Synthetic Considerations

Of the C2-symmetric metallocene catalysts used to prepare iPP, the bis(indenyl)- and bis(tetrahydroindenyl)-type complexes form the most important classes. Thus, the synthetic 

FIGURE 1.18 Bis(l-methylfluorenyl)metallocenes 35a-b for isoselective propylene polymerization. 

Arylamines are commonplace. They are part of molecules with medicinally important properties, of molecules with structurally interesting properties, of materials with important electronic properties, and of transition metal complexes with catalytic activity. An aryl-nitrogen linkage is present in nitrogen heterocydes such as indoles [1, 2] and benzopyr-azoles, conjugated polymers such as polyanilines [3-9], and readily oxidizable triarylamines used in electronic applications [10-13]. The ability of aryl halides and triflates to form arylamines allows a single group to be used as a synthetic intermediate in aromatic carbon- 

Modem Arene Chemistry. Edited by Didier Astruc 

Copyright 2002 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim 

Data should be acquired, processed and archived to ensure data integrity. 

Most pharmaceuticals are small synthetic molecules, most of which are based upon nitrogen heterocycles. These molecules are typically made by multi-step syntheses. The best synthesis is one that gives the desired compound with the best quality and the lowest cost. Often lowest cost is determined by the number of steps, the yield of each step, and the complexity of each step. It is important for pharmaceutical companies to develop attractive syntheses and considerable resources are expended in process development. 

As an example, consider the drug losartan K (Cozaar), which is commonly prescribed for hypertension. The drug was invented by Dupont workers and developed and marketed with Merck Co. Inc. The patent [25] covering the composition expired in 2009 and the drug is now offered in generic form. Several early syntheses originated from 4 -methyl-biphenyl-2-carbonitrile. 

Losartan K is an example of a drug that can exist in different crystalline forms. The occurrence of different crystalline forms of the same drug is called polymorphism. Polymorphs can have different chemical properties such as dissolution rate, hygroscopicity, stability, and bioavailability. Therefore, it is important for pharmaceutical companies to understand the possibility of polymorphism. Ignoring this could lead to possible quality problems. There have been instances where a specific polymorph has been patented after a patent had issued for the pharmaceutical active itself. This effectively extends the patent protection of a drug. 

The purity of the flnal product is a critical factor in selecting a synthetic route. Any impurities must be below 0.1% by weight or must be studied for their health effects. A synthesis which gives impurities which are difficult to remove is often rejected even if the yields are higher. Scale-up considerations are also important. The use of high pressures, flammable solvents, or processes which create a lot of waste all add cost due to equipment, safety, and 

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Syntheses of radioactive tracers involve all of the classical biochemical and synthetic chemical reactions used in the synthesis of nonradio active chemicals. There are, however, specialized techniques and considerations required for the safe handling of radioactive chemicals, strategic synthetic considerations in terms of their relatively high cost, and synthesis scale constraints governed by specific activity requirements. 

In parallel with polymer synthesis, many activities have been directed towards soluble, well-defined oligomers. Aside from purely synthetic considerations, access to oligomers is, important for the optimization of polymer generation and for the understanding of structure/property relations in the class of PPP... 

With the above synthetic considerations as a backdrop, the use of the arene-alkene cycloaddition in complex molecule total synthesis can now be examined. The emphasis here will be on the meta cycloaddition process since it has received the most study. It will become apparent, however, that even this reaction has received relatively little attention in synthesis in spite of its enormous potential. This situation is likely to change riqiidly as recent theoretical and synthetic advances are assimilated. 

One reason Saunders proposed using the set of isotopomers presented in Eq. (11.17) was for synthetic considerations. For reactants with two hydrogenic sites attached to the same atom, it is typically much simpler to prepare the DD isotopomer than it is to synthesize a compound with high abundance D in an H D compound. The HT and DT isotopomers are generally easier to prepare because the tritium is at tracer levels. Figure 11.11 shows an example [89] of the labeled reactants needed for an experiment. 

The rare earth elements represent the largest subgroup in the periodic table and offer a unique, gradual variation of those properties which provide the driving force for various catalytic processes. Their peculiar electronic configuration and the concomitant unique physicochemical properties also have to be consulted for the purpose of synthetic considerations. The highly electropositive character of the lanthanide metals, which is comparable to that of the alkali and alkaline earth metals, leads as a rule to the formation of predominantly ionic compounds, Ln(III) being the most stable oxidation state [9]. This and other intrinsic properties are outlined in Scheme 1 which will serve as a point of reference in this section [10-13]. 

The Sn2 reaction is a powerful method for inserting functional groups into a carbon skeleton. There are several important synthetic considerations. The poor reactivity of sterically hindered halides dictates that primary or secondary substrates be used. A typical example is the 8 2 reaction of cyanide ion with the primary tosylate unit in 64, which gave nitrile 65 in Mulzer s synthesis of the C1-C12 segment of the antitumor... 

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