Ketones bulky

Reaction with P-Donors. In accord with the expectations dis-cussed above, Cp2Mo2(C0K reacts readily with two equivalents of soft nucleophiles, e.g., phosphines, phosphites, CO, etc., to give exclusively the trans-products indicated in eq. 7. With one equivalent of ligand, only disubstituted product (1/2 equiv.) and unreacted 1 (1/2 equiv.) are isolated. Hence, the addition of the first ligand is the slow step (eq. 18). Complex 1 does not react with hard bases, e.g., aliphatic amines, pyridine, ethers, alcohols, or ketones. Bulky phosphines, e.g., (cyclohexyl)3P, and Ph3As or Ph3Sb also fail to react at room temperature. Rather... 

NaBlLt does not seem to be the best reagent for the stereoselective reduction of chiral unfunctionalized acyclic ketones. Bulky complex hydrides such as Li(s-Bu)3BH usually afford better results. When a heteroatom is present in the a- or fi-position, the stereochemical course of the reduction depends also on the possible intervention of a cychc chelated transition state. Also, in this case other complex hydrides are often better suited for favoring chelation (see Zinc Borohydride). Nevertheless, cases are known where excellent degrees of stereoselection have been achieved with the simpler and less expensive NaBUj. Some... 

Enzymes Sources Coenzyme needed Alde- hydes Acyclic ketones Simple cyclic ketones Bulky cyclic ketones Aromatic ketones Dike- tones Unsaturated ketones 3-Oxo- acid esters 4-Oxo- acid esters 5-Oxo- acid esters... 

Ketones, in which one alkyl group R is sterically demanding, only give the trans-enolate on deprotonation with LDA at —12°C (W.A. Kleschick, 1977, see p. 60f.). Ketones also enolize regioseiectively towards the less substituted carbon, and stereoselectively to the trans-enolate, if the enolates are formed by a bulky base and trapped with dialkyl boron triflates, R2BOSO2CF3, at low temperatures (D A. Evans, 1979). Both types of trans-enolates can be applied in stereoselective aldol reactions (see p. 60f.). 

The condensation of aldehydes or ketones with secondary amines leads to "encunines via N-hemiacetals and immonium hydroxides, when the water is removed. In these conjugated systems electron density and nudeophilicity are largely transferred from the nitrogen to the a-carbon atom, and thus enamines are useful electroneutral d -reagents (G.A. Cook, 1969 S.F. Dyke, 1973). A bulky heterocyclic substituent supports regio- and stereoselective reactions. 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Other limitations of the reaction are related to the regioselectivity of the aryl radical addition to double bond, which is mainly determined by steric and radical delocalization effects. Thus, methyl vinyl ketone gives the best results, and lower yields are observed when bulky substituents are present in the e-position of the alkene. However, the method represents complete positional selectivity because only the g-adduct radicals give reductive arylation products whereas the a-adduct radicals add to diazonium salts, because of the different nucleophilic character of the alkyl radical adduct. ... 

Thioketals are readily prepared by reaction of saturated 3-ketones with thiols or dithiols in the presence of boron trifluoride or hydrogen chloride catalysts. Selective protection of the 3-ketone in the presence of a 6-ketone is possible by carrying out the reaction in diluted medium. Similarly, 3-ketones react selectively with monothiols " " or with bulky dithiols in the presence of 6-, 7-, 11- and 12-ketones. 

Risaliti et al. (22), have shown that in the addition of the electrophilic olefins to the enamines of cyclohexanone, the formation of the less substituted enamine is favored when a bulky group is present at the electrophilic carbon atom. For instance, the reaction of (8-nitrostyrene with the morpholine enamine of cyclohexanone gave only the trisubstituted isomer (30) with the substituent in the axial orientation (23). The product on hydrolysis led to the ketone (31) to which erythro configuration was assigned on the grounds illustrated in Scheme 3 (24). 

Buchwtild and co-workers have developed highly aedve cattilysts consisting of bulky, electron-rich phosphine ligands v/ith a biphenyl backbone combined v/ith PdfOAci for the aryladon of ketones or niiroalkanes fEq 5 73 ... 

Now that the allylic oxidation problem has been solved adequately, the next task includes the introduction of the epoxide at C-l and C-2. When a solution of 31 and pyridinium para-tolu-enesulfonate in chlorobenzene is heated to 135°C, the anomeric methoxy group at C-l 1 is eliminated to give intermediate 9 in 80% yield. After some careful experimentation, it was found that epoxy ketone 7 forms smoothly when enone 9 is treated with triphenyl-methyl hydroperoxide and benzyltrimethylammonium isopropoxide (see Scheme 4). In this reaction, the bulky oxidant adds across the more accessible convex face of the carbon framework defined by rings A, E, and F, and leads to the formation of 7 as the only stereoisomer in a yield of 72%. 

With alkyl aryl ketones, it is the aryl group that generally migrates to the nitrogen, except when the alkyl group is bulky. The reaction has been applied to a few aldehydes, but rarely. With aldehydes the product is usually the nitrile (16-21). Even with ketones, conversion to the nitrile is often a side reaction, especially with the type of ketone that gives 17-31. A useful variation of the Schmidt reaction treats a cyclic ketone with an alkyl azide (RN3) in the presence of TiCU, generating a... 

Reaction of cyclic tetrasulfido complexes of heavier group 14 elements bearing bulky substituents such as Tbt(Ar)MS4 (M=Si, Ar=Tip M=Ge, Ar=Tip M=Sn, Ar=Ditp) with 3 equivalents of phosphines afforded the successful isolation of the first stable double-bonded compounds between heavier group 14 elements and sulfur atom (heavy ketones), Tbt(Ar)M=S, accompanied by the quantitative formation of the corresponding phosphine sulfides (Scheme 40) [13, 15, 112, 113]. On the other hand, their lead an-... 

Another method that has been used to prepare phosphaalkenes is the phos-pha-Peterson reaction, a phosphorus analog of the Peterson olefination [46-49]. In this reaction a lithium silylphosphide is treated with an aldehyde or ketone to yield the phosphaalkene (9). Analogous reactions can be conducted with bis(trimethylsilyl)phosphines (10) and ketones (11) using a catalytic quantity of anhydrous base (i.e., NaOH, KOH) [50]. Generally, the reactions proceed cleanly and in high yield. Sufficiently bulky substituents must be employed to stabilize the P=C bond and prevent rapid dimerization to 1,3-diphosphetaines. 

Scheme 1.1 shows data for the regioselectivity of enolate formation for several ketones under various reaction conditions. A consistent relationship is found in these and related data. Conditions of kinetic control usually favor formation of the less-substituted enolate, especially for methyl ketones. The main reason for this result is that removal of a less hindered hydrogen is faster, for steric reasons, than removal of a more hindered hydrogen. Steric factors in ketone deprotonation are accentuated by using bulky bases. The most widely used bases are LDA, LiHMDS, and NaHMDS. Still more hindered disilylamides such as hexaethyldisilylamide9 and bis-(dimethylphenylsilyl)amide10 may be useful for specific cases. 

A similar preference for formation of the syn aldol is found for other Z-enolates derived from ketones in which one of the carbonyl substituents is bulky. Ketone enolates with less bulky substituents show a decreasing stereoselectivity in the order r-butyl > i-propyl > ethyl.2c This trend parallels a decreasing preference for stereoselective formation of the Z-enolate. 

From these and many related examples the following generalizations can be made about kinetic stereoselection in aldol additions of lithium enolates. (1) The chair TS model provides a basis for analyzing the stereoselectivity observed in aldol reactions of ketone enolates having one bulky substituent. The preference is Z-enolate syn aldol /(-enolate anti aldol. (2) When the enolate has no bulky substituent, stereoselectivity is low. (3) Z-Enolates are more stereoselective than /(-enolates. Table 2.1 gives some illustrative data. 

The requirement that an enolate have at least one bulky substituent restricts the types of compounds that give highly stereoselective aldol additions via the lithium enolate method. Furthermore, only the enolate formed by kinetic deprotonation is directly available. Whereas ketones with one tertiary alkyl substituent give mainly the Z-enolate, less highly substituted ketones usually give mixtures of E- and Z-enolates.7 (Review the data in Scheme 1.1.) Therefore efforts aimed at increasing the stereoselectivity of aldol additions have been directed at two facets of the problem (1) better control of enolate stereochemistry, and (2) enhancement of the degree of stereoselectivity in the addition step, which is discussed in Section 2.1.2.2. 

Boron enolates can be prepared by reaction of the ketone with a dialkylboron trifluoromethanesulfonate (triflate) and a tertiary amine.16 Use of boron triflates and a bulky amine favors the Z-enolate. The resulting aldol products are predominantly the syn stereoisomers. 

Palladium-Catalyzed Arylation of Enolates. Very substantial progress has been made in the use of Pd-catalyzed cross coupling for arylation of enolates and enolate equivalents. This reaction provides an important method for arylation of enolates, which is normally a difficult transformation to accomplish.171 A number of phosphine ligands have been found to promote these reactions. Bulky trialkyl phosphines such as /n. v-(/-butyl)phosphinc with a catalytic amount of Pd(OAc)2 results in phenylation of the enolates of aromatic ketones and diethyl malonate.172... 

---