Conventional methods for carrying out carbon–hydrogen functionalization and carbon–nitrogen bond formation are typically conducted at elevated temperatures, and rely on expensive catalysts as well as the use of stoichiometric, and perhaps toxic, oxidants. In this regard, electrochemical synthesis has recently been recognized as a sustainable and scalable strategy for the construction of challenging carbon–carbon and carbon–heteroatom bonds. Here, electrosynthesis has proven to be an environmentally benign, highly effective and versatile platform for achieving a wide range of nonclassical bond disconnections via generation of radical intermediates under mild reaction conditions. This review provides an overview on the use of anodic electrochemical methods for expediting the development of carbon–hydrogen functionalization and carbon–nitrogen bond formation strategies. Emphasis is placed on methodology development and mechanistic insight and aims to provide inspiration for future synthetic applications in the field of electrosynthesis.

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Electrochemical strategies for C-H functionalization and C-N bond formation.

Macrolactonizations in the Total Synthesis of Natural Products

Further advances in the chemistry of mannich bases

Alkyl and aryl phosphites and phosphines react with compounds having weak heteroatom–heteroatom bonds, such as SS, OO, etc., and with azo compounds to form reactive phosphonium salts. These phosphonium salts in turn promote “redox” condensation reactions with compounds having active hydrogens. The condensation reaction of alcohols using the redox couple of a triaryl- or trialkylphosphine and a dialkyl azodicarboxylate has become known as the Mitsunobu reaction, based on his pioneering work in the late 1960s. The overall reaction is summarized, wherein the alcohol (R1OH) and acidic compound (H–Nu) are condensed to form product (R1–Nu), while triphenylphosphine is oxidized to triphenylphosphine oxide and the azodicarboxylate is reduced to the hydrazine. Although the typical redox combination is diethyl azodicarboxylate (DEAD) and triphenylphosphine, many other combinations have found selected use. The reaction is generally limited to primary and secondary alcohols, although tertiary alcohols react in a few intramolecular and intermolecular reactions. For secondary alcohols the reaction usually proceeds with clean inversion of stereochemistry. The acidic component of the reaction generally has an aqueous pKa < 15, with intramolecular reactions providing the exceptions. Examples of H–Nu include oxygen nucleophiles such as carboxylic acids and phenols; nitrogen nucleophiles such as imides, hydroxamates, and heterocycles; sulfur nucleophiles such as thiols and thioamides; and carbon nucleophiles such as β-ketoesters.



Major reviews of the Mitsunobu reaction were published in 1981 by Mitsunobu and in 1983 by Castro. The former review concentrated on reactions using DEAD/triphenylphosphine, while the latter review focused on reactions in which halogens replaced the hydroxy group using reagents such as triphenylphosphine/carbon tetrachloride, triphenyl phosphite/iodomethane, and triphenylphosphine/N-halosuccinimide. Reactions involving the DEAD/triphenylphosphine redox system are the principal subject of this chapter, with emphasis on the literature between 1981 and 1988.


Keywords:

Mitsunobu reaction;
adduct formation;
alcohol activation;
SN2 reaction;
mechanisms;
carbon–oxygen bond;
carbon–nitrogen bond;
carbon–sulfur bond;
carbon–halogen bond;
carbon–carbon bond;
ambident nucleophiles;
dehydration;
alkenes;
method comparison;
ester formation;
lactone formation;
akyl aryl ether;
epoxides;
dialkyl ethers;
enol ethers;
dialkyl ethers;
imides;
azides;
experimental procedures;
scope;
limitations

The Mitsunobu Reaction

Products A. Parenty,† X. Moreau,†,§ Gilles Niel,‡ and J.-M. Campagne*,†,‡ †Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, F-91198 Gif sur Yvette, France Institut Lavoisier de Versailles, UMR CNRS 8180, Universite ́ de Versailles-Saint-Quentin-en-Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France ‡Institut Charles Gerhardt, UMR5253, Ecole Nationale Supeŕieure de Chimie, 8 rue de l’Ecole Normale, F-34296 Montpellier, France

Update 1 of: macrolactonizations in the total synthesis of natural products.

An efficient and highly regioselective intramolecular Mannich-type reaction: A construction of the AEF ring system of aconitine-type diterpene alkaloids

Tandem electrocyclic-sigmatropic reaction of benzocyclobutenes. 21. A new route to isochroman-3-one-4-spiro-1′-cycloalk-3′-enes

An efficient total synthesis of (±)-decaline and (±)-vertaline, lactonic biphenyl ether Lythraceae alkaloids, was achieved. The [3+2] cycloaddition of the nitrone (24) with the olefin (10), prepared via the Ullmann reaction catalyzed by a phase-transfer reagent, produced the adduct (11) which, upon treatment with methanesulfonyl chloride followed by reductive cleavage of the N-O bond, gave the isomeric quinolizidinols (13 and 14) in a one-pot operation. Through the use of inter-and intramolecular Mitsunobu reaction as an inversion procedure at C-2, 13 was converted into (±)-decaline (1). On the other hand, the cis-quinolizidinol (14) was transformed in two steps to (±)-vertaline (2).

Synthetic Studies on Lythraceae Alkaloids via [3+2] Cycloaddition. II. Total Synthesis of (±)-Decaline and (±)-Vertaline

Studies on the syntheses of heterocyclic compounds—DXLVIII

A partir de l'oxyde-1 de tetrahydro-2,3,4,5 pyridine et d'aryl-1 butene-3ols-1, syntheses regio- et stereoselectives des cis- et trans-[hydroxy-3' methoxy-4' phenyl]-4 quinolizidinols-2, de l'hydroxy-4 cinnamate de l'isomere cis, d'abresoline et de lasubine II

K. Shishido

Papers

An efficient and highly regioselective intramolecular Mannich-type reaction: A construction of the AEF ring system of aconitine-type diterpene alkaloids

Tandem electrocyclic-sigmatropic reaction of benzocyclobutenes. 21. A new route to isochroman-3-one-4-spiro-1′-cycloalk-3′-enes

Synthetic Studies on Lythraceae Alkaloids via [3+2] Cycloaddition. II. Total Synthesis of (±)-Decaline and (±)-Vertaline

Studies on the syntheses of heterocyclic compounds—DXLVIII

Synthetic studies on lythraceae alkaloids via [3+2]cycloaddition. I: Total synthesis of some simple phenylquinolizidine alkaloids and ester alkaloids