The ruthenium(ii)-catalyzed C-H olefination of indoles with alkynes: The facile construction of tetrasubstituted alkenes under aqueous conditions

Article abstract of DOI:10.1039/d0ob00508h

An environmentally-friendly and facile protocol for the construction of tetrasubstituted alkenes has been established with Ru(ii)-catalyzed C-H bond functionalizations under mild conditions. The method features the usage of readily available substrates, without external oxidants and additives, 100% atom economy, and excellent regioselectivity, thus enhancing the practicability of this protocol. Moreover, this transformation proceeded smoothly under aqueous conditions and could be extended to the gram scale. N-Methoxyamide, as a directing group (DG), played a vital role in the transformation.

Full text of DOI:10.1039/d0ob00508h

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DOI: 10.1039/D0OB00508H
ARTICLE
Ruthenium(II)-catalyzed C–H olefination of indoles with alkynes:
facile construction of tetrasubstituted alkenes under aqueous
conditions
Ming Li, Tian-Yu Yao, Sheng-Zheng Sun, Ting-Xun Yan, Li-Rong Wen, Lin-Bao Zhang*
An environmentally-friendly and facile protocol for the construction of tetrasubstituted alkenes has been established by
Ru(II)-catalyzed C-H bond functionalizations under mild conditions. The method was featured by the usage of readily
available substrates, without external oxidants and additives, 100% atom economy, and excellent regioselectivity, thus
enhancing the practicability of this protocol. Moreover, this transformation underwent smoothly under aqueous conditions
and could be extended to gram scale. N-Methoxy amide, as a directing group (DG) played a vital role in the transformation.
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
could also be used as viable techniques to achieve the goal.5a,8
In spite of the great development in this area, the relatively
harsh reaction conditions including the use of the
stoichiometric organometallic reagents or strong base limit
their practical application in organic synthesis. In light of the
importance of tetrasubstituted alkenes, there is an urgent
demand to develop an efficient and practical synthetic protocol
to construct such motifs.
Recently, the use of ruthenium(II)-catalysts has contributed
to the discovery of milder reaction conditions and efficient
catalytic systems, following the pioneering work of Oi, Inoue,9
and Ackermann.10 Especially, the development of Ru(II)-
catalyzed C-H bond transformations “in-water” has attracted
great attention due to the fact that water as the undoubtedly
green solvent possesses the abundant, cheap, non-toxic,
environmentally benign and safe property.11 Such as, Dixneuf
group performed the direct arylation of arenes with aryl
chlorides in water under the assist of 2-phenylpyrimidine as the
directing group without the requirement of surfactant (Scheme
1a).12 The group of Ackermann reported an efficient direct
arylations of unactivated C-H bonds using phenols as the
coupling reagents under aqueous conditions (Scheme 1b).13
Recently, they also disclosed a micellar catalysis system for
Ru(II)-catalyzed C−H arylation in H2O, which the weak
coordinating thioketone group enable the transformation
Introduction
Transition-metal-catalyzed C−H activation has been recognized
as a practical tool for the synthesis of biologically important
molecular scaffolds and characterized by several appealing
features, such as step- and atom-economy, unnecessity of
preactivated substrates and synthetic practicality.1 However,
one of the challenges associated with the strategy is the low
reactivity of C-H bonds, which suggests that harsh reaction
conditions are often required in the process.2 Moreover, the
developments “in-water” reactions remain relatively scare,
probably due to the decreasing the solubility of substrates or
catalysts in water.3 Moreover, 100% selective conversion of
starting material is also one of the vital principles in green
chemistry, which could minimize the generation of side
products.4 Therefore, the development of highly atom-
economical organic reaction under aqueous conditions to
construct valuable compounds is highly desirable.
Tetrasubstituted alkenes are widely existed in biologically
active natural products and drugs such as Tamoxifen or Vioxx
(Figure 1).5 They are also key starting reagents for various
transformations such as hydrogenations, epoxidations, and
other processes.6 However, the synthesis of tetrasubstituted
alkenes remains a challenging topic due to the strong steric
effect. Generally, the frequently applied synthetic routes to
such molecules employ alkynyl carbometallation intermediate.7
In addition, strategies such as the classical Wittig reactions,
olefin metathesis, radical sequences, and ynolate chemistry
OH OH
O
O
Me2N
State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and
Molecular Engineering, Qingdao University of Science and Technology, Qingdao
266042, P. R. China. E-mail: zhang_linbao@126.com.
OH
Brasilenol
MeO2S
O
OH
Tamoxifen
Vioxx
epi-Illudol
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Figure 1. Selected examples of biologically active compounds
bearing a tetrasubstituted alkene core.
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Table 1. Optimization of the reaction conditions.a,b
Previous work:
View Article Online
DOI: 10.1039/D0OB00508H
Ph
Ph
N
Cl
N
N
Catalyst, Oxidant
Ru(II)
N
N
Ph
N
+
(a)
+
+
OMe
H
O
Ph
Ph
Ph
Base, Solvent
air, rt
in water, 80 o
C
N
NH2
O
NH
H
Ph
O
MeO
4
1a
2a
3aa
1.2 equiv
1.0 equiv
Entry
Catalyst
Base
Solvent
3aa
4
N
N
OH
N
1
2
[RuCl2(p-cymene)]2
[Cp*RhCl2]2
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
Na2CO3
NaOAc
CsOAc
Et3N
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
43%
35%
trace
N.R.
N.R.
54%
49%
76%
65%
41%
trace
77%
52%
35%
73%
87%
13%
9%
Ru(II)
+
(b)
Ph
in water, 100 o
C
3
[Cp*IrCl2]2
trace
-
1.0 equiv
1.2 equiv
Br
4
Cp*Co(CO)I2
t-Bu
S
t-Bu
S
5
None
-
H
Ru(II)
6c
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
12%
11%
14%
13%
10%
trace
13%
12%
15%
14%
-
(c)
Fe
TPGS-750M/H2O
100 o
Fe
7c
C
1.0 equiv
8c
1.2 equiv
9c
This work
R1
10c
11c
12c,d
13c,d
14c,d
15c,d
16c,d,e
R1
Ru(II)
N
O
R2
N
None
+
OMe
(d)
H
O
H2O, air, rt
N
NH
H
R2
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
MeO
operational simplicity
ambient temperature
broad substrate scope
100% atom economy
easily avalable substrate
indole : alkyne = 1:1
redox-neutral
scalable
in water
DMF
MeOH
H2O
Scheme 1. The development of Ru(II)-catalyzed C-H bond
transformations in water.
aReaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.15 mmol, 1.5 equiv), catalyst
(5.0 mol %), Cu(OAc)2 (0.1 mmol, 1.0 equiv), NaOPiv (0.2 mmol, 2.0 equiv), DCM
(1.0 mL), air, room temperature, 1 h. bIsolated yields. cNo oxidant. d2a (0.1 mmol,
1.0 equiv). eRection time: 10 h. N.R. = no reaction.
(Scheme 1c).14 In these cases, high temperature was inevitable
during the transformation. Beyond the arylation, the diverse
reaction types need to be further developed in water. Within
our constant interest in transition-metal-catalyzed C–H
functionalizations and green chemistry,15 we presented a C–H
olefination of indoles assisted by CONHOMe directing group
under aqueous conditions, providing an effective and practical
route for the synthesis of tetrasubstituted alkenes (Scheme 1d).
entry 11).16 Moreover, decreasing the amount of 2a to 1.0
equivalent, the product 3aa could also be obtained without the loss
of the yield (Table 1, entry 12). The solvents showed a profound
effect on the transformation (Table 1, entries 13-16), H2O as a green
solvent presented a better performance without the detection of by-
product 4, albeit a longer reaction time was required (Table 1, entry
16).
Under the optimized reaction conditions, we explored the
substrate scope of indoles 1 for this reaction (Table 2). Various
electron-donating and electron-withdrawing groups including
methyl (3ga), methoxyl (3ba and 3fa), fluoro (3ha), chloro (3ca,
3ia and 3na), bromo (3da, 3ja and 3oa), iodo (3ka) and ester
(3ea and 3la) at 4-, 5- and 6- positions of indole could be
tolerated in the reaction, furnishing the desired products in
good yields (75%-87%). However, when strong electron-
withdrawing group nitro was at the C5 position of indole (1m),
the transformation did not occur. Moreover, the desired
products (3pa and 3qa) could be obtained in good yields when
the C3 position of indole was methyl substituent. However, the
methyl was replaced by phenyl substituent at the C3 position of
indole, the yields were greatly decreased due to steric
hindrance factor (3ra-3ua). Noteworthy, natural product
derivatives such as 1v and 1w were also applicable in the
reaction, affording the target products 3va and 3wa in 73% and
Results and discussion
We commenced the study by using N-methoxy-1H-indole-1-
carboxamide 1a and alkyne 2a as the substrates. Initially, various
metal catalysts were screened for this reaction. To our delight, when
the reaction was performed in the presence of 5.0 mol % [RuCl2(p-
cymene)]2, 1.0 equivalent of Cu(OAc)2, 2.0 equivalent of NaOPiv in
DCM at room temperature for 1 hour, the desired product 3aa was
obtained in 43% yield along with 13% of by-product 4 (Table 1, entry
1). Other metal catalysts such as Rh, Ir, Co catalysts showed poor
catalytic activity (Table 1, entries 2-4). No product was obtained in
the absence of Ru catalyst (Table 1, entry 5). Subsequently, further
exploration indicated that oxidants were dispensable as the yield was
increased to 54% without oxidants (Table 1, entry 6). Next, various
bases were screened and NaOAc could play as an effective base, the
others such as Na2CO3, CsOAc or Et3N, showed the inferior results
(Table 1, entries 7-10). Only trace of 3aa was afforded upon removal
of NaOAc, indicating that base was critical to the reaction (Table 1,
2 | J. Name., 2012, 00, 1-3
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72% yields, respectively.
Table 2. Scope of N-alkoxyamides.a,b
in the rate-limiting step.17 Intermolecular competition
Table 3. Scope of alkynes.a,b
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DOI: 10.1039/D0OB00508H
R2
R1
R2
R1
Ph
Ph
[RuCl2(p-cymene)]2 (5 mol %)
[RuCl2(p-cymene)]2 (5 mol %)
R1
N
R2
NH
R1
N
+
+
H
OMe
NaOAc (2 equiv)
H2O, air, rt, 10 h
N
Ph
NaOAc (2 equiv)
H2O, air, rt, 10 h
O
N
H
N
R2
OMe
O
O
Ph
H
N
NH
MeO
O
H
MeO
1a
2
3
2a
1
3
Symmetrical alkynes
R
R
Ph
Ph
R
R
R
Ph
N
Ph
N
Ph
R
H
H
N
Ph
O
O
H
N
O
NH
NH
H
O
NH
MeO
MeO
N
MeO
3aa
NH
N
R
H
3fa
R = OMe,
, 85%
H
O
MeO
O
R = H,
, 87%
3ba
3ga
3na
3oa
R = Me,
, 86%
R = Cl,
R = Br,
, 82%
, 81%
NH
NH
3ag
R = OMe,
R = Me, 3ah, 88%
, 89%
R = OMe,
, 75%
, 77%
3da
3ha
R = F,
R = Cl,
R = Br,
, 78%
MeO
MeO
3ca
R = Cl,
R = Br,
3ia
3ja
, 84%
, 83%
, 81%
3ai
, 85%
COOMe
COOMe
NH
3ab
3ac
3ad
3ae
R = t-Bu,
R = Me,
R = Cl,
R = Br,
R = CF3,
, 73%
S
3ea
R = COOMe,
, 82%
3ka
R = I,
, 81%
, 76%
, 80%
, 80%
3la
R = COOMe,
R = NO2,
, 77%
, N.R.
S
3ma
N
NthPh
N
H
O
H
3af
, 81%
MeOOC
O
Ph
Ph
NH
R
R
MeO
Ph
Ph
Ph
MeO
3aj
, trace
3ak
, 66%
N
Ph
N
Ph
N
N
Ph
Ph
H
H
O
H
H
O
O
O
Unsymmetrical alkynes
NH
NH
NH
NH
R
MeO
MeO
MeO
MeO
3ra
R = H,
, 43%
3sa
3va
3wa
, 72%
, 73%
3pa
R = H,
R = OMe,
, 92%
3qa
R = OMe,
, 48%
, 46%
3ua
, 70%
3ta
R = Cl,
R = Br,
N
H
,44%
N
R
N
O
H
O
H
O
NH
aReaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.1 mmol, 1.0 equiv), [RuCl2(p-
cymene)]2 (5.0 mol %), NaOAc (0.2 mmol, 2.0 equiv), H2O (1.0 mL), air, room
temperature, 10 h. bIsolated yields.
NH
NH
MeO
3ap
MeO
MeO
c
3al 3al
', 92% (52:48)
, 82%
R = Me,
+
'
, 83% (3:2)c
3am 3am
R = CF3,
+
Ts
N
N
H
To investigate the generality of this reaction, the scope of
alkynes 2 was also evaluated (Table 3). For symmetrical alkynes,
both electron-donating and electron-withdrawing groups at the
para-position of the benzene ring were tolerated, providing the
desired products (3ab-3af) in good yields (73%-81%).
Substitution at the meta-position with methoxyl (3ag) and
methyl (3ah) provided the 89% and 88% yields, respectively.
Besides, 2-naphthyl alkyne also worked well to give the desired
product (3ai) in good yield of 85%. However, it did not provide
the desired product (3aj) using 3-thienyl alkyne as the
substrate. Surprisingly, the ester-substituted alkyne was used as
the candidate, the desired product (3ak) was obtained in a yield
of 66%. For unsymmetrical alkynes with phenyl group on one
O
N
N
H
O
NH
H
O
MeO
NH
NH
MeO
MeO
3aq
, 67%
c
3an 3an'
+
, 81% (11:1)
N
N
Ph
O
Ph
O
N
N
NH
N
N
N
H
H
H
O
O
O
NH
NH
NH
MeO
3ar
MeO
MeO
c
, 73%
3ao 3ao'
+
 70% (2:1)
aConditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.1 mmol, 1.0 equiv), [RuCl2(p-
cymene)]2 (5.0 mol %), NaOAc (0.2 mmol, 2.0 equiv), H2O (1.0 mL), air, room
temperature, 10 h. bIsolated yields. cThe ratio is determined by 1H NMR
analysis.
side
of
the
alkynes
and
4-methylphenyl,
4-
trifluoromethylphenyl or 1-naphthyl groups on another side,
they gave two unseparated isomers (3al-3an) in 81%-92%
yields. Natural product derivative 2o also can work well,
provided two isomers (3ao+3ao') in total 70% yield.
Interestingly, it was found that only single products (3ap-3ar)
were obtained while unsymmetrical alkynes (2p-2r) were
employed in the reaction.
Several control experiments had been performed to explore
the mechanism (Scheme 2). The kinetic isotope effect (KIE)
experiments were conducted, and an intermolecular KIE (KH/KD
= 0.88) was observed for the competition reactions of 1a and
deuteriumlabeled 1a-D with 2a (Scheme 2, eq 1). Two parallel
reactions gave a similar KIE value of 0.8 (Scheme 2, eq 2). These
results suggested that C-H bond cleavage was unlikely involved
experiments between 1g (R = Me) and 1h (R = F) with 2a were
performed, and the results revealed electron-withdrawing N-
alkoxyamides 1 to be functionalized preferentially (Scheme 2,
eq 3). However, the effect of substituents on the transformation
was negligible in terms of alkynes 2 (Scheme 2, eq 4). The
presence of a radical quencher such as 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) or 2,6-diisopropyl-4-methylphenol
(BHT) did not inhibit the reaction, suggesting that radical
process was not involved in the transformation (Scheme 2, eq
5). Only two products (3pa and 3Aa) were obtained when the
two different amides (1p and 1A) reacted with the alkyne 2a,
indicating that the process of intramolecular nucleophilic
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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substitution was more likely compared with procedure of
Based on the preliminary mechanistic experimVeienwtsArtaicnledOntlhinee
directing group removal (Scheme 2, eq 6).18 Further exploration previous literatures, a possible reaction pathway is proposed
DOI: 10.1039/D0OB00508H
(Scheme 3). Initially, a catalytically active Ru catalyst is
Kinetic Isotope Effect (KIE) Study
generated through the chloride ligand of [RuCl2(p-cymene)]2 as
The Intermolecular competition
well as ligand exchange to sodium acetate. After coordination
Ph
H\D
H\D
OMe
standard conditions
of N-alkoxyamide 1a to the active Ru catalyst, C−H bond
metalation generates the ruthenacycle A through a concerted
[RuCl2(p-cymene)]2
3aa 1
+
N
N
+
OMe
2 h, KH/KD = 0.88
N
N
Ph
O
H
O
H
1a 1a-D
2a
:
=1:1
1a 1a-D
:
R
NaOAc
H
Two parallel reactions
L = p-cymene
N
R
N
NaCl
LRu(OAc)2
OMe
H
standard conditions
O
N
2a
2a
1a
+
+
3aa
3aa
NH
O
H
3aa
MeO
2 h
standard conditions
2 h
KH/KD = 0.8
2
1a
1a-D
2AcOH
R
Competitive Experiments
L
RuII
N
N
O
N
R
Ph
R
OMe
R
Ph
OMe
N
RuII
O
standard conditions
N
Ph
3
A
N
+
H
OMe
L
D
O
1h
1g
, R = F, , R = Me
N
H
R
Ph
NH
O
MeO
1h 1g
:
2a
3ha 3ga
= 1:1
:
= 2:1
R
R
R
R
R
R
R
RuII
N
N
RuII
N
N
standard conditions
2f 2c
4
OMe
N
R
R
N
L
O
H
OMe
N
O
, R = CF3, , R = Me
2f 2c
OMe
O
O
H
C
NH
B
:
= 1:1
MeO
1a
3af 3ac
:
= 1.1:1
Scheme 3. Proposed mechanism.
Radical Inhibition Experiments
Ph
Ph
standard conditions
N
N
Ph
(5)
Ph
+
OMe
Ph
H
O
TEPMO (2.0 equiv), 80%
BHT (2.0 equiv), 82%
N
[RuCl2(p-cymene)]2 (5 mol %)
O
NH
H
Ph
N
H
Ph
+
N
MeO
NaOAc (2 equiv)
H2O, air, rt, 10 h
O
OMe
3aa
1a
2a
Ph
N
NH
O
H
MeO
Directing Group Migration Process Study
1a
(5.0 mmol)
2a
(5.0 mmol)
3aa
(1.35 g, 73%)
Ph
Ph
NH
Ph
N
H
N
Scheme 4. Gram scale experiment.
Ph
H
2a
(2 equiv)
O
O
[RuCl2(p-cymene)]2
NH
Ph
N
(10 mol %)
MeO
3pa
EtO
N
OEt
(6)
OMe
N.D.
NaOAc (4 equiv)
H2O, air, rt, 10 h
N
N
O
H
Ph
O
H
1p
(1 equiv)
1A
(1 equiv)
metalation-deprotonation (CMD) mechanism. Subsequently,
RuII-species coordinates to the internal alkynes 2 to form
complex B and migratory insertion of internal alkynes 2 results
in intermediate C. Then, C undergoes an intramolecular
nucleophilic substitution to provide directing group migrated
species D. Product 3aa is obtained followed by proto-
demetalation of D with AcOH, while AcOH regenerates the
active catalyst to complete the catalytic cycle.
N
Ph
N
Ph
H
O
H
O
NH
NH
MeO
N.D.
EtO
3Aa
Scheme 2. Mechanistic studies.
To further test the utility of the reaction, we conducted the
reaction on gram scale of N-alkoxyamide 1a with internal alkyne
2a, and 3aa was isolated in 73% yield (Scheme 4).
indicated N-alkoxyamide moiety was critical for the
transformation since other amides installing hydroxyl (1B) and
alkyl group (1C) did not work. No reaction was detected in the
case of the structurally similar but methylation of directing
groups in 1D (Figure 2).
N
N
N
OH
OMe
N
N
N
O
O
O
H
H
1B
1C
1D
Figure 2. Unsuccessful directing groups.
4 | J. Name., 2012, 00, 1-3
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View Article Online
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In conclusion, we have developed a Ru(II)-catalyzed C–H
olefination of at the C-2 position of N-methoxycarbamoyl
indoles by reacting with internal alkynes, furnishing
tetrasubstituted alkenes in high yields assisted by CONHOMe
directing group. This redox-neutral reaction is featured by the
mild reaction conditions, compatibility with various functional
groups, operational simplicity, 100% atom economy, and
excellent regioselectivity. In addition, the transformation could
be completed at room temperature under aqueous conditions
and easily performed on gram scale, which meet the vital
principles of green chemistry.
7
8
9
Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21801152 and 21572110), the Natural
Science Foundation of Shandong Province (ZR2019BB005 and
ZR2019MB010), the Youth Innovation Science and Technology
Plan of Colleges and Universities in Shandong Province
(2019KJC003).
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