Non-symmetrical ketones

Non-symmetrical ketones suffer from the fact that the regiochemistry cannot be predicted. Since both adjacent C-C bonds migrate, the yield is decreased. 

Bronsted acid (Scheme 2.42) [26-28]. (For experimental details see Chapter 14.9.4). These catalysts mediate the addition of ketones to nitroalkenes at room temperature in the presence of a weak acid co-catalyst, such as benzoic acid or n-butyric acid or acetic acid. The acid additive allows double alkylation to be avoided, and also increases the reaction kinetic. The Jacobsen catalyst 24 showed better enantio- and diastereoselectivity with higher n-alkyl-ethyl ketones or with branched substrates (66 = 86-99% dr = 6/1 to 15/1), and forms preferentially the anti isomer (Scheme 2.42). The selectivity is the consequence of the preferred Z-enamine formation in the transition state the catalyst also activates the acceptor, and orientates in the space. The regioselectively of the alkylation of non-symmetric ketones is the consequence of this orientation. Whilst with small substrates the regioselectivity of the alkylation follows similar patterns (as described in the preceding section), leading to products of thermodynamic control, this selectivity can also be biased by steric factors. 

Rearrangement of an enamine to an equilibrium mixture of isomeric enamines will occur under acid catalysis, but will not take place under neutral or basic conditions304. The reaction of non-symmetric ketones 193 with secondary enamines leads to a mixture of both possible enamines 194 and 195 (equation 20) as was shown by -NMR spectroscopy305. 

The effect of oxygen on cyclic 1,3-diradicals shows that conformation can affect the triplet state lifetime ST Time resolved resonance Raman spectroscopy has been used to examine triplet states produced from different isomers of p-carotene. A theoretical study has also been reported on the a-cleavage of the triplet states of symmetric and non-symmetric ketones S mechanism for triplet state relaxation of aromatic molecules has been used to explain experimental data for substituted benzenes. The decay kinetics of triplet-triplet fluorescence in the mesitylene biradical (two sub-levels) have been measured between 10 and 77K in Shpolski matrices triplet state of dimesityl... 

Inspection of Scheme 1 shows that the use of non-symmetrical ketones will result in two isomeric enehydrazine tautomers and hence in two isomeric indoles. When it is desired to obtain a single isomer, either a difficult separation procedure is required or, alternatively, the Fischer synthesis should be conducted with the... 

Alkali amides seem unsuitable for the generation of kinetic enolates from non-symmetrical ketones, since in the presence of ammonia a ready transformation (via proton donation and abstraction) into the thermodynamic enolate can occur. 

As is shown in Scheme 1, the use of non-symmetrical ketones in the Fischer synthesis will result in two isomeric indoles, 4 and 5. A detailed reaction mechanism is described in refs. [6] and [7], but some important characteristics will be given here. 

T. S. Hendren, Kinetics of Catalyzed Acid/Acid and Acid/Aldehyde Condensation Reactions to Non-Symmetric Ketones, M.S. Thesis, Louisiana State University, Baton Rouge (2001). 

Although aldol additions to aldehydes are robust methods and the corresponding theory is well developed, aldol additions to ketones are still largely unexplored, possibly because of the additional complexity of differentiating sterically between the two different alkyl groups of ketones. The difficulty of aldol additions to ketones is apparent from the lack of asymmetric methods available for addition of titanium enolates to ketones. The notion of syn and anti products also tends to break down when dealing with non-symmetrical ketones with similar substituents. 

The regiochemistry of alkylation of simple, non-symmetric ketones may be problematic to control, and polyalkylation can be a competing reaction. The most useful strategy is to ensure complete deprotonation of the carbonyl compound using the strong, non-nucleophilic base LDA, followed by inverse addition of the enolate to an excess of the alkylating agent. 

For satisfactory diemo- and stereoselectivity, most catalytic, direct cross-aldol methods are limited to the use of non enolizable (aromatic, a-tert-alkyl) or kineti-cally non enolizable (highly branched, ,/funsaturated) aldehydes as acceptor carbonyls. With aromatic aldehydes, however, enantioselectivity is sometimes moderate, and the dehydration side-product may be important. With regard to the donor counterpart, the best suited pronucleophile substrates for these reactions are symmetric ketones (acetone) and ketones with only one site amenable for enolization (acetophenones). With symmetric cyclic or acyclic ketones superior to acetone, syn/anti mixtures of variable composition are obtained [8b, 11, 19a]. Of particularly broad scope is the reaction of N-propionylthiazolidinethiones with aldehydes, which regularly gives high enantioselectivity of the syn aldol adduct of aromatic, a,fi-unsaturated, branched, and unbranched aldehydes [13]. 

The selective monoalkylation of ketones at the a-position had no general solution for a long time. A classical approach to this problem, based upon the selective activation of this site via the introduction of additional electron withdrawing substituents e.g. alkoxycarbonyl group), is applicable only for symmetrical ketones. Non-symmetrical compounds react non-selectively in this auxiliary step. The synthetic importance of this problem triggered a thorough study of enolate chemistry in the 1960s and, as a result, at present the selective substitution at any of the a-positions of carbonyl compounds can be achieved via a number of routes. 

The ability of non-C2 symmetric ketones to promote a highly enantioselective dioxirane-mediated epoxidation was first effectively demonstrated by Shi in 1996 [114]. The fructose-derived ketone 44 was discovered to be particularly effective for the epoxidation of frans-olefins (Scheme 17 ). frans-Stilbene, for instance, was epoxidized in 95% ee using stoichiometric amounts of ketone 44, and even more impressive was the epoxidation of dialkyl-substituted substrates. This method was rendered catalytic (30 mol %) upon the discovery of a dramatic pH effect, whereby higher pH led to improved substrate conversion [115]. Higher pH was proposed to suppress decomposition pathways for ketone 44 while simultaneously increasing the nucleophilicity of Oxone. Shi s ketone system has recently been applied to the AE of enol esters and silyl enol ethers to provide access to enantio-enriched enol ester epoxides and a-hydroxy ketones [116]. Another recent improvement of Shi s fructose-derived epoxidation reaction is the development of inexpensive synthetic routes to access both enantiomers of this very promising ketone catalyst [117]. 

Non-symmetric or symmetric ketones can be produced by the decarboxylative condensation of carboxylic acids. Rajadurai has also reviewed the process and possible reaction mechanisms. The general reaction is ... 

This reaction is of great importance in its chiral variant as an asymmetric aldol reaction. There are many practical methods for stereochemical control in either the non-catalytic or catalytic variant of this reaction. Two stereogenic centers are formed in a single reaction step, with an exception when the terminal methyl group reacts as an enol component (Scheme 4.8) or symmetrical ketone and formaldehyde as a carbonyl component (Scheme 4.9). Aldehydes are much more convenient than ketones as an electrophilic carbonyl counterpart and are preferably used. In Scheme 4.9 pairs of syn- and anti -diastereomers formed in an asymmetric aldol reaction are presented. 

Both former examples reveal an important limitation of this method. To complete an unambiguous pinacol rearrangement, the starting pinacol should be the product of dimerization of two moles of ketone. Two different ketones afford non-symmetric pinacol in low yield, which in turn rearranges into more products. 

Substituted v-butyrolactones can be prepared by reaction of aldehydes or ketones with tbe dianion (28), and direct condensation of symmetrical ketones with diethyl 2-oxomalonate provides a useful synthetic route to the butenolides (29). A number of initiators have been used previously to promote the free-radical addition of ketones to alkenes now transition-metal oxides have been shown to be effective. Pent-4-enal is cyclized to cyclopentanone by chlorotris(triphenylphos-phine)rhodium(i) through a non-radical pathway. ... 

As the aUylated enamine has higher reactivity (i.e., lower ionization potential) the selective mono-aUylation of cyclohexanone required excess (2 equiv.) ketone reagent. Nevertheless 20 equivalents of cyclobutane were necessary for the selective reaction with cyclobutanone and only 2,5-bis-allylated cyclopentanone was obtained, as the second oxidation occurred immediately on the iminium intermediate prior to hydrolysis with this substrate. The allylation reaction was compatible with alkyl and heteroatom substituents at the P and y positions. When non-symmetrical heteroatom containing substrates were used, C(4) allylation occurred selectively in high yields (70-86%) and in high ee (80-99%) (Figure 39.2). 

---