Ketones unsymmetrical, alkylation

S)-Proline also catalyzed Mannich reactions of ketone donors in a three-component (donor ketone, 4-methoxyaniline, aryaldehyde) protocol, as shown in Table 2.16 [84b, 90, 91]. In these three component reactions, the C-C bond formation occurred at both a-positions of unsymmetrical alkyl ketones (entry 3), and the ratio of the regioisomers depended on the reactant ketones and aldehydes. When the reaction was performed using a ketone donor possessing an a-hydroxy or methoxy group, C-C bond formation occurred exclusively at the oxy-substituted a-carbon (entries 5-7) the major diastereomer was again the syn-product. The enantioselectivities of (S)-proline-catalyzed three-component... 

An enolizable position is always a, even if there are two of them as in an unsymmetrical alkyl ketone, while enolizable carbons may happen to have any number in simple lUPAC nomenclature such as C2 and C4 in the example above. 

Xanthenyliumsodium (from sodamide and xanthene) reacts with aziridines to give a mixture of 9-mono- (271) or 9,9-di-substituted xanthenes (272).Addition of perchloric acid to unsymmetric allenes such as the 9-xanthylidene derivative (273) (prepared by a new route from 9,9-dichloroxanthene and an alkene) gave a red xanthylium salt (274), which was converted into a colourless spiro-indene (275) on heating.Full details have now been published of the properties and of the reactions of 9-diazoxanthene (276) and 9-xanthylidene (278) with methyl acrylate, substituted styrenes, several ketones, and alkyl-benzenes. The kinetics of the reaction with styrenes were studied and the conversion of (276) into (278) was achieved by photolysis of the tosylhydrazone (277) at —25 °C. 

On the other hand, Ghosh and co-workers [48] found that when (silylmethylene) malonate was used as acceptor, excellent regio- and enantioselectivity could be obtained for the Michael reaction with unsymmetric alkyl methyl ketones. The combination of (5)-l-(2-pyrroIidmylmethyl)pyrrolidine 19 with trifluoroacetic (3 1) proved to be effective catalytic system for such reactions, and the silyl group is the key to this success (Scheme 5.24). To emphasize the synthetic utility of the products, further application in the synthesis O- and iV-heterocyclic natural products was reported by the same group [49]. 

The Stork variation was pioneered by Stork and co-workers in 1963. It entails the reaction of pyrrolidine or morpholine enamine derived from unsymmetrical cyclohexanones with methyl vinyl ketones. The alkylation is directed to the less substituted carbon opposite to the alkylation regioisomer formed by the standard Robinson annulation conditions. Cyclization to the corresponding octalone then occurs. The morpholine enamine is less reactive than the pyrrolidine and hence pyrrolidine enamine has been mostly used for this approach. An example of such annulation is shown in the s mthesis of 8-methyl-2-oxo-A octalone (19). The pyrrolidine enamine of 2-methylcyclo-hexanone is refluxed in benzene with MVK for 24 h followed by the addition of an acetate buffer and reflux for 4 h, and after the reaction is worked up purification gives 19 in 45% yield. 

Alkylation.—The use of the trimethylsilyl enol ether of a ketone in alkylation procedures is legion. Now such enol ethers have been shown to be obtainable from the ketone using ethyl trimethylsilylacetate and a catalytic amount of tetra-n-butylam-monium fluoride. At low temperatures the less-substituted enol ether is formed from unsymmetrical ketones with high selectivity. ... 

The palladium-catalyzed three-component cross-coupling reaction between organoboron compounds, carbon monoxide, and electrophiles represents a straightforward route to the synthesis of unsymmetrical ketones [93], Recently, new catalytic systems have opened up new opportunities [94], However, there are only sporadic results for the applications of this protocol to the synthesis of alkyl- and aryl-1-alkenyl ketones [95]. Alkyl-... 

Out first example is 2-hydroxy-2-methyl-3-octanone. 3-Octanone can be purchased, but it would be difficult to differentiate the two activated methylene groups in alkylation and oxidation reactions. Usual syntheses of acyloins are based upon addition of terminal alkynes to ketones (disconnection 1 see p. 52). For syntheses of unsymmetrical 1,2-difunctional compounds it is often advisable to look also for reactive starting materials, which do already contain the right substitution pattern. In the present case it turns out that 3-hydroxy-3-methyl-2-butanone is an inexpensive commercial product. This molecule dictates disconnection 3. Another practical synthesis starts with acetone cyanohydrin and pentylmagnesium bromide (disconnection 2). Many 1,2-difunctional compounds are accessible via oxidation of C—C multiple bonds. In this case the target molecule may be obtained by simple permanganate oxidation of 2-methyl-2-octene, which may be synthesized by Wittig reaction (disconnection 1). 

The haloform reaction of unsymmetrical perfluoroalkyl and co-hydroper-fluoroalkyl trifluororaethyl ketones gives the alkane corresponding to the longer alkyl chain [54] (equation 53) If the methyl group contains chlorine, the reaction can take different pathways, leading to loss of chlorine (equation 54), because of the variable stability of the chlorine-substituted methyl carbanions in alkali. 

The general rule has been formulated (P) that the less substituted enamine is formed from unsymmetrical ketones such as the 2-alkylcyclohexanones. In enamine 21 the R, group and the N-alkyl groups would interfere with one another if overlap is to be maintained between the nitrogen unshared electrons and the double bond. There would be less repulsion if the isomeric enamine (22) were formed. 2-Phenylcyclohexanone and pyrrolidine with p-toluenesulfonic acid as catalyst in refluxing benzene gave enamine... 

Addition to thioamides.s Alkyl- or aryllithiums add to the carbon-sulfur bond of aromatic thioamides to give adducts that are hydrolyzed to unsymmetrical ketones. Reduction of the adducts with LiAlHj before hydrolysis provides a-alkylated amines. 

FORMATION AND ALKYLATION OF SPECIFIC ENOLATE ANIONS FROM AN UNSYMMETRICAL KETONE 2-BENZYL-2-METHYLCY-CL0HEXAN0NE AND 2-BENZYL— 6-METHYLCYCLOHEXANONE, 52,... 

Electrogenerated bases (see Chap. 14) can be prepared in situ and tailored for regioselective deprotonation. Regioselective alkylation of an unsymmetrical cyclic ketone was achieved by using an electrogenerated triphenylmethyl anion (Eq. 5, RX = CH3I,... 

Apart from the electrocarbonylation reactions of organic halides described in Sect. 6, other Ni-catalyzed reactions leading to ketones have been reported. Thus the electroreductive coupling between acylchlorides and alkyl halides, catalyzed by NiBr2bpy leads to unsymmetrical ketones [129]. Recently acylchlorides have been converted to symmetrical ketones in an undivided cell fitted with a nickel or stainless steel anode. In this reaction the active metallic species... 

The metalation chemistry of the imidazoline system has received attention only recently, with the lithiation of l-benzyl-2-imidazoline being found to occur at the 2-position (90TL1767). Although the reactivity of the lithi-ated species with alkyl halides was poor, better results were achieved with disulfide and carbonyl electrophiles (90TL1767,90TL1771). The products formed by reaction with ketones were found to be unstable with respect to fragmentation, and this result was utilized to provide a new route for the synthesis of unsymmetric ketones (Scheme 138). 

Hydrazones can also be deprotonated to give lithium salts which are reactive toward alkylation at the j> carbon. Hydrazones are more stable than alkylimines and therefore have some advantages in synthesis.79 The / A Alimcthy I hydrazones of methyl ketones are kinetically deprotonated at the methyl group. This regioselectivity is independent of the stereochemistry of the hydrazone.80 Two successive alkylations of the A A -dimethylby-drazone of acetone can provide unsymmetrical ketones. 

Whereas branched ketimines are metalated at the less substituted carbon, metalation and alkylation of unsymmetric imines leads to regioisomers2,4,27. For this reason, only symmetrical ketones and unsymmctrical ketones with one substituent having no a-hydrogens have been applied in alkylation reactions via imines (see Table 4). 

Regioselectivity is not a problem in the metalation and alkylation of SAMP-hydrazones derived from aldehydes, symmetrical ketones and unsymmetrical ketones having one substituent without a-hydrogens. On the other hand, SAMP-hydrazones of unsymmetrical ketones react regioselectively at the less substituted carbon, regardless of the E/Z ratio of the starting hydrazone33. 

In cases involving unsymmetrical ketones (154) (R1 + CH3), the C-C bond formation occurs regiospecifically at the less substituted alkyl group in a-position to the carbonyl function. 

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