Other Alkylating Agents

Alkylation with other alkylating agents such as ethyl iodide (43. 180, 181j, chloracetic acid and its esters (182). and dialkylaminoalkylhalides (40.43) occurs also on the ring nitrogen. 

The monoacetate 9a (R1 = Ac) and the diacetate 10a (R1 = R2 = Ac) are obtained by treatment of 8 with acetic anhydride in anhydrous pyridine at room temperature 4 the oxo group in position 5 of 8 is more reactive towards acetylation. Similarly, the S,S-dioxidc of 8 can be converted to the bisacetylated S,5-dioxide of 10a in 78 % yield.74 Methylation of 8 with diazomethane gives 9c (65 % yield), along with 14 % of the 3-methoxy compound 11. Other alkylation agents, such as dimethyl sulfate in the presence of potassium carbonate, selectively give 9c, albeit in lower (30 %) yield.90 The dimethyl enol ether 10c (R1 = R2 = Me) is obtained by a subsequent methylation of 9c (R1 = Me) with dimethyl sulfate and potassium teri-butoxide.90... 

Cisplatin administration requires adequate hydration and forced diuresis to prevent kidney damage. Cisplatin is intensely emetogenic and its use requires adequate antiemetic prophylaxis. Myelosuppression is less evident than with other alkylating agents. 

In other reactions also the OH-group of the phenols shows itself to be more reactive than that of the aliphatic alcohols. Phenols, but not alcohols, react easily with diazomethane. With other alkylating agents also, such as alkyl halides, and dialkyl sulphates, the phenols react even in aqueous alkaline solution whilst the alcohols do not react under such conditions. Benzoyl derivatives, most of which crystallise readily, are excellently adapted for the characterisation of phenols (Schotten-Baumann reaction). 

Neither elevated serum bromide levels nor formation of methylated adducts are, by themselves, specific for bromomethane exposure. For example, increased bromide levels could result from exposure to bromide in the diet or ingestion of bromate- or bromide-containing medicines, and increased methyl adducts might result from exposure to other methyl halides, various methyl nitrosoamines, or other alkylating agents. However, the combination of these two methods (i.e., a finding of increased bromide and increased methylation) would strongly indicate that bromomethane exposure had occurred. 

R = alkyl or benzyl n = 1 or 2) with alkyl halides and other alkylating agents. The crystal structure of cis-[Fe2(ri-CsH4Me)2(CO)3 C(NMe2)p ]l. /. Chem. Soc., Dalton Trans., 186-91. 

Alkyl halides, alkyl sulfonates and other alkylating agents have also been subject to scmtiny in spheres other than pharmaceuticals, such as in environmental analysis. Various approaches have included two-step SPE, derivatisation with trifluoroacetic anhydride followed by GC/MS (for cyclophosphamide and its analogues in sewage water) SPE on surface water to isolate the antineoplastic agents carmustine, chlorambucil, cyclophosphamide and melphalan for LC-UV and LC-fluorescence measurements and derivatisation of alkyl halides and epoxides with 4-nitrothiophenol followed by HPLC-UV detection (claimed to be better than NBP derivatisation). A patent exists for a field test kit for mustard gases in military use based on NBP derivatisation. 

J. H. Kim and J. J. Thomas, Use of 4-(nitrobenzyl)pyridine (4-NBP) to test mutagenic potential of slow-reacting epoxides, their corresponding olefins, and other alkylating agents. Bulletin of Environmental Contamination and Toxicology, 1992, 49(6), 879-885. 

Dacarbazine DTIC-Dome) is activated by photodecomposition and by enzymatic A-demethylation. Eventual formation of a methyl carbonium ion results in methylation of DNA and RNA and inhibition of nucleic acid and protein synthesis. As with other alkylating agents, cells in all phases of the cell cycle are susceptible to dacarbazine. 

There has been much interest in diquaternary salts of 4,4 -bipyridine, the electrochemistry of which has recently been reviewed. l.l -Dialkyl diquaternary salts of 4,4 -bipyridines are prepared by treating 4,4 -bipyri-dines with excess of an alkyl halide or a dialkyl sulfate or other alkylating agent. This method has been used extensively and provides diquaternary salts of type 92 where both alkyl quaternizing groups are the same (i.e., 92 R = 211,467,689,962,967,968 Qf particular interest is the diquater-... 

These drugs appear to be non-cross-resistant with other alkylating agents all require biotransformation, which occurs by nonenzymatic... 

There is an increased risk of secondary cancers in the form of acute leukemia, and the carcinogenic potential of procarbazine is thought to be higher than that of most other alkylating agents. 

Ahmed Alder James Sinnott Whiling Chem. Commun. 1968, 1533 Ahmed Alder Chem. Commun. 1969, 1389 Alder Chem. Ind. (London) 1973, 983. For a discussion of the hazards involved in the use of these and other alkylating agents, see Alder Sinnott Whiting Evans Chem. Br. 1978, 324. 

Alkylation with Alkanes. Alkylation of aromatic hydrocarbons with alkanes, although possible, is more difficult than with other alkylating agents (alkyl halides, alkenes, alcohols, etc.).178 This is due to the unfavorable thermodynamics of the reaction in which hydrogen must be oxidatively removed. 

With the aid of the Bronsted equation [Eq. (15)] the reactivities of simple azoles or benzazoles may be predicted from a knowledge of their pKa values. While this equation was derived for N-methylation reactions using solvents such as DMSO and dimethyl sulfate, it can be applied to estimate nucleophilicity toward other alkylating agents in various solvents provided that (a) the Bronsted / values for the new systems are similar to the old one, and (b) that steric factors are unimportant. The foregoing discussion serves as a guide to indicate when such limitations apply. 

There are many other alkylating agents which often display widely varying reactivity and specificity toward particular nucleic acid bases and particular nucleotide sequences. 

Other alkylating agents react through nucleophilic addition to a carbon-carbon double bond. Thus, acrylonitrile reacts with the nitrogen or oxygen atoms of nucleic acids in the same manner as does the SH group in Eq. 3-25. The water-soluble carbodiimides react as in the first step of Eq. 3-10 to form adducts of the following type ... 

Support-bound alkylating agents have been used to N-alkylate pyridines and dihydropyridines (Entries 7 and 8, Table 15.21). Similarly, resin-bound pyridines can be N-alkylated by treatment with a-halo ketones (DMF, 45 °C, 1 h [267]) or other alkylating agents [246]. Polystyrene-bound l-[(alkoxycarbonyl)methyl]pyridinium salts can be prepared by N-alkylating pyridine with immobilized haloacetates (Entry 8, Table 15.21). These pyridinium salts react with acceptor-substituted alkenes to yield cyclopropanes (Section 5.1.3.6). Pyridinium salts have also been prepared by reaction of resin-bound primary amines with /V-(2,4-dinitrophenyl)pyridinium salts [268,269]. 

The asymmetric benzylation of 16 was promoted by phosphonium salt 12 in moderate yield with encouraging levels of enantioselectivity when the catalyst loading was as low as 0.20 mol % (Table 7.1, entry 3). Further, a low temperature improved the enantiomeric excess to 50% ee (entry 5). A low enantiomeric excess obtained using the phosphonium salt 13 (entry 6) suggested a critical role for two mandelamide units in the catalytic efficiency of phosphonium salt 12. Unfortunately, this reaction proved to be highly substrate-sensitive, and other alkylating agents or different ester substituents in 16 afforded low enantioselectivities. 

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