Selective C–H Bond Fluorination of Phenols with a Removable Directing Group: Late-Stage Fluorination of 2-Phenoxyl Nicotinate Derivatives

ACS Catalysis ◽  
2015 ◽  
Vol 5 (5) ◽  
pp. 2846-2849 ◽  
Author(s):  
Shao-Jie Lou ◽  
Qi Chen ◽  
Yi-Feng Wang ◽  
Dan-Qian Xu ◽  
Xiao-Hua Du ◽  
...  
Keyword(s):  
Late Stage ◽  
Directing Group

scholarly journals Merging Directed C−H Activations with High-Throughput Experimentation: Development of Predictable Iridium-Catalyzed C−H Aminations Applicable to Late-Stage Functionalization

2021 ◽  
Author(s):  
Erik Weis ◽  
Maria Johansson ◽  
Pernilla Korsgren ◽  
Belén Martín-Matute ◽  
Magnus J Johansson
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
Late Stage ◽  
Functional Group ◽  
Chemical Space ◽  
Material Consumption ◽  
Modern Drug ◽  
High Throughput Experimentation ◽  
Directing Group ◽  
Group Chemical

Herein, we report an iridium-catalyzed directed C−H amination methodology developed using a high-throughput experimentation (HTE)-based strategy, applicable for the needs of automated modern drug discovery. The informer library approach for investigating accessible directing group chemical space for the reaction, in combination with functional group tolerance screening and substrate scope investigations, allowed for the generation of an empirical predictive model to guide future users. Applicability to late-stage functionalization of complex drugs and natural products, in combination with multiple deprotection protocols leading to the desirable aniline matched pairs, serve to demonstrate the utility of the method for drug discovery. Finally reaction miniaturization to a nano molar range highlights the opportunities for more sustainable screening with decreased material consumption.

scholarly journals Peptide late-stage C(sp3)–H arylation by native asparagine assistance without exogenous directing groups

2020 ◽  
Vol 11 (34) ◽  
pp. 9290-9295 ◽  
Author(s):  
Yiyi Weng ◽  
Xingxing Ding ◽  
João C. A. Oliveira ◽  
Xiaobin Xu ◽  
Nikolaos Kaplaneris ◽  
...  
Keyword(s):  
Efficient Method ◽  
Late Stage ◽  
Side Chain ◽  
Directing Group

An efficient method for peptide late-stage C(sp3)-H arylations assisted by unmodified side chain of asparagine (Asn) without any exogenous directing group has been reported.

Late-stage diversification of biologically active pyridazinones via a direct C–H functionalization strategy

2015 ◽  
Vol 13 (2) ◽  
pp. 539-548 ◽  
Author(s):  
Wei Li ◽  
Zhoulong Fan ◽  
Kaijun Geng ◽  
Youjun Xu ◽  
Ao Zhang
Keyword(s):  
Late Stage ◽  
Biologically Active ◽  
Directing Group

Divergent ortho-selective C–H functionalization was successfully established using a pyridazinone moiety as an internal directing group.

scholarly journals γ-Selective C(sp3)–H amination via controlled migratory hydroamination

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Changseok Lee ◽  
Huiyeong Seo ◽  
Jinwon Jeon ◽  
Sungwoo Hong
Keyword(s):  
Computational Methods ◽  
Late Stage ◽  
Alkyl Chain ◽  
Value Added ◽  
Amino Groups ◽  
Olefin Isomerization ◽  
Directing Group ◽  
Walking Mechanism ◽  
Chain Lengths ◽  
Chain Walking

AbstractRemote functionalization of alkenes via chain walking has generally been limited to C(sp3)–H bonds α and β to polar-functional units, while γ-C(sp3)–H functionalization through controlled alkene transposition is a longstanding challenge. Herein, we describe NiH-catalyzed migratory formal hydroamination of alkenyl amides achieved via chelation-assisted control, whereby various amino groups are installed at the γ-position of aliphatic chains. By tuning olefin isomerization and migratory hydroamination through ligand and directing group optimization, γ-selective amination can be achieved via stabilization of a 6-membered nickellacycle by an 8-aminoquinoline directing group and subsequent interception by an aminating reagent. A range of amines can be installed at the γ-C(sp3)–H bond of unactivated alkenes with varying alkyl chain lengths, enabling late-stage access to value-added γ-aminated products. Moreover, by employing picolinamide-coupled alkene substrates, this approach is further extended to δ-selective amination. The chain-walking mechanism and pathway selectivity are investigated by experimental and computational methods.

scholarly journals Nickel-Catalyzed Regio- and Diastereoselective Arylamination of Unactivated Alkenes

2021 ◽  
Author(s):  
Chao Wang ◽  
Shenghao Wang ◽  
Lanlan Zhang ◽  
Leipeng Xie ◽  
Lei Zhao ◽  
...  
Keyword(s):  
Late Stage ◽  
Functional Group ◽  
Arylboronic Acids ◽  
Directing Group ◽  
Site Selective ◽  
Pharmaceutical Agents

Abstract An intermolecular syn-1,2-arylamination of unactivated alkenes with arylboronic acids and O-benzoylhydroxylamine electrophiles has been developed with Ni(II) catalyst. The cleavable bidentate picolinamide directing group facilitated formation of stabilized 4-, 5- or 6-membered nickelacycles and enabled the difunctionalization of diverse alkenyl amines with high levels of regio-, chemo- and diastereocontrol. This general and practical protocol was compatible with broad substrate scope and high functional group tolerance. The utility of this method was further demonstrated by the site-selective late-stage modification of pharmaceutical agents.

scholarly journals Sterically Controlled Late-Stage C–H Alkynylation of Arenes

2019 ◽  
Author(s):  
Arup Mondal ◽  
Hao Chen ◽  
Lea Flämig ◽  
Philipp Wedi ◽  
Manuel van Gemmeren
Keyword(s):  
Organic Chemistry ◽  
Late Stage ◽  
Functional Materials ◽  
Bioactive Molecules ◽  
Sonogashira Coupling ◽  
Traditional Methods ◽  
Complementary Product ◽  
Complementary Approach ◽  
Synthetic Intermediates ◽  
Directing Group

Phenylacetylenes are key structural motifs in organic chemistry, which find widespread applications in bioactive molecules, synthetic intermediates, functional materials and reagents. These molecules are typically prepared from pre-functionalized starting materials, e.g. using the Sonogashira coupling, or using directing group-based C–H activation strategies. While highly efficient, these approaches remain limited by their inherent selectivities for specific regioisomers. Herein we present a complementary approach based on an arene-limited nondirected C–H activation. The reaction is predominantly controlled by steric rather than electronic factors and thereby gives access to a complementary product spectrum with respect to traditional methods. A broad scope as well as the suitability of this protocol for late-stage functionalization are demonstrated.<br>

scholarly journals Sterically Controlled Late-Stage C–H Alkynylation of Arenes

2019 ◽  
Author(s):  
Arup Mondal ◽  
Hao Chen ◽  
Lea Flämig ◽  
Philipp Wedi ◽  
Manuel van Gemmeren
Keyword(s):  
Organic Chemistry ◽  
Late Stage ◽  
Functional Materials ◽  
Bioactive Molecules ◽  
Sonogashira Coupling ◽  
Traditional Methods ◽  
Complementary Product ◽  
Complementary Approach ◽  
Synthetic Intermediates ◽  
Directing Group

Phenylacetylenes are key structural motifs in organic chemistry, which find widespread applications in bioactive molecules, synthetic intermediates, functional materials and reagents. These molecules are typically prepared from pre-functionalized starting materials, e.g. using the Sonogashira coupling, or using directing group-based C–H activation strategies. While highly efficient, these approaches remain limited by their inherent selectivities for specific regioisomers. Herein we present a complementary approach based on an arene-limited nondirected C–H activation. The reaction is predominantly controlled by steric rather than electronic factors and thereby gives access to a complementary product spectrum with respect to traditional methods. A broad scope as well as the suitability of this protocol for late-stage functionalization are demonstrated.<br>

scholarly journals Geminal group-directed olefinic C-H functionalization via four- to eight-membered exo-metallocycles

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Keke Meng ◽  
Tingyan Li ◽  
Chunbing Yu ◽  
Cong Shen ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Late Stage ◽  
Preparative Scale ◽  
Selective Transformation ◽  
Directing Group ◽  
Stark Contrast ◽  
Made In

Abstract Great efforts have been made in the activation of a C(alkenyl)-H bond vicinal to the directing group to proceed via five- or six-membered endo-metallocycles. In stark contrast, functionalization of a C(alkenyl)-H bond geminal to the directing group via exo-metallocycle pathway continued to be elusive. Here we report the selective transformation of an olefinic C-H bond that is geminal to the directing group bearing valuable hydroxyl, carbamate or amide into a C-C bond, which proceeds through four- to eight-membered exo-palladacycles. Compared to the reported mechanisms proceeding only through six-membered exo-palladacycles via N,N-bidentate chelation, our weak and O-monodentate chelation-assisted C(alkenyl)-H activations tolerate longer or shorter distances between the olefinic C-H bonds and the coordinating groups, allowing for the functionalizations of many olefinic C-H bonds in alkenyl alcohols, carbamates and amides. The synthetic applicability has been demonstrated by the preparative scale and late-stage C-H functionalization of steroid and ricinoleate derivatives.

scholarly journals Mechanism of the Arene-Limited Nondirected C–H Activation of Arenes with Palladium

2021 ◽  
Author(s):  
Philipp Wedi ◽  
Mirxan Farizyan ◽  
Klaus Bergander ◽  
Christian Mück-Lichtenfeld ◽  
Manuel van Gemmeren
Keyword(s):  
Amino Acid ◽  
Late Stage ◽  
Palladium Catalysts ◽  
Method Development ◽  
Organic Molecules ◽  
Active Species ◽  
Mechanistic Studies ◽  
Catalytically Active ◽  
Directing Group ◽  
Complex Organic

Recently palladium catalysts have been discovered that enable the directing group-free C–H activation of arenes without requiring an excess of the arene substrate, thereby enabling methods for the late-stage modification of complex organic molecules. The key to success has been the use of two complementary ligands, an N-acyl amino acid and an N-heterocycle. Detailed experimental and computational mechanistic studies on the dual ligand-enabled C–H activation of arenes have led us to identify the catalytically active species and a transition state model that explains the exceptional activity and selectivity of these catalysts. These findings are expected to be highly useful for further method development using this powerful class of catalysts.

How Rhodium(I)-Catalyzed Phosphorus(III)-Directed C–H Bond Functionalizations Can Improve the Catalytic Activities of Phosphines

Synlett ◽  
2022 ◽  
Author(s):  
Jean-François Soulé ◽  
Zhuan Zhang ◽  
Natacha Durand
Keyword(s):  
Late Stage ◽  
Bond Activation ◽  
Materials Science ◽  
Phosphine Ligands ◽  
Coupling Reactions ◽  
Catalytic Activities ◽  
Cross Coupling Reactions ◽  
Phosphorus Containing ◽  
Directing Group ◽  
Metal Catalyzed

AbstractTrivalent-phosphorus-containing molecules are widely used in fields ranging from catalysis to materials science. Efficient catalytic methods for their modifications, providing straightforward access to novel hybrid structures with superior catalytic activities, are highly desired to facilitate reaction improvement or discovery. We have recently developed new methods for synthesizing polyfunctional phosphines by C–C cross-couplings through rhodium-catalyzed C–H bond activation. These methods use a native P(III) atom as a directing group, and can be used in regioselective late-stage functionalization of phosphine ligands. Interestingly, some of the modified phosphines outperform their parents in Pd-catalyzed cross-coupling reactions.1 Introduction2 Early Examples of Transition-Metal-Catalyzed P(III)-Directed C–H Bond Activation/Functionalizations3 Synthesis of Polyfunctional Biarylphosphines by Late-Stage Alkylation: Application in Carboxylation Reactions4 Synthesis of Polyfunctional Biarylphosphines by Late-Stage Alkenylation: Application in Amidation Reactions5 Conclusion

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