Ruthenium-catalyzed aerobic oxidative cyclization of aromatic and heteroaromatic nitriles with alkynes: A new route to isoquinolones

Article abstract of DOI:10.1039/c3cc42683a

The oxidative cyclization of aromatic and heteroaromatic nitriles with alkynes in the presence of a catalytic amount of [{RuCl₂(p-cymene)} ₂], Cu(OAc)₂·H₂O and KPF₆ in acetic acid under air gave isoquinolones in good to excellent yields.

Full text of DOI:10.1039/c3cc42683a

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Ruthenium-catalyzed aerobic oxidative cyclization of
aromatic and heteroaromatic nitriles with alkynes: a
new route to isoquinolones†
Cite this: DOI: 10.1039/c3cc42683a
Received 12th April 2013,
Accepted 16th May 2013
Mallu Chenna Reddy, Rajendran Manikandan and Masilamani Jeganmohan*
DOI: 10.1039/c3cc42683a
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The oxidative cyclization of aromatic and heteroaromatic nitriles we report for the first time an unprecedented aerobic oxidative
with alkynes in the presence of a catalytic amount of [{RuCl2(p- cyclization of aromatic and heteroaromatic nitriles with alkynes in
cymene)}2], Cu(OAc)2ꢀH2O and KPF6 in acetic acid under air gave the presence of a catalytic amount of [{RuCl2(p-cymene)}2], KPF6 and
isoquinolones in good to excellent yields.
Cu(OAc)2ꢀH2O to give isoquinolone derivatives in good to excellent
yields.7 Interestingly, the present catalytic reaction was conducted
Substituted isoquinolones are one of the important classes of under an air atmosphere.
heterocyclic compounds. This core is present in various natural
When 3,4-dimethoxybenzonitrile (1a) was treated with diphenyl-
products and biologically active molecules.1 Due to their interesting acetylene (2a) in the presence of [{RuCl2(p-cymene)}2] (5.0 mol%),
biological properties, the development of a highly efficient and easily KPF6 (20 mol%) and Cu(OAc)2ꢀH2O (30 mol%) in acetic acid at 120 1C
accessible method to synthesise isoquinolone derivatives is highly for 10 h under an air atmosphere, isoquinolone derivative 3a was
important in organic synthesis. Several methods to synthesise observed in an isolated yield of 83% (eqn (1)) (for detailed optimiza-
isoquinolone derivatives are available in the literature.2 Among tion studies see ESI†). The cyclization reaction was completely
them, metal-catalyzed oxidative cyclization of heteroatom substi- regioselective, in which a less hindered C–H bond of 1a was involved
tuted aromatics with alkynes via chelation-assisted C–H bond in the cyclization reaction with 2a. It is important to point out that to
activation is one of the promising and practical methods.3 Rhodium date only substituted benzamides have been used as key reactants to
and ruthenium complexes have been widely used as catalysts for this synthesize isoquinolone derivatives in the presence of a metal catalyst
type of cyclization reaction. Oxidative cyclization of N-alkyl or aryl via C–H bond activation. In the present work, an aromatic nitrile is
substituted benzamides (Ph-CONHR) with alkynes in the presence used as a key reactant to synthesize isoquinolone derivatives.
of rhodium- or ruthenium catalysts and a stoichiometric amount of
external oxidants gave N-alkyl or aryl substituted isoquinolone
derivatives.4 In the meantime, N-alkoxy benzamides (Ph-CONHOR)
(1)
reacted with alkynes in the presence of rhodium- or ruthenium
catalysts to provide isoquinolone derivatives.5 In the reaction, the
N-alkoxy moiety acted as an internal oxidant. But, in the cyclization
The present cyclization reaction was tested with various substi-
of benzamides (Ph-CONH2) with alkynes, only 1 : 2 oxidative cycliza- tuted aromatic nitriles and heteroaromatic nitriles (Table 1). Reaction
tion products (one benzamide and two alkynes) were observed, and of electron-donating groups such as OH, OMe, Me and NMe2 at the
the expected isoquinolone derivatives were not observed.4a,6 In order para position of the aromatic nitriles 1b–e with 2a gave isoquinolone
to attain the isoquinolone derivatives selectively and to avoid the derivatives 3b–e in 76%, 78%, 72% and 82% yields, respectively
competitive 1 : 2 cyclization product, N-alkyl or aryl or alkoxy sub- (entries 1–4). A highly sensitive free OH substituent on the aromatic
stituted benzamides were used.
ring of 1b was not affected in the reaction (entry 1). Similarly, highly
In the chelation-assisted metal-catalyzed cyclization reactions, sensitive halogen groups such as I, Br, Cl and F at the para position of
ketone, COOH, amide, imine and oxime substituted aromatics have the aromatic nitriles 1f–i also efficiently participated in the reaction,
been used for the cyclization with alkynes. To date, there is no report affording isoquinolone derivatives 3f–i in 72%, 70%, 68% and 65%
discussing the cyclization of aromatic nitriles with alkynes. Herein, yields, respectively (entries 5–8). The catalytic reaction was tested with
4-cyanophenylboronic acid (1j). In the reaction, the corresponding
cyclization product 3j was observed in 72% yield (entry 9). But, the
boronic acid moiety was cleaved under the reaction conditions. In the
Department of Chemistry, Indian Institute of Science Education and Research,
Pune 411021, India. E-mail: mjeganmohan@iiserpune.ac.in
meantime, benzonitrile (1k) reacted with 2a yielding product 3j in
76% yield (entry 10). Very interestingly, electron-withdrawing groups
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and spectroscopic data. See DOI: 10.1039/c3cc42683a
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Table 1 The reaction of substituted nitriles 1 with diphenylacetylene (2a)a
Entry Nitriles 1b–u
Products 3b–t
Yieldb (%)
1
2
3
4
5
6
7
8
1b: R1 = OH
1c: R1 = OMe
1d: R1 = Me
1e: R1 = NMe2
1f: R1 = I
3b: R1 = OH
3c: R1 = OMe
3d: R1 = Me
3e: R1 = NMe2
3f: R1 = I
76
78
72
82
72
70
68
65
72
76
73
75
63
74
1g: R1 = Br
1h: R1 = Cl
1i: R1 = F
3g: R1 = Br
3h: R1 = Cl
3i: R1 = F
9
1j: R1 = B(OH)2
1k: R1 = H
3j: R1 = H
10
11
12
13
14
3j: R1 = H
1l: R1 = CHO
3k: R1 = CHO
1m: R1 = COMe 3l: R1 = COMe
1n: R1 = CO2Me 3m: R1 = CO2Me
1o: R1 = NO2
3n: R1 = NO2
Scheme 1 Regioselective studies of substituted alkynes.
15
16
1p: R2 = OMe
1q: R2 = Cl
3o + 3o0: R2 = OMe
3p + 3p0: R2 = Cl
41 + 30
25 + 40
93% (entry 17). Similarly, 3-cyanoindole (1s) and 3-cyanothiophene (1t)
yielded the corresponding cyclization products 3r and 3s in 86% and
88% yields, respectively (entries 18 and 19). Interestingly, a less reactive
2-cyanothiophene (1u) also efficiently reacted with 2a, giving cylization
product 3t in 74% yield (entry 20). In substrate 1u, the electron
rich C3–H bond was activated efficiently. (For the reaction of ortho
substituted benzonitriles with alkynes see ESI†).
The scope of the catalytic reaction was further tested with various
symmetrical and unsymmetrical alkynes (Scheme 1). Thus, symme-
trical alkynes such as 1,2-bis(4-methoxyphenyl)ethyne (2b) and
1,2-di(thiophen-2-yl)ethyne (2c) reacted efficiently with 1a or 1t to
afford the corresponding cyclization products 4a–c in 76%, 77% and
67% yields, respectively (Scheme 1). Unsymmetrical alkynes such
as 1-phenyl-1-propyne (2d) and 1-phenyl-1-butyne (2e) cyclized effi-
ciently with 3,4-dimethoxybenzonitrile (1a), giving cyclization products
4d and 4e in 85% and 82% yields, respectively. The catalytic reaction
is completely regioselective, in which the less hindered C–H bond of
17
18
19
93
86
88
74
20
a
All reactions were carried out using 1a–u (1.0 mmol), diphenylacety-
lene (2a) (1.0 mmol), [{RuCl2(p-cymene)}2] (5 mol%), KPF6 (20 mol%)
and Cu(OAc)2ꢀH2O (30 mol%) in acetic acid (3.0 mL) at 120 1C for 10 h 1a was connected to the alkyl (Me and Et) substituted carbon of
b
under an air atmosphere. Isolated yield.
alkynes 2d and 2e. However, 1-phenyl-1-hexyne (2f) reacted with 1a,
providing a mixture of regioisomeric products 4f and 4f0 in a
such as CHO, COMe, CO2Me and NO2 at the para position of combined yield of 80% with a 95 : 5 ratio of regioisomers. Whereas,
the aromatic nitriles 1l–o provided the corresponding isoquinolone methoxy substituted alkyne 2g afforded regioisomeric products 4g
derivatives 3k–n in 73%, 75%, 63% and 74% yields, respectively and 4g0 in a combined yield of 73% (98 : 2 ratio). It is nice to know
(entries 11–14). It is important to mention that C–H bond activation that the OMe substituent on the phenyl group of the alkyne 2a
of aromatics substituted with electron-withdrawing groups is quite increases the selectivity of the reaction. Further, the catalytic reaction
difficult. Interestingly, in the present reaction, the C–H bond of was tested with ethyl 3-phenylpropiolate (2h) under the optimized
aromatics substituted with electron-withdrawing groups was activated reaction conditions. In the reaction, the corresponding cyclization
efficiently. Next, the catalytic reaction was tested with meta substituted product 4h was observed in 64% yield in a highly regioselective
aromatic nitriles such as 3-methoxy 1p and 3-chlorobenzonitrile 1q manner, in which the less hindered C–H bond of 1a was connected to
with 2a. However, the catalytic reaction was not completely regioselec- the ester substituted carbon of alkyne 2h.
tive and a mixture of regioisomeric products 3o–3o0 in 41% and 30%
The isoquinolone derivatives were further converted into highly
and 3p–3p0 in 25% and 40% yields, respectively, was observed (entries useful 1-chloro and 1-bromo isoquinoline derivatives (eqn (2)). Thus,
15 and 16). To demonstrate the scope of the cyclization reaction, the reaction of 3a and 3q with POCl3 at 100 1C for 2 h gave
various heteroaromatic nitriles 1r–u were examined (entries 17–20). 1-chloroisoquinoline derivatives 5a and 5b in 91% and 87% yields,
Thus, the treatment of 3-cyanofuran (1r) with diphenylacetylene (2a) respectively. Similarly, 3a and 3s reacted with PBr3 at 120 1C for
yielded the corresponding cyclization product 3q in an excellent yield of 6 h to yield 1-bromoisoquinoline derivatives 5c and 5d in 90%
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and 88% yields, respectively (eqn (2)). Further, isoquinolone deriva-
tives 3i and 3n reacted with diphenylacetylene (2a) in the presence of
[{RuCl2(p-cymene)}2], Na2CO3 and Cu(OAc)2ꢀH2O in chlorobenzene
(2.0 mL) at 120 1C for 16 h to yield tricyclic compounds 5e and 5f in
95% and 93% yields, respectively (eqn (3)).4f In the reaction, the
ortho C–H bond of one of the phenyl groups and the amide N–H
bond of 3i or 3n were involved in the cyclization reaction.
(2)
Scheme 2 Proposed mechanism.
presence of ruthenium and copper catalysts. Further extension
of cyclization of substituted nitriles with other p-components
and detailed mechanistic investigation are in progress.
We thank the DST (SR/S1/OC-26/2011), India, for the support
of this research. M.C.R. thanks the CSIR for a fellowship.
(3)
A cooperatively ruthenium- and copper-catalyzed reaction
mechanism is proposed for the present cyclization reaction as
shown in Scheme 2. In the copper-catalyzed reaction, Cu(OAc)2
likely acts as a Lewis acid to which the CN group of benzonitrile 1
is coordinated to give intermediate 5. In this stage, Cu(OAc)2 likely
reduces the electron density of the nitrile group. Subsequently,
nucleophilic addition of AcOH to the CN group in intermediate 5
followed by hydrolysis affords benzamide 11 and regenerates
Cu(OAc)2.8 In the ruthenium-catalyzed reaction, KPF6 likely
removes the chloride ligand from the [{RuCl2(p-cymene)}2]
complex followed by the ligand exchange with Cu(OAc)2, giving
cationic ruthenium species 7. Coordination of the nitrogen group
of 11 to the ruthenium cationic species 7 followed by ortho-
metalation in the presence of AcOH affords a five-membered
ruthenacycle 9.9 Coordinative insertion of alkyne 2 into the Ru–
carbon bond of ruthenacycle 9 provides intermediate 10. Reduc-
tive elimination of intermediate 10 in the presence of Cu(OAc)2
gives product 3 and regenerates the active ruthenium species 7 for
the next catalytic cycle. In the reaction, only 30 mol% of Cu(OAc)2
is used as an internal oxidant. The remaining amount of Cu(OAc)2
source is regenerated under oxygen or air from the reduced
copper source in the presence of AcOH.
Notes and references
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(4)
The proposed mechanism was strongly supported by the follow-
ing mechanistic evidence (eqn (4)). Treatment of 1a (1.0 mmol)
with AcOH in the presence of Cu(OAc)2ꢀH2O (15 mol%) at 120 1C
in air gave 3,4-dimethoxy benzamide 11a in 95% yield. Further,
the treatment of 11a with 2a (1.0 equiv.) in the presence
of [{RuCl2(p-cymene)}2] (5.0 mol%), KPF6 (20 mol%) and
Cu(OAc)2ꢀH2O (30 mol%) in acetic acid at 120 1C for 10 h in air
provided isoquinolone 3a in an isolated yield of 75%.
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In conclusion, we have demonstrated the oxidative cycliza-
tion of aromatic and heteroaromatic nitriles with alkynes in the
c
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