Ru(II)/PEG-400 as a highly efficient and recyclable catalytic media for annulation and olefination reactions: Via C-H bond activation

Article abstract of DOI:10.1039/c6gc01581f

In this report synthesis of isoquinolinones, isocoumarins, and N-methyl isoquinolinones and olefination of the Weinreb amides by C-H bond activation using Ru(ii)/PEG-400 as green and recyclable media are documented. This developed methodology is capable o

Full text of DOI:10.1039/c6gc01581f

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Ru(II)/PEG-400 as a Highly Efficient and Recyclable Catalytic
Media for Annulation and Olefination Reactions via C-H Bond
Activation
Received 00th January 20xx,
Accepted 00th January 20xx
Subhash L. Yedage and Bhalachandra M. Bhanage*
DOI: 10.1039/x0xx00000x
In this report synthesis of isoquinolinones, isocoumarins, N-methyl isoquinolinones and olefination of Weinreb amides by
C-H bond activation using Ru(II)/PEG-400 as green and recyclable media is documented. This developed methodology is
capable for the regioselective and steroselctive construction of new C‒C, C‒O and C‒N bonds by the one step cleavage of
C‒H, N‒H, O‒H and N‒O bonds. This method is environmentally benign due to its peculiar characteristics such as i) high
atom economy, ii) reuse of expensive ruthenium based homogeneous catalytic system, iii) mild reaction conditions with
simple extraction process and, iv) importantly, all the systems derived from this protocol are scalable up to gram level.
www.rsc.org/
biological activities, including antifungal, antiallergic,
antitumor, phytotoxic, antimicrobial, anti-inflammatory,
antidiabetic, and immunomodulatory activities.4 The
Introduction
Isoquinolinones and isocoumarins are the six membered
lactams and lactones which are useful intermediates in organic
synthesis.1 isoquinolinone is the class of the most powerful
heterocycle, which is found in many natural products as well as
biologically active molecules.2 For instance, natural product
isocoumarin framework also represents one of the advantaged
structures for the development of natural product inspired
compounds of biological interest (Scheme 1).5 Traditionaly,
multistep synthesis of isoquinolinone and isocoumarin has
reported by many groups.6 However, remain some limitations
such as low yields, poor regioselectivity, and harsh reaction
conditions in some cases.
Antinoplanone
A
and
(
−
)-kibdelone C, as an anticancer
rare Australian
polyketide which were isolated from
a
actinomycete and both have the isoquinolinone skeleton
(Scheme 1).3
For the last decade, research is focused to avoid the
multistep synthesis. The transition metal-catalyzed direct C–H
bond functionalization is one of the key emerging strategies
that is currently attracting tremendous attention to provide
alternative environmentally friendly and efficient ways for one
step construction of C–C, C‒O and C–N bonds.7 Recently, some
groups like Fagnou’s group and Wang’s group have reported
the isoquinolinone synthesis by Rh(III)/Ru(II) catalyzed ortho-
C‒H bond activation of amides.8 Whereas, some groups like
Miura’s group and Ackermann’s group reported the
isocoumarin synthesis from acid using Rh(III)/Ru(II) catalytic
system.9
Cl
Me
N
H
Me
O
C3H7
Cl
O
N
O
OH
OH
H2N
O
O
OH
O
OH
HO
OH
HO
OMe
OH
O
OMe
OH
MeO
AntinoplanoneA
(-)-kibdelone C
O
O
OH
O
O
OH
COOEt
MeO
O
O
O
COOH
MeO
O
OH
One time use of expensive catalysts and solvents
previous reports
NM3
Rubromycin
s
t
n
Scheme 1. Examples of important drug molecules containing isoquinolinone and
isocoumarin skeleton.
e
)
I
v
I
l
I
O
(
o
O
s
h
.
R
g
r
R
R
Y
o
X
As well as, isocoumarins have also the greatest attention to
synthetic and medicinal chemists due to their diverse
P
E
R
R
u
G
ꢀ
4
(
R
0
I
I
X = NHOMe
OH, NMeOMe
0
)
Y = NH
O, NMe
present work
Reuse of expensive catalyst and biodegradable solvent
a.Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai-
400 019, India.
Scheme 2. Previous reports and Ru(II) catalysed annulations via C‒H bond activation.
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available:
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This method compares favorably with conventional (Table 1, entries 4-7). The mixture of PEG-400 and H2O was not
transformations in terms of atom and step-economy. Mostly, set up to be more effective than PEG-400 (Table 1, entry 8).
the homogeneous transition metals like Pd(II),10 Ru(II)11 and Instead of Cu(OAc)2∙H2O, other oxidants such as CuO, NaOAc,
Rh(III)12 homogeneous complexes have attracted considerable AgOAc and CsOAc were also tested during the screening of the
attention for C‒H bond activation. Nevertheless, the use of reaction and all these oxidants are found to be ineffective for
homogeneous catalytic system in industrial scale is challenging this transformation (Table 1, entries 9-12). The effect of
because they are highly expensive and one time use. The temperature was studied (110, 80, 60 and 50 °C), in between
o
separation of homogeneous catalyst from the reaction mixture 110 C - 60 °C showed the best result (Table 1, entries 13-15).
is also the serious issue in the pharmaceutical industries. The The yield of product 1aa decreased with time decreases less
main drawback is the wastage of rarely available and than 12 h. (Table 1, entries 16-18). Thus, the final optimized
expensive metal precursor. With these great importance, reaction conditions for isoquinolinone synthesis are: 1a (0.5
some groups reported the heterogeneous recyclable catalytic mmol), 2a (0.5 mmol), [{RuCl2(p-cymene)}2] (3 mole%),
system for the C-H bond activation,13 but they have limited Cu(OAc)2∙H2O (0.5 mmol), AgSbF6 (10 mol%), PEG-400 (4 mL) at
scope. The leaching of metal catalyst into the reaction mixture 60 °C for 12 h.
causes the serious problem. In order to gratify recyclability and
Later on the synthesis of isoquinolinones, we went towards
environmental concerns, more facile and efficient approach is the optimization study for synthesis of isocoumarin from
to immobilize the catalyst in a liquid phase by dissolving it into aromatic benzoic acid. With changes of optimization
a nonvolatile and non mixing liquid, such as ionic liquids14 and parameters like temperature, oxidant concentration and time.
poly (ethylene glycols) (PEGs). Although ionic liquids provide In the full optimization condition, the isocoumarin synthesis
some disadvantages, such as a complicated method for the requires 80 OC temperature and 18 h, this might be due to the
synthesis of ionic liquids as well as their environmental safety weak directing group properties of –OH group of acid. The
is still debated because the toxicity and environmental issues.
final optimized reaction conditions for isocoumarin synthesis
It is well documented that PEG is stable at high from acid are: 8a (0.5 mmol), 2a (0.5 mmol), [{RuCl2(p-
temperature, easily available, inexpensive, recoverable, cymene)}2] (3 mol%), Cu(OAc)2∙H2O (0.5 mmol), AgSbF6 (10
biodegradable and nontoxic material.15 PEG also serves as an mol%), PEG-400 (4 mL) at 80 °C for 18 h. Evaluation of the C−H
efficient medium for environmentally friendly and safe bond activation for annulations strategy examined by the
chemical reactions. In recent years, PEGs have been coupling of diphenylacetylene 2a with various amides and acid
successfully utilized as reaction media for the metal-catalyzed derivatives (Table 3). Firstly, to investigate the scope of N-
cross-coupling reactions with facile recyclability of solvents as substituted benzamides such as the amide containing N‒O and
well as catalysts.16 Considering the importance of Ru(II)/PEG as N‒H bond, such as NHOMe 1a NHOBn 2a, NHOH 3a, provided
green, environmentally and economically benign catalytic
system for the development of C‒C and C‒O bond
formations.17 Herein we report the Ru(II)/PEG catalytic system
for the synthesis of isoquinolinones, isocoumarin, N-methyl
isoquinolinones and ortho-olefinated products via C‒H bond
activation of aromatic amides and acids.
Table 1. Optimization of reaction parametersa
Entry
Catalyst
Solvent
Oxidant
Yield
(%)b
trace
15
61
93
37
-
-
23
Results and discussion
1
2
3
4
5
6
7
8
RuCl3.3H2O
Cp*Ru(COD)Cl
PEG-200
PEG-200
PEG-200
PEG-400
PEG-600
PEG-2000
PEG-6000
PEG-400/H2O
(3:1)
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
For initial tests, we chose the N-methoxybenzamide 1a and
diphenylacetylene 2a as model substrates for the anuulation
reaction using RuCl3.3H2O (3 mol%), Cu(OAc)2∙H2O (0.5 mmol),
AgSbF6 (10 mol%), PEG-400 (4 mL) at 100 °C for 24 and trace
amount of isoquinolinone product 1aa was observed (Table 1).
Next, different Ru-catalysts were tested, and series of
experiments were extended out to examine the essence of
various reaction parameters such as solvents, oxidants,
temperature, time and catalyst loading on the takings of the
desired product. The Ru based catalysts were screened such
as, Cp*Ru(COD)Cl, and [{RuCl2(p-cymene)}2] (Table 1, entries
2–3). It was observed that [{RuCl2(p-cymene)}2] catalysts
showed best catalytic activity for the annulations and forms
isoquinolinone 1aa with maximum yield (Table 1, entry 3). The
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
9
10
11
12
13c
14d
15e
16f
17g
18h
[{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]
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
CuO
NaOAc
AgOAc
CsOAc
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
trace
trace
trace
trace
93
93
81
93
93
87
product was purified and confirmed by the charcterisation of aReaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst (3 mol%), oxidant
(0.5 mmol), solvent (4.0 mL), 100 oC, 24 h, bGC yield, c80 oC, d60 oC, e50 oC, f18 h,
1H and 13C NMR.
g12 h, h10 h.
Among the various PEG solvents, it was found that PEG-400
is superior to PEG-200, PEG-600, PEG-2000 and PEG-6000
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excellent yields of product 1aa
-
3aa and this is due to good Table 3. Ruthenium catalyzed oxidative annulations of N-methoxybenzamides and
benzoic acids with alkyne
leaving group (–OR) of the N-O bond. Interestingly, in the
absence of N‒H bond like NMe (OMe) of 4a, the ‒OMe also
acts as a good leaving group and resulted in N-methyl
isoquinolinone product 4aa. It indicates that the high activity
of the Ru(II) catalyst for the N−O inserꢀon. Also, amide
containing N-H bond like NH2 5a and NHMe 6a showen lower
yield of 5aa and 6aa. However, in the absence of N‒H and N‒O
bond, such as N(Me)2 amide 7a is difficult to convert into the
desired product 7aa. Parallel to amide, the same catalytic
system shows great use for isocoumarin synthesis from
aromatic acid derivatives. The Benzoic acid 8a requires 80 oC
temperature for 18 h to the maximum conversion of 8aa
However, acid derivatives containing good leaving group like
benzoyl peroxide 9a showed an excellent yield of 9aa
.
.
With optimal reaction conditions at hand, we explored the
detail substrate scope with Ru(II)/PEG catalyzed annulations of
N-methoxy aromatic amides and acids with respect to the
alkyne (Table 3). The reaction tolerates a remarkably broad
range of functional groups. Amides/Acid containing neutral,
electron-donating and electron-withdrawing groups afforded
the desired products in excellent yields. The model reaction
for the synthesis of isoquinolinone and isocoumarin showed
an excellent yield of products 1aa and 8aa respectively. The
effects of electron donating and withdrawing groups on N-
Table 2. Ruthenium-catalyzed reactivity of different amide and acid derivatives with
diphenylacetylene
aReaction conditions: N-methoxy-N-methyl benzamide (1a, 0.5 mmol),
diphenylacetylene 2a (0.5 mmol), [{RuCl2(p-cymene)}2] 3 mol%, PEG-400 (4 mL),
Cu(OAc)2∙H2O (0.5 mmol), PEG-400 (4 mL), 60 °C, 12 h, for acid derivatives 80 oC,
18 h, bYield of isolated product.
The meta-substituted N-mehoxybenzamide 1e and benzoic
acid 8e regioselective coupled with 2a at the less hindered C–H
bond of 1e and 8e exclusively to give coupling product 1ea and
8ea in 93 and 80% yields respectively. The regioselective
reactivity of alkyene toward less hindered side was confirmed
aReaction conditions: amide/acid derivatives 1a-9a (0.5 mmol), diphenylacetylene
2a (0.5 mmol), [{RuCl2(p-cymene)}2] (3 mol %), Cu(OAc)2∙H2O (0.5 mmol), PEG-
400 (4.0 mL), 60 oC bGC yield.
1
by H NMR spectroscopy. The singlet present at 8.27 ppm of
1ea and singlet at 8.20 ppm of 8ea indicate that exclusively
formation of 1ea and 8ea (ESI, S2). Similarly, N-methoxy-2-
naphthamide 1f and 2-naphthoic acid 8f also underwent the
annulation reaction regioselectively with 2a and exclusively
formation of isoquinolinone 1fa [confirmed by singlet at 9.08
ppm] and isocoumarin 8fa [confirmed by singlet at 9.01 ppm]
in 90 and 83% yield, respectively. In addition, the catalytic
methoxybenzamide 1a and benzoic acid 8a were studied. It
was found that electron donating groups such as ‒Me, ‒OMe
and ‒tbutyl produced corresponding products 1ba
8ba 8da in good to excellent yields. Next, the regioselectivity
of substituted amide and acid 1e 1f and 8e 8f was examined.
-1da and
-
-
-
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reaction proceeded very well with ortho-substituted aromatic explore the substrate scope, diphenylacetylene as the internal
N-methoxyamide such as N-methoxy-2-methylbenzamide 1g alkyne was studied under the optimized reaction conditions. It
and 2-methylbenzoic acid 8g, which yielded coupling products was observed that diphenylacetylene reacts with different
1ga and 8ga in 86 and 79% yield, respectively. To explore the substituted N-methoxy-N-methyl amides to furnish respective
scope of the coupling reaction, various substituted aromatic N- products in good yield. The N-methoxy-N-methyl amides
methoxyamides 1i–1k and acids 8h
-8k were examined and containing electron-donating groups like –Me and –OMe
provided 1ia–1ka, 8ha-8ka in excellent to good yields, provided excellent yields of 4ba and 4ca. Weak electron
respectively. The heterocyclic amides are not reactive, withdrawing groups –Cl and –Br gave the respective products
products of 1la and 8la were not observed. The catalytic 4da and 4ea. In the regioselective annulations of N-methoxy-2-
1
system is selectively important for annulations of aliphatic naphthamide, in H spectrum the singlet at 9.20 ppm confirms
internal alkyne and N-methoxyamide to give the product 1ab the exclusive synthesis of 3,4-diphenylbenzo[g]isoquinolin-
and the 8ab, 1kb and 8kb were not observed. Unfortunately, 1(2H)-one 4fa instead of 1,2-diphenylbenzo[f]isoquinolin-
under the reported reaction conditions, terminal alkynes failed 4(3H)-one (ESI, S2).
to afford the corresponding cyclist products.
After the successful synthesis of isoquinolinones,
To extend the scope of catalytic system, for the C–H isocoumarin, and N-methyl isoquinolinones, we extended this
activation/cyclization of N-methoxy-N-methylbenzamide (W. protocol for the olefintion reaction of W.A and alkene to
A.) 4a with diphenylacetyle 2a was investigated. The reaction synthesize (E)-N-methyl-2-styrylbenzamide 4aa. The metal
was performed at previously reported optimized parameters, catalyzed ortho-olefination of W.A. to (E)-N-methyl-2-
unfortunately 67% yield of product 4aa. Importantly, the styrylbenzamide using alkene via C-H activation have great
product 4aa is nothing but the industrially important N- intense interest due its importance in pharmaceuticals.19,20
protected cyclic amide and number of groups have synthesized Under the optimized reaction condition, the olefination
using N-alkyl amide.18 With the existing reports N-methoxy-N- reaction of N-methoxy-N-methylbenzamide 4a using styrene
methylbenzamide acts as a good directing group and also 2a’ as a model reaction was performed (Table 5). With
provides good leaving group (‒OMe).19 To increase the yield of screening of different reaction parameters like oxidant
product, studied reaction parameters such as concentration of temperature and time, the 0.1 mmol of oxidant is sufficient for
oxidizing agent, temperature and time. Finally, 100 oC the maximum conversion of product (E)-N-methyl-2-
temperature is a key point for maximum conversion at styrylbenzamide 4aa’
.
In 1H spectroscopy, the coupling
optimized reaction condition and 89% yield of product 4aa was constant more than 12 Hz clearly indicates the stereoselctivity
observed. The results demonstrated that the oxidative towards the trans-olefinated products (ESI, S2). With
annulation process smoothly occurred with internal alkynes. optimization condition in hand, we moved towards the
We observed that the desired 89% product 4aa. The optimized olefination of various derivatives of N-methoxy-N-methyl
reaction conditions are: 4a (0.5 mmol), 2a (0.5 mmol), amides and styrene (Table 5). It was observed that, the styrene
[{RuCl2(p-cymene)}2] 3 mol%, Cu(OAc)2.H2O (1 mmol%), AgSbF6 derivatives having electron donating substituents such as –CH3
(10 mol%) and PEG-400 (4 mL) at 100 °C for 12 h. To
and –OCH3 results in good yields of 4ab’ and 4ac’. While, weak
electron-withdrawing groups such as –Br on the aromatic ring
of styrene provide excellent yields of products 4ad’. The strong
electron withdrawing group (–NO2) containing styrene also
provided an excellent yield of 4ae’. After studying different
styrene derivatives, the reactivity of different N-methoxy-N-
methyl amide derivatives were also investigated. The electron
rich N-methoxy-N,4-dimethylbenzamide 4b and N, 4-
dimethoxy-N-methylbenzamide 4c were smoothly reacting
with styrene and provided the excellent yield products 4ba’
and 4ca’. The N-methoxy-N-methyl benzamide derivatives with
weak electron withdrawing substitutes such as –Br results in
better yield of 4da’. The N-methoxy-N,3-dimethylbenzamide
4e regioselectively coupled with 2e’ towards less hindered side
exclusively and provides 89% yield of 4ee’ which was
Table4. Scope on the ruthenium-catalyzed annulations of N-methoxy-N-
mthylbenzamide derivativesa
1
confirmed by H spectroscopy shown singlet at 7.60 ppm (ESI,
S2). Unfortunately, a strong electron withdrawing group
containing Weinreb Amide 4f and pyridine derivatives of
amide and styrene does not provide the yield of 4fa-4af’.
After all the study of annulation and olefination reactions,
to show the consistency of this one-pot protocol we moved
towards exploration this methodology for gram scale level
(Table 6). In anulation reaction, at optimized reaction
aReaction conditions: N-methoxy-N-methyl benzamide 4a-4f (0.5 mmol),
diphenylacetylene 2a (0.5 mmol), [{RuCl2(p-cymene)}2] 3 mol%, Cu(OAc)2∙H2O (1
mmol), PEG-400 (4 mL), 100 °C, 12 h, b80 oC, cIsolated yields.
4 | J. Name., 2012, 00, 1-3
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Table 5. Substrate scope of ruthenium-catalyzed oxidative olefination
R2
O
O
O
Me
N
Me
[RuCl2(p.cymene)]2
N
+
Me
H
Cu(OAc)2—H2O, AgSbF6 (10 mol%)
PEGꢀ400
R1
4a-4g
R2
R1
2a'-2e'
4aa'-4ga'
Br
OMe
O
O
O
O
Me
Me
Me
Me
N
N
H
N
N
H
H
H
4ab'; 90%
4ac'; 83%
4aa'; 87%
4ad'; 79%
NO2
O
O
O
O
Me
Me
Me
Me
N
H
N
H
N
H
N
H
Br
MeO
4da'; 71%
4ae'; 77%
4ba'; 87%
4ca'; 82%
Br
N
O
O
O
exclusively
O
Me
Me
Me
Me
N
N
H
N
H
N
H
H
N
O2N
4fa'; 00%
4ga'; 00%
4af'; 00%
4ee'; 89%
aReaction conditions: 4a-4g (0.5 mmol), 2a’-2e’ (0.7 mmol), [{RuCl2(p-cymene)}2] Fig.1 a) Procedure for reuse of catalyst and solvent system, b) catalyst
(3 mol%), Cu(OAc)2∙H2O (0.1 mmol), PEG-400 (4 mL), 100 °C, 16 h. bIsolated yield.
recyclability study for the annualtions and olefination reactions.
the color changed to blue
at room temperature, 5-7 mL of diethyl ether was added and
shakes, the two layers were generated. The upper layer of
2. With cooling the reaction mixture
condition 1.06 g (7 mmol) of 1a, 1.10 g (9 mmol) 3a and 1.16
g (7 mmol) of 4a has taken as stating substrate and 1.54 g (74
%) of 1aa, 1.79 g (67%) of 8aa and 1.58 g (73%) of 4aa
observed respectively. After the successful gram scale study of
annulations moved towards gram scale study of ortho-
olefination reaction. The 1.16 gm (7 mmol) of 4a provided 1.17
gm (71%) of product 4aa’.To investigate the reusability of the
catalyst and solvent for annulation and ortho-olefination
reactions of amide with alkyne and styrene at the optimized
reaction conditions. The observations of recyclability are
demonstrated in Fig. 1, before the reaction brown colour of
3
diethyl ether contains a product mixture directly uses for
purification and the lower layer contains PEG with catalytic
o
system. The PEG layer was heated to 40-50 C for 10 min to
remove the miscible quantity of ether. The cooled PEG-
catalytic system used for the next cycle. With the same
procedure, the recyclability and reusability were performed for
the synthesis of 1aa (93, 92, 92 and 90%), 8aa (83, 81, 80 and
80%), 4aa (90, 89, 89 and 87%) and 4aa’ (89, 89, 88 and 86%)
(Fig 1). It was observed that the catalyst was effective to 4th
recyclability without much loss in its activity and the decrease
in yield might be loss during work up.
mixture 1 was observed, while after completion of the reaction
Table 6. Gram scale study
Amide/Acid
Reaction conditions
Product
On the basis of experimental observations and previous
reports,11,20a a proposed mechanism for the Ru(II) catalyzed
oxidative annulation and ortho-olefination by C–H bond
activation as well N–O bond cleavage in the presence of
Cu(OAc)2.H2O is depicted in Scheme 3. As below, the proposed
1a
[{RuCl2(p-cymene)}2](3 mol%),
1aa
74%
1.54 g
8aa
67%
1.79 g
4aa
73%
1.58 g
4aa’
71%
(7 mmol)
1.06 g
3a
(9 mmol)
1.10 g
4a
(7 mmol)
1.16 g
4a
(7 mmol)
1.16 g
Cu(OAc)2∙H2O (3.5 mmol), AgSbF6 (10
mol%), PEG-400 (10 mL), 60 °C, 12 h.
[{RuCl2(p-cymene)}2](3 mol%),
Cu(OAc)2∙H2O (4.5 mmol), AgSbF6 (10
mol%), PEG-400 (10 mL), 80 °C, 18 h.
[{RuCl2(p-cymene)}2](3 mol%),
Cu(OAc)2∙H2O (7 mmol), AgSbF6 (10
mol%), PEG-400 (10 mL), 100 °C, 12 h.
[{RuCl2(p-cymene)}2](3 mol%),
Cu(OAc)2∙H2O (0.7 mmol), AgSbF6 (10
mol%), PEG-400 (10 mL), 100 °C, 16 h.
mechanism shown in two paths like the path
path is annulations and olefination of N-Methoxy-N-methyl
benzamide 4a and path II is the aanulations of N-Methoxy
benzamide 1a and benzoic acid 8a with diphenylacetylene 2a
I and path II. The
I
.
The first step of the transformation is unknown. It might be –Cl
of catalyst absorbs by Ag salt and form AgCl.21
1.17 g
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Journal Name
and high atom economy are the most attractive part of this
reaction. The developed protocol is also constructive for the of
stereoselective synthesis of trans-ortho-olefinationated
products.
Experimental
General experimental procedure:
All reactions were carried out in oven-dried glassware. All acid
derivatives, styrene derivatives, diphenyl acetylene, [{RuCl2(p-
cymene)}2], AgSbF6, Cu(OAc)2∙H2O and all the solvents were
purchased from Aldrich, Alfa Aesar, Spectrochem or Thomas
Baker. All W.A. derivatives were synthesized by reported
method.23 Analytical TLC was performed with 60 F254 silica gel
plates (0.25 mm thickness). Column chromatography was
performed with silica gel (100-200 mesh). NMR spectra were
recorded with Agilent Technologies (1H NMR at 500 or 400
MHz, 13C NMR at 125 or 100 MHz) spectrometer. The chemical
shifts are reported in ppm relative to tetramethylsilane as an
internal standard and the coupling constant in Hz. The High-
resolution mass spectra (HRMS) were recorded on a Thermo
Scientific Q-Exactive with Accela 1250 pump, LRMS analysed
by Agilent Tripal-Quard LC MS 6520. GC-MS-QP 2010
instrument (Rtx-17, 30 m × 25 mm ID, film thickness (df) = 0.25
µm) (column flow 2 mL min−1, 80 °C to 240 °C at 10 °C min−1
rise) was used for the mass analysis of the products. GC yields
were obtained using Perkin Elmer Clarus 400 instruments with
an ELITE-1 column.
Scheme 3. Plausible reaction mechanism, I) for annulations and olefination of N-
methoxy-N-methylbenzamide, II) annulations of N-methoxybenzamide and
benzoic acid with alkyne.
In path
and which made complex
the release of protons and coordination with carbonyl of
4a 19,21
This is followed by coordination of the metal to the
alkene/alkyne B’ and subsequent carbometallation and
generates intermediate and C’
19,21 The β hydride elimination
of gives the product 4aa’ and reductive elimination of C’
I,
the Ru(II) forms complex with hexafluroantimonate
A
by ortho-C‒H bond activation with
.
B/
Experimental procedure for the ruthenium catalyzed
isoquinolinone, isocoumarin and N-methyl isoquinolinone
synthesis
C
.
C
affords the product 4aa and. In path II, the Ru(II) forms
complex with hexafluro antimonate and which made complex
A 15 mL pressure tube containing N-methoxybenzamide 1a
(0.5 mmol, 76 mg)/Benzoic acid 8a (0.5 mmol, 61 mg)/W.A. 4a
(0.5 mmol, 83 mg), diphenylacetylene (0.5 mmol, 89 mg),
[{RuCl2(p-cymene)}2] (3 mol% 18 mg), Cu(OAc)2.H2O (as
menstioned above) and AgSbF6 (10 mol%, 34 mg) was added.
To the tube 4 mL of PEG-400 was added. The reaction mixture
was allowed to stir at mentioned temperature for 12-18 h. At
the end of the reaction, the reaction mixture was diluted with
diethyl ether. The upper layer of diethyl ether contains a
product mixture directly uses for purification. The product was
purified through a silica gel column using toluene and ethyl
A
by ortho-C‒H bond activation of 1a and 8a with the release
of protons This is followed by coordination of the metal to the
diphenylacetylene 2a forms B’’ and subsequent
carbometallation and generates intermediate C’’ 8b
The
reductive elimination of C’’ gives annulated product 1aa 8aa
The Ru0 generates final step of path path
and II, which is
.
.
/
.
I
oxidized by Cu(II) to regenerate a Ru(II) catalyst for the next
catalytic cycle. In the developed protocol of annulations and
olefinations, only 0.1 mmol to 1 mmol of Cu(OAc)2 is used as
the internal oxidant, the remaining amount of Cu(OAc)2 might
be regenerated in the presence of oxygen or air from the
reduced CuOAc as a copper source.22
acetate as eluent to give pure 1aa/8aa/4aa
.
Experimental procedure for the ruthenium catalyzed ortho-
olefination of aromatic W.A.
Conclusions
A 15 mL pressure tube containing W.A. 4a (0.5 mmol, 83 mg)
[{RuCl2(p-cymene)}2] (3 mol%, 18 mg), Cu(OAc)2∙H2O (0.1
mmol, 20 mg), AgSbF6 (10 mol%) were added. To the tube, 4
mL of PEG-400 solvent was added and styrene 2a’ (0.7 mmol,
73 mg) via a syringe. The reaction mixture was allowed to stir
at 100 °C for 16 h. At the end of the reaction, the reaction
mixture was diluted with diethyl ether. The upper layer of
diethyl ether contains a product mixture directly uses for
purification. The product was purified through a silica gel
In summary, we utilized Ru(II)/PEG-400 as a reusable catalytic
system for the construction of C‒C, C‒O and C‒N bond
formations via C‒H bond activations. This developed protocol
is superior than previous methods due its advantageous
features such as i) cost effective, ii) recycilibility of
homogeneous catalyst, iii) multitasking catalyst for C‒H
activations, iv) mild reaction conditions, v) wide range of the
substrate scope with excellent yield, vi) scalable up to gram
level, and vii) simple work up process. The C‒H bond activation
6 | J. Name., 2012, 00, 1-3
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ARTICLE
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DOI: 10.1039/C6GC01581F
Graphical Abstract
Ru(II)/PEG-400 as a Highly Efficient and Recyclable Catalytic Media for
Annulation and Olefination Reactions via C-H Bond Activation
Subhash L. Yedage and Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai–400019, India.
Tel.: +91-22-33612603; Fax: +91-22-33611020
E-mail: bm.bhanage@gmail.com, bm.bhanage@ictmumbai.edu.in