Green chemistry meets medicinal chemistry: a perspective on modern metal-free late-stage functionalization reactions

2021 ◽  
Author(s):  
Juan D. Lasso ◽  
Durbis J. Castillo-Pazos ◽  
Chao-Jun Li
Keyword(s):  
Green Chemistry ◽  
Functional Groups ◽  
Late Stage ◽  
Medicinal Chemistry ◽  
Metal Free ◽  
Recent Advances

This review summarizes the most recent advances of metal-free late-stage functionalization (LSF) of pharmaceutically relevant molecules. Particular emphasis is placed on C–H activation as well as the use of endogenous functional groups.

Five-Membered Hetarene N-Oxides: Recent Advances in Synthesis and Reactivity

Synthesis ◽  
2021 ◽  
Author(s):  
Leonid Fershtat ◽  
Fedor Teslenko
Keyword(s):  
Transition Metal ◽  
Medicinal Chemistry ◽  
Materials Science ◽  
State Of The Art ◽  
Short Review ◽  
Advanced Materials ◽  
Metal Free ◽  
Recent Advances ◽  
Application Potential ◽  
Metal Catalyzed

Five-membered heterocyclic N-oxides attracted special attention due to their strong application potential in medicinal chemistry and advanced materials science. In this regard, novel methods for their synthesis and functionalization are constantly required. In this short review, recent state-of-the-art achievements in the chemistry of isoxazoline N-oxides, 1,2,3-triazole 1-oxides and 1,2,5-oxadiazole 2-oxides are briefly summarized. Main routes to transition-metal-catalyzed and metal-free functionalization protocols along with mechanistic considerations are outlined. Transformation patterns of the hetarene N-oxide rings as precursors to other nitrogen heterocyclic systems are also presented.

scholarly journals Late stage C–H functionalization via chalcogen and pnictogen salts

2020 ◽  
Vol 11 (37) ◽  
pp. 10047-10060
Author(s):  
Christopher B. Kelly ◽  
Rosaura Padilla-Salinas
Keyword(s):  
Functional Groups ◽  
Late Stage ◽  
Potential Application ◽  
Medicinal Chemistry

Three unrelated cationic groups, which can replace C–H bonds late stage, have been identified as progenitors to various functional groups. This review discusses the chemistry of these salts and their potential application in medicinal chemistry.

scholarly journals Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2783 ◽  
Author(s):  
Shu-Guang Zhang ◽  
Chao-Gen Liang ◽  
Wei-Hua Zhang
Keyword(s):  
Functional Groups ◽  
Medicinal Chemistry ◽  
Biological Activities ◽  
Drug Molecules ◽  
Recent Advances

Indazole-containing derivatives represent one of the most important heterocycles in drug molecules. Diversely substituted indazole derivatives bear a variety of functional groups and display versatile biological activities; hence, they have gained considerable attention in the field of medicinal chemistry. This review aims to summarize the recent advances in various methods for the synthesis of indazole derivatives. The current developments in the biological activities of indazole-based compounds are also presented.

scholarly journals Recent Advances in Transition-Metal-Free Late-Stage C-H and N-H Arylation of Heteroarenes Using Diaryliodonium Salts

2021 ◽  
Vol 14 (7) ◽  
pp. 661
Author(s):  
Thierry Besson ◽  
Corinne Fruit
Keyword(s):  
Transition Metal ◽  
Late Stage ◽  
Heterocyclic Compounds ◽  
Environmentally Friendly ◽  
Direct Arylation ◽  
Stepping Stone ◽  
Metal Free ◽  
Bond Forming ◽  
Diaryliodonium Salts ◽  
Recent Advances

Transition-metal-free direct arylation of C-H or N-H bonds is one of the key emerging methodologies that is currently attracting tremendous attention. Diaryliodonium salts serve as a stepping stone on the way to alternative environmentally friendly and straightforward pathways for the construction of C-C and C-heteroatom bonds. In this review, we emphasize the recent synthetic advances of late-stage C(sp2)-N and C(sp2)-C(sp2) bond-forming reactions under metal-free conditions using diaryliodonium salts as arylating reagent and its applications to the synthesis of new arylated bioactive heterocyclic compounds.

scholarly journals Synthesis of Heterobenzylic Fluorides

Synthesis ◽  
2018 ◽  
Vol 50 (06) ◽  
pp. 1228-1236 ◽  
Author(s):  
Robert Britton ◽  
Michael Meanwell
Keyword(s):  
Late Stage ◽  
Medicinal Chemistry ◽  
Short Review ◽  
New Methods ◽  
Electrophilic Fluorination ◽  
Recent Advances ◽  
Direct Fluorination ◽  
Displacement Reactions ◽  
Halide Exchange ◽  
Drug Leads

Fluorination at heterobenzylic positions can have a significant impact on basicity, lipophilicity, and metabolism of drug leads. As a consequence, the development of new methods to access heterobenzylic fluorides has particular relevance to medicinal chemistry. This short review provides a survey of common methods used to synthesize heterobenzylic fluorides and includes fluoride displacement reactions of previously functionalized molecules (e.g., deoxyfluorination and halide exchange) and electrophilic fluorination of resonance-stabilized heterobenzylic anions. In addition, recent advances in the direct fluorination of heterobenzylic C(sp3)–H bonds and monofluoromethylation of heterocyclic C(sp2)–H bonds are presented.1 Introduction2 Heterobenzylic Fluorides2.1 Deoxyfluorination2.2 Halide Exchange2.3 Electrophilic Fluorination of Heterobenzylic Anions2.4 Late Stage C–H Bond Fluorination2.5 Monofluoromethylation of C(sp2)–H Bonds3 Conclusions

A Practical and General Approach to the Late-Stage Functionalization of Complex Sulfonamides

2019 ◽  
Author(s):  
Patrick Fier ◽  
Kevin M. Maloney
Keyword(s):  
Functional Groups ◽  
Late Stage ◽  
Building Blocks ◽  
Pharmaceutical Compounds ◽  
Stage Conversion

Herein we describe the development and application of a method for the mild, late-stage conversion of primary sulfonamides to several other other functional groups. These reactions occur via initial reductive deamination of sulfonamides to sulfinates via an NHC-catalyzed reaction of transiently formed <i>N</i>-sulfonylimines. The method described here is tolerant of nearly all common functional groups, as exemplified by the late-stage derivatization of several complex pharmaceutical compounds. Based on the prevalence of sulfonamide-containing drugs and building blocks, we have developed a method to enable sulfonamides to be applied as versatile synthetic handles for synthetic chemsitry.

A Practical and General Approach to the Late-Stage Functionalization of Complex Sulfonamides

2019 ◽  
Author(s):  
Patrick Fier ◽  
Kevin M. Maloney
Keyword(s):  
Functional Groups ◽  
Late Stage ◽  
Building Blocks ◽  
Pharmaceutical Compounds ◽  
Stage Conversion

Herein we describe the development and application of a method for the mild, late-stage conversion of primary sulfonamides to several other other functional groups. These reactions occur via initial reductive deamination of sulfonamides to sulfinates via an NHC-catalyzed reaction of transiently formed <i>N</i>-sulfonylimines. The method described here is tolerant of nearly all common functional groups, as exemplified by the late-stage derivatization of several complex pharmaceutical compounds. Based on the prevalence of sulfonamide-containing drugs and building blocks, we have developed a method to enable sulfonamides to be applied as versatile synthetic handles for synthetic chemsitry.

A Revised Modular Approach to D8-THC and Derivatives Through Late-Stage Suzuki-Miyaura Cross-Coupling Reactions

2019 ◽  
Author(s):  
Victor Bloemendal ◽  
Floris P. J. T. Rutjes ◽  
Thomas J. Boltje ◽  
Daan Sondag ◽  
Hidde Elferink ◽  
...  
Keyword(s):  
Biological Activity ◽  
Late Stage ◽  
Medicinal Chemistry ◽  
Cross Coupling ◽  
Modular Approach ◽  
Coupling Reactions ◽  
One Pot ◽  
Biologically Relevant ◽  
Cross Coupling Reactions ◽  
Chemistry Research

<p>In this manuscript we describe a modular pathway to synthesize biologically relevant (–)-<i>trans</i>-Δ<sup>8</sup>-THC derivatives, which can be used to modulate the pharmacologically important CB<sub>1</sub> and CB<sub>2</sub> receptors. This pathway involves a one-pot Friedel-Crafts alkylation/cyclization protocol, followed by Suzuki-Miyaura cross-coupling reactions and gives rise to a series of new Δ<sup>8</sup>-THC derivatives. In addition, we demonstrate using extensive NMR evidence that similar halide-substituted Friedel-Crafts alkylation/cyclization products in previous articles were wrongly assigned as the para-isomers, which also has consequence for the assignment of the subsequent cross-coupled products and interpretation of their biological activity. </p> <p>Considering the importance of the availability of THC derivatives in medicinal chemistry research and the fact that previously synthesized compounds were wrongly assigned, we feel this research is describing a straightforward pathway into new cannabinoids.</p>

Reductive Cleavage of Secondary Sulfonamides: Converting Terminal Functional Groups into Versatile Synthetic Handles

2019 ◽  
Author(s):  
Patrick Fier ◽  
Suhong Kim ◽  
Kevin M. Maloney
Keyword(s):  
Functional Groups ◽  
Late Stage ◽  
Reductive Cleavage ◽  
Bioactive Molecules ◽  
General Method

Sulfonamides are pervasive in drugs and agrochemicals, yet are typically considered as terminal functional groups rather than synthetic handles. To enable the general late-stage functionalization of secondary sulfonamides, we have developed a mild and general method to reductively cleave the N-S bonds of sulfonamides to generate sulfinates and amines, components which can further react <i>in-situ</i> to access a variety of other medicinally relevant functional groups. The utility of this platform is highlighted by the selective manipulation of several complex bioactive molecules.

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