Latent alkylating agents

Cyclophosphamide (72) was made as a latent form of nitrogen mustard with fairly low toxicity. It undergoes oxidation by microsomes in the liver and then breaks down to give much more reactive derivatives of 2,2 -dichlorodiethylamine (Scheme 3). Several aziridines are used as alkylating agents. They include triethylenemelamine (73), triaziquone (74), TEPA (triethylenephosphoramide) (75 X = O) and thio-TEPA (75 X = S). Ethylene oxide... 

Latent forms of MMPs can be activated by mechanisms which cause the dissociation of the intramolecular complex between a particular cysteine residue and the required zinc metal ligand (a complex that blocks the active site) [47], This occurs because the cysteine of the latent enzyme is coordinated to the active site in a particular way that blocks the MMP active site. Collectively, the activation of MMPs occurs through a process which has been termed the cysteine-switch . Activators of the MMPs include proteases (e.g. plasmin), conformational perturbants (SDS, NaSCN), heavy metals and organomercurials (e.g. Au(I) compounds, Hg(II)), oxidants (e.g. OC1-), disulfide compounds (e.g. GSSG) and sulfhydryl alkylating agents (e.g. V-ethylmaleimide) [47 and refs, therein]. 

Whitesell and Whitesell" have tabulated some of the many types of electrophilic reagents that C-al-kylate metallated imines. These are potent nucleophiles and undergo substitution reactions even with weakly electrophilic species such as epoxides and oxetanes. Lithiated ketimines and aldimines have been frequently used in reactions with alkylating agents containing latent 2-keto (or aldehydo) groupsor 3-keto (or aldehydo) groups. ... 

Interestingly, this same effect has been observed for the addition of a rubber toughening agent to ethyl cyanoacrylate-based adhesives, as was reported previously. The rubber must contain enough latent acid functionality on the polymer backbone or in an additive to inhibit the thermally activated decomposition of the alkyl cyanoacrylate adhesive polymer. 

Alkylation of the dihydroxyacetophenone, 44, with epichloro-hydrin results in condensation of two molecules of the phenol with the latent glycerol (45). Reaction of the intermediate with ethyl oxalate affords the chromone ester, 46. Saponification leads to the bronchiodilator cromoglycic acid (47). The agent is usually administered by oral insufflation as its extremely insoluble disodium salt. 

Adhesives which are meant to cure at temperatures of 120 or 171°C require curatives which are latent at room temperature, but react quickly at the cure temperatures. Dicyanodiamide [461-58-5], (TH INI is one such latent curative for epoxy resins. It is insoluble in the epoxy at room temperature but rapidly solubilizes at elevated temperatures. Other latent curatives for 171°C are complexes of imidazoles with transition metals, complexes of Lewis acids (eg, boron trifluoride and amines), and diaminodiphenylsulfone, which is also used as a curing agent in high performance composites. For materials which cure at lower temperatures (120°C), these curing agents can be made more soluble by alkylation of dicyanodiamide. Other materials providing latency at room temperature but rapid cure at 120°C are the blocked isocyanates, such as the reaction products of toluene diisocyanate and amines. At 120°C the blocked isocyanate decomposes to regenerate the isocyanate and liberate an amine which can initiate polymerization of the epoxy resin. Materials such as Monuron can also be used to accelerate the cure of dicyanodiamide so that it takes place at 120°C. 

Cyano groups a to a nitrogen atom can be replaced smoothly by hydrogen upon reaction with NaBFLj. Since a-cyano derivatives of trisubstituted amines can be easily alkylated with electrophilic agents, the a-aminonitrile functionality can be used as a latent a-amino anion, as exemplified by eq 7 which shows the synthesis of ephedrine from a protected aminonitrile. The reduction, proceeding with concurrent benzoyl group removal, is only moderately stereoselective (77 23). 

The dipolar cycloaddition of nitrile oxides with species containing unsaturation is a very attractive means of forming crosslinks in polymer systems, since the reaction is rapid and yields thermally stable links. Latent nitrile oxide precursors can be prepared by reaction of an isocyanate and an alkyl nitroacetate. These precursors release alkanol and carbon dioxide when heated to liberate the highly reactive nitrile oxide species. An improved synthetic procedure is developed to afford novel crosslinking agents based on difunctional, trifunctional and aliphatic precursors. Application of these agents to polymer crosslinking is demonstrated. 9 refs. 

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