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This article can be cited before page numbers have been issued, to do this please use: J. Hu, H. Qin, W. Xu, J. Li, F. Zhang and H. zheng, Chem. Commun., 2014, DOI: 10.1039/C4CC06653G.
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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Cite this: DOI: 10.1039/c0xx00000x
View Article Online
DOI: 10.1039/C4CC06653G
COMMUNICATION
www.rsc.org/xxxxxx
TfOH-catalyzed synthesis of 3-aryl isoindolinones via tandem reaction Jiaxing Hu, Hua-Li Qin, Wengang Xu, Junli Li, Fanglin Zhang* and Hua Zheng* Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x
10
Previous Work
A convenient metal-free method for the synthesis of 3-aryl isoindolinones via TfOH catalyzed aromatic C−H functionalization of electron-rich arenes with 2formylbenzonitriles is developed. This process provided a new efficient synthetic strategy to isoindolinone derivatives by forming two bonds in good to high yields and regioselectivities.
O
O LDA, Et3N
N
R1
O
15
20
25
30
35
40
45
This journal is © The Royal Society of Chemistry [year]
R1
Ph Me
CHO MeNH2, AcOH
Ph
Isoindolinones can be found in natural products including stachybotrin C,1 indoprofen,2 Lennoxamineand,3 and also in some pharmacologically important synthetic compounds, such as zopiclone4 and pagoclone.5 Numerous synthetic and natural molecules containing the isoidolinone skeleton have been reported to display significant biological activities including antimicrobials,6 antiviras,7 HIV-1 inhibitors,8 TACE inhibitors,9 antitumor activities,2,10 hypnotic agents,11 antidopaminergic agents and also protein kinase inhibiting activities.12 Some isoindoline derivatives were also reported to exhibit local anesthetic activity superior to that of procaine.13 Furthermore, these heterocyclic scaffolds have been found to have special fluorescent properties recently.14 Numerous methods for the construction of the isoindolinone ring system have been reported, among which. the more commonly used approaches are those from aromatic monocarbonyl compounds, from 1,2-dicarbonyl compounds, and from the transformations of heterocycles, via the Diels–Alder reaction, and through the Wittig reaction.7,15 Cyclizations of aryl lithium species of different N-acyl-benzylamine derivatives such as Nbenzyl-N,N-dimethylureas were also reported in the literature with the using of strong basic organo-lithium regents, which are normally incompatible with functional groups sensitive to nucleophilic attack.16 More recently, several metal-catalyzed approaches have been described for the synthesis of isoindolinones including carbonylation of benzylamines under CO atmosphere using the catalytic system Pd(OAc)2-Cu(OAc)2, a tandem limination-cyclization-Suzuki approach, Heck-SuzukiMiyaura domino reaction involving ynamides, a Sonogashira reaction of 2-halobenzamides with terminal alkynes and alkynylation/lactamization cascade of available o-formyl methyl benzoates and o-formyl methyl arylacetates.17 Other approaches to the isoindolinone system generally involved electrophilic cyclization, and an intramolecular cyclization of acyl radicals onto an azide group.18 Above all, most of the existing methods suffer from certain limitations with respect to yield, substrate scope, or apparative
NH
R1
Ph
NHR
+ CO
Pd(OAc)2
N
O
Ph
R1
50
NH C O
This Work
Scheme 1 Synthetic approaches for isoindolinones.
55
60
65
70
75
requirements, and are not suitable for the preparation of compound libraries. Therefore, there remains considerable scope for improvement, such as a more versatile catalyst and reaction conditions which prevent catalyst leakage, a voiding the use of highly toxic CO, and obtaining higher yields. It was known that several classes of catalysts have been successfully applied to the FC reaction of aldehydes with nucleophiles, including brφnsted acids, conventional lewis acids, and transition metals.19 Keeping the proposed intermediates of the FC reaction in view, we wished to construct the isoindolinone core from corresponding 2-formylbenzonitrile with arenes via the Friedel-Crafts reaction followed by assisted ring closing reaction route. Our recent studies have been focusing on the development of new synthetic pathways for the preparation of heterocyclic compounds.20 Herein, we report a novel and efficient route to isoindolinones through tandem reaction of 2-formylbenzonitriles with benzene derivatives catalysed by TfOH. To the best of our knowledge, this process was established for the first time as the tandem construction of isoindolinones. For the synthesis of isoindolinones 3 via FC-ring closing reaction, 2-formylbenzonitriles 1a and mesitylene 2a was chosen as the model starting material. Accordingly different lewis acid21 such as FeCl3, CuCl, CuBr, CuI, BF3•Et2O and proton acid22 such [journal], [year], [vol], 00–00 | 1
ChemComm Accepted Manuscript
Published on 28 October 2014. Downloaded by University of Pittsburgh on 30/10/2014 22:19:19.
5
ChemComm
5
as H2SO4, CF3COOH, TfOH, was selected as the catalyst. As anticipated in the previous section, the nature of the acid plays an important role in the efficiency of the process (Table 1). In fact, as reported in Table 1, it can be seen that the use of lewis acid (0.2 equiv) in 1, 2-dichloroethane (Table 1, entries 1-5) led to only less than 10% yields after 24 h. To our delight, a slight
Page 2 of 5
transformation. Table 2 Reaction of substituted isoindolinones under optimized View Article Online conditionsa DOI: 10.1039/C4CC06653G
Table 1 Optimization of the reaction conditions screening for the synthesis of isoindolinonea
F
Cl
Entry Catalyst (eq.) Solvent Yieldb (%) 1 FeCl3 (0.2 eq) ClCH2CH2Cl
ChemComm Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: J. Hu, H. Qin, W. Xu, J. Li, F. Zhang and H. zheng, Chem. Commun., 2014, DOI: 10.1039/C4CC06653G.
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
www.rsc.org/chemcomm
ChemComm
Page 1 of 5
Dynamic Article Links ►
ChemComm
Cite this: DOI: 10.1039/c0xx00000x
View Article Online
DOI: 10.1039/C4CC06653G
COMMUNICATION
www.rsc.org/xxxxxx
TfOH-catalyzed synthesis of 3-aryl isoindolinones via tandem reaction Jiaxing Hu, Hua-Li Qin, Wengang Xu, Junli Li, Fanglin Zhang* and Hua Zheng* Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x
10
Previous Work
A convenient metal-free method for the synthesis of 3-aryl isoindolinones via TfOH catalyzed aromatic C−H functionalization of electron-rich arenes with 2formylbenzonitriles is developed. This process provided a new efficient synthetic strategy to isoindolinone derivatives by forming two bonds in good to high yields and regioselectivities.
O
O LDA, Et3N
N
R1
O
15
20
25
30
35
40
45
This journal is © The Royal Society of Chemistry [year]
R1
Ph Me
CHO MeNH2, AcOH
Ph
Isoindolinones can be found in natural products including stachybotrin C,1 indoprofen,2 Lennoxamineand,3 and also in some pharmacologically important synthetic compounds, such as zopiclone4 and pagoclone.5 Numerous synthetic and natural molecules containing the isoidolinone skeleton have been reported to display significant biological activities including antimicrobials,6 antiviras,7 HIV-1 inhibitors,8 TACE inhibitors,9 antitumor activities,2,10 hypnotic agents,11 antidopaminergic agents and also protein kinase inhibiting activities.12 Some isoindoline derivatives were also reported to exhibit local anesthetic activity superior to that of procaine.13 Furthermore, these heterocyclic scaffolds have been found to have special fluorescent properties recently.14 Numerous methods for the construction of the isoindolinone ring system have been reported, among which. the more commonly used approaches are those from aromatic monocarbonyl compounds, from 1,2-dicarbonyl compounds, and from the transformations of heterocycles, via the Diels–Alder reaction, and through the Wittig reaction.7,15 Cyclizations of aryl lithium species of different N-acyl-benzylamine derivatives such as Nbenzyl-N,N-dimethylureas were also reported in the literature with the using of strong basic organo-lithium regents, which are normally incompatible with functional groups sensitive to nucleophilic attack.16 More recently, several metal-catalyzed approaches have been described for the synthesis of isoindolinones including carbonylation of benzylamines under CO atmosphere using the catalytic system Pd(OAc)2-Cu(OAc)2, a tandem limination-cyclization-Suzuki approach, Heck-SuzukiMiyaura domino reaction involving ynamides, a Sonogashira reaction of 2-halobenzamides with terminal alkynes and alkynylation/lactamization cascade of available o-formyl methyl benzoates and o-formyl methyl arylacetates.17 Other approaches to the isoindolinone system generally involved electrophilic cyclization, and an intramolecular cyclization of acyl radicals onto an azide group.18 Above all, most of the existing methods suffer from certain limitations with respect to yield, substrate scope, or apparative
NH
R1
Ph
NHR
+ CO
Pd(OAc)2
N
O
Ph
R1
50
NH C O
This Work
Scheme 1 Synthetic approaches for isoindolinones.
55
60
65
70
75
requirements, and are not suitable for the preparation of compound libraries. Therefore, there remains considerable scope for improvement, such as a more versatile catalyst and reaction conditions which prevent catalyst leakage, a voiding the use of highly toxic CO, and obtaining higher yields. It was known that several classes of catalysts have been successfully applied to the FC reaction of aldehydes with nucleophiles, including brφnsted acids, conventional lewis acids, and transition metals.19 Keeping the proposed intermediates of the FC reaction in view, we wished to construct the isoindolinone core from corresponding 2-formylbenzonitrile with arenes via the Friedel-Crafts reaction followed by assisted ring closing reaction route. Our recent studies have been focusing on the development of new synthetic pathways for the preparation of heterocyclic compounds.20 Herein, we report a novel and efficient route to isoindolinones through tandem reaction of 2-formylbenzonitriles with benzene derivatives catalysed by TfOH. To the best of our knowledge, this process was established for the first time as the tandem construction of isoindolinones. For the synthesis of isoindolinones 3 via FC-ring closing reaction, 2-formylbenzonitriles 1a and mesitylene 2a was chosen as the model starting material. Accordingly different lewis acid21 such as FeCl3, CuCl, CuBr, CuI, BF3•Et2O and proton acid22 such [journal], [year], [vol], 00–00 | 1
ChemComm Accepted Manuscript
Published on 28 October 2014. Downloaded by University of Pittsburgh on 30/10/2014 22:19:19.
5
ChemComm
5
as H2SO4, CF3COOH, TfOH, was selected as the catalyst. As anticipated in the previous section, the nature of the acid plays an important role in the efficiency of the process (Table 1). In fact, as reported in Table 1, it can be seen that the use of lewis acid (0.2 equiv) in 1, 2-dichloroethane (Table 1, entries 1-5) led to only less than 10% yields after 24 h. To our delight, a slight
Page 2 of 5
transformation. Table 2 Reaction of substituted isoindolinones under optimized View Article Online conditionsa DOI: 10.1039/C4CC06653G
Table 1 Optimization of the reaction conditions screening for the synthesis of isoindolinonea
F
Cl
Entry Catalyst (eq.) Solvent Yieldb (%) 1 FeCl3 (0.2 eq) ClCH2CH2Cl
