Alternative synthetic transformations

Alternative Synthetic Transformations and Alternative Reagents. In the goal to reduce risk to human health and the environment through the elimination or reduction of toxic substances, there are significant opportunities to substitute more benign chemicals for the reagents that are necessary to carry out particular transformations or change the actual transformations themselves. 

Often more than one synthetic route may be available to prepare a particular com pound Indeed it is normal to find m the chemical literature that the same compound has been synthesized m a number of different ways As we proceed through the text and develop a larger inventory of functional group transformations our ability to evaluate alternative synthetic plans will increase In most cases the best synthetic plan is the one with the fewest steps... 

Synthesis of a-alkoxyketones from a-diazocarbonyl compounds and alcohols under the influence of copper or rhodium catalysts is well established as an alternative to the Lewis or proton acid catalyzed variant of this synthetic transformation. The sole recent contribution to the aspect of general reactivity deals with the competition between O/H insertion and cyclopropanation of unsaturated alcohols 162). The results... 

Because solvents are required in such high volumes compared to all other materials used in a synthetic transformation, hazards associated with solvents and safety issues associated with their use have always been a consideration in the development and selection of solvents. Some of the earliest and most obvious hazards, that if solvents were found to possess would cause them to be selected against, include properties such as high flammability or explosivity. With the greater understanding of the health and environmental effects that could be caused by other hazardous properties that solvents may possess or by their use in such large volumes, alternative solvents are... 

In the preceding example we did not consider cycloaddition reactions since these would not offer any suitable alternative synthetic pathway. The bicyclic isoquinuclidine derivative given below (G. Biichi, 1963, 1966A) contains only unstrained six-membered rings, and the refro-Diels-Alder transform is obviously the furthest-reaching simplification and the fastest antithetical route to commercial starting materials. Both bridgehead atoms can be introduced in one step. 

Imidazole-containing compounds have been utilized as reagents for various synthetic transformations. A convenient access to substituted allyl enol carbonates was established through the reaction of ketone enolates with the complex of allyl l//-imidazole-l-carboxylates 74 and boron trifluoride etherate <07JOC9372>. Relatively mild and highly efficient Cul-catalyzed /V-arylation procedures for imidazoles with aryl and heteroaryl bromides or chlorides have been developed in the presence of ligands 75 and cesium carbonate <07JOC2737>. a, -Unsaturated 2-acyl imidazoles 76 are an alternative and practical class of dienophiles for the DNA-based catalytic asymmetric Diels-Alder reaction in... 

As the product 39 still contains the xanthate group, alternative radical transformations can be performed, which also include its removal with tris(trimethylsilyl)silane. Further manipulations of the dithiane ring comprise desulfurization or hydrolysis, thus confirming the use of such xanthates as the synthetic equivalent of a methyl and formyl radical. Two examples of the use of this chemistry for the extension of alkene-containing sugars were successfully examined, as illustrated in Scheme 27. 

A series of simple transformations (Scheme 10) from en /o-dicyclopentadiene has provided alternative synthetic routes to ( )-sequifenchene (97) and ( )-epi-/8-santalene (98). The suggested intermediacy of /S-bergamotene (99) in ovalicin (100) biosynthesis has been supported by recent studies using [l,2- C]acetate and [4- C]mevalonate as precursors cf. Chapter 6). 

A typical synthetic transformation using the Hofmann elimination also illustrates an alternative synthetic approach to this reaction. Reaction of iodomethane with the dimethylamino moiety in 215 leads to the trimethylammonium salt. This ammonium leaving group allows the usual Hofmann elimination sequence, with thermal syn-elimination giving the vinyl derivative, 216.203 204 j is variation is important since using an amine as a Hofmann precursor is often more convenient than relying on an Sn2 reaction of an amine and a halide to produce the requisite ammonium salt (sec. 2.1.A). 

The following transformations are very convenient using a hydroboration strategy. Discuss the possibility of alternative synthetic routes that do not involve hydroboration. 

The second key step is lactone formation from the carboethoxy substituted cyclohexanone unit in 44. The third key step is construction of the tricyclic ring system by asymmetric radical cyclization of 43, and construction of 43 from 2-isopropylphenol (42) using alcohol chiral auxiliaries (R OH) was designated as the fourth key step. This disconnection scheme represents Yang s specific approach using key chemical transformations such as radical cyclization (see sec. 13.7). Clearly, other disconnections are possible, and at each stage other disconnections could lead to alternate synthetic trees. 

IBX is also tolerant of amine functionality, and therefore is used for the successful oxidation of amino alcohols to amino carbonyls. Frequently, this synthetic transformation requires the protection of the amino group, as a nonhasic derivative, prior to oxidation. IBX also provides an alternative method to oxidize alcohols selectively in the presence of primary, secondary, or tertiary amines, although the in situ protonation of the amine with acid is usually required (e.g., trifluoroacetic acid, 1-1.5 equiv) to avoid reduced yields. Oxidation of an aminocyclohexanol occurs selectively upon treatment with both IBX and TEA (1 1 ratio), without degradation of the amine functionality, to give cyclohexanone in 91% yield (eq 3). ... 

One approach toward solvent alternatives to VOCs is the increased use of aqueous reaction systems. There have been a number of investigations on conducting synthetic transformations in water which have previously only been carried out routinely in organic solvents (28). 

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