Highly stereoselective ruthenium(II)-catalyzed direct C2- syn -alkenylation of indoles with alkynes

Article abstract of DOI:10.1021/ol503618m

A carboamide-directed ruthenium-catalyzed C2-hydroindolation of alkynes has been described. This transformation provides a rapid access to free (N-H) C2-syn-alkenylated indole derivatives with the assistance of copper(II) salts, in which the directing group is removed via a one-pot process.

Full text of DOI:10.1021/ol503618m

Letter
pubs.acs.org/OrgLett
Highly Stereoselective Ruthenium(II)-Catalyzed Direct C2-syn-
Alkenylation of Indoles with Alkynes
Wei Zhang,† Jun Wei,† Shaomin Fu, Dongen Lin,* Huanfeng Jiang, and Wei Zeng*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, China
S
* Supporting Information
ABSTRACT: A carboamide-directed ruthenium-catalyzed C2-
hydroindolation of alkynes has been described. This trans-
formation provides a rapid access to free (N−H) C2-syn-
alkenylated indole derivatives with the assistance of copper(II)
salts, in which the directing group is removed via a one-pot
process.
rylalkene derivatives belong to important structural motifs
of many naturally occurring products and pharmaceutical
alkenylation of indoles, and the alkyne scope was further
extended to electron-poor internal alkynes and acyl- or alkyl-
substituted terminal alkynes (Scheme 1b).8 However, although
directing group assisted C−H functionalizations provided an
important approach to the C2-alkenylation indoles, existing
methods were only limited to constructing C2-trans alkenylated
indole derivatives, and the stereoselective C2-syn-alkenylation
of indoles via the Csp2−H activation process was rarely
reported. Furthermore, the removal of directing groups
frequently suffers from tedious reaction workup and harsh
reaction conditions.9 For example, the pyrimidyl and pyridyl
directing groups from indole derivatives (Scheme 1a,b) could
be removed generally using strong base (NaOEt)6 and
combined MeOTf/NaOH reagents,8 respectively. Thus,
developing one-pot chelation-assisted C2-syn-alkenylation of
indoles/dedirecting group cascade is a subject of great
importance because C2-syn-alkenylated indoles were widely
used in synthetic organic chemistry.10 Herein, we described a
carboamide-directed C2-hydroindolation of alkynes to furnish
free (N−H) C2-syn-alkenylated indoles11 by using cheaply
available ruthenium catalysts in which the regioselectivities
from unasymmetric internal alkynes were explored (Scheme
1c).
A
molecules.1 In the past few decades, traditional transition-
metal-catalyzed Csp2−Csp2 bond-formation reactions between
prefunctionalized aryl (pseudo)halides2 or arylmetallic re-
agents3 and alkenes have matured into reliable tools for
constructing these compounds, except that this method is
accompanied by the formation of a stoichiometric amount of
hazardous heavy metal and halide salts. Recently, transition-
metal-catalyzed direct cross-coupling of aryl Csp2−H bonds
with alkenyl Csp2−H bonds or alkynyl Csp−H bonds has
gained significant interest due to its high atom- and step-
economy.4 Among these various synthetic strategies, hydro-
indolation of alkynes through chelation assistance has already
been demonstrated to enable site-selective installation of an
alkenyl group into indole molecules. In this regard, Schipper,
Yoshikai, and Kanai groups successively reported that Rh(III)
catalysts,5 Co(II)/Grignard reagent catalytical system (Scheme
1a),6 or Co(III) catalysts7 could enhance intermolecular C2-
trans-alkenylation of indoles, in which an N,N-dimethylcarbonyl
or pyrimidyl group was employed as a directing group,
respectively. More recently, we also successfully employed
ruthenium catalyst to realize pyridyl-directed C2-trans-
It is known that the carbonyl carbon atom of urea
(−HNCONH−) derivatives is easily attacked by nucleophilic
reagents and leads to cleavage of the N−C bonds,12 so we
initially designed and synthesized N-amido-substituted indoles
1a, 1b, and 1c to investigate the effect of carbamide type on the
C2-Hydroindolation of the alkyne/dedirecting group cascade
(HADC). First, we screened various Ru catalysts (5 mol %)
including RuCl3, Ru3(CO)12, RuH2(CO)(PPh3)2, and
[RuCl2(p-cymene)]2, etc., and confirmed that [RuCl2(p-
cymene)]2 (C) could realize the C2-HADC between indole-
1-carboxylic acid phenylamide 1a and diphenylacetylene 2a
with very poor yield (5%) in the presence of KH2PO4 (1.0
equiv) and AcOH (1.0 equiv) using DCE as solvent at 100 °C
Scheme 1. Different Approach to Free (N−H)
Alkenylindoles via Csp2−H Functionalization
Received: December 16, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503618m
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
for 12 h (Table 1, compare entries 1−4 with 5). Subsequently,
the dimeric species Ru(II) catalyst C was found to enable a
(compare entry 13 with 21) (see the Supporting Informationfor
more details about screening of reaction conditions).
Having established an efficient reaction protocol that enables
the addition of an N-substituted indole C2−H bond to alkyne
(2a), we first surveyed the reaction scope using a variety of N-
substituted indoles and diphenylacetylene 2a. As shown in
Scheme 2, the C2-syn-alkenylation of various 5- or 6- or 7- N-
benzylamido-substituted indole substrates proceeded smoothly
to afford good to excellent yields of free (N−H) 2-alkenylated
indoles with exclusive Z-stereochemistry, no matter whether
a
Table 1. Optimization of the Reaction Parameters
b
a
entry
Ru salts
RuCl3
1
additives
proton source
yield (%)
Scheme 2. Substrate Scope
c
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
KH2PO4
KH2PO4
KH2PO4
KH2PO4
KH2PO4
KH2PO4
KH2PO4
K2CO3
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
i-PrOH
PhCO2H
CH3OH
H2O
(E)-3a, nr
c
Ru3(CO)12
(E)-3a, nr
d
c
A
(E)-3a, nr
e
c
B
(E)-3a, nr
f
C
(E)-3a, 5
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
(E)-3j, 7
(E)-3a, 10
(E)-3a, 60
(E)-3a, 55
(Z)-3a, trace
(Z)-3a, 43
(E)-3a, 60
(Z)-3a, 67
(Z)-3a, 53
(Z)-3a, 60
(Z)-3a, 58
(Z)-3a, 45
(Z)-3a, 59
g
8
9
NaHCO3
Ag2CO3
10
11
12
13
14
15
16
17
18
19
20
AgOAc
NaOAc
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
h
AcOH
AcOH
AcOH
(Z)-3a, 60
i
(Z)-3a, 65
g
j
21
(Z)-3a, 80
a
Unless otherwise noted, all of the reactions were carried out using N-
acylindole (1) (0.10 mmol) and alkyne (2a) (0.20 mmol) with Ru
catalyst (5 mol %) in the presence of additives (1.0 equiv) and proton
source (1.0 equiv) in DCE (1, 2-dichloroethane, 2.0 mL) at 100 °C for
12 h under Ar in a sealed reaction tube, followed by flash
chromatography on SiO2. The different stereochemistries were
assigned according to the results of single-crystal data of 3t in Scheme
b
c
2 and mechanistic studies from Scheme 3. Isolated yield. nr = no
d
e
f
reaction. A = RuH2(CO)(PPh3)2. B = RuHCl(CO)(PPh3)3. C =
[RuCl2(p-cymene)]2. No product 3a was observed in the absence of
catalyst C. The reaction temperature is 80 °C. The reaction
temperature is 120 °C. 10 mol % of Ru catalyst C and 0.5 equiv of
g
h
i
j
Cu(OAc)2 were used, and the reaction time was 24 h.
further increase of the yield of 3a from 5% to 10% when indole-
1-carboxylic acid phenylamide 1a was switched to indole-1-
carboxylic acid benzylamide 1c (entries 5−7). Although the
conversion of 1c was very low (entry 7), these positive results
further encouraged us to employ 1c as a model substrate and
investigate the effect of various additives and proton sources on
this transformation (entries 8−17). Gratifyingly, we quickly
found the ruthenium catalyst C/Cu(OAc)2/AcOH system
could provide us 67% yield of 3a (entry 13). It is worth noting
that 59% yield of 3a could also be obtained in the absence of
any proton sources (compare entry 13 with 18). By the way,
lowering or increasing the reaction temperature led to a
decreased conversion of 1c to some degree (compare entries 19
and 20 with 13). Finally, the best yield of 3a (80%) was
obtained at 100 °C for 24 h by using 10 mol % of a Ru catalyst
C/Cu(OAc)2 (0.5 equiv)/AcOH (1.0 equiv) catalytic system
a
Unless otherwise noted, all of the reactions were carried out using N-
substituted indole or pyrrole (1) (0.10 mmol) and alkyne (2) (0.20
mmol) with RuCl2(p-cymene)2 catalyst (10 mol %) in the presence of
AcOH (1.0 equiv) and Cu(OAc)2 (0.5 equiv) in DCE (2.0 mL) at 100
°C for 24 h under Ar in a sealed reaction tube followed by flash
chromatography on SiO2. Isolated yield. Total isolated yield of the
mixture. The ratio was determined by H NMR spectroscopy. nr =
b
c
d
e
1
no reaction.
B
DOI: 10.1021/ol503618m
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Organic Letters
Letter
electronic-withdrawing (such as 5-CO2Et, 5-halide, 6-halide,
etc.) or electron-donating groups including 5-MeO and 7-Me
are introduced to the benzene ring. For example, the C2-syn-
alkenylation of diphenylacetylene (2a) with 5-ethoxycarbonyl-
N-(benzylamido) indole and 7-methyl-N-(benzylamido)indole
could furnish the desired alkenylation product 3f and 3i in 79%
and 74% yield, respectively. Moreover, the 3-methyl-substituted
indole could also furnish the desired syn-alkenylated indole 3j
in 82% yield. Interestingly, this reaction protocol could also
smoothly convert N-(phenylamido)pyrrole and N-(benzyl-
amido)pyrrole to the corresponding 2-alkenylated pyrrole 3k
and 3l in 55% and 53% yield, respectively, in which the amide
directing groups were not removed.
Scheme 3. Preliminary Mechanistic Studies
Subsequently, the scope of the C2-HADC with regard to
alkynes was then explored using 1c as an indole source. It was
found that this transformation tolerated a variety of electron-
rich and electron-poor diaryl internal alkynes which could
provide the desired (Z)-alkenylation indoles in moderate to
excellent yields. Among the tested unsymmetric internal
alkynes, 4-methoxylphenyl phenyl internal alkynes, 2-methox-
ylphenyl phenyl internal alkynes, and strong electron-with-
drawing group substituted phenyl phenyl interal alkynes could
high regioselectively furnish syn-alkenylated indoles (3m,n,s−v)
in 49−82% yield. By the way, the lower yields of 3s−u might be
caused by the hydration of electron-poor alkynes. It is worth
noting that the single crystal structure of 3t13 further
demonstrated that C2-HADC occurred preferentially at
electron-deficient Csp atom of alkyne and the alkenyl moiety
belonged to Z conformation.14 On the contrary, the m-Me-
phenyl phenyl internal alkyne and 4-Cl, 4-Br, or 4-hydroxyl
phenyl phenyl internal alkynes produced the desired syn-alkenyl
products with different regioselectivity. Moreover, aryl alkyl
alkynes, dialkyl alkyne, and aryl methoxymethyl internal alkyne
also allowed for this transformation and afforded the
corresponding (Z)-alkenes (3w−z) in good yields with high
regioselectivity. Unfortunately, when terminal alkyne was
applied to this reaction system, no desired 1,1-disubstituted
alkene 3za was formed.
Scheme 4. Proposed Catalytic Cycle
To further investigate the mechanism, the H/D exchange of
1m was conducted in a Ru(II)/CD3OD system for 96 h in the
absence of alkyne 2a, and 90% deuterium incorporation at C2-
position was observed (Scheme 3, eq 1). It is worth noting that
no H/D exchange of 1m was observed in the absence of Ru(II)
catalyst or only in the presence of AcOD. On the other hand,
the content of C2-deuterium in d-1ma under the Ru(II)/
CH3OH system could be decreased from 90% to 2% (eq 2)
to produce the cycloruthenium intermediates B with
concomitant loss of a proton.17 Then, the lone-pair electrons
from amide nitrogen of B triggered the nucleophilic attack to
the alkynes (C) activated by Cu(II) cations to lead to the
formation of the alkenylation intermediates (D) and
isocyanates (F), and F was trapped by acetate anions to form
the corresponding byproduct amides H18 with the release of
CO2. Simultaneously, the alkenylation metal intermediate D
could be further isomerized and protonated to produce the final
free (N−H) (Z)-alkenyl indoles (E).
In conclusion, we have described an efficient carboamide-
directed ruthenium-catalyzed C2-syn-alkenylation of indoles
with the assistance of copper salts. This transformation was
compatible with variety electron-poor and electron-rich indoles,
aryl aryl internal alkynes, aryl alkyl internal alkynes, and alkyl
alkyl internal alkynes. More importantly, the present reaction
system allows for the rapid assembly of free (N−H) C2-syn-
alkenylated indoles via a one-pot process. Further studies on
the reaction mechanism and synthetic application of this
transformation are underway in our laboratory.
1
(see the Supporting Information for the corresponding H
NMR spectrum). These results remarkably demonstrated that
the first step of a reversible Csp2−H bond cleavage process was
involved in the transformation. Subsequently, the intermolec-
ular isotope effect (KH/KD = 1.015) further indicated that the
reversible Csp2−H bond breaking was not the rate-limiting step
of the reaction (eq 3). Moreover, Ru(II)-catalyzed C-2-trans-
alkenylation of 1c in the absence of Cu(OAc)2 confirmed that
copper salts played a key role in controlling the steroselectivity
of this transformation (eq 4).16 Finally, the C2-HADC of
indole 1a with 2a provided 80% yield of N-phenylacetamide 5
whose formation demonstrated that acetate salts assisted in
removal of the amido group.
The possible mechanism for the C2-HADC is proposed in
Scheme 4 on the basis of the above results and the (Z)-
configuration of the indole-substituted alkenes. First, the
transformation was initiated by an acetate-assisted metalation
C
DOI: 10.1021/ol503618m
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Organic Letters
Letter
Park, J.; Kwak, J. H.; Shin, B. S.; Jung, Y. H.; Kim, I. S. Tetrahedron
Lett. 2014, 55, 3104.
(12) (a) Kurzer, F. Chem. Rev. 1952, 50, 1. (b) Bremner, J. B.;
ASSOCIATED CONTENT
* Supporting Information
■
S
Details for experimental conditions, characterization data,
copies of 1H and 13C NMR spectra for all isolated compounds,
and the single crystal data of 3t. This material is available free of
charge via the Internet at http://pubs.acs.org.
Sengpracha, W. Tetrahedron 2005, 61, 5489.
(13) See the Supporting Information for the single-crystal structure
and data of 3t.
(14) The NOE 1H−1H spectrum of 3n and 3x, as well as the single-
crystal structure of 3t, demonstrated that the configuration of the
alkenyl moiety belongs Z stereochemistry, so the other remaining
alkenylated products in Scheme 2 were also assigned the Z
configuration by assuming an analogous reaction pathway.
(15) The KIE value (1.25) was obtained under Ru(II)/Cu(II)/
AcOH system; see the Supporting Information for more details.
(16) The 1H NMR of 3a-1 consisted with Co(II)-catalyzed C2-trans-
alkenylation of indoles with alkynes; see ref 6 and the Supporting
Information for more details.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: denlin@scut.edu.cn.
*E-mail: zengwei@scut.edu.cn.
Author Contributions
†W.Z. and J.W. contributed equally to this work.
(17) For a review about the carboxylated-assisted ruthenium-
catalyzed C−H functionalizations, see: Ackermann, L. Acc. Chem.
Res. 2014, 47, 281 and references cited therein.
Notes
The authors declare no competing financial interest.
(18) The structure of byproduct N-phenylacetamide (5) was already
1
confirmed by its H NMR and 13C NMR spectra; see the Supporting
ACKNOWLEDGMENTS
■
Information.
We thank the NSFC (No. 21372085) and the GNSF (No.
10351064101000000) for financial support.
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D
DOI: 10.1021/ol503618m
Org. Lett. XXXX, XXX, XXX−XXX