The direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.

C-H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals

Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aube rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

Metal-catalysed C–H bond functionalisation has had a significant impact on how chemists make molecules. Translating the methodological developments to their use in the assembly of complex natural products is an important challenge for the continued advancement of chemical synthesis. In this tutorial review, we describe selected recent examples of how the metal-catalysed C–H bond functionalisation has been able to positively affect the synthesis of natural products.

Recent developments in natural product synthesis using metal-catalysed C–H bond functionalisation

C-H oxidation has a long history and an ongoing presence in research at the forefront of chemistry and interrelated fields. As such, numerous highly useful articles and reviews have been written on this subject. Logically, these are generally written from the perspective of the scope and limitations of the reagents employed. This Minireview instead attempts to emphasize chemoselectivity imposed by the nature of the substrate. Consequently, many landmark discoveries in the field of C-H oxidation are not discussed, but hopefully the perspective taken herein will allow C-H oxidation reactions to be more readily incorporated into synthetic planning.

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If C-H bonds could talk: selective C-H bond oxidation.

Alan Ford,† Hugues Miel, Aoife Ring,† Catherine N. Slattery,† Anita R. Maguire,*,†,‡ and M. Anthony McKervey* †Department of Chemistry and ‡School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork, Ireland Almac Discovery Ltd., David Keir Building, Stranmillis Road, Belfast BT9 5AG, United Kingdom Almac Sciences Ltd., Almac House, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, United Kingdom

Modern Organic Synthesis with α-Diazocarbonyl Compounds

The stereocontrolled total synthesis of (−)-ephedradine A has been accomplished. The synthesis features an asymmetric C−H insertion reaction, an intramolecular ester−amide exchange reaction, and a Sharpless asymmetric aminohydroxylation reaction. Construction of the complex macrocyclic ring was performed by Ns-strategy and an intramolecular aza-Wittig reaction.

Stereocontrolled total synthesis of (-)-ephedradine A (orantine).

Total synthesis of (−)-ephedradine A: an efficient construction of optically active dihydrobenzofuran-ring via C–H insertion reaction

N-(4-Methoxybenzyl)-3-phenylpropylamine




R 4-Methoxybenzylamine




2-Nitrobenzenesulfonyl chloride




I N-(4-Methoxybenzyl)-2-nitrobenzenesulfonamide




N-(4-Methoxybenzyl)-N-(3-phenylpropyl)-2-nitrobenzenesulfonamide




P N-(4-Methoxybenzyl)-3-phenylpropylamine





Keywords:

sulfur compounds;
amides;
sulfonation, N-sulfonation;
protection, nitrogen;
sulfur compounds;
amides;
deprotection, cycloaddition;
alkylation, n-alkylation;
amines (and salts), aliphatic;
esters, halogen compounds, chlorine compounds

Preparation of Secondary Amines From Primary Amines Via 2‐Nitrobenzenesulfonamides: N‐(4‐Methoxybenzyl)‐3‐Phenylpropylamine

Sequential treatment of a 1,2-disubstituted olefin with m-CPBA, Br3CCO2H, and DBU results in the one-pot, stereospecific conversion of the olefin to the corresponding disubstituted cyclic carbonate (1,3-dioxolan-2-one). The reaction proceeds via an initial epoxidation followed by SN2-type epoxide ring opening by Br3CCO2H and subsequent base-promoted carbonate formation upon elimination of bromoform. When a solution of a secondary allylic or homoallylic amine and Br3CCO2H is sequentially treated with m-CPBA then DBU, the product of the reaction is a cyclic carbamate (1,3-oxazolidin-2-one or 1,3-oxazinan-2-one).

Wataru Kurosawa

Papers

Stereocontrolled total synthesis of (-)-ephedradine A (orantine).

Total synthesis of (−)-ephedradine A: an efficient construction of optically active dihydrobenzofuran-ring via C–H insertion reaction

Preparation of Secondary Amines From Primary Amines Via 2‐Nitrobenzenesulfonamides: N‐(4‐Methoxybenzyl)‐3‐Phenylpropylamine

One-Pot Conversions of Olefins to Cyclic Carbonates and Secondary Allylic and Homoallylic Amines to Cyclic Carbamates

The Chiral Auxiliary N-1-(1′-Naphthyl)ethyl-O-tert-butylhydroxylamine: A Chiral Weinreb Amide Equivalent