Subject synthetic utility

Like so many other reactions, the ene reaction has been given new life by metal catalysis. The use of metals ranges from common Lewis acids, which simply lower the barrier of activation of the hetero-ene reactions to transition metal catalysts which are directly involved in the bond-breaking and -forming events, rendering reactions formal ene processes. This review is meant to serve as a guide to the vast amount of data that have accumulated in this area over the past decade (1994-2004). If a particular subject has been reviewed recently, the citation is provided and only work done since the time of that review is included here. Finally, the examples included within are meant to capture the essence of the field, the scope, limitations, and synthetic utility therefore, this review is not exhaustive. 

When furan or substituted furans were subjected to the classic oxidative coupling conditions [Pd(OAc)2 in refluxing HOAc], 2,2 -bifuran was the major product, whereas 2,3 -bifuran was a minor product [12,13]. Similar results were observed for the arylation of furans using Pd(OAc)2 [14]. The oxidative couplings of furan or benzo[i]furan with olefins also suffered from inefficiency [15]. These reactions consume at least one equivalent of palladium acetate, and therefore have limited synthetic utility. 

The third edition contains major improvements over the previous two editions. I have updated references. Each reaction is now supplemented with two to three representative examples in synthesis to showcase its synthetic utility. As Emil Fischer stated Science is not an abstraction but as a product of human endeavor it is inseparably bound up in its development with the personalities and fortunes of those who dedicate themselves to it. To that end, I added biographical sketches for most of the chemists who discovered or developed those name reactions. Furthemore, I have significantly beefed up the subject index to help the reader navigate the book more easily. 

The synthetic utility of reactions of coordinated ligands is an important and varied subject. It is based on the enhancement in reactivity of organic ligands as a consequence of metal coordination. For example, the metal can act as a super add and cause enhanced nucleophilic attack on coordinated carbonyl and imine ligands. The metal ion can also enable the ligand itself to act as a nucleophile, sometimes by direct activation, sometimes by protecting other parts of the ligand and sometimes by a combination of both. 

A somewhat arbitrary selection of areas is based on their perceived synthetic utility. P-Diketone and a-amino acid chelate reactions have received much attention over the years and the latter are still at the forefront of current activity. Finally, some reactions of simple ketones are affected by metal coordination and this subject will also be considered. 

The synthetic utility of a-phosphorus- and a-thio-stabilized carbanions is the subject of numerous reviews.21 Notable are additions of phosphonium ylides (237),183 sulfonium ylides (238),l84 ° oxosulfo-nium ylides (239)184 " and sulfoximine ylides (240)184,1 to electron-deficient alkenes which afford nucleophilic cyclopropanation products. In contrast, with a-(phenylthio)-stabilized carbanions, which are not acyl anion equivalents, either nucleophilic cyclopropanation or retention of the hetero substituent occurs, depending on the acceptor and reaction conditions used. For example, carbanion (241) adds to 1,1-... 

The stabilisation of an enolate (intermediate or product) is also important in the decarboxylation reaction of /3-ketoacids. The decarboxylation of such compounds is facile, and is the key to the synthetic utility of ethyl acetoacetate and diethyl malonate. The mechanism of decarboxylation involves the formation of an enol (Fig. 5-21), and so is expected to be subject to metal ion control. 

Peptide synthesis is an extremely important area of chemistry for the pharmaceutical industry, and like any specialized area of chemistry, has its own set of unique problems associated with it. Racemization and purification of final products are two of the most difficult problems in this area. The use of enzymes has been explored as a possible answer to these problems since 1938 [29]. However, proteases needed to catalyze peptide synthesis are subject to rapid autolysis under the conditions needed to affect peptide coupling, so this has generally not been a practical approach until cross-linked enzyme crystals of proteases became available. The synthetic utility of protease-CLCs was demonstrated by the thermolysin CLC (PeptiCLEC -TR)-catalyzed preparation of the aspartame precursor Z-... 

The pentaammineosmium(II) metal center also binds in a dihapto fashion to several other classes of aromatic molecules, including benzenes, naphthalenes, phenols, anisoles, anilines, furans, and thiophenes, activating them toward further functionalization. The reactivity and synthetic utility of these complexes are the subject of a recent review Harman, W. D. Chem. Rev. 1997, 97,1953. 

Hydrogenation of the carbon-carbon triple bonds, particularly to the olefinic bonds, has been the subject of numerous investigations since the very early stage of the study on catalytic hydrogenation, not only in terms of its synthetic utility but also with respect to the selectivity of catalytic metals for the semihydrogenation.1-6... 

As the focus of this chapter is on the synthetic utility of the rDA reaction, an overview of mechanism is beyond the scope of this review however, the subject has beoi reviewed previously. Structural and medium effects on the rate of the rDA reaction are of prime importance to their synthetic utility, and therefore warrant discussion here. A study of steric effects cm the rate of cycloreversicHi was the focus of early work by Bachmann and later by Vaughan. The effect of both diene and dioiophile substituticHi on Ae rate of the rDA reaction in anthracene cycloadducts has been reported in a study employing 45 different adducts. If both cycloaddition and cycloreversion processes are fast on the time scde of a given experiment, reversibility in the DA reaction is observed. Reversible cycloaddition reactions involving anthracenes, furans, fulvenes and cyclopentadienes are known. Herndon has shown that the well-known exception to the endo rule in tiie DA reaction of furan with maleic anhydride (equation 2) occurs not because exo addition is faster than endo addition (it is not), but because cycloreversion of the endo adduct is about 10 000 times faster than that of the exo adduct. ... 

Within the year a wide range of photoreactions in which an aromatic residue undergoes change in substitution has been published. As previously, the diversity of the various processes makes any classification of the reactions unrealistic, and so their order of presentation here is somewhat arbitrary. Aromatic photosubstitution reactions have been reviewed by Parkanyi although the treatment is not extensive, the processes of free radical, electrophilic, and nucleophilic photoinduced substitutions of arenes are well covered.Arene photoreactions initiated by electron transfer with electron donors or acceptors are the subject of a review by Pac and Sakurai. The requirements for the efficient photogeneration of the ion radicals are considered and the synthetic utility of the photoreactions, which include reduction, cyanation, and amination, is discussed. 

The synthetic utility of the Wolff-Kishner reduction has been the subject of several reviews. However, the latest of these is over 20 years old and fails to incorporate adequately many of the important advancements which have occurred in the past 25 years. This is particularly evident regarding the emergence over the past two decades of the above-mentioned reductions of sulfonylhydrazones with hydride donors as alternatives to standard Wolff-Kishner conditions. Consequently, this discussion will focus primarily on the period since the last major review (1968), although some overlap with earlier work is essential for continuity and completeness. For further information and references to the older literature, the excellent aforementioned treatments should be consulted. Reference 3 contains extensive tables of Wolff-Kishner reductions up to about 1947. 

Of aU the anhydro sugars, 1,6-anhydrohexopyranoses are the most studied and are of the greatest synthetic utility. 1,6-Anhydrohexopyranoses have been the subject of several comprehensive reviews, which the interested reader should consult for more details [3,4,5,6]. 1,6-Anhy-dro- 8-D-glucopyranose (1 0 Fig. 1) (also known as glucosan or levoglucosan on account... 

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