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Nitrogen heterocycles are found in am ajority of approved small-molecule pharmaceuticals,and the number of approved fluorinated drugs is increasing each decade.T herefore,n ew approaches for accessing fluorinated nitrogen heterocycles are of great significance.Anovel, scalable,a nd metal-free method for accessing aw ide range of fluorinated indoles is described. This oxidative-dearomatization-enabled approach assembles 2-trifluoromethyl NH-indole products from simple commercially available anilines with hexafluoroacetylacetone in the presence of an organic oxidant. The nature of the aniline N-capping group is critical for the success of this new reaction. Furthermore,t he indole products contain a3 -trifluoroacetyl group,w hichc an be exploited to access aplethora of useful functional groups.Nitrogen heterocycles are structural components of alarge number of bioactive natural and unnatural compounds.O ur recent analysis revealed that 59 %o fa ll US FDA( FDA = Food and Drug Administration) approved small-molecule drugs contain at least one nitrogen heterocycle.[1] Additionally,t he fluorine atom is undoubtedly one of the most successful additions to the drug discovery toolkit in the last few decades,a si ts incorporation impacts solubility,l ipophilicity,a nd metabolic activity,a mong other drug properties.[2]Fluorinated drugs make up 11 %ofsmall-molecule drugs,and around 20 %o fd rugs in the current decade.[3] Thec ombination of fluorine substituents with nitrogen heterocycles has resulted in numerous blockbuster drugs,f ive of which are shown in Figure 1. As such, we are interested in the development of robust methods for forming fluorinated nitrogen heterocycles from simple building blocks.Indoles [4] are one of the most common nitrogen heterocycles found in pharmaceuticals, [1] and they have been referred to as "privileged structures" in drug discovery. [5] Inspired by the oxidative dearomatization [6] reaction used in our synthesis of vinigrol, [7] we decided to apply this approach to the synthesis of 2-trifluoromethyl substituted indoles. [8] Recently,o ur group has been interested in using strategic dearomatization/rearomatizationc ascades to result in an et C À Hf unctionalization, as trategy we used to form fused oxygenated aromatic heterocycles.[9] Based on the insights of the hypervalent iodine [10] mediated oxidative dearomatization mechanism, we postulated that strategically substituted anilines (Scheme 1a)c ould be dearomatized to create quinone imines (2). We then expected that these cationic acceptors would electronically guide soft nucleophiles,s uch as hexafluoroacetylacetone (hfacac; 3), to add ortho to the resulting
Nitrogen heterocycles are found in am ajority of approved small-molecule pharmaceuticals,and the number of approved fluorinated drugs is increasing each decade.T herefore,n ew approaches for accessing fluorinated nitrogen heterocycles are of great significance.Anovel, scalable,a nd metal-free method for accessing aw ide range of fluorinated indoles is described. This oxidative-dearomatization-enabled approach assembles 2-trifluoromethyl NH-indole products from simple commercially available anilines with hexafluoroacetylacetone in the presence of an organic oxidant. The nature of the aniline N-capping group is critical for the success of this new reaction. Furthermore,t he indole products contain a3 -trifluoroacetyl group,w hichc an be exploited to access aplethora of useful functional groups.Nitrogen heterocycles are structural components of alarge number of bioactive natural and unnatural compounds.O ur recent analysis revealed that 59 %o fa ll US FDA( FDA = Food and Drug Administration) approved small-molecule drugs contain at least one nitrogen heterocycle.[1] Additionally,t he fluorine atom is undoubtedly one of the most successful additions to the drug discovery toolkit in the last few decades,a si ts incorporation impacts solubility,l ipophilicity,a nd metabolic activity,a mong other drug properties.[2]Fluorinated drugs make up 11 %ofsmall-molecule drugs,and around 20 %o fd rugs in the current decade.[3] Thec ombination of fluorine substituents with nitrogen heterocycles has resulted in numerous blockbuster drugs,f ive of which are shown in Figure 1. As such, we are interested in the development of robust methods for forming fluorinated nitrogen heterocycles from simple building blocks.Indoles [4] are one of the most common nitrogen heterocycles found in pharmaceuticals, [1] and they have been referred to as "privileged structures" in drug discovery. [5] Inspired by the oxidative dearomatization [6] reaction used in our synthesis of vinigrol, [7] we decided to apply this approach to the synthesis of 2-trifluoromethyl substituted indoles. [8] Recently,o ur group has been interested in using strategic dearomatization/rearomatizationc ascades to result in an et C À Hf unctionalization, as trategy we used to form fused oxygenated aromatic heterocycles.[9] Based on the insights of the hypervalent iodine [10] mediated oxidative dearomatization mechanism, we postulated that strategically substituted anilines (Scheme 1a)c ould be dearomatized to create quinone imines (2). We then expected that these cationic acceptors would electronically guide soft nucleophiles,s uch as hexafluoroacetylacetone (hfacac; 3), to add ortho to the resulting
Nitrogen heterocycles are found in a majority of approved small-molecule pharmaceuticals, and the number of approved fluorinated drugs is increasing each decade. Therefore, new approaches for accessing fluorinated nitrogen heterocycles are of great significance. A novel, scalable, and metal-free method for accessing a wide range of fluorinated indoles is described. This oxidative-dearomatization-enabled approach assembles 2-trifluoromethyl NH-indole products from simple commercially available anilines with hexafluoroacetylacetone in the presence of an organic oxidant. The nature of the aniline N-capping group is critical for the success of this new reaction. Furthermore, the indole products contain a 3-trifluoroacetyl group, which can be exploited to access a plethora of useful functional groups.
The field of hypervalent iodine chemistry has been prevalent since 1886. Its journey from obscurity to coming into the limelight has witnessed many effective transformations which have benefited the synthetic community at large. The reactivity of primary amines with hypervalent iodine reagents causes difficulty in synthetic outcome or not feasible due to high exothermicity of amine iodine which is an acid base reaction. This minireview highlights the worthwhile reactivity of hypervalent iodine reagents with aromatic and aliphatic primary amines. Some recent literature has been discussed to make a clear understanding on how such high reactivity of primary amine is controlled by introducing modulation in either substrate or reaction conditions, most of which are carried out under ambient reaction conditions.
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