A tethering directing group strategy for ruthenium-catalyzed intramolecular alkene hydroarylation

Article abstract of DOI:10.1039/c7cc08704g

We report a new catalyst design for N-heterocycle synthesis that utilizes an alkene-tethered amide moiety as a directing group for aromatic C-H activation. This tethering directing group strategy is demonstrated in a ruthenium-catalyzed intramolecular alk

Full text of DOI:10.1039/c7cc08704g

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Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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A Tethering Directing Group Strategy for Ruthenium-Catalyzed
Intramolecular Alkene Hydroarylation
Praveen Kilaru, Sunil P. Acharya and Pinjing Zhao*
dsReceived 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report a new catalyst design for N-heterocycle synthesis that incorporation of DGs into the tethered alkene moiety would
utilizes alkene-tethered amide moiety as a directing group for eliminate the need for additional DGs and achieve broader
aromatic C-H activation. This tethering directing group strategy is substrate scopes (Scheme 1c). However, there are no reports
demonstrated in a ruthenium-catalyzed intramolecular alkene on catalytic applications of such tethering DG strategy.
hydroarylation with N-aryl acrylamides to form oxindole products. Although several substrate classes in reported intramolecular
alkene hydroarylation contain alkene-tethering amide, ester or
Transition metal-catalyzed hydroarylation of alkenes, the
sulfamide moieties that are potential DGs, relevant
experimental results indicated that they did not provide
chelation-assistance in corresponding catalytic cyclization
processes.3,4a We hypothesize that a major challenge for the
tethering DG strategy is the requirement of a balanced metal-
formal alkene addition by an aromatic C−H bond, has evolved
into a powerful strategy for atom-efficient synthesis of alkyl-
substituted arenes and heteroarenes.1,2 Recently, applications
of intramolecular alkene hydroarylation for the synthesis of
nitrogen- and oxygen-benzoheterocycles have drawn
significant attention.3,4 Existing reports on such cyclization
processes have focused on two general approaches to
transform arenes containing heteroatom-tethered alkene
moieties: (1) electrophilic aromatic substitution (EAS) via
DG coordination that not only promotes ortho-aromatic C
activation (formation of intermediate in Scheme 1c), but also
allows facile ligand substitution on the resulting metallacycle
via DG dissociation and tethered alkene coordination ( ).
−H
C
CꢀD
Such alkene complexation is necessary for subsequent ring-
closure via intramolecular alkene insertion into the metal-aryl
alkene activation by
a Lewis-acidic metal catalyst and
subsequent intramolecular alkene attack by the arene
nucleophile (Scheme 1a);3,5 (2) deprotonation-based
linkage (
We herein report
directing group strategy in Ru-catalyzed intramolecular alkene
hydroarylation of N-aryl acrylamides ( ) to form oxindoles (
DꢀE).
a
demonstration of the tethering
cyclometalation via chelation-assisted aromatic C−H activation
with an ortho-directing group (DG) and subsequent
intramolecular alkene insertion into the resulting metal-aryl
linkage (Scheme 1b).4,6 The resulting alkene arylmetalation
1
2)
(Scheme 1d), which are important synthetic targets due to
their biological activities.8 Using the amide moiety as a alkene-
intermediates in both pathways (complexes
A and B) can
tethered DG for aromatic C
cyclization process does not require additional DG assistance
and tolerates broad range of aromatic- and vinyl-
−H activation (1ꢀC1), this catalytic
transform into hydroarylation products via protonation3,4 or
other products via oxidative functionalization such as Heck-
type olefination.7 From a mechanistic perspective, these two
catalytic cyclization strategies are inherently limited in
substrate scopes regarding aromatic substituents. For the EAS
approach, the reactions generally require electron-donating
substituents for substrate activation and suffer significant loss
of reactivity with electron-withdrawing substituents.5 For the
cyclometalation approach, the substrate structures are limited
by the requirement of having carbonyl derivative-based DGs at
a meta-position of the tethered alkene moiety.4 In principle,
a
substituents. With the redox-neutral nature and high atom-
efficiency of alkene hydroarylation, the current method for
oxindole synthesis complements existing strategies such as N-
aryl acrylamide cyclizations via free radical processes and
Heck-type oxidative alkene functionalizations.7a,7b,8-10
Current catalyst development has been guided by results from
our previous study on Ru/N-heterocyclic carbene (NHC)-
catalyzed [3+2] annulation between N-H aromatic ketimines
and alkynes, which was promoted by [Ru(cod)(η3-methallyl)2]
(
3a) as pre-catalyst and IPr ligand (4a) (Scheme 2a).11 The
proposed mechanism shared key common features with the
envisioned pathway for target oxindole synthesis, which
included DG assistance for aromatic C-H activation (imine C=N
Department of Chemistry and Biochemistry, North Dakota State University, Fargo,
ND 58108-6050, USA. E-mail: pinjing.zhao@ndsu.edu.
†Electronic Supplementary Information (ESI) available: detailed experimental
procedures and analytical data. See DOI: 10.1039/x0xx00000x
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vs. amide C=O) and 5-exo-trig ring-closure by intramolecular with para-electron-donating groups. The p-anisyl substrate led
1,2-insertion (imine into M-alkenyl vs. alkene into M-aryl).12 to product 2c in a moderate yield of 65%, while the p-tolyl
Thus, we focused our attention on Ru(II)/NHC catalysts to substrate required the use of CF3CO2H additive in place of
evaluate conditions for a model reaction with N-methyl-N- acetic acid to form 2b in 61% yield.13 With ortho-fluoro
phenyl methacrylamide (1a) (see Table S1 in Supplementary substituent, harsher reaction conditions of 140
Information for detailed results). We found that intramolecular was necessary to give product 2k in 73% yield. With meta-
alkene hydroarylation with 1a was promoted by 10 mol% fluoro substituent, mixed regioisomers 2l 2l corresponding to
[Ru(cod)(η3-C4H7)2]/IPr (3a
4a) and 2 equivalents of acetic acid H activation para- vs. ortho-to-F were formed in 84%
at 120°C and in dioxane solvent. Under these conditions, the combined yield and 10:1 selectivity favoring ortho-isomer 2l
oxindole product 2a was formed in 81% yield over 24 hours Replacing N-methyl with N-phenyl or N-benzyl moiety led to
°C over 48 h
/
′
/
C−
′
.
and no other by-products were detected.
products 2m and 2n in satisfactory yields, with the latter
providing a convenient handle for NH-oxindole synthesis via N-
deprotection. However, N-acetyl substitution led to substrate
decomposition and no detectable oxindole formation.
(a) Electrophilic aromatic substitution (EAS) via alkene activation
MLn
MLn
H
H
- H
Scope of the alkene moiety was studied by modification of
X = NR or O
MLn
X
X
A
X
α
- and
β
form products 2o
-vinyl substituents in N-aryl-N-methyl substrates to
2v. Replacing -methyl with ethyl and
(b) Directing group (DG)-assisted tandem cyclometalation/alkene insertion
-
α
ML
n Y = anionic -donor ligand
DG
DG
DG
Ln
M
acetoxymethyl groups in methacrylamide backbone did not
cause major loss of reactivity and gave products 2o and 2p in
71% and 74% yield respectively. In contrast, the cis-2,3-
dimethylacrylamide analog was much less reactive and
required the use of CF3CO2H additive, 20 mol% Ru/NHC
(chloride, acetate, etc.)
H
X
LnM
Y
DG = carbonyl derivative
(ketone, imine & amide)
- HY
X
B
X
(c) Alkene-tethering DG for tandem cyclometalation/alkene insertion
MLn
Ln
M
Ln
M
H
X
LnM
Y
catalyst loading, as well as 155
°C over 72 h to give 2o in 59%
DG
DG
DG
- HY
DG
X
yield. Such harsher conditions were also required for the
α
-CF3
X
X
C
D
E
analog of 1a to form product 2q in 61% yield, giving a rare
example of synthesizing 3-CF3-substituted oxindoles that were
not accessible via established methods such as free radical
(d) This study: amide as alkene-tethering DG in Ru-catalyzed oxindole synthesis
R"
R'
[Ru]
CH2R"
R'
O
H
[Ru]
cyclization.9 The scope of
with N-4-nitrophenyl-N-methyl acrylamides to afford products
2r 2t in 69-82% yields containing 3-butyl, -methoxymethyl, and
α
-substituents was further explored
FG
FG
O
FG
N
O
N
R
R"
N
R
R
H
1
C1
R'
2
-
Scheme 1. Transition metal-mediated intramolecular alkene arylmetalation
processes via C H activation.
-benzyl groups. Considering the high values of spiro-oxindoles
in drug development,8 we attempted the synthesis of product
2u with a 1-cyclopentenecarboxylic amide substrate. However,
only trace amount of 2u was formed under standard
conditions. A modified catalyst-ligand combination of 10 mol%
[Ru(p-cymene)Cl2] (3b) and 20 mol% 1,10-phenanthroline
ligand allowed 2u to be synthesized in 38% yield over 48 h of
−
heating at 140 °C. Lastly, removing
led to total loss of reactivity and failure to form corresponding
oxindole product 2v 14
α-methyl from substrate 1a
.
Current results on structure-reactivity correlations provide
important mechanistic insight as follows: (1) The generally
higher reactivity for electron-poor arene substrates than
electron-rich arenes (products 2a
hydroarylation pathway via electrophilic aromatic substitution.
Thus, we propose an amide-directed C H activation that
-j) strongly argues against a
Scheme 2. Ru/NHC-catalyzed cyclization processes via directed aromatic C
activation.
−H
−
With the standard reaction conditions established, various
N-aryl acrylamides were studied for Ru(II)-catalyzed
occurs by a proton abstraction pathway such as concerted
metalation-deprotonation (CMD),15 and is either the rate-
limiting step or a pre-rate-limiting equilibrium. This hypothesis
(1)
intramolecular hydroarylation (Scheme 3). In general, oxindole
products were formed without the detection of 2-quinolone
by-products.12 Scope of the N-aryl moiety was studied with N-
resonates with the proposed C−H activation mechanism in our
prior report on Ru/NHC-catalyzed imine/alkyne [3+2]
annulation.11 (2) The significantly lower reactivity for
substrates with ortho-F or relatively large vinyl substituents
aryl-N-methylmethacryl-amides to generate products 2a-2l′.
Good yields were acquired for substrates with para-electron-
withdrawing groups including halogens, CF3, NO2, acyl, and
(products 2k, 2o, 2q and 2u) suggests that the cyclization step
ester moieties (products 2d-2j), although para-iodine and –
by intramolecular alkene arylmetalation is sterically inhibited
by bulky alkene or arene moieties. (3) The exclusive formation
of 5-membered oxindoles over 6-membered 2-quinolones
cyano functionality led to no product formation. In
comparison, reduced reactivity was observed for substrates
2 | J. Name., 2012, 00, 1-3
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further supports a pronounced steric effect on the cyclization yield. Although
COMMUNICATION
5
was obtained as a racemic mixture, the
process, with the former favored by formation of a less current method can be potentially developed towards
crowded alkyl C Ru bond and the later favored by electronic enantioselective catalysis based on the proposed catalyst
stabilization of the resulting enolate C
With a major focus on new method development for C
−
−
Ru bond.16
control in construction of a quaternary chiral center at the
oxindole 3-position via intramolecular alkene arylmetalation.
−
H
functionalization, we carried out the following kinetic
experiments to explore details of the proposed deprotonation
R1
3a
10 mol% [Ru(cod)(C4H7)2] (
)
H
R2
O
O
4a
10 mol% IPr (
)
pathway for C
−
H activation (Scheme 4). Firstly, intramolecular
R'
R'
R'
N
R
R2
competition with unsymmetrical N,N-diaryl substrates 1w and
1x under standard catalytic conditions showed slightly higher
2 equiv acetic acid
N
R
dioxane, 120 oC, 24 h
R1
O
1
2
2a
2b
2c
2d
2e
2f
2g
2h
2i
R' = H
81%
61%
65%
88%
86%
79%
89%
91%
83%
84%
C−H alkylation reactivity for more electron-deficient aryls
[b]
R' = Me
R' = OMe
R' = F
R' = Cl
R' = Br
R' = CF3
R' = NO2
R' = COMe
R' = CO2Et
based on yield comparison (1.2:1 for phenyl vs. p-anisyl, and
1.6:1 for 4-fluorophenyl vs. phenyl) (Scheme 4a). Such small
differences in reactivity may be caused by intramolecular
electronic effects imposed by the un-transformed aryl on
reacted aryl groups. Secondly, initial-rate 1H NMR kinetics with
O
2k 73%[c]
N
N
Me
Me
F
F
O
O
N
N
F
Me
Me
electronically differentiated substrates 1a, 1c and 1g showed a
2l
2l'
clear reactivity disparity that favored more electron-deficient
aryls, with 8:5:1 relative rate for 4-trifluoromethylphenyl vs.
phenyl vs. p-anisyl moiety (Scheme 4b). Thirdly, reaction rate
2j
84% (1:10)
R1
R1 = Et, R2 = H
R1 = R2 = Me
R1 = CH2OAc, R2 = H
R1 = CF3, R2 = H
2o 71%
2o 59%[b][d]
R = Ph
R2
2m
90%
O
O
comparison between 1a and its C6D5-analog (d5
-1a) led to the
2p
74%
R = Bn
2n
N
N
2q 61%[d]
81%
R1
R
Me
determination of a normal isotope effect (kH/kD=2.1) (Scheme
4c). The reaction with d5-1a under standard catalytic
conditions led to a 1.2:1 product mixture of d4-2a and d3-2a in
R1
=
nBu
82%
2r
O2N
R1 = CH2OMe
O
O
O
41% overall yield. Compared to d4-2a, d3-2a contained one less
2s
78%
N
N
N
Me
Me
[c][e]
Me
R1 = Bn
2t 69%
aromatic deuterium, which can be attributed to ortho-H/D
exchange of d5-1a via equilibrium between Ru-mediated
cyclometalation and protonation of Ru-aryl linkage (likely by
2u
2v
0%
38%
1
3a
[a] General reaction conditions: (0.17 mmol, 1.0 equiv),
(0.10 equiv),
(0.10 equiv), AcOH (2.0 equiv), dioxane (1.0 mL), 120 ºC, 24h;
averaged isolated yields of two runs. [b] Using CF3CO2H in place of AcOH.
3a 4a
4a
1
acetic acid). Based on H NMR integration analysis, deuterium
[c] Reaction at 140 °C for 48 h. [d] Using 0.20 equiv
and ; reaction at
incorporation at 3,3-dimethyl substituents was estimated to
be 10% and >90% for reactions with d5-1a using regular and
deuterated acetic acid reagents (AcOH and AcOD) respectively.
This result supports the involvement of acetic acid additive as
an external proton source in the proposed hydroarylation
pathway.13,17 Overall, results from these studies are consistent
3b
155 °C for 72 h. [e] Using 10 mol % [Ru(p-cymene)Cl2] ( ) as Ru catalyst
precursor and 20 mol% 1,10-phenanthroline ligand.
Scheme 3. Scope of Ru-catalyzed intramolecular alkene hydroarylation for
oxindole synthesis.[a]
with a reversible, amide-directed aromatic C−H activation via
proton abstraction, which precedes the rate-limiting alkene
arylmetalation via insertion into the Ru-aryl linkage.16,18
To explore the current method for practical synthetic
applications, we first studied hydroarylation of 1a under scale-
up conditions (Scheme 5a). Gratifyingly, solvent volume
reduction enabled scale-up reactions to proceed smoothly at
reduced catalyst loadings. Thus, gram-scale synthesis of 2a was
successfully carried out with 0.70 mM substrate concentration
and 2.5 or 5 mol% catalyst loading to achieve 80% and 92%
isolated yield respectively. Next, we incorporated the
hydroarylation method into a new synthetic route for an
oxindole-based progesterone receptor antagonist (5) (Scheme
5b).19 The synthesis started with turning ethylmalonic acid into
2-ethylacryloyl chloride via an established procedure.20 The
crude product was subjected to Et3N-mediated amidation with
4-bromo-N-methylaniline to afford N-4-bromophenyl-N-
methyl-2-ethylacrylamide (1y) in 79% yield over two steps.
Intramolecular hydroarylation with 1y was carried out using 10
mol% Ru/NHC catalyst (3a/4a) to form oxindole product 2y in
Scheme 4. Results from kinetic studies and deuterium labeling experiments.
71% yield. Lastly, Pd-catalyzed Suzuki coupling between 2y and
4-fluorophenylboronic acid gave desired product
5 in 78%
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5
6
Scheme 5. Studies towards practical synthetic applications of Ru-catalyzed
intramolecular alkene hydroarylation.
7
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In summary, we have demonstrated the tethering directing
group strategy in
a Ru-catalyzed oxindole synthesis by
intramolecular alkene hydroarylation with N-aryl acrylamides.
This redox-neutral, 5-exo-trig cyclization occurs via a proposed
8
9
(a) M. M. M. Santos, Tetrahedron 2014, 70, 9735-9757. (b) G.
S. Singh and Z. Y. Desta, Chem. Rev. 2012, 112, 6104-6155.
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629.
tandem sequence of chelation-assisted aromatic
C−H
activation and intramolecular alkene arylmetalation. By
utilizing the amide moiety as an alkene-tethering directing
group, the current method complements existing strategies for
10 (a) S. Jaegli, J. Dufour, H.-I. Wei, T. Piou, X.-H. Duan, J.-P.
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intramolecular alkene hydroarylation with
a broadened
substrate scope and does not require the assistance of
additional directing groups for aromatic C-H activation.
Ongoing efforts are focused on better understanding of the
ligand effect on catalyst activity and ligand-based catalyst
modification for broader synthetic applications.
11 J. Zhang, A. Ugrinov and P. Zhao, Angew. Chem. Int. Ed. 2013
52, 6681-6684.
,
Financial support for this work was provided by NSF (CHE-
1301409) and NIH (1R15GM120688-01). We also thank ND
EPSCoR (EPS-0447679) for funding the purchase of
departmental NMR instrumentation.
12 See refs 3d and 4e for heterocycle synthesis via Co-catalyzed
6-endo-trig intramolecular alkene hydroarylation.
13 Carboxylic acids are known to facilitate Ru(II)-catalyzed C-H
functionalizations: E. F. Flegeau, C. Bruneau, P. H. Dixneuf
and A. Jutand, J. Am. Chem. Soc. 2011, 133, 10161-10170.
14 We did not detect formation of the corresponding 3-
methylene oxindole as possible by-product from competitive
intramolecular dehydrogenative Heck olefination.
15 D. Lapointe and K. Fagnou, Chem. Lett. 2010, 39, 1118-1126.
16 See Scheme S1 in Supplementary Information for a detailed
mechanism description.
Conflicts of interest
There are no conflicts to declare.
17 Another possible role for acetic acid additive is to facilitate
DG/alkene ligand exchange as described in Scheme 1c by
reversible protonation of the amide carbonyl to promote its
dissociation from the Ru center of complex C1 in Scheme 1d.
18 Q. Gui, L. Hu, X. Chen, J. Liu and Z. Tan, Asian J. Org. Chem.
2015, 4, 870-874.
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Lobkovsky and A. K. Ganguly, Tetrahedron Lett. 2011, 52,
3945-3948.
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4 | J. Name., 2012, 00, 1-3
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