Aldol acyclic ketones

Aldol Condensations of Acyclic Ketone Boryl Enolates (6)... 

A straightforward method for aldolizing unsymmetrical ketones on the more hindered side involves the use of catalytic titanium(lV) chloride in toluene at room temperature. For examples using acyclic and cyclic ketones, and linear, branched, and aromatic aldehydes, the regioselectivity varied from 7 1 to >99 1, while the symanti ratios were moderate to good, and yields were in the range 62-91%. In contrast to other methods, base is not required, and the ketone can be used as is (i.e. the silyl enol ether is not required). 

The work on organocatalytic aldol condensation continues unabated. In a recent advance, Armando Cdrdova of Stockholm University has found Angew. Chem. Int. Ed. 2004,43, 6528) that (S)-proline also will catalyze the Mannich reaction with high enantiomeric excess. Acyclic ketones also participate efficiently. 

A much more generally useful process was developed by Robinson to prepare cyclohexenones from ketones and methyl vinyl ketone or its derivatives. Again, because good compilations of the Robinson annulation exist,8 only a few examples are given here. The first step of this process, the Michael addition, is carried out by normal base catalysis, while the second step, the aldol condensation, is best accomplished by the use of a secondary amine to form the enamine of the acyclic ketone, which then cyclizes... 

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 alkylation of asymmetric acyclic ketones takes place regioselectively on the most-substituted carbon, thus affording the syn isomers as major products. a-Hydroxyketones showed anti selective additions similar to that observed in related aldol, and Mannich-type additions (Scheme 2.39). Such selectivity is due to the preferred formation of the Z-enamine intermediate, stabilized by intramolecular hydrogen bonding between the hydroxy group and the tertiary amine of the catalyst [23]. 

Although enamines readily undergo intramolecular condensation with ketones (Section VI.D) the only intermolecular reaction we are aware of is that with diethyl ketomalonate156. Whereas cyclic ketone enamines gave the aldol product, with enamines of acyclic ketones only the morpholine enamine of pentan-3-one gave the aldol product (73). The more reactive pyrrolidine enamine cyclysed onto the ester group to give the... 

Kinetic enolates are obtained by slow addition of the ketone (1.00 eq) to an excess of a hindered strong base (1.05 eq) at low temperature in an aprotic solvent (nonequilibrating conditions). It should be noted that deprotonation of acyclic ketones may furnish ( )/(2)-mixtures of enolates. Since the stereochemistry of enolates plays a pivotal role in controlling the product stereochemistry in aldol reactions, methodologies used for selectively preparing either one of the isomers are discussed in the following subsections. 

It is all very well knowing what enolates give rise to what aldol products, but this is not much use unless we can choose to have cis or trans enolates. Clearly with cyclopentanone there is no option but to form a trans enolate. But with an acyclic ketone we will need a little more care. Boron enol ethers provide an answer. Two common boron reagents used are 9-BBN chloride 46 (derived from 9-BBN 45) and another is dicyclohexylboron chloride 47. Other reagents include the corresponding triflates. There are also the chiral boron reagents that we shall meet later chapters. 

The Mukaiyama version of the aldol reaction is well known a carbonyl-titanium tetrachloride complex reacts with a trimethylsilyl enol ether. Under these conditions there is no titanium enolate involved. Another procedure has been reported a trimethylsilyl enol ether reacts with titanium tetrachloride to give the titanium enolate addition of the carbonyl compound generates the aldol product (although with slightly lower diastereoselectivity than with Mukaiyama s procedure). (Z)-Enolsilanes from acyclic ketones react rapidly and stereospecifically with TiCU to form (Z)-configured CbTi enolates, while the ( )-isomers react slowly to afford low yields of mixtures of ( )- and (Z)-Cl3Ti enolates (Scheme 41). 

Titanium enolates of cyclic and acyclic ketones, like their zirconium counterparts, usually give rise to syn aldol products irrespective of enolate geometry. Tri(alkoxy)- or tri(dialkylamino)-titanium enolates... 

E)-Lithium enolates of acyclic ketones of the type required are not readily available, but the kinetic enolate of ethyl mesityl ketone (3) consists of the (E)-and (Z)-isomers in the ratio 92 8. Reaction of this mixture affords the /Areo-aldol... 

Nakajima developed an enantioselective aldol-Tishchenko reaction by using chiral lithium binaphtholate 8, to afford 1,3-diol derivatives with three contiguous chiral centres and high stereoselectivities (Scheme 2.6). Acyclic ketones gave l,2-a ff-l,3-a ff-diols such as 9 via TS-11 and cyclic ketones... 

The aldol reaction of cyclic ketones and acetone with aromatic aldehydes were carried out in combination with triflic acid in water at 25°C [250]. Other chiral primary-tertiary diamine catalyst such as compound 167 (20 mol%) was used in combination with solid polyoxometalate acid support (6.67% mol) in the aldol reaction between dihydroxyacetone (149a) and aromatic aldehydes in NMP as solvent at 25°C to afford mainly iyn-aldol products in good yields (59-97%) and high diastereo- and enantioselectivities (78-99% de, 84-99% ee). The combination of catalyst 167 with triflic acid was used in the reaction of acyclic ketones and a-hydroxyketones 8 with aromatic aldehydes also with good results [251]. Simple chiral diamine 168 (10 mol%) in the presence of Iriflic acid (20 mol%) was applied as catalyst in the reaction between acetone and cyclohexanone with aromatic aldehydes in water at 25°C, giving aldol adducts 4 in low yields (15-58%) and moderate diastereo- and enantioselectivities (50-98% de, 45-93% ee) [252]. 

At reflux in dilute aqueous sodium hydroxide, however, the 3-alkylcyclopentenone (491) was converted into cis-jasmone (486). Particular attention to experimental conditions was required. A number of analogous transformations have been reported. It was also noted that dealdolization of the p-aldol occurs more readily in acyclic ketones and cyclohexanones than in cyclopentanones. In order to cleave the C-3—C-4... 

Tin(IV)-chloride-mediated double aldol reaction of acyclic ketones is rendered stereoselective by a chiral phosphine oxide, (5)-BE JAPO it is proposed that the catalyst controls the first aldol and the substrate controls the second. Another chiral diphosphine oxide, this one based on thiophene, catalyses direct aldols in high delee Chiral a-silyloxy ketones derived from lactate (61) undergo titanium(IV)-mediated aldols giving diastereomerically pure syn-syn adducts (62) in high yield, irrespective of the alkyl groups fianking the silyl or carbonyl. 

Few chiral secondary amine organocatalysts have been applied to the asymmetric aldol reaction, in 2008. As an example, Maruoka and Kano have designed a binaphthyl-based amino acid, which was applied to induce the asymmetric aldolisation of both acyclic and cyclic ketones with both aliphatic and aromatic aldehydes performed in DMF. ° Remarkable results were obtained in general with enantioselectivities of up to 99% ee for either cyclic or acyclic ketones, which led to the <2 n-products (Scheme 2.41). Furthermore, these authors have used a closely related binapthyl-based amino sulfonamide to promote the cross-aldol reaction between aldehydes, which yielded the corresponding syn products in moderate to high yields (71-91%) and diastereoselectivities (72-90% de) combined with excellent enantioselectivities (94-99% ee). 

Aldol reactions of acyclic ketones with aldehydes. 

---