Ruthenium(II)-Catalyzed Regio- and Stereoselective C-H Allylation of Indoles with Allyl Alcohols

Article abstract of DOI:10.1021/acs.orglett.8b00567

A ruthenium-catalyzed C-H allylation of indoles with allyl alcohols via β-hydroxide elimination is reported. Without external oxidants and expensive additives, this reaction features mild reaction conditions, compatibility with various functional groups, and good to excellent regioselectivity and stereoselectivity.

Full text of DOI:10.1021/acs.orglett.8b00567

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ruthenium(II)-Catalyzed Regio- and Stereoselective C−H Allylation of
Indoles with Allyl Alcohols
Xiaowei Wu† and Haitao Ji*,†,‡
†Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida
33612-9416, United States
‡Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33612, United States
S
* Supporting Information
ABSTRACT: A ruthenium-catalyzed C−H allylation of
indoles with allyl alcohols via β-hydroxide elimination is
reported. Without external oxidants and expensive additives,
this reaction features mild reaction conditions, compatibility
with various functional groups, and good to excellent
regioselectivity and stereoselectivity.
overcome these drawbacks is highly desirable. In addition, as
ver the past decades, the direct functionalization of C−H
Obonds via transition metal-catalyzed reactions represents for the allylation reagents, preactivated allyl alcohol derivatives
are necessary for transition metal-catalyzed C−H allylation of
arenes. By contrast, the examples of utilizing unactivated allyl
alcohols as the allylation reagents are limited with few
reported.7,8 We aim to functionalize position 2 of the indole
ring through C−H activation reactions to design and synthesize
potent inhibitors for the β-catenin/T-cell factor (Tcf) protein−
protein interaction.10 Herein, we report a ruthenium(II)-
catalyzed C−H allylation at the C-2 position of N-ethoxycarba-
moyl indoles with allyl alcohols via β-hydroxide elimination,
wherein the N-ethoxycarbamoyl directing group is crucial for this
reaction. Further, this method does not require high temper-
ature, external oxidants, and expensive additives.
an efficient approach for the construction and rapid modification
of heterocyclic compounds.1 The allylation of arenes is important
in organic synthesis due to the versatility of olefin trans-
formations to generate many useful functional groups. Classic
methods for the introduction of the allyl moiety rely on
nucleophilic substitutions, Lewis acid-mediated Friedel−Crafts
type allylation, and cross-coupling reactions.2 These methods
usually suffer from limited reaction scope, harsh reaction
conditions, and prefunctionalized substrates. In this context,
the direct C−H allylation reactions of the aromatic rings with
various allylation reagents under transition metals have attracted
much attention.3
As a starting point, we chose the coupling reaction between N-
ethoxycarbamoyl indole (1a) and 1-phenylprop-2-en-1-ol (2a)
in the presence of inexpensive [{RuCl2(p-cymene)}2] and
NaOAc in MeOH at 45 °C as the catalytic condition. This
reaction afforded the desired C2-allylated product 3a in only 8%
yield (Table 1, entry 1). After screening various solvents, we
found that the yield was increased to 77% with E/Z > 25:1 when
the reaction was conducted in 1,2-dichloroethane (entry 6). In
contrast, other polar solvents, such as CH3CN, dioxane, and
THF hardly provided the desired product (entries 2−4). Further
investigation of different bases demonstrated that NaOH and
Na2CO3 led to no reaction (entries 8 and 10). The yield of
product was decreased when CsOAc was used as the additive
(entry 9). When 0.3 equiv of NaOAc was employed, the yield of
product was only 32% (entry 11). We also investigated the
consequence of the use of different directing groups in the
reaction. The results indicated that all of the other directing
groups (entries 12−16) did not work under the optimized
reaction conditions. Further, the reaction cannot afford the
Recently, Ma and Cramer reported an efficient Rh(III)-
catalyzed ortho allylation of N-methoxybenzamides with
polysubstituted allenes, independently.4 Subsequently, Rh(III)-
catalyzed direct C−H allylation reactions utilizing preactivated
allyl alcohol derivatives, such as allyl acetates, allyl carbonates, or
allyl halides, were documented by Glorius, Loh, Li, Wang, and
other groups.5 As a cost-effective transition metal catalyst,
Glorius and Ackermann reported Cp*Co(III) catalyzed C−H
allylation reactions of indoles, pyrroles, 2-phenylpyridines, and
benzamides using preactivated allyl alcohol derivatives under
mild reaction conditions.6 In 2015, Kanai and Matsunaga
pioneered that unactivated allyl alcohols could be used as the
allylation reagents for C−H allylation under Cp*Co(III)
catalysis.7 Subsequently, Ru(II)-catalyzed C−H allylation using
allyl alcohols was reported by Kupar.8 This reaction requires
external oxidants and high temperature. Kim disclosed Ru(II)-
catalyzed oxidative allylation of (hetero)aromatics with allylic
carbonates.9a Although notable advances were made in this
particular context, most of these reactions require high reaction
temperatures and stoichiometric amounts of external oxidants
and expensive additives (such as copper salts and silver salts).5−9
Therefore, the development of new approaches that can
Received: February 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a,b
Table 1. Optimization of Reaction Conditions
Scheme 1. Scope of Indoles
b
c
No.
solvent
base
3a yield (%)
E/Z ratio
1
2
3
4
5
6
7
8
9
10
MeOH
CH3CN
dioxane
THF
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
Na2CO3
CsOAc
NaOH
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
8
trace
6
trace
toluene
DCE
43
>25:1
>25:1
>25:1
77(72)
DCM
DCE
56
trace
64
0
DCE
>25:1
>25:1
DCE
d
11
DCE
32
0
e
12
DCE
f
13
DCE
0
g
14
DCE
trace
0
h
15
DCE
i
16
j
DCE
0
17
DCE
0
a
k
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), [{RuCl2(p-
cymene)}2] (5 mol %), NaOAc (1 equiv) in DCE at 45 °C, Ar
atmosphere, 6−12 h. Unless otherwise noted, the E/Z ratios of all
18
DCE
trace
0
l
19
DCE
NaOAc
b
c
products are >25:1. Isolated yields are reported. Methyl(1-
phenylallyl)carbonate 2a′ was used.
yield with excellent stereoselectivity (3i), while the chlorine
substituted substrate afforded the product in moderate yield (3j).
Additionally, the methyl and phenyl substituents were
introduced to the C-3 position to explore the effect of steric
hindrance. The desired products were obtained in good yields
when the standard conditions were applied (3k and 3l).
We next explored the scope of the reaction with respect to allyl
alcohols as the coupling partners (Scheme 2). In general, the
coupling reaction of substrate 1a and various substituted allyl
alcohols afforded the corresponding products in good yields
(3m−3v). The desired products were obtained in good yields
with either electron-withdrawing groups (F, Cl, and Br) or
electron-donating groups (Me and MeO−) attaching to the
para-position of the benzene ring of allyl alcohols (3m−3q). The
substrates in which the phenyl moiety of allyl alcohols was
replaced with the thiophenyl and naphthyl groups also
underwent the coupling reaction smoothly with good yields
(3r and 3s). When the alkyl substituted allyl alcohols were
explored, the reaction afforded the desired products in good
yields with satisfactory stereoselectivity (3t−3v). The higher
stereoselectivity of 3a−3l, when compared with 3t−3v, was
probably triggered by the bulky aryl group of 2a. Unfortunately,
the reaction did not proceed to produce 3w when prop-2-en-1-ol
was used as the coupling partner. However, the product 3w can
be obtained in good yield using allyl methyl carbonate as the
coupling partner under the standard reaction conditions. It
should be noted that the use of nonterminal crotyl alcohol 2m
(or its methyl carbonate 2m′) and cinnamyl alcohol 2n, and
tertiary alcohol 2o (or its methyl carbonate 2o′) did not offer the
products.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (5 mol
b
%), base (1 equiv) in 2 mL of solvent at 45 °C, Ar atmosphere. NMR
yields using CH2Br2 as an internal standard, and isolated yields in
parentheses. Determined by H NMR analysis of the crude reaction
mixtures. 0.3 equiv of NaOAc was employed. 1a-1 instead of 1a. 1a-
2 instead of 1a. 1a-3 instead of 1a. 1a-4 instead of 1a. 1a-5 instead
of 1a. No [{RuCl2(p-cymene)}2]. No NaOAc. 5 mol % Pd(OAc)2
was used.
c
1
d
e
f
g
h
i
j
k
l
desired product without NaOAc or the catalyst [{RuCl2(p-
cymene)}2] (entries 17 and 18). The reaction did not proceed
when Pd(OAc)2 was used as the catalyst (entry 19).
With the optimized reaction conditions in hand, the scope of
the reaction was investigated. In general, the reaction was
compatible with a variety of indoles bearing electron-donating
and electron-withdrawing substituents to produce the desired
allylation products in moderate to good yields with excellent
regioselectivity and stereoselectivity (Scheme 1). It afforded the
desired product 3a in moderate yield with E/Z > 25/1 when
methyl(1-phenylallyl)carbonate was used as the coupling
partner. The introduction of halogen groups, such as bromine
and chlorine to the C-5 position of indoles offered the
corresponding products in good yields (3b and 3c), while the
substrates bearing the fluorine group resulted in decreased yield
(3d). When other electron-donating groups (−Me and −OMe)
and electron-withdrawing groups (such as −CO2Me) were
introduced to the C-5 position of the indole ring, the reaction
afforded the corresponding products smoothly (3e−3g). It also
afforded the product in moderate yield when a fluorine group was
attached to the C-6 position (3h). The methyl group at the C-4
position of the indole ring provided the desired product in good
To shed light on the mechanism of this catalytic reaction, a
series of deuterium-labeling experiments were conducted. The
reversibility of the step of the C−H bond cleavage was
B
DOI: 10.1021/acs.orglett.8b00567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Scheme 2. Scope of Allyl Alcohols
Scheme 3. Preliminary Mechanism Studies
a
Scheme 4. Proposed Mechanism
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), [{RuCl2(p-
cymene)}2] (5 mol %), NaOAc (1 equiv) in DCE at 45 °C, Ar
atmosphere, 6−12 h. Unless otherwise noted, the E/Z ratios of all
b
c
products are >25:1. Isolated yields are reported. Allyl methyl
carbonate was used.
determined by removing allyl alcohol 2a and performing the
reaction with an excess amount of methanol-d4 (Scheme 3a).
The results revealed that about 52% deuteration and 32%
deuteration were incorporated at the C-2 and C-3 positions of
the indole ring, respectively (see the Supporting Information for
the experimental details). Carrying out the same reaction in the
absence of NaOAc led to no deuterium incorporation at the C-2
and C-3 positions of the indole ring. Further, performing the
reaction in the presence of 2a resulted in 40% deuteration at the
C-3 position. These results suggest that the step of C−H
activation might be reversible, the base NaOAc is critical for the
step of C−H activation, and the cycloruthenation can proceed by
the concerted metalation−deprotonation (CMD) with the aid of
acetate ion.11 Further, the kinetic isotope effect (KIE) experi-
ments were conducted. An intermolecular KIE kH/kD = 0.81 was
observed for the competition reaction of 1a and deuterium-
labeled 1a-D with 2a (Scheme 3b). Two independent reactions
using 1a and 1a-D gave a KIE value of 0.79. The results suggested
that the step of the C−H bond cleavage was unlikely involved in
the rate-limiting step.12
to give the ruthenacycle I. Insertion of the allyl alcohol results in
intermediate II. Subsequently, the β-hydroxide elimination of II
affords the product 3, and regenerates the active catalyst by
AcOH to complete the catalytic cycle.
In summary, we have reported a ruthenium-catalyzed C−H
allylation at the C-2 position of N-ethoxycarbamoyl indoles by
using allyl alcohols as allylating reagents, wherein the N-
ethoxycarbamoyl directing group proves to be crucial for this
reaction. This method provides access to C2-allylated indoles in
moderate to good yields with good to excellent regioselectivity
and stereoselectivity. In addition, this reaction features mild
Based on the preliminary mechanistic experiments and the
previous literatures,7,8 a possible reaction pathway was proposed
(Scheme 4). Initial ionization in the presence of sodium acetate
led to the active catalyst. Coordination of substrate 1a to the
active ruthenium catalyst is followed by the C−H bond activation
C
DOI: 10.1021/acs.orglett.8b00567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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reaction conditions, compatibility with various functional groups,
and broad substrate scope.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00567.
Experimental procedures, characterization data, and
copies of NMR (PDF)
(8) Kumar, G. S.; Kapur, M. Org. Lett. 2016, 18, 1112−1115.
(9) (a) Kim, M.; Sharma, S.; Mishra, N. K.; Han, S.; Park, J.; Kim, M.;
Shin, Y.; Kwak, J. H.; Han, S. H.; Kim, I. S. Chem. Commun. 2014, 50,
11303−11306. (b) Oi, S.; Tanaka, Y.; Inoue, Y. Organometallics 2006,
25, 4773−4778. (c) Manikandan, R.; Madasamy, P.; Jeganmohan, M.
Chem. - Eur. J. 2015, 21, 13934−13938. (d) Manikandan, R.;
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: haitao.ji@moffitt.org.
ORCID
Haitao Ji: 0000-0001-5526-4503
Notes
(10) Huang, Z.; Zhang, M.; Burton, S. D.; Katsakhyan, L. N.; Ji, H. ACS
Chem. Biol. 2014, 9, 193−201.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Susan G. Komen Career
Catalyst Research Grant CCR16380693. The H. Lee Moffitt
Cancer Center & Research Institute is an NCI-designated
Comprehensive Cancer Center, supported under NIH grant
P30-CA76292.
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