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

Electrochemistry represents one of the most intimate ways of interacting with molecules. This review discusses advances in synthetic organic electrochemistry since 2000. Enabling methods and synthetic applications are analyzed alongside innate advantages as well as future challenges of electroorganic chemistry.

Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance

A new iron(III) halide-promoted aza-Prins cyclization between γ,δ-unsaturated tosylamines and aldehydes provides six-membered azacycles in good to excellent yields. The process is based on the consecutive generation of γ-unsaturated-iminium ion and further nucleophilic attack by the unsaturated carbon−carbon bond. Homoallyl tosylamine leads to trans-2-alkyl-4-halo-1-tosylpiperidine as the major isomer. In addition, the alkyne aza-Prins cyclization between homopropargyl tosylamine and aldehydes gives 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines as the only cyclic products. The piperidine ring is widely distributed throughout Nature, e.g., in alkaloids,1 and is an important scaffold for drug discovery, being the core of many pharmaceutically significant compounds.2,3 The syntheses of these type of compounds have been extensively studied in the development of new drugs containing six-membered-ring heterocycles.4 Reactions between N-acyliminium ions and nucleophiles, also described as amidoalkylation or Mannich-type condensations, have been frequently used to introduce substituents at the R-carbon of an amine.5 There are several examples that involve an intramolecular attack of a nucleophilic olefin into an iminium cation for the construction of a heterocyclic ring system.6 Traditionally, the use of hemiaminals or their derivatives as precursors of N-acyliminium intermediates has been a common two-step strategy in these reactions.6a Among this type of cyclization is the aza-Prins cyclization,7 which uses alkenes as intramolecular nucleophile. However, cy† X-ray analysis. E-mail address: malopez@ull.es. (1) (a) Fodor, G. B.; Colasanti, B. Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 23, pp 1-90. (b) Baliah, V.; Jeyarama, R.; Chandrasekaran, L. Chem. ReV. 1983, 83, 379-423. (2) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679-3681. (3) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103, 893-930. (4) Buffat, M. G. P. Tetrahedron 2004, 60, 1701-1729 and references therein. (5) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3187- 3856 and references therein. (6) (a) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, O., Heathcock, C. H., Eds.; Pergamon: New York, 1991; Vol. 2, pp 1047-1081. (b) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367-4416. (7) (a) Dobbs, A. P.; Guesne, S. J. J.; Hursthouse, M. B.; Coles, S. J. Synlett 2003, 11, 1740-1742. (b) Dobbs, A. P.; Guesne, S. J. J.; Martinove, S.; Coles, S. J.; Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880-7883. (c) Hanessian, S.; Tremblay, M.; Petersen, F. W. J. Am. Chem. Soc. 2004, 126, 6064-6071 and references therein. (d) Dobbs, A. P.; Guesne, S. J. Synlett 2005, 13, 2101-2103. ORGANIC

Iron-Catalyzed Reactions in Organic Synthesis

Direct C-H transformation via iron catalysis.

Over the last decade, substantial research has led to the introduction of an impressive number of efficient procedures which allow the selective construction of CC bonds by directly connecting two different CH bonds under oxidative conditions. Common to these methodologies is the generation of the reactive intermediates in situ by activation of both CH bonds. This strategy was introduced by the group of Li as cross-dehydrogenative coupling (CDC) and discloses waste-minimized synthetic alternatives to classic coupling procedures which rely on the use of prefunctionalized starting materials. This Review highlights the recent progress in the field of cross-dehydrogenative C sp 3C formations and provides a comprehensive overview on existing procedures and employed methodologies.

The Cross-Dehydrogenative Coupling of C sp 3H Bonds: A Versatile Strategy for CC Bond Formations

k R I + A r . * R. + A r I . k>109 M-~s ' (18) A l t h o x h ba th r e a c t i o n s gave good r e s u l t s i n many cases (Table 8), some l i m i t a t i o n s a re encountered wi th both r a d i c a l sources . Aroyl peroxides do r e a c t wi th t a l k p l iod ides , hu t do not produce t a l k y l rad i c a l s due t o i n compet i t ive i o n i c r e a c t i o n s . Moreover t h e thermal o r induced decomposition of a r o y l peroxides a t f i r s t produce aroyloxy r a d i c a l s , A r C O O , which r e a c t wi th s e v e r a l s u b s t r a t e s ( a c t i v a t e d aromatics, o l e f i n s , a lcohols , e t h e r s , amines) i n s t e a d o f gene ra t ing a r y l r a d i c a l s by decarboxyla t ion. HETEROCYCLES, Vol 28, No 1, 1989 The main limitation encountered with diazonium salts is due to the high addition rates of the nucleophilic radicals to the diazonium group, leading to the "free-radical diazo-coupling reaction" 27 (eq. 19). This competition can be in part restricted by keeping low the stationary concentration of the diazonium salt during the reaction. TABLE 8 Alkylation of heteroaromatic bases by diazonium salt, benzoyl peroxide and alkyl iodides 11 Heteroaromatic base Radical source Alkyl iodide Orientation Yield % a )

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Recent developments of free-radical substitutions of heteroaromatic bases

Substitutions by nucleophilic free radicals: A new general reaction of heteroaromatic bases

The silver-catalyzed decarboxylation of α-keto acids by persulfate leads to acyl radicals, which can effect the selective homolytic acylation of pyridine and pyrazine derivatives. Compared with the previously developed source of acyl radicals by hydrogen abstraction from aldehydes, this procedure is more effective in monoacylation when multiple positions of high nucleophilic reactivity are available in the heterocyclic ring. Although the introduction of an acyl group strongly activates the heterocyclic ring toward further substitution, monoacylation can be achieved by taking advantage of the difference in basicity and lipophilicity between the starting base and the monoacylation products in a two-phase system

Homolytic acylation of protonated pyridines and pyrazines with .alpha.-keto acids: the problem of monoacylation

Les constantes de vitesse pour l'addition du radical phenyle a des pyridines substituees en 4 protonees ou non sont determinees par competition avec l'abstraction de chlore a partir de CCl 4 . A partir de ces constantes de vitesse, l'utilisation du radical phenyle a partir de sel de diazonium ou du peroxyde de benzoyle pour generer des radicaux alkyles par enlevement d'iode ou d'hydrogene a ete developpee en tant que procede general d'alkylation de bases heteroaromatiques

Elena Vismara

Papers

Recent developments of free-radical substitutions of heteroaromatic bases

Substitutions by nucleophilic free radicals: A new general reaction of heteroaromatic bases

Homolytic acylation of protonated pyridines and pyrazines with .alpha.-keto acids: the problem of monoacylation

Polar effects in free-radical reactions. Rate constants in phenylation and new methods of selective alkylation of heteroaromatic bases.

Polar effects in free-radical reactions. New synthetic developments in the functionalization of heteroaromatic bases by nucleophilic radicals