Chloral, carbonylation

Chloral forms well-crystallized adducts (126) with diaziridines containing at least one NH group (B-67MI50800). Carbonyl addition products to formaldehyde or cyclohexanone were also described. Mixtures of aldehydes and ammonia react with unsubstituted diaziridines with formation of a triazolidine ring (128). Fused diaziridines like (128) are always obtained in ring synthesis of diaziridines (127) from aldehyde, ammonia and chloramine. The existence of three stereoisomers of compounds (128) was demonstrated (76JOC3221). Diaziridines form Mannich bases with morpholine and formaldehyde (64JMC626), e.g. (129). 

The [ 2 + 4]-cycloaddition reaction of aldehydes and ketones with 1,3-dienes is a well-established synthetic procedure for the preparation of dihydropyrans which are attractive substrates for the synthesis of carbohydrates and other natural products [2]. Carbonyl compounds are usually of limited reactivity in cycloaddition reactions with dienes, because only electron-deficient carbonyl groups, as in glyoxy-lates, chloral, ketomalonate, 1,2,3-triketones, and related compounds, react with dienes which have electron-donating groups. The use of Lewis acids as catalysts for cycloaddition reactions of carbonyl compounds has, however, led to a new era for this class of reactions in synthetic organic chemistry. In particular, the application of chiral Lewis acid catalysts has provided new opportunities for enantioselec-tive cycloadditions of carbonyl compounds. 

There are some special cases where tetrahedral intermediates are unusually stable there are three phenomena which lead to this stability enhancement. The first is an unusually reactive carbonyl (or imine) compound which is very prone to addition. An example of such a compound is trichoroacetaldehyde or chloral, for which the covalent hydrate can be isolated. A simple way to recognize such compounds is to think of the carbonyl group as a (very) stabilized carbocation, bearing an substituent. 

Just as electron-donating substituents inhibit hydrate formation, electron-withdrawing ones promote it. Thus K for the hydration of CljCCHO (16) is 2-7 x 104, and this aldehyde (tri-chloroethanal, chloral) does indeed form an isolable, crystalline hydrate (17). The powerfully electron-withdrawing chlorine atoms destabilise the original carbonyl compound, but not the hydrate whose formation is thus promoted ... 

For the hydrate to revert to the original carbonyl compound it has to lose eOH or H2CF, which is rendered more difficult by the electron-withdrawing group. The hydrate from chloral is also stabilised... 

Further development of this idea led to the proposal (56) that reactive B=C groups, for instance carbonyl systems, would be able to activate alcohol acceptors AH by generating a related A—B—C—H intermediate (Scheme 8, path I). It seemed that chloral might act as a catalyst along these lines. However, it turned out that the rate of decay in the transition state is too low in all systems tested thus far. Therefore, the carbonyl compound is more or less a substitute for a Lewis acid catalyst, as indicated in Scheme 8, path II. The high reactivity and diastereoselectivity in chloral-catalyzed reactions is attributable to the nitriles used as solvents in these reactions [see Section III.3.b and Ref. (62)]. 

Under analogous conditions, carbonylation of chloral affords cis or trans 2,5-bis(trichloromethyl)-l,3-dioxolan-4-ones. The stereochemical outcome of the reactions can be controlled by the concentration of the employed sulfuric acid (90-99%) and the reaction time. The cis isomer is predominantly formed under more acidic conditions after 10 min (cis/trans 95/5 48% yield), whereas complete isomerization to the trans isomer (cisltrans 0/100 65% yield) takes place at lower acidity (90%) and prolonged reaction time (7 h) [63]. 

The reduction of carbonyl compounds with trialkyaluminum reagents has been known for several decades (140,141). Meerwein and co-workers observed that chloral is reduced to 2,2,2-trichloroethanol with triethylaluminumetherate (142). Organoaluminum reagents can function as reducing agents if they contain A1—H bonds or if they have hydrogen at a p (particularly a branched) position. 

If there is a suitable electron-withdrawing substituent, hydrate formation may be favoured. Such a situation exists with trichloroacetaldehyde (chloral). Three chlorine substituents set up a powerful negative inductive effect, thereby increasing the 8- - charge on the carbonyl carbon and favouring nucleophilic attack. Hydrate formation is favoured, to the extent that chloral hydrate is a stable solid, with a history of use as a sedative. 

The Ti(0 Pr)2Cl2/D-DIPT poison has also been used for the Ti(0 Pr)2Cl2/ BINOL-catalyzed asymmetric carbonyl-ene reaction with chloral (Scheme 8.8). With the Ti(0 Pr)4/D-DIPT poison in a 1 3 ratio, both the regioselectivity and the enantioselectivity of the ene product are improved. 

For preparative purposes, the reaction of thiocarbonyl ylides with carbonyl compounds can be considered as an alternative method for the synthesis of 1,3-oxathiolanes. Aromatic aldehydes, chloral, glyoxalates, mesoxalates, pyruvates as well as their 3,3,3-trifluoro analogues are good intercepting reagents for thioketone (5)-methylides (36,111,130,163). All of these [3 + 2] cycloadditions occur in a regioselective manner to produce products of type 123 and 124. 

Metal-Oxygen Compounds. Trialkyltin alkoxides are remarkable for the variety of addition reactions they undergo with carbonyl and thiocarbonyl compounds. Bloodworth and Davies have reported reactions of tri-w-butyltin alkoxides with isocyanates, carbon dioxide, sulfur dioxide, isothiocyanates, carbon bisulfide, chloral, and ketene. The reactions observed were as follows ... 

Another approach to the synthesis of polyimides from chloral derivatives involves the use of dianhydrides of isomeric tetracarboxylic acids containing central carbonyl or 1,1-dichloroethylene groups and two ether bonds as the starting electrophilic compounds [31-33] (Scheme 3.8). 

With very reactive carbonyl compounds, such as chloral CI3C.CHO, we can even add aromatic compounds in strong acid. Draw a mechanism for the first step, the formation of the alcohol ... 

Chlorinated Fatty Acids. Chlorination of carboxylic acids is much more difficult because the contribution or the carbonyl group toward proton removal is offset by the electron donation effect from the hydroxyl group. This hindrance is obviated by reaction with the acid chloride or anhydride. Chlorination is normally accomplished hy use of n catalyst, such as phosphorus trichloride. Monochloroacelic acid is an important industrial chemical. Dichloro- and trichloroacetic acids can he produced by further chlorination, although the latter can be produced convenienlly by nitric acid oxidation of chloral. Higher chlorinalcd tally acids can be produced by treatment or the hydroxy carboxylic acid or ester with HCI ur PCL ... 

Yamamoto et al. have reported the asymmetric catalysis of a chiral Lewis acid in a carbonyl-ene reaction, which uses chloral as the enophile and an aluminum catalyst with enantiopure 3,3 -bissilylated binaphthol (BINOL) to give the corresponding homoallylic alcohol with 78% ee in 79% yield (Scheme 8C.2) [6]. It should be noted that 3,3 -diphenyl-BINOL-derived aluminum catalyst provides the racemic product in low yield. 

The first addition of allylsilane 1 to activated carbonyl compounds, such as chloral 2 or a-chloroacetone 4, leading to y-d -un saturated alcohols 3 or 5, was reported by Calas et al. [3, 4] in 1974 and Abel and Rowley [5] in 1975. A Lewis acid, such as AlCfi, GaCfi or InCl3 is required to promote this condensation (Scheme 13.1). 

---