2,4-Hexanedione, formation

The optimal conditions for generating the major products formed from cystine and DMHF are as follows 3,5-dimethyl-l,2,4-trithio-lane, thiophenones and 2,4-hexanedione are all found preferentially in an aqueous medium heated to 160°C. The trithiolane and thiophe-none are optimized at 75% H2O and pH 4.5, while 2,4-hexanedione formation is better at 100% H2O and lower pH. Thiazoles, on the other hand, require a higher temperature and a nonaqueous medium. 

Other PK variations include microwave conditions, solid-phase synthesis, and the fixation of atmospheric nitrogen as the nitrogen source (27—>28). Hexamethyldisilazane (HMDS) is also an excellent ammonia equivalent in the PK synthesis. For example, 2,5-hexanedione and HMDS on alumina gives 2,5-dimethylpyrrole in 81% yield at room temperature. Ammonium formate can be used as a nitrogen source in the PK synthesis of pyrroles from l,4-diaryl-2-butene-l,4-diones under Pd-catalyzed transfer hydrogenation conditions. 

The aldol reactions we ve seen thus far have all been intermolecular, meaning that they have taken place between two different molecules. When certain r/zcar-bonyl compounds are treated with base, however, an mtramolecular aldol reaction can occur, leading to the formation of a cyclic product. For example, base treatment of a 1,4-diketone such as 2,5-hexanedione yields a cyclopcntenone... 

The aldol reaction can be applied to dicarbonyl compounds in which the two groups are favorably disposed for intramolecular reaction. Kinetic studies on cyclization of 5-oxohexanal, 2,5-hexanedione, and 2,6-heptanedione indicate that formation of five-membered rings is thermodynamically somewhat more favorable than formation of six-membered rings, but that the latter is several thousand times faster.170 A catalytic amount of acid or base is frequently satisfactory for formation of five- and six-membered rings, but with more complex structures, the techniques required for directed aldol condensations are used. 

In a study being conducted at Case Western Reserve University under the direction of Dr. Lawrence Sayre, trifluoromethyl-substituted analogs of 2,5-hexanedione will be synthesized, compared with the parent compound in chemical model studies, and evaluated for neurotoxicity in rats. This is part of an effort to address how gamma-diketone-induced pyrrole formation at neurofilament-based lysine epsilon-amino groups leads to neurofilament accumulations. Nuclear magnetic resonance (NMR) studies will provide direct visualization of the nature of chemical modification. 

Anthony DC, Boekelheide K, Anderson CW, et al. 1983. The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione. II. Dimethyl substitution acccelerates pyrrole formation and protein crosslinking. [Abstract] Toxicol AppI Pharmacol 71 372-382. 

Sayre LM, Shearson CM, Wongmongkolrit T, et al. 1986. Structural basis of gamma-diketone neurotoxicity Non-neurotoxicity of 3,3-dimethyl-2,5-hexanedione, a gamma-diketone incapable of pyrrole formation. [Abstract] Toxicol AppI Pharmacol 84 36-44. 

A plausible mechanism involves the reaction of the dihydride precursor with t-butylethylene to the 14-e complex [Ir(C6H3-2,6 CH2P-f-Bu2 2)]> which undergoes the oxidative-addition reaction of the alcohol to afford a hydride alkoxide complex. Further /i-hydride ehmination gives the alde-hyde/ketone and regenerates the dihydride active species [55]. In the particular case of 2,5-hexanediol as the substrate, the product is the cycHc ketone 3-methyl-2-cyclopenten-l-one. The formation of this ketone involves the oxidation of both OH groups to 2,5-hexanedione followed by an internal aldol reaction and further oxidation as in the final step of a Robinson annotation reaction [56]. 

After characterization of the systems, biotra ns formations were performed to produce chiral alcohols using 10 mM acetophenone, 15 mM 2,5-hexanedione, and 25 mM t-butyl 6-chloro-3,5-dioxohexanoate as substrates (Scheme 2.2.4.5). 

The cyclization steps are facilitated by the ready susceptibility of the pyrrole ring to electrophilic attack. Step-wise approaches such as these give much better yields than attempts at cyclizative annelation of pyrroles with potentially bifunctional reagents. For example, the cyclizative condensation of pyrrole with 2,5-hexanedione, which gives 4,7-dimethylindole (equation 138), is plagued with by-product formation to the extent that the indole is obtained in only 28% yield (68AJC2053). 

Amarath has shown that meso- and c//-3,4-diethyl-2,5-hexanediones cyclize at unequal rates, and that the stereochemical configuration of the unchanged dione is preserved during the reaction. Any mechanism that involves the formation of an enamine before the rate-determining step - the cyclization - must be ruled out. 

The volatile components identified from the reaction of cystine and DMHF in aqueous medium are shown in Table I. 2,4-Hexanedione, 3,5-dimethyl-l,2,4-trithiolanes and thiophenes are the major compounds. The mechanistic relationship of the three thiophenones produced has been postulated (23). The major groups of volatile components identified from the reaction in the glycerol medium are 1,3-dioxolanes and thiazoles (Table II). 1,3-Dioxolanes are formed by the reaction of glycerol and the degraded carbonyls by ketal or acetal formations. Comparison of the reaction of cystine and DMHF in water and in glycerol is outlined in Table III. 

The effect of reaction time on the major components of the reaction of cystine and DMHF in water is shown in Table IV. It is noteworthy that amounts of 2,4-hexanedione, 3,5-dimethyl-l,2,4-trithiolanes and thiophenones were found at a maximum after one hour. It was also found that the amount of 2-acetylthiazole increased with time and that acetol acetate decreased with time as expected. In the glycerol medium, the effect of reaction time on the major components is shown in Table V. Apparently, the 1,3-dioxo-lane, which is a ketal formed from glycerol and acetone, decreased over time. Also, long reaction time favors the formation of cyclic compounds, including 2,5-dimethyl-2-hydroxy-3(2H)-thiophene, cyclo-pentenones and 4,5-dimethyl-l,2-dithiolenone. 

The water content significantly affects the formation of some compounds. Figure 2 shows that the formation of thiazoles decreases as the water content increases. Figure 3 shows the relationship between water content and the formation of a 3,5-dimethyl-1,2,4-trithiolane, 3-hydroxy-pentanone and 2,4-hexanedione. The highest level of trithiolanes was obtained from the sample prepared with 75% water. Figure 4 shows that these three thiophenones were also produced at maximum at 75% water medium. 

Figure 3. The effect of water content on the formation of 3,5-dimethyl-l,2,4-trithiolane, 3-Hydroxy-2-pentanone and 2,4-Hexanedione from the reaction of cystine and DMHF.

C, no esters and furanones are found, but thiazoles, cyclopen-tenones and other heterocyclic compounds dominate. These data imply that esters and furanones are stable at mild temperatures while the formation of thiazoles, cyclopentenones and other heterocyclic compounds require a higher temperature. Also at 160°C, trithiolanes, thiophenones and 2,4-hexanedione predominate, indicating that formation of such compounds is favored by a medium temperature. Bread, crusty and caramel aromas were found in the 100°C sample, pot-roasted, roasted, meaty and clean aromas were found at 160°C, and roasted, roasted-meat, chemical and off-notes were produced at 200°C. 

Probl mi 27.13 When mesityl oxide, (CH3>2C CHCOCHu is treated with ethyl malonate in the presence of sodium ethoxide, compound M is obtained, (a) Outline the steps in its formation, (b) How could M be turned into 5,5-dimethyl-1,3-cyclo-hexanedione ... 

The dissonant charge pattern for 2,5-hexanedione exhibits a positive (-1-) polarity at one of the a-carbons, as indicated in the acceptor synthon above. Thus, the a-carbon in this synthon requires an inversion of polarity Umpolung in German) from the negative (-) polarity normally associated with a ketone a-carbon. An appropriate substrate (SE) for the acceptor synthon is the electrophilic a-bromo ketone. It should be noted that an enolate ion might act as a base, resulting in deprotonation of an a-halo ketone, a reaction that could lead to the formation of an epoxy ketone Darzens condensation). To circumvent this problem, a weakly basic enamine is used instead of the enolate. 

Even though the Paal-Knorr pyrrole synthesis has been around for 120 years, its precise mechanism was the subject of debate. In 1991, V. Amarnath et al. investigated the intermediates of the reaction and determined the most likely mechanistic pathway. The formation of pyrroles was studied on various racemic and meso-3,4-diethyl-2,5-hexanediones. The authors found that the rate of cyclization was different for the racemic and meso compounds and the racemic isomers reacted considerably faster than the meso isomers. There were two crucial observations 1) the stereoisomers did not interconvert under the reaction conditions and 2) there was no primary kinetic isotope effect for the hydrogen atoms at the C3 and C4 positions. These observations led to the conclusion that the cyclization of the hemiaminal intermediate is the rate-determining (slow) step. 

Allenes possessing a hydroxyl group at the allylic position undergo arylation which is accompanied by epoxide formation. A 3-aryl group is readily introduced to 1,2-cyclo-hexanedione and 2-ethoxy-2-cyclohexenone. Ethyleneacetals of aryl methyl ketones are obtained on arylation of hydroxyethoxy vinyl ether. ... 

Figure 1 The common solvents n-hexane and methyl n-butyl methane are converted by co-1 hydroxy lation and oxidation to the ultimate toxicant, 2,5-hexanedione (2,5-HD). 2,5-HD reacts with lysyl e-amines of proteins (black rectangle) to form pyrrolylated proteins, which undergo intra- and intermolecular cross-linking reactions, including dimer formation.

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