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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
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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
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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.
