Synthesis of Heterobenzylic Fluorides

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

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

Synthesis ◽

10.1055/a-1529-7678 ◽

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.

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Recent advances in process development for opiate-derived pharmaceutical agents

Canadian Journal of Chemistry ◽

10.1139/cjc-2014-0552 ◽

2015 ◽

Vol 93 (5) ◽

pp. 492-501 ◽

Cited By ~ 12

Author(s):

Tomas Hudlicky

Keyword(s):

Process Development ◽

Short Review ◽

New Methods ◽

Naturally Occurring ◽

Recent Advances ◽

Overall Efficiency ◽

Pharmaceutical Agents

This short review summarizes our work on the process development for the synthesis of buprenorphine, naltrexone, naloxone, and nalbuphine from naturally occurring opiates such as thebaine and oripavine. Several new methods for N-demethylation of morphinans have been developed during the pursuit of this research. The article traces the evolution of various approaches and provides a comparison for overall efficiency.

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Backbone-Enabled Peptide Macrocyclization through Late-Stage Palladium-Catalyzed C–H Activation

Synlett ◽

10.1055/s-0039-1691495 ◽

2019 ◽

Vol 31 (03) ◽

pp. 199-204 ◽

Cited By ~ 2

Author(s):

Zengbing Bai ◽

Huan Wang

Keyword(s):

Natural Products ◽

Small Molecules ◽

Late Stage ◽

Cyclic Peptides ◽

Medicinal Chemistry ◽

Materials Science ◽

Three Dimensional ◽

Chemical Methods ◽

New Methods ◽

Palladium Catalyzed

Peptide macrocycles are widely used in fields ranging from medicinal chemistry to materials science. Efficient chemical methods for the synthesis of cyclic peptides with novel three-dimensional structures are highly desired to facilitate the development of this unique class of compounds. However, the range of methods available for constructing peptide macrocycles is limited compared with that for small molecules. We recently developed new methods for synthesizing highly constrained cyclic peptides with C–C crosslinks through Pd-catalyzed C–H activation reactions. These methods use endogenous backbone amides as directing groups and, therefore, have the potential for use in late-stage functionalization of peptide natural products.

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

Chemical Society Reviews ◽

10.1039/d1cs00380a ◽

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.

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Recent advances in the chemistry of bicyclo- and 1-azabicyclo[1.1.0]butanes

Pure and Applied Chemistry ◽

10.1515/pac-2019-1007 ◽

2020 ◽

Vol 92 (5) ◽

pp. 751-765 ◽

Cited By ~ 2

Author(s):

Alexander Fawcett

Keyword(s):

Nitrogen Atom ◽

Short Review ◽

Future Research ◽

The Past ◽

New Methods ◽

Recent Advances ◽

Recent Developments ◽

The 1950S ◽

Highly Strained

AbstractBicyclo[1.1.0]- and 1-azabicyclo[1.1.0]butanes are structurally unique compounds that exhibit diverse chemistry. Bicyclo[1.1.0]butane is a four-membered carbocycle with a bridging C(1)-C(3) bond and 1-azabicyclo[1.1.0]butane is an analog of bicyclo[1.1.0]butane featuring a nitrogen atom at one bridgehead. These structures are highly strained, allowing them to participate in a range of strain-releasing reactions which typically cleave the central, strained bond to deliver cyclobutanes or azetidines. However, despite these molecules being discovered in the 1950s and 1960s, and possessing a myriad of alluring chemical features, the chemistry and applications of bicyclo[1.1.0]- and 1-azabicyclo[1.1.0]butanes remain underexplored. In the past 5 years, there has been a resurgent interest in their chemistry driven by the pharmaceutical industry’s increasing desire for new methods to access cyclobutanes and azetidines. This short review intends to provide a timely summary of the most recent developments in the chemistry of bicyclo[1.1.0]- and 1-azabicyclo[1.1.0]butane to highlight the diverse chemistry they can access, their value as synthetic precursors to cyclobutanes and azetidines, and to identify areas for future research.

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Recent Advances in the Synthesis of β-Ketonitriles

Synthesis ◽

10.1055/s-0036-1589128 ◽

2017 ◽

Vol 50 (03) ◽

pp. 485-498 ◽

Cited By ~ 8

Author(s):

Kensuke Kiyokawa ◽

Satoshi Minakata ◽

Takaya Nagata

Keyword(s):

Transition Metal ◽

Carbonyl Compounds ◽

Medicinal Chemistry ◽

Short Review ◽

Coupling Reactions ◽

Important Class ◽

The Past ◽

Recent Advances ◽

Ketone Enolates ◽

Metal Catalyzed

β-Ketonitriles are an important class of compounds in the field of organic and medicinal chemistry. Over the past decades, numerous efforts have been devoted to the development of new and efficient methodologies for the synthesis of these derivatives, and a number of efficient methods to accomplish this have been developed in recent years. In this context, this short review highlights recent advances in the synthesis of β-ketonitriles.1 Introduction2 Acylation of Alkyl Nitriles3 Electrophilic Cyanation of Ketone Enolates4 Electrophilic Cyanation of β-Keto Carbonyl Compounds5 Transition-Metal-Catalyzed Carbonylative Coupling Reactions6 Miscellaneous Examples7 Outlook

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

10.26434/chemrxiv.7553444.v1 ◽

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

In this manuscript we describe a modular pathway to synthesize biologically relevant (–)-trans-Δ8-THC derivatives, which can be used to modulate the pharmacologically important CB1 and CB2 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 Δ8-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. 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.

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