ChemInform Abstract: Regioselective Oxyfunctionalization of Unactivated Tertiary and Secondary C‐H Bonds of Alkylamines by Methyl(trifluoromethyl)dioxirane in Acid Medium.

Asensio, Gregorio; González‐Núñez, María Elena; Bernardini, Carmen Boix; Mello, Rossella; Adam, Waldemar

doi:10.1002/chin.199350113

Cited by 3 publications

(5 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 18 We examined Brønsted acid and Lewis acid complexation strategies that have been demonstrated to circumvent such issues in the context of aliphatic C–H hydroxylations. 33 – 35 Both protection methods produced the desired product in good yield ( 26 , 58% and 51% yields, entries 2–3). Analogous to previous reports, HBF 4 has proven to be more effective for tertiary amines having steric bulk.…”

Section: Resultsmentioning

confidence: 99%

Manganese-catalysed benzylic C(sp3)–H amination for late-stage functionalization

et al. 2018

View full text Add to dashboard Cite

Reactions that directly install nitrogen into C–H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Although selective intramolecular C–H amination reactions are known, achieving high levels of reactivity, while maintaining excellent site-selectivity and functional-group tolerance, remains a challenge for intermolecular C–H amination. Herein, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C–H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site-selectivity. In the presence of Brønsted or Lewis acid, the [MnIII(ClPc)]-catalyzed C–H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C–H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C–H cleavage is the rate-determining step of the reaction. Collectively these mechanistic features contrast previous base-metal catalyzed C–H aminations and provide new opportunities for tunable selectivities.

show abstract

Section: Resultsmentioning

confidence: 99%

Manganese-catalysed benzylic C(sp3)–H amination for late-stage functionalization

et al. 2018

View full text Add to dashboard Cite

show abstract

“…3,4 Recent disclosures from our lab and others capitalize on seminal work by Adam and co-workers to address the intrinsic problems with oxidative cross-reactivity of amines and azaheterocycles. 5,6 To this end, we have demonstrated that a mononuclear Ru-catalyst derived from 4,4′-di-tert-butyl-2,2′bipyridine (dtbpy), cis-[Ru(dtbpy) 2 X 2 ], functions as an efficient precatalyst for oxidation of 3°and benzylic C−H bonds in aqueous acid medium. 7 Efforts to improve the scope and performance of this chemistry have motivated mechanistic studies to understand off-pathway reactions that limit catalyst turnover numbers.…”

Section: ■ Introductionmentioning

confidence: 99%

Mechanistic Study of Ruthenium-Catalyzed C–H Hydroxylation Reveals an Unexpected Pathway for Catalyst Arrest

et al. 2019

View full text Add to dashboard Cite

We have recently disclosed [(dtbpy) 2 RuCl 2 ] as an effective precatalyst for chemoselective C−H hydroxylation of C(sp 3 )−H bonds and have noted a marked disparity in reaction performance between 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy)and 2,2′-bipyridine (bpy)-derived complexes. A desire to understand the origin of this difference and to further advance this catalytic method has motivated the comprehensive mechanistic investigation described herein. Details of this reaction have been unveiled through evaluation of ligand structure−activity relationships, electrochemical and kinetic studies, and pressurized sample infusion high-resolution mass spectrometry (PSI-MS). Salient findings from this investigation include the identification of more than one active oxidant and three disparate mechanisms for catalyst decomposition/arrest. Catalyst efficiency, as measured by turnover number, has a strong inverse correlation with the rate and extent of ligand dissociation, which is dependent on the identity of bipyridyl 4,4′-substituent groups. Dissociated bipyridyl ligand is oxidized to mono-and bis-Noxide species under the reaction conditions, the former of which is found to act as a potent catalyst poison, yielding a catalytically inactive tris-ligated [Ru(dtbpy) 2 (dtbpy N-oxide)] 2+ complex. Insights gained through this work highlight the power of PSI-MS for studies of complex reaction processes and are guiding ongoing efforts to develop high-performance, nextgeneration catalyst systems for C−H hydroxylation.

show abstract

“…Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, including treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukemia (alvocidib), schizophrenia (risperidone, belaperidone), and nicotine addiction (cytisine and varenicline) 5 . However, existing methods for the C–H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited 6,7 . Here we report a new approach to selectively manipulate the carbon–hydrogen bonds of alicyclic amines at sites remote to nitrogen.…”

mentioning

confidence: 99%

“…Late stage functionalization approaches are particularly valuable in the context of drug development, since they enable the rapid synthesis of analogues to optimize pharmacokinetic properties. Transition metal-catalyzed C–H bond functionalization offers a powerful approach for the late stage functionalization of bioactive molecules, 1-4 and recent progress in this field has led to thousands of new synthetic methods for selective C–H functionalization in a variety of molecular contexts 3-6,8,9 . However, methods for the C–H functionalization of saturated nitrogen heterocycles remain extremely limited 5,6 , and are dominated by functionalization of the highly activated C–H bonds α-to nitrogen 10,11,12,13,14 (Fig.…”

mentioning

confidence: 99%

“…Selective C–H functionalization reactions on complex molecular scaffolds provide valuable opportunities for streamlining analog generation and thereby accelerating structure activity relationship studies 5,6 . The bicyclo[3.1.0] scaffold appears in numerous pharmaceutical candidates, including the serotonin-norepinephrine-dopamine reuptake inhibitor amitifadine ( 7 ) 26,27 .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Palladium-catalysed transannular C–H functionalization of alicyclic amines

Topczewski

Cabrera

Saper

et al. 2016

Nature

301

157

View full text Add to dashboard Cite

The discovery of pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. Carbon-hydrogen bonds are present in almost all pharmaceutical agents. As such, the development of selective, rapid, and efficient methods for converting carbon-hydrogen bonds into new chemical entities has the potential to dramatically streamline pharmaceutical development1,2,3,4. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, including treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukemia (alvocidib), schizophrenia (risperidone, belaperidone), and nicotine addiction (cytisine and varenicline)5. However, existing methods for the C–H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited 6,7. Here we report a new approach to selectively manipulate the carbon–hydrogen bonds of alicyclic amines at sites remote to nitrogen. Our reaction leverages the boat conformation of the substrates to achieve the palladium-catalyzed amine-directed conversion of C–H bonds to C–C bonds on various alicyclic amine scaffolds. This approach is applied to the synthesis of novel derivatives of several bioactive molecules, including the top-selling smoking cessation drug varenicline (Chantix®). We anticipate that this method should prove broadly useful in medicinal chemistry.

show abstract

ChemInform Abstract: Regioselective Oxyfunctionalization of Unactivated Tertiary and Secondary C‐H Bonds of Alkylamines by Methyl(trifluoromethyl)dioxirane in Acid Medium.

Cited by 3 publications

References 1 publication

Manganese-catalysed benzylic C(sp3)–H amination for late-stage functionalization

Manganese-catalysed benzylic C(sp3)–H amination for late-stage functionalization

Mechanistic Study of Ruthenium-Catalyzed C–H Hydroxylation Reveals an Unexpected Pathway for Catalyst Arrest

Palladium-catalysed transannular C–H functionalization of alicyclic amines

Contact Info

Product

Resources

About