Alkylation, -hydroxyketones

The 1,6-difunctional hydroxyketone given below contains an octyl chain at the keto group and two chiral centers at C-2 and C-3 (G. Magnusson, 1977). In the first step of the antithesis of this molecule it is best to disconnect the octyl chain and to transform the chiral residue into a cyclic synthon simultaneously. Since we know that ketones can be produced from add derivatives by alkylation (see p. 45ff,), an obvious precursor would be a seven-membered lactone ring, which is opened in synthesis by octyl anion at low temperature. The lactone in turn can be transformed into cis-2,3-dimethyicyclohexanone, which is available by FGI from (2,3-cis)-2,3-dimethylcyclohexanol. The latter can be separated from the commercial ds-trans mixture, e.g. by distillation or chromatography. 

Amidines and related systems such as guanidines react with a-halogenoketones to form imidazoles. a-Hydroxyketones also take part in this reaction to form imidazoles, and a variety of substituents can be introduced into the imidazole nucleus by these procedures. Reaction of the a-halogenoketone (73) with an alkyl- or aryl-substituted carboxamidine (76) readily gave the imidazole (77) (01CB637, 48JCS1960). Variation of the reaction components that successfully take part in this reaction process is described in Chapter 4.08. 

Although these reactions are thus closely related to the acyl-alkyl diradical disproportionation to ketenes, the stereospecificity of (55) -> (56) and (57) -> (58) shows that these hydroxyketones cannot proceed through free radicals capable of rotating about single bonds prior to the intramolecular hydrogen... 

The well established chemistry of acyclic secondary-alkyl peroxides 12> suggested that bases should catalyse the isomerization of related bicyclic peroxides to cyclic hydroxyketones 62 via abstraction of bridgehead hydrogen and heterolysis of the peroxide bond (Eq. 48). 

Hydride and 1,2-alkyl shifts represent the most common rearrangement reactions of carbenes and carbenoids. They may be of minor importance compared to inter-molecular or other intramolecular processes, but may also become the preferred reaction modes. Some recent examples for the latter situation are collected in Table 23 (Entries 1-10, 15 1,2-hydride shifts Entries 11-15 1,2-alkyl shifts). Particularly noteworthy is the synthesis of thiepins and oxepins (Entry 11) utilizing such rearrangements, as well as the transformations a-diazo-p-hydroxyester - P-ketoester (Entries 6, 7) and a-diazo-p-hydroxyketone -> P-diketone (Entry 8) which all occur under very mild conditions and generally in high yield. 

The 1,3-dipolar addition to terminal alkenes of nitrile oxides, generated from nitromethylene derivatives of bicycloheptane, provides 9,ll-ethano-13,15-isoxazolinoprostanoids, PGH analogs, with alkyl, phenyl, or additional heterocyclic fragment in the oo-chain (461). Chemical transformations of 9,11-ethano-13,15-isoxazolinoprostanoids furnish prostanoids with bifunctional fragments of P-hydroxyketone and a-aminoalcohol in the oo-chain. The reaction of P-hydroxy ketones with methanesulfonyl chloride gives rise to prostanoids with an enone component in the oo-chain. 9,ll-Ethano-16-thiaprostanoids have been prepared, for the first time, by nucleophilic addition of thiols to the polarized double bond in the oo-chain. The 1,3-dipolar addition to terminal alkenes of nitrile oxides, generated from nitromethylene derivatives of bicycloheptane provides 9,ll-ethano-13,15-isoxazolinoprostanoids with an alkyl, phenyl, or additional heterocyclic fragment in the oo-chain (462). 

Regiospecific and enantioselective aldol reactions 168) were also performed with SAMP (137). Lithiated hydrazones obtained from ketones (154) as described above were alkylated with carbonyl compounds and the adducts then treated with chloro-trimethylsilane. The resulting trimethylsilylethers (155) were finally oxidatively hydrolyzed to yield the chiral (3-hydroxyketones (156) (e.e. = 31-62%)168),... 

Skraup quinoline synthesis, 443 Smiles rearrangement, phenothiazine, 534 Spiroalkylation, 222, 280 Spirocyclization, conjugate addition, 386 Spiroimidazolone formation, 335 Spiropyrazolopiperidine, 375 Stannylation, alkyne, 15 Stereoselective dehydration, 198 Grignard addition, 198, 199 reduction, 129, 226 hydroxyketone, 400 iminoketone beta, 553 oxazaborohydride, 585 transfer chirality, 321 Stilbene formation, self alkylation, 525 Stobbe condensation, benzophenone, 103... 

These studies have been extended by Pearson et al. (1993a,b), who showed that a number of metabolites contribute to protein binding in addition to 2-bromoacrolein. The major metabolic pathw ay leading to protein binding is C-2 oxidation of the 2,3-dibromo-propyl groups, giving a reactive a-bromoketone which might either alkylate proteins directly or be hydrolysed to bis(2,3,-dibromopropyl) phosphate and an a-bromo-a -hydroxyketone w hich could mediate the alkylation of protein. 

The Perkin reaction makes available Bz-alkyl Bz-hydroxyketones, which are difficult or impossible to obtain by other methods.799-801 It also applies in the field of furocoumarins 2-isopropylpsoralene (363), a... 

Several of the above approaches have proved appropriate for the preparation of alkylated derivatives whilst related but somewhat modified chemistry is required for other substituted compounds routes depicted in Scheme 24 are examples of methods for the preparation of alkoxy derivatives (47JA2449). Compounds such as 2-hydroxyketones and 2-mercap-toketones dimerize reversibly to give 2,5-dihydroxy derivatives of 1,4-dioxanes and 1,4-dithianes respectively (B-57MI22600, 66HC(21-2)104l). 

Experimental procedures are given in Expt 6.107 for o- and p-hydroxy-propiophenones (R = Et). The ortho-para ratio in the product is influenced by the nature of the alkyl residue, the temperature, the solvent and the amount of aluminium chloride used generally low temperatures favour the formation of p-hydroxyketones. It is usually possible to separate the two hydroxyketones by fractional distillation under reduced pressure through an efficient fractionating column or by steam distillation the ortho isomers, being chelated, are more steam volatile. It may be mentioned that Clemmensen reduction (cf. Sections 5.1.3, p. 476 and 6.1.1, p. 826) of the hydroxyketones affords an excellent route to alkyl phenols. 

The bimolecular reductive coupling of carboxylic esters by reaction with metallic sodium in an inert solvent under reflux gives an a-hydroxyketone, which is known as an acyloin. This reaction is favoured when R is an alkyl. With longer alkyl chains, higher boiling solvents can be used. The intramolecular version of this reaction has been used extensively to close rings of different sizes, e.g. paracyclophanes or catenanes. 

Although significant improvements have been made in the synthesis of phenol from benzene, the practical utility of direct radical hydroxylation of substituted arenes remains very low. A mixture of ortho-, meta- and para-substituted phenols is typically formed. Alkyl substituents are subject to radical H-atom abstraction, giving benzyl alcohol, benzaldehyde, and benzoic acid in addition to the mixture of cresols. Hydroxylation of phenylacetic acid leads to decarboxylation and gives benzyl alcohol along with phenolic products [2], A mixture of naphthols is produced in radical oxidations of naphthalene, in addition to diols and hydroxyketones [19]. 

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]. 

Alkyl iodides upon oxidation by BTI in presence of lithium perchlorate afforded alkyl perchlorates in a reaction where trifluoroacetate competed with perchlorate [55] a-iodoketones were directly converted into a-hydroxyketones [56]. This transformation gave better yields than an analogous hydroxylation of ketones directly with BTI (Section 4.2). 

The desymmetrization of 2-alkyl-1,3-diketones to the corresponding chiral hydroxyketones was also successfully achieved with the same catalyst system. For example, 2-methyl-l,3-diphenyl-l,3-propanedione was reduced with an equimolar amount of NaBH4 together with THFA and ethanol in the presence of 0.05 equivalents of (R,R)-15 to afford (lk,2S)-2-methyl-3-oxo-1,3-diphenyl-propane (anti syn=99 l) in 99% ee (Scheme 10) [55], 2-Allyl- and 2-benzyl-sub-... 

Maycock has recently reported the use of an optically pure 2-alkyl-2-acyl-l,3-dithiolane 1-oxide to synthesize optically active a-hydroxyketone derivatives.83 The acyl dithiolane 1-oxide was prepared by an enantioselective sulfoxidation procedure. Interestingly, Maycock has recently reported enhanced diastereo- and... 

In the reaction of y-hydroxyketones 453 or e-hydroxyketones" with DCC, cyclic products 454 are obtained resulting from intramolecular alkylation. 

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