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Communication
Bifunctional Organocatalysts for the Enantioselective Synthesis of Axially Chiral Isoquinoline N-Oxides Ryota Miyaji, Keisuke Asano, and Seijiro Matsubara J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 16 May 2015 Downloaded from http://pubs.acs.org on May 16, 2015
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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Journal of the American Chemical Society
Bifunctional Organocatalysts for the Enantioselective Synthesis of Axially Chiral Isoquinoline N-Oxides Ryota Miyaji, Keisuke Asano,* and Seijiro Matsubara* Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan
Supporting Information Placeholder ABSTRACT: Bifunctional catalysts bearing amino and urea functional groups have been applied for a novel, highly enantioselective synthesis of axially chiral isoquinoline N-oxides, which are promising chiral ligands or organocatalysts in organic synthesis. This is the first example of highly enantioselective synthesis of axially chiral biaryls by bifunctional organocatalysts. Good-toexcellent enantioselectivities were obtained with a range of substrates.
Scheme 1. Construction of Axially Chiral Structure by Using Bifunctional Organocatalysts
Bifunctional organocatalysts have significantly contributed to the field of asymmetric synthesis.1 In these catalysts, the (thio)urea and tertiary amino functional groups cooperatively realize the simultaneous activation of a nucleophile and an electrophile in a suitable spatial configuration. Previously, we have used these organocatalysts for several asymmetric cyclization reactions via intramolecular hetero-Michael addition,2 in which multipoint recognition by the catalysts stabilizes the specific conformations of the substrates in the transition state before the construction of a chiral center. Inspired by the success of these results, we envisaged that the utility of this class of small-molecule catalysts could be expanded by translating the molecular torsion induced by bifunctional organocatalysts into axial chirality. Recently, although some organocatalysts have been reported to be useful for the enantioselective syntheses of axially chiral compounds,3 thus far, methods employing this type of bifunctional organocatalysts have rarely been developed.4 Here, we demonstrate the novel competence of bifunctional organocatalysts as an efficient avenue for the asymmetric construction of axially chiral compounds. In this study, we report the highly enantioselective aromatic electrophilic bromination of 1-(3-hydroxyphenyl)isoquinoline 2oxides (Scheme 1). The 1-(3-hydroxyphenyl)isoquinoline 2-oxide substrates have an isoquinoline N-oxide moiety, which can interact with a hydrogen-bond donor, and a phenol moiety, which can interact with a hydrogen-bond acceptor; such interactions are expected to twist the molecule in one direction. Meanwhile, the axially chiral N-oxides obtained are promising chiral ligands or organocatalysts in organic synthesis,5 although thus far, their catalytic enantioselective synthesis has been thus far underdeveloped, to the best of our knowledge.
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Table 1. Optimization of Conditionsa
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Figure 1. Brominating reagents.
entry
catalyst
brominating reagent
solvent
temp. (°C)
yield (%)b
ee (%)
1
3a
NBA (4a)
CH2Cl2
–40
95
54
2
3a
NBA (4a)
toluene
–40
7
74
3
3a
NBA (4a)
EtOAc
–40
50
93
4
3a
NBA (4a)
Et2O
–40
95% ee (see the Supporting Information for details). Thus, we currently consider that the bromination at the ortho position of the hydroxy group occurs before the bromination at the para position of the hydroxy group. The reaction of 3-hydroxy-N,N-dicyclohexylbenzamide (5b) afforded the corresponding tribromide, 2,4,6-tribromo-N,Ndicyclohexyl-3-hydroxybenzamide (6b) in 99% yield with 79% ee; the absolute configuration of 6b was determined by X-ray analysis (see the Supporting Information for details).
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Communication
Bifunctional Organocatalysts for the Enantioselective Synthesis of Axially Chiral Isoquinoline N-Oxides Ryota Miyaji, Keisuke Asano, and Seijiro Matsubara J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 16 May 2015 Downloaded from http://pubs.acs.org on May 16, 2015
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 5
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of the American Chemical Society
Bifunctional Organocatalysts for the Enantioselective Synthesis of Axially Chiral Isoquinoline N-Oxides Ryota Miyaji, Keisuke Asano,* and Seijiro Matsubara* Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan
Supporting Information Placeholder ABSTRACT: Bifunctional catalysts bearing amino and urea functional groups have been applied for a novel, highly enantioselective synthesis of axially chiral isoquinoline N-oxides, which are promising chiral ligands or organocatalysts in organic synthesis. This is the first example of highly enantioselective synthesis of axially chiral biaryls by bifunctional organocatalysts. Good-toexcellent enantioselectivities were obtained with a range of substrates.
Scheme 1. Construction of Axially Chiral Structure by Using Bifunctional Organocatalysts
Bifunctional organocatalysts have significantly contributed to the field of asymmetric synthesis.1 In these catalysts, the (thio)urea and tertiary amino functional groups cooperatively realize the simultaneous activation of a nucleophile and an electrophile in a suitable spatial configuration. Previously, we have used these organocatalysts for several asymmetric cyclization reactions via intramolecular hetero-Michael addition,2 in which multipoint recognition by the catalysts stabilizes the specific conformations of the substrates in the transition state before the construction of a chiral center. Inspired by the success of these results, we envisaged that the utility of this class of small-molecule catalysts could be expanded by translating the molecular torsion induced by bifunctional organocatalysts into axial chirality. Recently, although some organocatalysts have been reported to be useful for the enantioselective syntheses of axially chiral compounds,3 thus far, methods employing this type of bifunctional organocatalysts have rarely been developed.4 Here, we demonstrate the novel competence of bifunctional organocatalysts as an efficient avenue for the asymmetric construction of axially chiral compounds. In this study, we report the highly enantioselective aromatic electrophilic bromination of 1-(3-hydroxyphenyl)isoquinoline 2oxides (Scheme 1). The 1-(3-hydroxyphenyl)isoquinoline 2-oxide substrates have an isoquinoline N-oxide moiety, which can interact with a hydrogen-bond donor, and a phenol moiety, which can interact with a hydrogen-bond acceptor; such interactions are expected to twist the molecule in one direction. Meanwhile, the axially chiral N-oxides obtained are promising chiral ligands or organocatalysts in organic synthesis,5 although thus far, their catalytic enantioselective synthesis has been thus far underdeveloped, to the best of our knowledge.
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Journal of the American Chemical Society
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Table 1. Optimization of Conditionsa
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Figure 1. Brominating reagents.
entry
catalyst
brominating reagent
solvent
temp. (°C)
yield (%)b
ee (%)
1
3a
NBA (4a)
CH2Cl2
–40
95
54
2
3a
NBA (4a)
toluene
–40
7
74
3
3a
NBA (4a)
EtOAc
–40
50
93
4
3a
NBA (4a)
Et2O
–40
95% ee (see the Supporting Information for details). Thus, we currently consider that the bromination at the ortho position of the hydroxy group occurs before the bromination at the para position of the hydroxy group. The reaction of 3-hydroxy-N,N-dicyclohexylbenzamide (5b) afforded the corresponding tribromide, 2,4,6-tribromo-N,Ndicyclohexyl-3-hydroxybenzamide (6b) in 99% yield with 79% ee; the absolute configuration of 6b was determined by X-ray analysis (see the Supporting Information for details).
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Journal of the American Chemical Society
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