds via direct
C2-allylation or initial C3-allylation followed by migration, a series
of selective migration experiments were designed. First, C3-
allylated indole 5a was reacted with electron-poor, p-nitro allylic
alcohol 1e (Scheme 4, a). The idea was that if the reaction
proceeded via initial C3-allylation, dearomatized intermediate 6
would first form, which would presumably be followed by migration
of the more electron-rich allyl substituent, in view of its higher
migratory aptitude, thus furnishing C2-allylated product 7a.
However, if the reaction progressed via direct C2-attack, C2-
allylated product 7b would instead be formed. The outcome of this
reaction was clear; the sole isolation of indole 7b[25] (confirmed
using NOE experiments), provided strong support that, in this
case, the reaction proceeded via the direct C2-pathway.
Selectivity between electronically similar substituents was next
investigated (Scheme 4, b), via the reaction of C3-allylated indole
5a with deuterated allylic alcohol 1r. Due to the very similar
electronic nature of the two allyl groups, a mixture of products was
expected if the reaction proceeded via C3-C2 migration, but in
fact, bis-allylated product 8a was selectively formed (confirmed by
NOE experiments), indicating again that the reaction proceeded
via the direct C2-pathway. The same direct C2-allylation pathway
was also observed in the reaction of linear C3-allylated indole 9
with phenyl allylic alcohol 1a (Scheme 4, c).
Scheme 4. Mechanistic investigations[a,b]
With experimental evidence supporting a direct C2-allylation
pathway obtained, we then turned to DFT to gain a deeper
understanding of the reaction mechanism (Figure 1). All possible
transition states for intermolecular C2- or C3-allylation between
indole 2a and π-allyl complex 11 were calculated. The most stable
transition states for direct C2-attack (TS-2, 0.0 kcal/mol) and
direct C3-attack (TS-3, 2.6 kcal/mol) are represented in Figure 1.
The lower energy of TS-2 suggests a direct C2-allylation pathway.
The innate electronic property of indole favors C3-attack, which is
exhibited by the more negative NPA (natural population analysis)
charge at C3 of TS-3 (–0.11) compared with that at C2 of TS-2 (–
0.03). This property is supported by the direct C3-allylation of
indoles not possessing a C3-substituent (Scheme 3). However,
the preference for direct C2-attack, by virtue of the more stabilized
TS-2 over TS-3, stems from the compromise of several
competitive effects: (1) the C3-methyl substituent causes
unfavorable steric congestion due to the close non-bonding
hydrogen atom pairs in TS-3 [B(H2•••H5) = 2.15 Å and B(H2•••H3)
= 2.29 Å] and (2) TS-2 enables superior π-π stacking between the
electron-rich indole ring and the phenyl group of the electrophilic
cinnamyl moiety, both of which contribute to the lower barrier of
the direct C2-allylation pathway (see the Supporting Information
for more details).[26]
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202001956
Angewandte Chemie International Edition
RESEARCH ARTICLE
[a]Reaction conditions: 2a (0.52 mmol), 1a or 1p (0.40 mmol), [Ir(cod)Cl]2 (4
mol%), L1 (16 mol%), Mg(ClO4)2 (0.10 mmol) in CH2Cl2 (2.0 mL) at 40 °C, 20 h.
[b]1H NMR yields reported based on trimethoxybenzene internal standard.
Enantiomeric excess (ee) values were determined by HPLC analysis with chiral
stationary phase.
Scheme 5. Aliphatic allylic alcohol experiment[a]
On the basis of the experimental data described above, in addition
to previously described theoretical evidence,[29] the following
mechanism for the enantioselective direct C2-allylation of indole
is proposed (Scheme 6). The catalyst precursor [Ir(cod)Cl]2
coordinates to (S)-L1 and the racemic allylic alcohol [i.e., (±)-1a]
to generate complex 13. In the presence of Mg(ClO4)2, the
carbon−oxygen bond of the secondary alcohol undergoes
heterolytic cleavage which results in the formation of π-allyl
intermediate 14. Nucleophilic attack on intermediate 14 by the
indole (i.e., 2a) proceeds via transition state TS-2, which is
stabilized via the π-π stacking interaction between the electron-
rich indole ring and the aryl group of the π-allyl intermediate.
Rearomatization of intermediate 15 and allylic alcohol exchange
occurs to release the product (i.e., 3a) and regenerate active Ir(I)
complex 13.[30]
Figure 1. Optimized structures of TS-2 and TS-3 and their calculated relative
Gibbs free energy (in kcal/mol). (a) and (b) side views; (c) and (d) Newman
projections along the forming C–C bond. The ligands associated to the Ir center
are omitted for clarity.
Finally, to examine how π-stacking, identified in the above DFT
studies (illustrated in Figure
1 c and d), influences the
regioselectivity of the reaction experimentally, alkyl allylic alcohol
1p, which is unable to undergo aryl π-stacking, was reacted under
the standard conditions. The reaction afforded a near equal
mixture of the C2-product 12a and N1-product 12a’ (42% and
41% yield respectively, Scheme 5) suggesting that the aryl π-
stacking plays a key role in controlling the C2-regioselectivity
when reacting aryl allylic alcohols. Both products were formed
with high enantioselectivity.[27] Thus, at present we are only able
to achieve high levels of C2-regioselectivity using aryl substituted
allylic alcohols. Nonetheless, we were pleased to observe that
allylic substitution is still possible under our usual reaction
conditions with aliphatic allylic alcohol 1p, given that π-allyl
complex formation is known to be more challenging for such
alcohols compared with the more activated benzylic systems that
are the main focus of this study.[28]
Scheme 6. Proposed mechanism
Conclusion
In summary, a highly enantioselective, directing group-free
intermolecular C2-allylation procedure has been demonstrated for
the first time, furnishing a wide range of C2-allylated products in
excellent yields with high regiocontrol.
A combination of
experimental migration studies and DFT calculations suggest the
reaction proceeds via direct C2-attack rather than C3-allylation
followed by in situ migration; this mode of reaction results in
greater reaction predictability than might be expected via a C3-C2
migration pathway, in which isomeric products could form as a
result of unselective migration. This unprecedented C2-selectivity
was achieved due to the combination of several factors: (1) steric
congestion at the C3-position of indole increases the relative
reactivity of the C2- and N1-positions; (2) π-π stacking
interactions between the electron-rich indole ring and the aryl
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202001956
Angewandte Chemie International Edition
RESEARCH ARTICLE
[3]
For selected non-dearomative intermolecular asymmetric indole C3-
allylic substitution reactions, see: (a) H. Y. Cheung, W.-Y. Yu, F. L. Lam,
T. T.-L. Au-Yeung, Z. Zhou, T. H. Chan, A. S. C. Chan, Org. Lett. 2007,
9, 4295. (b) W.-B. Liu, H. He, L.-X. Dai, S.-L. You, Org. Lett. 2008, 10,
1815. (c) F. A. Cruz, Y. Zhu, Q. D. Tercenio, Z. Shen, V. M. Dong, J. Am.
Chem. Soc. 2017, 139, 10641. For selected dearomative intermolecular
asymmetric indole C3-allylation examples, see: (d) B. M. Trost, J.
Quancard, J. Am. Chem. Soc. 2006, 128, 6314. (e) Y. Liu, H. Du, Org.
Lett. 2013, 15, 740. (f) X. Zhang, L. Han, S.-L. You, Chem. Sci. 2014, 5,
1059. (g) X. Zhang, W.-B. Liu, H.-F. Tu, S.-L. You, Chem. Sci. 2015, 6,
4525. (h) M. Jia, M. Monari, Q.-Q. Yang, M. Bandini, Chem. Commun.
2015, 51, 2320. (i) J. M. Muller, C. W. Stark, Angew. Chem., Int. Ed. 2016,
55, 4798. (k) R.-D. Gao, Q.-L. Xu, B. Zhang, Y. Gu, L.-X. Dai, S.-L. You,
Chem. Eur. J. 2016, 22, 11601. (l) S. Panda, J. M. Ready, J. Am. Chem.
Soc. 2017, 139, 6038. (m) R.-D. Gao, L. Ding, C. Zheng, L.-X. Dai, S.-L.
You, Org. Lett. 2018, 20, 748. (n) L. Ding, R.-D. Gao, S.-L. You, Chem.
Eur. J. 2019, 25, 4330.
group of the π-allyl intermediate increases selectivity for C2-
allylation over N1-allylation; (3) a suitable Lewis acid was
identified able to activate the allylic alcohol and influence the N1
vs C2 selectivity, without compromising enantioselectivity. The
nature of both the cationic and anionic components of the Lewis
acid were shown to be crucial for high selectivity and
enantioselectivity. During the investigation, indole substrates
without a C3-substitutent were also explored using the optimized
allylic substitution conditions affording C3-allylated indoles in
excellent enantioselectivities, further showcasing the mildness
and broad suitability of the identified reaction conditions.
General Procedure
[4]
[5]
L. M. Stanley, J. F. Hartwig, Angew. Chem., Int. Ed. 2009, 48, 7841.
W.-B. Liu, X. Zhang, L.-X. Dai, S.-L. You, Angew. Chem., Int. Ed. 2012,
51, 5183.
To an oven-dried Schlenk tube charged with a magnetic stirrer
bar was added [Ir(cod)Cl]2 (0.016 mmol, 0.04 eq) and (S)-
Carreira’s Ligand L1 (0.064 mmol, 0.16 eq). The reaction vessel
was purged by alternating vacuum and argon three times before
dry CH2Cl2 (2 mL) was added. This mixture was stirred at RT for
15 min to form the active catalyst during which the solution turns
from yellow to a deep red colour. Allylic alcohol (0.400 mmol, 1.0
eq) was then added followed by the addition of indole derivative
(0.520 mmol, 1.3 eq) and Mg(ClO4)2 (0.100 mmol, 0.25 eq) under
a back pressure of argon. The reaction mixture was then heated
to reflux and stirred for 15 h. The reaction mixture was directly
concentrated on to silica and purified by column chromatography
affording the desired allylated product.
[6]
[7]
S. W. Kim, T. T. Schempp, J. R. Zbieg, C. E. Stivala, M. J. Krische,
Angew. Chem., Int. Ed. 2019, 58, 7762.
(a) L.-Y. Chen, X.-Y. Yu, J.-R. Chen, B. Feng, H. Zheng, Y.-H. Qi, W.-J.
Xiao, Org. Lett. 2015, 17, 1381. (b) Q.-A. Chen, Z. Chen, V. M. Dong, J.
Am. Chem. Soc. 2015, 137, 8392.
[8]
For selected examples of intermolecular indole C2-allylation reactions
that proceed via lithiation, see: (a) Y. Kondo, A. Yoshida, T. Sakamoto,
J. Chem. Soc., Perkin Trans. 1, 1996, 2331. (b) S. Zhao, T. Gan, P. Yu,
J. M. Cook, Tetrahedron Lett. 1998, 39, 7009. (c) M. Ararbi, J. Thibonnet,
L. Bérillon, F. Dehmel, M. Rottländer, P. Knochel, J. Org. Chem. 2000,
65, 4618. (d) S. H. Wunderlich, P. Knochel, Angew. Chem., Int. Ed. 2007,
46, 7685.
[9]
For selected examples of intermolecular indole C2-allylation using a
directing group at the N1-position, see: (a) H. Wang, N. Schröder, F.
Glorius, Angew. Chem., Int. Ed. 2013, 52, 5386. (b) D.-G. Yu, T. Gensch,
F. de Azambuja, S. Vásquez-Céspedes, F. Glorius, J. Am. Chem. Soc.
2014, 136, 17722. (c) S. Yu, X. Li, Org. Lett. 2014, 16, 1200. (d) Y. Suzuki,
B. Sun, K. Sakata, T. Yoshino, S. Matsunaga, M. Kanai, Angew. Chem.,
Int. Ed. 2015, 54, 9944. (e) T. Gensch, S. Vásquez-Céspedes, D.-G. Yu,
F. Glorius, Org. Lett. 2015, 17, 3714. (f) M. Moselage, N. Sauermann, J.
Koeller, W. Liu, D. Gelman, L. Ackermann, Synlett, 2015, 1596. (g) G. S.
Kumar, M. Kapur, Org. Lett. 2016, 18, 1112. (h) Z. Qi, L. Kong, X. Li, Org.
Lett. 2016, 18, 4392. (i) J. Xia, L. Kong, X. Zhou, G. Zheng, X. Li, Org.
Lett. 2017, 19, 5972. (j) H. Wang, M. M. Lorion, L. Ackermann, Angew.
Chem., Int. Ed. 2017, 56, 6339. (k) X. Wu, H. Ji, Org. Lett. 2018, 20, 2224.
(l) X. Wu, H. Ji, Org. Biomol. Chem. 2018, 16, 5691. (m) M. M. Lorion, N.
Kaplaneris, J. Son, R. Kuniyil, L. Ackermnann, Chem., Int. Ed. 2019, 58,
1684. For selected examples of intermolecular indole C2-allylation using
a directing group at the C3-position, see: (n) R. Manikandan, P.
Madasamy, M. Jeganmohan, Chem. Eur. J. 2015, 21, 13934. (o) M. R.
Sk, S. S. Bera, M. S. Maji, Org. Lett. 2018, 20, 134.
Acknowledgements
The authors would like to thank the EPSRC (A.K.C.
EP/R013748/1), the University of York (J.A.R.-A., W.P.U.), the
Leverhulme Trust (for an Early Career Fellowship, ECF-2015-013,
W.P.U.), National Natural Science Foundation of China
(21772219, C.Z.), the Science and Technology Commission of
Shanghai Municipality (18QA1404900, C.Z.) and Youth
Innovation Promotion Association of the Chinese Academy of
Sciences (2017302, C.Z.) for financial support. We are also
grateful for the provision of an Eleanor Dodson Fellowship (to
W.P.U.) by the Department of Chemistry, University of York. Dr
Adrian C. Whitwood and Mr Sam Hart (both University of York)
are thanked for X-ray crystallography. Finally, we are grateful to
the Wild Fund (University of York) and the Royal Society of
Chemistry (Mobility Grant) for supporting a 3-month research
placement for J.A.R.-A. at the Shanghai Institute of Organic
Chemistry.
[10] For selected examples of intermolecular indole C2-allylation using
directing group-free strategies, see: (a) D. Prajapati, M. Gohain, B. J.
Gogoi, Tetrahedron Lett. 2006, 47, 3535. (b) M. Mari, S. Lucarini, F.
Batoccini, G. Piersanti, G. Spadoni, Beilstein J. Org. Chem. 2014, 10,
1991. (c) J. Y. Lee, H. Ha, S. Bae, I. Han, J. M. Joo, Adv. Synth. Catal.
2016, 358, 3458. (d) M. Šiaučiulis, S. Sapmaz, A. P. Pulis, D. J. Proctor,
Chem. Sci. 2018, 9, 754. (e) J. M. Saya, E. D. H. van Wordragen, R. V.
A. Orru, R. Ruijter, Eur. J. Org. Chem. 2018, 5156.
Keywords: allylic substitution • enantioselective • iridium • indole
• density functional theory
[11] Other methods to modulate indole reactivity through N1-coordination,
see: (a) B. S. Lane, M. A. Brown, D. Sames, J. Am. Chem. Soc. 2005,
127, 8050. (b) A. Lin, J. Yang, M. Hashim, Org. Lett. 2013, 15, 1950.
[12] For selected examples of the formation of annulated indole derivatives
via intramolecular asymmetric C2-allylation, see: (a) M. Bandini, A.
Melloni, F. Piccinelli, R. Sinisi, S. Tommasi, A. Umani-Ronchi, J. Am.
Chem. Soc. 2006, 128, 1424. (b) M. Bandini, A. Eichholzer, Angew.
Chem., Int. Ed. 2009, 48, 9533. (c) Q.-F. Wu, C. Zheng, S.-L. You, Angew.
Chem., Int. Ed. 2012, 51, 1680. (d) M. Bandini, A. Bottoni, M. Chiarucci,
G. Cera, G. P. Miscione, J. Am. Chem. Soc. 2012, 134, 20690. (e) M. A.
[1]
[2]
For a comprehensive overview, see: A. R. Katritzky, C. A. Ramsden, E.
F. V. Scriven, R. J. K. Taylor, Comprehensive Heterocyclic Chemistry III,
Elsevier, Oxford, 2008, and references therein (especially Volume 3, Ed.
C. A. Ramsden, G. Jones). For a review of the biomedical applications
of indole derivatives, see: N. K. Kaushik, N. Kaushik, P. Attri, N. Kumar,
C. H. Kim, A. K. Verma, E. H. Choi, Molecules 2013, 18, 6620.
For a recent review, see: C. Zheng, S.-L. You, Nat. Prod. Rep. 2019, 36,
1589 and references therein
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202001956
Angewandte Chemie International Edition
RESEARCH ARTICLE
Schafroth, S. M. Rummelt, D. Sarlah, E. M. Carreira, Org. Lett. 2017, 19,
3235. (f) Y. Wang, P. Zhang, X. Di, Q. Dai, Z.-M. Zhang, J. Zhang, Angew.
Chem., Int. Ed. 2017, 56, 15905. (g) C. P. Grugel, B. Breit, Org. Lett.
2019, 21, 5798.
[26] For the effect of π-π stacking in transition-metal-catalyzed allylic
substitution reactions, see: (a) C. Zheng, C.-X. Zhuo, S.-L. You, J. Am.
Chem. Soc. 2014, 136, 16251. (b) B. Bhaskararao, R. B. Sunoj, J. Am.
Chem. Soc. 2015, 137, 15712. (c) L. Huang, Y. Cai, H.-J. Zhang, C.
Zheng, S.-L. You, CCS Chem. 2019, 1, 106.
[13] P. Maity, R. P. Pembeton, D. J. Tantillo, U. K. Tambar, J. Am. Chem.
Soc. 2013, 135, 16380.
[27] Although we think it likely that both products were formed with the same
sense of stereochemistry as that observed throughout this manuscript,
we do not have unambiguous supporting evidence for the absolute
stereochemical assignment of either products 12a and 12b.
[28] For allylic substitution processes that operate well using linear alkyl-
based allylic alcohol derivatives, see: (a) A. T. Meza, T. Wurm, L. Smith,
S. W. Kim, J. R. Zbieg, C. E. Stivala, M. J. Krische, J. Am. Chem. Soc.
2018, 140, 1275; (b) S. W. Kim, L. A. Schwartz, J. R. Zbieg, C. E. Stivala,
M. J. Krische, J. Am. Chem. Soc. 2019, 141, 671.
[14] The reaction of C3-substituted indoles under typical metal-mediated
allylic substitution conditions results in either dearomative C3 allylation
and/or the formation of N1-allylated indoles. See 3d, 3e, 11b and (a) A.
H. Jackson, P. P. Lynch, J. Chem. Soc., Perkin Trans. 2, 1987, 1215. (b)
M. Kimura, M. Futamata, R. Mukai, Y. Tamaru, J. Am. Chem. Soc. 2005,
127, 4592. (c) N. Kagawa, J. P. Malerich, V. H. Rawal, Org. Lett. 2008,
10, 2381. (d) T. M. Kaiser, J. Yang, Eur. J. Org. Chem. 2013, 3983. (e)
N. Kumar, A. Maity, V. R. Gavit, A. Bisai, Chem. Commun., 2018, 54,
9083. (f) B.-J. Hsueh, W.-T. Fülöp, S.-C. Yang, New J. Chem., 2019, 43,
58.
[29] S. L. Rössler, S. Krautwald, E. M. Carreira, J. Am. Chem. Soc. 2017, 139,
3603.
[15] For increased indole C2 selectivity due to C3 substituent, see reference
10c and B.-B. Huang, L. Wu, R.-R. Liu, L.-L. Xing, R.-X. Liang, Y.-X. Jia,
Org. Chem. Front. 2018, 5, 929.
[30] No significant kinetic isotope effect was observable when comparing the
rates of the reaction of alcohol 1a with both indole 2a and its C2-
deuterated analogue under the standard conditions (see SI). Therefore,
we are confident that a C2-metallation pathway does not operate, see:
C. Colletto, S. Islam, F. Juliá-Hernández, I. Larrosa, J. Am. Chem. Soc.
2016, 138, 1677.
[16] For successful implementation of this catalytic system in annulation
reactions, see: reference 10 (e). For other examples of this catalyst and
ligand system, see: (a) C. Defieber, M. A. Ariger, E. M. Carreira, Angew.
Chem., Int. Ed. 2007, 46, 3139. (b) M. Roggen, E. M. Carreira, J. Am.
Chem. Soc. 2010, 132, 11917. (c) M. Roggen, E. M. Carreira, Angew.
Chem., Int. Ed. 2011, 50, 5568. (d) M. A. Schafroth, D. Sarlah, S.
Krautwald, E. M. Carreira, J. Am. Chem. Soc. 2012, 134, 20276. (e) M.
Lafrance, M. Roggen, E. M. Carreira, Angew. Chem., Int. Ed. 2012, 51,
3470. (f) M. Roggen, E. M. Carreira, Angew. Chem., Int. Ed. 2012, 51,
8652. (g) S. Krautwald, D. Sarlah, M. A. Schafroth, E. M. Carreira,
Science 2013, 340, 1065. (h) J. Y. Hamilton, D. Sarlah, E. M. Carreira, J.
Am. Chem. Soc. 2013, 135, 994. (i) J. Y. Hamilton, D. Sarlah, E. M.
Carreira, Angew. Chem., Int. Ed. 2013, 52, 7532. For a recent review on
asymmetric allylic substitution reactions using Carreira ligands, see: (j)
S. L. Rꢀssler, D. A. Petrone, E. M. Carreira, Acc. Chem. Res. 2019, 52,
2657. For a general review on Ir-catalyzed asymmetric allylic substitution
reactions, see: (k) Q. Cheng, H.-F. Tu, C. Zheng, J.-P. Qu, G. Helmchen,
S.-L. You, Chem. Rev. 2019, 119, 1855.
[17] Based on literature precedent (e.g. references 4–7), we were confident
that we could identify conditions to avoid competing N1-allylation.
[18] For indole C3-C2 migration processes that proceed via an initial
intramolecular C3 functionalization (i.e spirocyclisation), see: reference
11 (c), also: (a) Z.-P. Yang, C.-X. Zhuo, S.-L. You, Adv. Synth. Catal.
2014, 356, 1731. (b) C. Zheng, Q.-F. Wu, S.-L. You, J. Org. Chem. 2013,
78, 4357. (c) C.-X. Zhuo, Q. Cheng, W.-B. Liu, Q. Zhao, S.-L. You,
Angew. Chem., Int. Ed. 2015, 54, 8475. (d) M. J. James, R. E. Clubley,
K. Y. Palate, T. J. Procter, A. C. Wyton, P. O’Brien, R. J. K. Taylor, W. P.
Unsworth, Org. Lett. 2015, 17, 4372. (e) Q.-F. Wu, C. Zheng, C.-X. Zhuo,
S.-L. You, Chem. Sci. 2016, 7, 4453. For a rare process where the initial
C3 functionalization is intermolecular, see: reference 10b.
[19] Absolute stereochemistry assigned in analogy to product 3ad, Scheme
2. Structural assignment is supported by X-ray crystallographic data.
CCDC 1942594 contains the crystallographic data for compound 3ad,
see: www.ccdc.cam.ac.uk/data_request/cif.
[20] A small decrease in enantioselectivity was sometimes observed at higher
temperatures (e.g. 98% to 97% ee for 3a).
[21] Chloro-substituted product 3s could serve as
a precursor to C3-
unsubstituted products by subjecting it to subsequent reductive
dehalogenation; for a prominent example of this type of approach being
used in indole functionalization, see J. R. Allen, A. Bahamonde, Y.
Furukawa, M. S. Sigman J. Am. Chem. Soc. 2019, 141, 8670. Attempts
were also made to isolate a 3-Br analogue of 3s but the product was
unstable during purification and could not be isolated cleanly.
[22] Simple indoles substituted at their C3-position with CHO, COCH3 and
CO2Me did not react under the standard optimized reaction conditions.
[23] Small amounts of bis-allylation led to slightly diminished yields.
[24] The absolute stereochemistry was assigned in analogy to previously
reported data for compound 5c see: W.-B. Liu, H. He, L.-X. Dai, S.-L.
You, Synthesis, 2009, 2076.
[25] The remaining mass balance consisted of unreacted starting materials.
7
This article is protected by copyright. All rights reserved.

10.1002/anie.202001956
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
An enantioselective C2-allylation of 3-substituted indoles is reported, providing C2-allylated products in typically high yields (40–99%)
and enantioselectivities (83–99% ee) with excellent regiocontrol. Experimental studies and DFT calculations suggest that the reaction
proceeds via direct C2-allylation with steric congestion at the indole-C3 position and π-π stacking interactions identified as major
contributors to the selectivity observed.
Institute and/or researcher Twitter usernames: @UnsworthChem, @aimeekclarke, @ChemistryatYork
8
This article is protected by copyright. All rights reserved.