Substitution ketone preparation

AEyl chloride reacts with sodamide in Hquid ammonia to produce benzene when sodamide is in excess, hexadiene dimer is the principal product, with some trimer and tetramer (C24, six double bonds). AEylation at carbon atoms alpha to polar groups is used in the preparation of a-aEyl-substituted ketones and nittiles. Preparation of P-diketone derivatives, methionic acid derivatives, and malonic ester, cyanoacetic ester, and P-keto-ester derivatives, etc, involving substitution on an alpha carbon between two polar carbonyl groups, is particularly facEe. 

If cyclic ketones are monosubstituted in the a-position, their rates of reaction decrease as compared to the rate for the parent ketone (9,41). More highly substituted ketones (e.g., diisobutyl ketone, diisopropyl ketone) can be caused to react using newer preparative techniques (39,43,44, see Section VII). Monosubstituted acetones often can give selfcondensation products, but the recent literature (13,39,43) contains reports of the successful formation of the enamines of methyl ketones. 

Combination of nickel bromide (or nickel acetylacetonate) and A. A -dibutylnorephcdrinc catalyzed the enantioselective conjugate addition of dialkylzincs to a./Tunsaturated ketones to afford optically active //-substituted ketones in up to ca. 50% ee53. Use of the nickel(II) bipyridyl-chiral ligand complex in acetonitrile/toluenc as an in situ prepared catalyst system afforded the //-substituted ketones 2, from aryl-substituted enones 1, in up to 90% ee54. 

The less highly substituted Mannich bases can also be prepared directly from ketones and dimethyl(methylene)ammonium trifluoroacetate by the procedure reported here, which takes advantage of the isomerization of Mannich bases in trifluoroacetic acid. (In acetic acid the Mannich bases undergo elimination of dimethylamine to give a-methylene ketones.) This method is rapid and affords products having an isomeric purity of at least 90% without difficult separations. The 49-57% yield of l-(di-methylamino)-4-methyl-3-pentanone obtained with this procedure compares favorably with the overall yields of amino ketones prepared by the indirect routes mentioned previously. 

Prochiral aryl and dialkyl ketones are enantioselectively reduced to the corresponding alcohols using whole-cell bioconversions, or an Ir1 amino sulfide catalyst prepared in situ.695 Comparative studies show that the biocatalytic approach is the more suitable for enantioselective reduction of chloro-substituted ketones, whereas reduction of a,/ -unsaturated compounds is better achieved using the Ir1 catalyst. An important step in the total synthesis of brevetoxin B involves hydrogenation of an ester using [Ir(cod)(py) P(cy)3 ]PF6.696... 

The general method for the preparation of diphenylpyrazolines is shown in Scheme 11.8, in which X is a suitable leaving group, usually chloro but sometimes dialkylamino. This reaction normally proceeds readily, although pH control may be important. Preparation of the substituted ketone and hydrazine intermediates needed for the synthesis may involve lengthy and complicated sequences. Further reactions are often required to modify the substitution in ring B after formation of the pyrazoline ring. The preparation of compound 11.26 shown in Scheme 11.9 illustrates one of the simpler instances. 

Okamoto, Y. and Sakurai, H., Preparation of (dialkoxyphosphinyl)-methyl-substituted ketone alkyl trimethylsilyl acetal derivatives, Synthesis, 497, 1982. 

The formation of 3-aryl-substituted aldehydes and 3-aryl-substituted ketones by the reaction of arylpalladium salts with allylic alcohols is a general reaction.2 Illustrations of the preparation of two aldehydes and two ketones are given in Table I. 

The system iV-halosuccinimide-hydrogen fluoride/pyridine can be used to prepare geminal chlorofluoro-, bromofluoro-, and fluoroiodo-substituted ketones and esters from the corresponding diazo compounds.35... 

Preparation of 5a,6/3-dichloro-3/3-hydroxy-androst-14-en-17-one acetate, 363 Preparation and elimination of /3-substituted ketones, 304... 

Lithium hexamethyldisilazide, 165 Other a-substituted ketones p-(Tolylsulfinyl)methyllithium, 115 Methods to prepare some specific types of ketones Benzyl ketones... 

Prakash, Olah, and co-workers256 have prepared Mosher s acid analogs by the hydroxyalkylation of substituted benzenes with ethyl trifluoropyruvate [Eq. (5.95)]. Deactivated aromatics (fluorobenzene, chlorobenzene) required the use of excess triflic acid indicative of superelectrophilic activation.3 5 In contrast to these observations, Shudo and co-workers257 reported the formation gem-diphenyl-substituted ketones in the alkylation of benzene with 1,2-dicarbonyl compounds [Eq. (5.96)]. In weak acidic medium (6% trifluoroacetic acid-94% triflic acid), practically no reaction takes place. With increasing acidity the reaction accelerates and complete conversion is achieved in pure triflic acid, indicating the involvement of diprotonated intermediates. 

Given that the MPT precursor is an a-substituted ketone, it is not surprising that 1,2-enedithiolates can be prepared from this moiety. Biologically, this conversion likely involves the thiol carboxylate residues of MPT synthase and, presumably, a molybdenum or tungsten oxyanion. Chemically, several reagents have been used to facilitate a similar conversion (Figure 18) [70-72,164-166],... 

Under conditions of kinetic control, the mixed Aldol Addition can be used to prepare adducts that are otherwise difficult to obtain selectively. This process begins with the irreversible generation of the kinetic enolate, e.g. by employing a sterically hindered lithium amide base such as LDA (lithium diisopropylamide). With an unsymmetrically substituted ketone, such a non-nucleophilic, sterically-demanding, strong base will abstract a proton from the least hindered side. Proton transfer is avoided with lithium enolates at low temperatures in ethereal solvents, so that addition of a second carbonyl partner (ketone or aldehyde) will produce the desired aldol... 

Willow-like cascade construction was facilitated by the preparation of the AB2-type building blocks, e.g., 6-bromo-l-(4-hydroxy-4 -biphenylyl)-2-(4-hydroxyphenyl)hexane (40 Scheme 6.12), 13-bromo-l-(4-hydroxyphenyl)-2-[4-(6-hydroxy-2-naphthalenylyl)-phenyljtridecane (41), and 13-bromo-l-(4-hydroxyphenyl)-2-(4-hydroxy-4"-p-terpheny-lyl)tridecane (42). Scheme 6.12 illustrates the monomer preparative strategy for the incorporation of the monomeric mesogenic moieties predicated on conformational (gauche versus anti) isomerism. Thus, one equivalent of 4-hydroxybiphenyl was allowed to react with 1,4-dibromobutane to yield the monobromide 43, which was converted under Finkelstein conditions to the corresponding iodide 44. Treatment of the latter with ketone 45 under phase transfer conditions afforded the a-substituted ketone 46. Reduc-... 

In the preparation of enamines from a-substituted ketones, e.g. 2-alkylcyclohexanones, the less-substituted enamine is always formed because of steric interactions77. This makes possible the introduction of a... 

Ester-substituted ketone enolates are stabilized, and these enolates can be alkylated (ace-toacetic ester synthesis). Alkylation is, however, also possible for enolates that are not stabilized. In the case of the stabilized enolates, the alkylated ketones are formed in two or three steps, while the nonstabilized enolates afford the alkylated ketones in one step. However, the preparation of nonstabilized ketone enolates requires more aggressive reagents than the ones employed in the acetoacetic ester synthesis. 

Alternative one-pot [4+2] cycloadditions producing highly-substituted pyridines have also been reported. For example, a practical and effective procedure adaptable to preparative scale utilizes silica gel to facilitate the elimination-aromatization of dihydropyridines, as shown below <07SL2217>. Substituted and unsubstituted 1,2,4-triazines 21 react with enamines, derived from pyrrolidine 22, and substituted ketones 23, to form highly substituted pyridines 24 in good to excellent yields. 

Reduction of a-silyloxy ketones. a-Hydroxy ketones are reduced by zinc boro-hydride with the expected anf/-selectivity, the extent of which varies somewhat with the substitution pattern. Preparation of the isomeric, v /i-diols can be effected by reduction of the a-r-butyidiphenylsilyloxy ketones with SMEAH in toluene at —78° followed by desilylation (equation I). Again, the selectivity varies with the nature of R and R-, and is low when R is a bulky alkyl group. 

Enantioselective Reduction of Aromatic Ketones. Aromatic substituted ketones and a-halo ketones are reduced by (EtO>3 SiH with good enantioselectivity in the presence of bis-oxazoline titanium complex [Ti(ciY-DiPh-Box)2F2], prepared from chiral bis-oxazoline, BuLi, and Tip4 (eq 4). 

FePc-derivatives (95) prepared from TCB and FeCl3 in ethylene glycol as mentioned before were used as electron transfer carriers for the reduction of a-substituted ketones and others with l-benzyl-l,4-dihydronicotinamide or benzenethiol (Eq. 50) -. ... 

A variety of a-substituted ketones (a-halo, -hydroxy, -methoxy and -amino) have been converted into alkenes by reductive elimination. Obviously, this approach, depends not only on the feasibility of a-functionalization but also on the ability to introduce the a-substituent regioselectively. a-Halo ketones, which are readily prepared from the starting ketone," have been subjected to reductive elimination conditions to afford the desired alkenic products. For example, in the preparation of ( )-eriolanin (Scheme 5)," the protected dihydroxy keto ester is treated sequentially with LDA and Br to afford the a-bromo... 

---