Addition to chloral

The equilibrium between propargyl- and allenyl-tin compounds is not spontaneous, but it occurs in the presence of Lewis acids or coordinating solvents, and an ion-pair mechanism has been proposed (159). Substitution by iodine, or addition to chloral, occurs with propargyl/al-lenyl rearrangement (160, 161), analogous to the allylic rearrangement already mentioned. 

In addition to chloral the polymerization of other chlorinated aldehydes was studied by Kambe et al., for example that of oi-chloro iso-butyraldehyde. It was also found in this case that the initiation was almost instantaneous and the growing polymer ends could be acetylated when acetylation was carried out immediately at the low polymerization... 

Deleris, G., Dunogues, J., Galas, R. Addition of silylated hydrocarbons with an activated silicon-carbon bond to some carbonyl compounds. I. Addition to chloral. J. Organomet. Chem. 1975, 93,43-50. 

A similar trend may be seen in a study of the reaction of chloral with unsymmetrical ketones (equation S3 Table 3). Reactions were carried out in glacial acetic acid with or without added sodium acetate as catalyst. Several control experiments showed that the isomer ratios obtained were kinetic. The lack of reversibility in this reaction implies that AG is much more negative than for the simple aldol reactions discussed previously. This is presumably because of the inductive effect of the chlorines, which is known to favor hydration and other nucleophilic additions to chloral. 

Trichloromethylallenes, e.. (289), are available by decarboxylation of oxetanones over an electrically heated wire the oxetanones are obtained by alkylchloroketen addition to chloral. ... 

In addition to chloroform, many other compounds containing the trichloro-methyl group, CI3C-, show marked physiological action. Thus trichloro-acetaldehyde or chloral hydrate, Cl3C CH(OH) (p. 342), and trichloro-tertiary-butanol or chloretone, CUC CfCHaliOH, are both hypnotics. Similarly, tribromo-ethanol or avertin, BraC-CHjOH, has strong anaesthetic properties. 

When chloral was usedasthealdehyde2equivalents reacted with 1 equivalent of the enamine (98) regardless of the ratio of reactants or order of addition to give 2,6-bis(trichloromethyl)-5,5-dimethyl-4-morpholino-/ i-dioxane (183) in 83 % yield (126). Hydrolysis of 183 with hydrochloric acid at room temperature gave the hemiaeetal (184), but when heated with acid, the aldol product (185) was formed. 

In 1966 Borrmann and Wegler (87) reported the base-catalyzed addition of ketenes to chloral to form (3-lactones (eq. [24]). Using brucine, these researchers were able to isolate optically active products when ketene itself was used. 

Bromomandelic acid has been prepared by the bromination of -bromoacetophenone followed by alkaline hydrolysis 3 by the alkaline hydrolysis of the product formed by the addition of chloral to -bromophenylmagnesium bromide 4 and by the condensation of bromobenzene and ethyl oxomalonate in the presence of stannic chloride followed by hydrolysis and decarboxylation.5 />-Bromomandelic acid is a valuable reagent in the analyses of zirconium and hafnium.6... 

Cycloaddition of ketene to chloral. Quinidine (1) catalyzes the addition of ketene to chloral to give the / -propiolactone (2) in 89% yield and in 98% ee. As expected, quinine (C.,-cpimer of 1) also catalyzes this reaction to give (R)-(-+-)-2 in 76% ee. Examination of 15 chiral tertiary amines has led to certain conclusions the chirality of the product depends on the chirality of the carbon adjacent to the amine function, and the presence or absence of a hydroxyl group [1 to the amine is unimportant in this case. Even simple amines such as 1,2-dimethylpyrrolidine or N,N-dime thyl-z-phenyle thy 1 amine are fairly effective (60 and 77% ee, respectively). 

Different. solubility behaviors were observed in organic solvent systems. Regenerated cellulose did not dissolve in the SOj-amine-DMSO system which, however, readily dissolved the native and mercerized samples [15-17]. Similarly, rayon and mercerized cellulose, unlike native cellulose, were insoluble in the dimethylformamide (DMS)-chloral-pyridine solvent system 114]. Thus, the morphology of the amorphous component in addition to its content plays a significant role in the overall reactivity of cellulose. 

Alkali metal salts with nucleophilic anions are notably good initiators for chloral anionic polymerization (Fig. 26). The most studied initiator is lithium ferf-butoxide. When 0.2 mole % of lithium ferf-butoxide (based on chloral) was added to neat chloral monomer at 60°C the alkoxide (CH3)3C0CH(CCl3)0 Li was formed instantaneously, but no further addition of chloral occurred. This reaction was observed by an NMR study of the system and confirmed by the chemical reactions of the product alkoxide, which acted as the initiator. Tertiary amines such as pyridine and NR3 where R is an alkyl group have been found to be good initiators for chloral polymerization. They are slower initiators than lithium... 

Other organo-silanes and -stannanes are relatively inert, and addition reactions to aldehydes or ketones have been quite limited. However, there seems to be no reason why these organometals should not find applications in the future through the development of appropriate promoters. Actually, several examples appear in the literature. Aryl- or vinyl-silanes, which possess sp C—Si bonds, add to chloral in the presence of AICI3 (Scheme 2). The intramolecular addition reactions of alkylstannanes to ketones proceed with TiCU (equations 13 and 14). ... 

Addition of a tin alkoxide to chloral generates a stannylacetal in which the Sn-0 bond has a similar reactivity to that of the initial alkoxide so that, with an excess of chloral, polychloral is formed.58... 

Trichloroethanol passes into the cerebrospinal fluid and has a half-life of 7-11 h. In addition to trichloroethanol, chloral hydrate is also metabolized to trichloroacetic acid, which is inactive. Both trichloroethanol and trichlo-... 

Addition to carbonyl compounds. Isocyanic acid adds to the carbonyl group of many aldehydes (formaldehyde, chloral, trifluoroacetaldehyde) and ketones (s-dichlorotetrafluoroacetone, perfluorocyclobutanone) to give a-hydroxy isocyanates, a new class of compounds." Isocyanic acid and the carbonyl compound are mixed in... 

With regard to the catalytic asymmetric reaction , only a few successful examples, except those reactions using chiral transition metal complexes, have been reported. For example, the cinchona-alkaloid-catalyzed asymmetric 1,4-addition of thiols or 6-keto esters to Michael acceptors quinidine catalyzed the asymmetric addition of ketene to chloral and the highly enantioselective 1,4-addition of ) -keto esters in the presence of chiral crown ethers to Michael acceptors have been most earnestly studied. 

This is probably not strictly a 2 + 2 cycloaddition but an addition of the chiral amine 169 to the ketene 166 to give a chiral enolate that adds to chloral in the step that induces asymmetry 167. Ring closure 168 gives the lactone 164 and regenerates the quinidine for the next cycle.38... 

Scattered examples exist of additions of other hetero nucleophiles to N-sul-fonyl imines. For example, Kresze and coworkers found that thiols add to imine 43 to afford adducts 44 in good yields [Eq. (13)] [6,34]. Similarly, aniline adds to chloral-derived N-sulfonyl imine 46 to afford 45, and ethanol adds to produce 47 (Scheme 11) [6]. 

In the group of phosphonic acid derivatives, 0,0-dimethyl-(l-hydroxy-2,2,2-trichloro)ethane phosphonate, known under the name trichlorfon (Dipterex , 68), occupies a special place both chemically and biologically. It is prepared by the addition of dimethyl phosphonate to chloral (Barthel et al., 1954 Lorenz, 1953a). 

Quinidine [3, (9S)-6 -methoxy-9-cinchonanol] is mostly applied for the same purposes as quinine, such as the addition of zinc alkyls to carbonyl compounds (Section D 1.3.1.4.), or addition of thiophenol to acrylic derivatives (Section D.2.I.). An important technical synthesis of malic acid is based on the quinidine catalyzed enantioselective [2 + 2] cycloaddition of ketene to chloral (see Section D. 1.6.1.3.). Esters and ethers of dihydroquinidine (4) (just like the corresponding derivatives of dihydroquinine) have been used as chiral ligands in osmium tetroxide catalyzed dihydroxylations of alkenes (Section D.4.4.). 

L-Malic acid ](S)-13] was the starting material for the synthesis of chiral dienophiles (Section D.l. 6.1.1.1.1.1.). The resolution with 1-phenylethylamine is comparatively difficult18, but asymmetric synthesis by the enantioselective addition of chloral to ketene catalyzed by cinchona alkaloids is an attractive alternative (Section D.l.6.1.3.)19. It is also commercially available. The chiral dienophile 14 is readily obtained in two steps (formation of cyclic imide and acid-catalyzed esterification)20. 

Phenol, (-) menthol and diethyl aluminium chloride were reacted in toluene to produce the required intermediate for the ensuing asymmetric synthesis. Addition of chloral and stirring for 24 h at 25 °C gave the product. (-)-2-(2,2,2-trichloro-1 -hydrojqfethyl)phenol. 

In addition to the formation of epoxides, heme adducts, and hydroxylated products, carbonyl products also are created. These latter products result from the migration of atoms to adjacent carbons (i.e., 1,2-group migration). For example, during the CYP450-catalyzed oxidation of trichloroethylene, a 1,2-shift of chloride occurred to yield chloral (Fig. 10.10). 

The action of light appears to be necessary for at least the initial formation of the peroxide catalyst. Anti-oxidants, such as hydroquinone, resorcinol, and and g - naphthols, decrease the oxidation rate, whereas complete protection is given bVoaniline, diphenylamine, and related compounds . In addition to the gaseous products of autoxidation, a solid polymer thought to be metachloral is formed. Chloral hydrate does not appear to undergo autoxidation unless it first dissociates to chloral and water f ... 

The formation of halogenated acetonitriles, known constituents of drinking water (McKinney et al., 1976 Oliver, 1983), was shown to be probably due to reactions of amino acids such as aspartic acid, tyrosine, and tryptophan (Trehy and Bieber, 1981 Trehy et al., 1988). Experiments by Oliver (1983) confirmed that either natural organic matter (fulvic acid) or algal products yielded these compounds under conditions similar to those used in water treatment. In addition to the nitrile derivatives, these amino acids also yield chloral and chloroform by variants of the basic pathway (Figures 5.13 and 5.14). 

In the absence of a solvent and excess of chloral, the reaction rate for this reaction may be expressed by a third-order equation-second order with respect to dimethyl H-phosphonate and first order with respect to the chloral [177]. In dioxane solution and excess dimethyl H-phosphonate, the dependence of the reaction rate on the chloral concentration is the same. In addition to the chloro-containing a-hydroxyalkyl phosphonate, which is the main product under the above conditions, a side product formed as a result of dehydrochlorination of the main product, followed by phosphonate-phosphate rearrangement, has been also isolated. The presence of a base such as triethylamine, alkali metal alkoxides and hydroxides, or sodium carbonate accelerates the dehydrochlorination process. An example of this side reaction is the transformation of dialkyl-2,2,2-trichloro-l-hydroxyethyl phosphonates into dialkyl-2,2-dichlQrovinyl phosphates in the presence of sodium hydroxide [181,182]. 

Scheme 15.9 Enantioselective addition of ketene to chloral derivatives.

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