Electrophilic agents treatment

The tetrasubstituted isomer of the morpholine enamine of 2-methyl-cyclohexanone (20) because cf the diminished electronic overlap should be expected to exhibit lower degree of enamine-type reactivity toward electrophilic agents than the trisubstituted isomer. This was demonstrated to be the case when the treatment of the enamine with dilute acetic acid at room temperature resulted in the completely selective hydrolysis of the trisubstituted isomer within 5 min. The tetrasubstituted isomer was rather slow to react and was 96% hydrolyzed after 22 hr (77). The slowness might also be due to the intermediacy of quaternary iminium ion 23, which suffers from a severe. 4< strain 7,7a) between the equatorial C-2 methyl group and the methylene group adjacent to the nitrogen atom, 23 being formed by the stereoelectronically controlled axial protonation of 20. 

Carbon disulfide can act as an electrophilic agent with enamines at room temperature. Therefore, treatment of an enamine with both elemental sulfur and carbon disulfide in a polar solvent can result in the formation of a 3H-l,2-dithiole-3-thione (such as 108) and/or a 2H-l,3-dithiole-2-thione (such as 109) (135,139,140). These products are the result of competing... 

Azafulvaleiies of type 7-10 constitute electron-poor compounds therefore, only a few reactions using electrophilic agents have been described. Tlius, heating 26a with methyl iodide or benzoyl chloride and subsequent treatment of the resulting products with FIBF4 gave the dithiolium salts... 

The hydroxylation of a phenol 1 upon treatment with a peroxodisulfate in alkaline solution, to yield a 1,2- or 1,4-dihydroxybenzene 3, is called the Elbs reaction The phenol is deprotonated by base to give a phenolate anion 4, that is stabilized by resonance, and which is activated at the ortho or the para position towards reaction with an electrophilic agent ... 

Another problem associated with the treatment of dilithium polymers with some electrophilic agents is the formation of an intractable anionic association or gel. The degree of association is related to the charge density of the electrophile and increases in the following order ... 

Treatment of 5//-furan-2-one with electrophilic agents (acid chlorides, etc.) yields 0-protected 2-hydroxyfurans (Equation (41)) <83585, 86SC69) O-silylated derivatives are prepared similarly <77CL167>. If 3-furanones are us as starting material, the corresponding 3-silylated derivatives are obtained <76H(4)1663, 80TL2891>. 

Isomer distributions have been determined for several electrophilic substitutions of thiophen, such as bromination by Bra and Br+, chlorination by tin tetrachloride, or iodine-catalysed acetylation by acetic anhydride, trifluoroacetylation, and Vilsmeyer formylation. The a. ratios vary from 100 to over 1000, according to the selectivity of the electrophilic agent. The results obtained, together with other data from the literature, permit a test of the applicability of linear free-energy treatments to electrophilic substitution at the a- and j8-positions of thiophen. Plots of log (Xf and log jSf against p for nine reactions were linear, and from the slopes values of = — 0.79 and 0)3+ = — 0.52 were obtained. Serious deviations were observed for mercuration and protodemercuration, while nitration and protodeboronation were not taken into account, as deviation could be expected for various reasons. The linearity was taken as evidence... 

N-Cyanoamidines, such as Nb(6pyridyl)methyl-N -cyanobenzamidine 308, which are precursors of insecticides, can be prepared by treatment of 3-(benzamidomethyl)-6-chloropyridine with electrophilic agents (e.g. phosgene in a solvent) in the presence of tertiary amines (MesN) at 0 °C, followed by treatment with an aq. suspension of Ca(CN)2 at 5 °C for 1 h. The yield in the case of308 was 44% [238]. 

C-8 carbanion, a mixture of 10 and 8 substituted derivatives was obtained after treatment with an electrophilic agent (alkyl halogenides, chloroformates, methyl isocyanate, dimethylsulfide) (Timms etal., 1989). 

When the 2-(trimethylsilyl)ethyl component is installed on an alkyl substrate, simple fluoride treatment fails to effect trimethy Isi-lylethyl removal. To employ a 2-(trimethylsilyl)ethyl alkyl thioether as a protected alkylthiol, the sulfur must flrst be functionalized with an electrophilic agent and once achieved, 2-(trimethy 1-silyljethyl loss from the intermediate sulfonium ion is facilitated. 

The six-position may be functionalized by electrophilic aromatic substitution. Either bromination (Br2/CH2Cl2/-5°) acetylation (acetyl chloride, aluminum chloride, nitrobenzene) " or chloromethylation (chloromethyl methyl ether, stannic chloride, -60°) " affords the 6,6 -disubstituted product. It should also be noted that treatment of the acetyl derivative with KOBr in THF affords the carboxylic acid in 84% yield. The brominated crown may then be metallated (n-BuLi) and treated with an electrophile to form a chain-extender. To this end, Cram has utilized both ethylene oxide " and dichlorodimethyl-silane in the conversion of bis-binaphthyl crowns into polymer-bound resolving agents. The acetylation/oxidation sequence is illustrated in Eq. (3.54). 

Fluorinatton of graphite with fluorine gives graphite fluorides that have interesting properties, as recently reviewed [63]. Pyridine and its derivatives add elemental fluorine to form unstable N-fluoro adducts [14, 26, 64, 65]. These may decompose to 2-fluoropyndines [65] or be stabilized by treatment with inflate salts to form useful electrophilic fluonnating agents [64]... 

Similarly to the P-CHj group, secondary phosphine-boranes react smoothly in the presence of a base (BuLi, NaH) under mild conditions to afford other kinds of functionalized phosphine-boranes in good to high yields, without racemi-zation. Yet the success of deprotonation/treatment with an electrophile process to afford substituted phosphine derivatives without any loss in optical purity may depend on the deprotonation agents employed. Use of butyllithium usually provides the products with high enantiomeric excess in good to high yields [73]. 

Acceptor-monosubstituted diazomethanes can be further converted into other types of diazo compound. C-Acylation of diazoacetic esters generally requires very reactive acylating agents, such as acid chlorides [969,970] or bromides [971]. C-Alkylations of acyldiazomethanes are best accomplished by metallation followed by treatment with a carbon electrophile [972-977], C-alkylation can also occur without any base if sufficiently electrophilic aldehydes or ketones are used [973,978 -982] or if the alkylation proceeds intramolecularly [983]. 

Several 2-fluoroerythromycin derivatives have also been prepared by means of electrophilic fluorination with Selectfluor of the enolate of the )S-ketoester fragment (Fig. 45) [121]. Fluorination is stereoselective and leads to the a-fluo-rine compound [122]. Two derivatives of 2-fluoroerythromycin are in clinical development HMR-3562 and HMR-3787). These compounds are promising agents for the treatment of respiratory pathogens resistant to erythromycin A (Fig. 45) [123]. 

As a further illustration of the reactivity of the 3 position toward electrophiles, the methoxyindole (25-1) readily undergoes Mannich reaction with formaldehyde and dimethylamine to afford the aminomethylated derivative (25-2). Treatment of that intermediate with potassium cyanide leads to the displacement of dimethylamine and the formation of the nitrile (25-3), possibly by an elimination-addition sequence involving a 3-exomethylene-indolenine intermediate. The protons on the methylene group adjacent to the nitrile are quite acidic and readily removed. Reaction of (25-3) with methyl carbonate in the presence of sodium methoxide gives the carbo-methoxylated derivative (25-4). Catalytic hydrogenation leads to reduction of the nitrile to a primary amine. There is thus obtained the antihypertensive agent indorenate (25-5) [26]. 

---