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

Starting from the early 1990’s, the chemistry of polyvalent iodine organic compounds has experienced an explosive development. This surging interest in iodine compounds is mainly due to the very useful oxidizing properties of polyvalent organic iodine reagents, combined with their benign environmental character and commercial availability. Iodine(III) and iodine(V) derivatives are now routinely used in organic synthesis as reagents for various selective oxidative transformations of complex organic molecules. Several areas of hypervalent organoiodine chemistry have recently attracted especially active interest and research activity. These areas, in particular, include the synthetic applications of 2-iodoxybenzoic acid (IBX) and similar oxidizing reagents based on the iodine(V) derivatives, the development and synthetic use of polymer-supported and recyclable polyvalent iodine reagents, the catalytic applications of organoiodine compounds, and structural studies of complexes and supramolecular assemblies of polyvalent iodine compounds.

The chemistry of polyvalent iodine has previously been covered in four books1–4 and several comprehensive review papers.5–17 Numerous reviews on specific classes of polyvalent iodine compounds and their synthetic applications have recently been published.18–61 Most notable are the specialized reviews on [hydroxy(tosyloxy)iodo]benzene,41 the chemistry and synthetic applications of iodonium salts,29,36,38,42,43,46,47,54,55 the chemistry of iodonium ylides,56–58 the chemistry of iminoiodanes,28 hypervalent iodine fluorides,27 electrophilic perfluoroalkylations,44 perfluoroorgano hypervalent iodine compounds,61 the chemistry of benziodoxoles,24,45 polymer-supported hypervalent iodine reagents,30 hypervalent iodine-mediated ring contraction reactions,21 application of hypervalent iodine in the synthesis of heterocycles,25,40 application of hypervalent iodine in the oxidation of phenolic compounds,32,34,50–53,60 oxidation of carbonyl compounds with organohypervalent iodine reagents,37 application of hypervalent iodine in (hetero)biaryl coupling reactions,31 phosphorolytic reactivity of o-iodosylcarboxylates,33 coordination of hypervalent iodine,19 transition metal catalyzed reactions of hypervalent iodine compounds,18 radical reactions of hypervalent iodine,35,39 stereoselective reactions of hypervalent iodine electrophiles,48 catalytic applications of organoiodine compounds,20,49 and synthetic applications of pentavalent iodine reagents.22,23,26,59

The main purpose of the present review is to summarize the data that appeared in the literature following publication of our previous reviews in 1996 and 2002. In addition, a brief introductory discussion of the most important earlier works is provided in each section. The review is organized according to the classes of organic polyvalent iodine compounds with emphasis on their synthetic application. Literature coverage is through July 2008.

Chemistry of Polyvalent Iodine

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.

Die direkte Funktionalisierung von C-H-Bindungen in organischen Molekulen hat sich in jungster Zeit zu einer wirksamen und idealen Methode entwickelt, mit der Kohlenstoff-Kohlenstoff- und Kohlenstoff-Heteroatom-Bindungen geknupft werden konnen. Der Aufsatz gibt einen Uberblick uber die Strategien, die durch Funktionalisierung von C-H-Bindungen eine rasche Synthese von biologisch aktiven Verbindungen wie Naturstoffen und pharmazeutischen Zielsubstanzen ermoglichen.

Funktionalisierung von C‐H‐Bindungen: neue Synthesemethoden für Naturstoffe und Pharmazeutika

This Perspective illustrates the defining characteristics of free radical chemistry, beginning with its rich and storied history. Studies from our laboratory are discussed along with recent developments emanating from others in this burgeoning area. The practicality and chemoselectivity of radical reactions enable rapid access to molecules of relevance to drug discovery, agrochemistry, material science, and other disciplines. Thus, these reactive intermediates possess inherent translational potential, as they can be widely used to expedite scientific endeavors for the betterment of humankind.

Radicals: Reactive Intermediates with Translational Potential

Intramolecular hydrogen abstraction. Iodosobenzene diacetate, an efficient and convenient reagent for alkoxy radical generation

Iodosobenzene diacetate, an efficient reagent for the oxidative decarboxylation of carboxylic acids

The photolyses of 5α-cholestane-3β,6β-diol 3-acetate (1), 5α-cholestan-2β-ol (4), 5α-cholestan-4β-ol (8), (20R)-pregn-5-ene-3β,20-diol 3-acetate (19), (20S)-pregn-5-ene-3β,20-diol 3-acetate (21), and dihydrotigogenin 3-acetate (25) in the presence of iodine and various hypervalent organoiodine compounds lead to alkoxyl radicals which undergo intramolecular hydrogen abstraction to produce, in most cases, 1,4-iodohydrins and tetrahydrofuran derivatives.

Intramolecular hydrogen abstraction. Hypervalent organoiodine compounds, convenient reagents for alkoxyl radical generation

3 pages, 2 schemes.-- Supporting information available: IR, 1H NMR, and mass spectral data for 1a-c, 2a-c, 3, 4, 5a,b, and 6 (5 pages). Ordering information is given on any current masthead page.

Intramolecular functionalization of nonactivated carbons by amidylphosphate radicals. Synthesis of 1,4-epimine compounds

Photolysis of 6β-nitroamino-5α-cholestane (4), 6β-nitroamino-5α-cholestan-3β-yl-acetate (5), 2β-nitroamino-5α-cholestane (13), 4β-nitroamino-5α-cholestane (17), (20R)-20-nitroaminopregn-5-en-3β-yl acetate (26), (20R)-(31) and (20S)-(34)-nitroamino-5α-pregnan-3β-yl acetate, (23R, 25S)-3β-acetoxy-23-nitroamino-5β-spirostan (46), 3β-nitroaminofriedelane (53), and methyl 3β-nitroaminofriedelan-29-oate (54) in the presence of iodine and various oxidative reagents leads to neutral nitroaminyl radicals which undergo intramolecular hydrogen-abstraction to produce in most cases N-nitroimine compounds. Best results were obtained with the system iodine and (diacetoxyiodo) benzene.

Rosendo Hernández

Papers

Intramolecular hydrogen abstraction. Iodosobenzene diacetate, an efficient and convenient reagent for alkoxy radical generation

Iodosobenzene diacetate, an efficient reagent for the oxidative decarboxylation of carboxylic acids

Intramolecular hydrogen abstraction. Hypervalent organoiodine compounds, convenient reagents for alkoxyl radical generation

Intramolecular functionalization of nonactivated carbons by amidylphosphate radicals. Synthesis of 1,4-epimine compounds

Steroidal N-nitroamines. Part 4. Intramolecular functionalization of N-nitroamine radicals: synthesis of 1,4-nitroimine compounds