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Iridium(III)-Catalyzed Direct C-7 Amination of Indolines with Organic Azides Kwangmin Shin, and Sukbok Chang J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 14 Sep 2014 Downloaded from http://pubs.acs.org on September 16, 2014
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.
The Journal of Organic Chemistry 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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The Journal of Organic Chemistry
Iridium(III)-Catalyzed Direct C-7 Amination of Indolines with Organic Azides Kwangmin Shin1,2 and Sukbok Chang*2,1 1
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejon 307-701, Republic of Korea
2
Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS), Daejon 307-701, Republic of Korea [email protected]
Abstract
Iridium-catalyzed regioselective C-7 amination of indolines has been achieved with organic azides as a facile nitrogen source. The developed procedure is convenient to perform even at room temperature and applicable to a wide range of substrates with high catalytic activity. Various types of organic azides (sulfonyl-, aryl-, and alkyl derivatives) were all successfully reacted under the present conditions as the viable reactant. Furthermore, indoline substrates bearing easily removable N-protecting groups such as N-Boc- or N-Cbz- could readily be employed, highlighting the synthetic utility of this methodology. Among various nitrogen-containing heterocycles, indole and indoline derivatives have been recognized especially as privileged core structures owing to their ubiquity in numerous biologically active compounds and natural products.1 In particular, C7-substituted indole and indoline scaffolds have been received a great attention due to their prevalence in important pharmaceutical agents.2 For this reason, synthetic methods for the introduction of functional groups at the C-7 position of indoles or indolines are in high demand. However, the development of synthetic routes allowing this transformation has been less explored. Indeed, whereas procedures for the selective C2- and C3-functionalization of indoles have been actively investigated,3-5 approaches to access C7-functionalized indole derivatives are relatively rare especially in respect to the transition metal-catalyzed C−H bond functionalization.6-7 Moreover, while examples of the direct C7-functionalization of indolines via chelationassisted C−H activation have been disclosed,8-11 most of those methods allowed for C−C bond formation in ACS Paragon Plus Environment
1
The Journal of Organic Chemistry
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reaction with alkenes8 or arylating reagents9 (Scheme 1a). Very recently, an elegant example of the Ru-catalyzed C-7 amidation of indolines using sulfonyl azides has been reported,11 although this procedure requires somewhat elevated temperature with limited scope (Scheme 1b).
Scheme 1. a) Previous studies: Pd- or Rh-catalyzed C-7 arylation or olefination of indolines R' N R
O
Ar X N
cat. [Pd(II)] or [Rh(III)]
H
O
R
N
cat. [Pd(II)]
Ar
O
R
R' b) Recent work: Ru-Catalyzed C-7 amidation of indolines using sulfonyl azides +
N H
O
ArO2S N3
R
cat. [Ru(II)] 80 oC
N ArO2S
NH
O
R
c) This work: Ir-catalyzed C-7 amination of indolines with various azides +
N H
O
R' N3
cat. [Cp*Ir(III)] 25 oC - 50 oC
R
N R'
NH
O
R
R = Me, Ot-Bu (Boc), OCH2Ph (Cbz), NEt2 R' = sulfonyl, aryl, alkyl Mild amination conditions Broad substrate scope
In a few recent years, our group has been engaged in developing selective and efficient C−N bond-forming reactions12 leading to the Rh- and Ru-catalyzed direct C(sp2)−H amination procedures by the use of organic azides working both as an amino source and as an internal oxidant via N−N2 bond cleavage.13-15 In addition, we also disclosed an iridium catalyst system that offers milder amination reaction conditions with enhanced activity and broader substrate scope.16 In this context, we report herein a new procedure for the Ir-catalyzed C-7 amination of indolines with a wide range of organic azides (Scheme 1c). Significance of the present direct C−Η amination route is threefold: (1) the reaction proceeds under mild reaction conditions at room temperature in most cases; (2) the scope of azides is highly broad including sulfonyl-, aryl- and alkyl variants as an efficient amino source; and (3) the present reaction can be applicable to indolines bearing readily removable N-protecting groups (e.g. Boc or Cbz), thus enabling subsequent transformations of the obtained aminated products.
ACS Paragon Plus Environment
2
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The Journal of Organic Chemistry
Table 1. Optimization of Ir-Catalyzed Amidationa
a
entry
catalyst (mol %)
additive (mol %)
solvent
1
[IrCp*Cl2]2 (4)
AgSbF6 (16)
ClCH2CH2Cl
yield (%)b 75
2
–
AgSbF6 (16)
ClCH2CH2Cl
N.R.
3
[IrCp*Cl2]2 (4)
–
ClCH2CH2Cl
N.R.
4
[RhCp*Cl2]2 (4)
AgSbF6 (16)
ClCH2CH2Cl
N.R.
5c
[RhCp*Cl2]2 (4)
AgSbF6 (16)
ClCH2CH2Cl
N.R.
Note
Iridium(III)-Catalyzed Direct C-7 Amination of Indolines with Organic Azides Kwangmin Shin, and Sukbok Chang J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 14 Sep 2014 Downloaded from http://pubs.acs.org on September 16, 2014
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.
The Journal of Organic Chemistry 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 21
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
The Journal of Organic Chemistry
Iridium(III)-Catalyzed Direct C-7 Amination of Indolines with Organic Azides Kwangmin Shin1,2 and Sukbok Chang*2,1 1
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejon 307-701, Republic of Korea
2
Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS), Daejon 307-701, Republic of Korea [email protected]
Abstract
Iridium-catalyzed regioselective C-7 amination of indolines has been achieved with organic azides as a facile nitrogen source. The developed procedure is convenient to perform even at room temperature and applicable to a wide range of substrates with high catalytic activity. Various types of organic azides (sulfonyl-, aryl-, and alkyl derivatives) were all successfully reacted under the present conditions as the viable reactant. Furthermore, indoline substrates bearing easily removable N-protecting groups such as N-Boc- or N-Cbz- could readily be employed, highlighting the synthetic utility of this methodology. Among various nitrogen-containing heterocycles, indole and indoline derivatives have been recognized especially as privileged core structures owing to their ubiquity in numerous biologically active compounds and natural products.1 In particular, C7-substituted indole and indoline scaffolds have been received a great attention due to their prevalence in important pharmaceutical agents.2 For this reason, synthetic methods for the introduction of functional groups at the C-7 position of indoles or indolines are in high demand. However, the development of synthetic routes allowing this transformation has been less explored. Indeed, whereas procedures for the selective C2- and C3-functionalization of indoles have been actively investigated,3-5 approaches to access C7-functionalized indole derivatives are relatively rare especially in respect to the transition metal-catalyzed C−H bond functionalization.6-7 Moreover, while examples of the direct C7-functionalization of indolines via chelationassisted C−H activation have been disclosed,8-11 most of those methods allowed for C−C bond formation in ACS Paragon Plus Environment
1
The Journal of Organic Chemistry
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reaction with alkenes8 or arylating reagents9 (Scheme 1a). Very recently, an elegant example of the Ru-catalyzed C-7 amidation of indolines using sulfonyl azides has been reported,11 although this procedure requires somewhat elevated temperature with limited scope (Scheme 1b).
Scheme 1. a) Previous studies: Pd- or Rh-catalyzed C-7 arylation or olefination of indolines R' N R
O
Ar X N
cat. [Pd(II)] or [Rh(III)]
H
O
R
N
cat. [Pd(II)]
Ar
O
R
R' b) Recent work: Ru-Catalyzed C-7 amidation of indolines using sulfonyl azides +
N H
O
ArO2S N3
R
cat. [Ru(II)] 80 oC
N ArO2S
NH
O
R
c) This work: Ir-catalyzed C-7 amination of indolines with various azides +
N H
O
R' N3
cat. [Cp*Ir(III)] 25 oC - 50 oC
R
N R'
NH
O
R
R = Me, Ot-Bu (Boc), OCH2Ph (Cbz), NEt2 R' = sulfonyl, aryl, alkyl Mild amination conditions Broad substrate scope
In a few recent years, our group has been engaged in developing selective and efficient C−N bond-forming reactions12 leading to the Rh- and Ru-catalyzed direct C(sp2)−H amination procedures by the use of organic azides working both as an amino source and as an internal oxidant via N−N2 bond cleavage.13-15 In addition, we also disclosed an iridium catalyst system that offers milder amination reaction conditions with enhanced activity and broader substrate scope.16 In this context, we report herein a new procedure for the Ir-catalyzed C-7 amination of indolines with a wide range of organic azides (Scheme 1c). Significance of the present direct C−Η amination route is threefold: (1) the reaction proceeds under mild reaction conditions at room temperature in most cases; (2) the scope of azides is highly broad including sulfonyl-, aryl- and alkyl variants as an efficient amino source; and (3) the present reaction can be applicable to indolines bearing readily removable N-protecting groups (e.g. Boc or Cbz), thus enabling subsequent transformations of the obtained aminated products.
ACS Paragon Plus Environment
2
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The Journal of Organic Chemistry
Table 1. Optimization of Ir-Catalyzed Amidationa
a
entry
catalyst (mol %)
additive (mol %)
solvent
1
[IrCp*Cl2]2 (4)
AgSbF6 (16)
ClCH2CH2Cl
yield (%)b 75
2
–
AgSbF6 (16)
ClCH2CH2Cl
N.R.
3
[IrCp*Cl2]2 (4)
–
ClCH2CH2Cl
N.R.
4
[RhCp*Cl2]2 (4)
AgSbF6 (16)
ClCH2CH2Cl
N.R.
5c
[RhCp*Cl2]2 (4)
AgSbF6 (16)
ClCH2CH2Cl
N.R.
