Chlorine function

Tolbutamide (Figure 7.8) is metabolized via the benzylic methyl group by CYP2C9 as the major clearance mechanism. Chlorpropamide is a related compound incorporating a chlorine function in this position. The resultant metabolic stability gives chlorpropamide a lower clearance and a longer half-life (approximately 35 h compared to 5 h) than tolbutamide, resulting in a substantial increase in duration of action [5]. 

The corresponding catalytic version of this reaction was performed using either naphthalene- or biphenyl-supported polymers 594 or 595, respectively, which were prepared by cross-coupling copolymerization of 2-vinylnaphthalene or 4-vinylbiphenyl with vinyl-benzene and divinylbenzene promoted by AIBN in THF and polyvinyl alcohoP . These polymers have been used as catalysts (10%) in lithiation reactions involving either chlorinated functionalized compounds or dichlorinated materials in THF at —78°C and were re-used up to ten times without loss of activity, which is comparable to the use of the corresponding soluble arenes. 

Figure 7 presents the overall, idealized reaction mechanism. The surface of MCM-48 contains 0.9 OH / nmJ, which react completely with DMDCS in the liquid phase, if NEt3 is used as a catalyst. The majority of the silanols react monofunctionally but a small fraction also reacts further, according to reaction (3) to yield inert, bidentate species. All chlorine functions on the surface are converted towards hydroxyls upon hydrolysis. The VO(acac)2 is reacted in a gas-phase reactor with this silylated, hydrolyzed surface. All recreated silanols react with the VO(acac)2 in a 1 1 stoichiometry, following a ligand-exchange mechanism. Upon calcination at 450°C, the acac ligands are decomposed but the methylsilyl functions remain intact. Most of the V-species are converted into isolated, tetrahedral VvOx species, as indicated in Figure 4. However, a small fraction clusters to form surface oligomers, hereby recreating a fraction of the silanols.

A convenient starting material for the synthesis of compounds (170)-(174) is 1,1-dichloroethene (see Equation (27)). Nucleophilic substitution of the chlorine functions by LiPPh2 leads to a substituted ethene, which easily adds HPRR. Adding PhAsH2 instead in the last step leads to (176). 

Electrophilic substitution on polystyrene through a chlorometallation reaction yields chlorine functionality. This has opened up the possibilities of making many derivatives of polystyrene. Starting with chlorometallated polystyrene, derivatives such as quaternary, ammonium, or phosphonium salts have been made. Similarly, ethers, esters, sulfonamides, silanes, and ketone derivatives have been made by replacing the chlorine atom on chlorometallated polystyrene. In the case of polystyrene, however, it was discovered that chain end functionalization can be realized if the chain ends were terminated by group I metals such as lithium and potassium. 

In the Friedel-Crafts polymerization, the nitrile compound need not necessarily bear a chlorine function, if another aromatic chlorine compound is present. Actually, a Friedel-Crafts polymerization using 2,6-di-phenoxybenzonitrile as the nitrile compound with the comonomers shown in Figure 8.5 has been used. ... 

Since the usage of PCMC in Europe is getting more difficult due to AOX problems in waste water treatment, despite the fact that the biodegradability of PCMC has been proven (Bayer AG, 1998), our research groups examined whether the chlorine atom in PCMC is necessary or whether a substitution of chlorine is possible. We found that a chlorine substitution by numerous functional groups also led to active ingredients, which were however not as active as PCMC. Also no compound had the well-balanced activity spectrum of PCMC. Therefore it can be concluded that the chlorine function in PCMC is necessary for its activity (Bayer AG, 2001a). 

The functional group can also be inserted on another carbon of the alkyl moiety. The groups of Hawker, Braslau, and Priddy prepared alkoxyamines 83, 84, and 85, respectively, in which hydroxy and chlorine functionalities were linked to the methyl group dose to the aminoxyl function instead of being in para-position of the phenyl ring. 

Another unique methodology for the highly stereoselective synthesis of the chlorinated peptides has been developed by Zakarian and co-workers (Scheme 43.51). Their method has culminated in the asymmetric total synthesis of neodysidenin 291. The new methodology for the stereoselective installation of chlorinated functionality relies on the highly diastereocontrolled radical assembly between a halogenated carbon, such as BrCCl3,... 

---