O-Alkyl Phenyl Ketones

Finally, pulse radiolysis has the advantage of being able to measure the kinetics of reactions, also in liquid solvents, where bimolecular reactions can be studied, with a time resolution down to tens of nanoseconds. It is with this technique, that the G bicki/Marcinek group in Lodz, who had previously applied it to follow the kinetics of the isomerizations of the Dewar benzene radical cation [8], was able to study the tunneling kinetics of the enolization of radical cations. 

We thus launched a program to explore the scope and limitations of such eno-lization reactions, by varying the steric constraints and influencing the electronic structure by substitution. We thereby encountered some interesting features that we had not expected, features from which we learned much about how these reactions occur. 

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FIGURE 15.3. Distribution data between water and sodium dodecyl sulfate micelles as a function of the solute McGowan volume for the entire database (a) and for categorized classes of solutes (b), data from Reference 25. Database labels in (a) as in Figure 15.2. (A) hexadecane-water partition data for alkanes, from Reference 16. Labels in (b) ( ) alkyl benzenes (O) alkyl phenyl ketones (A) alkyl phenols ( ) halo benzenes and ( ) halo phenols. 

Unlike in the case of photoenols, whose Z-conformations decay very rapidly back to the ketones by tunneling, exploratory quantum chemical calculations showed that this problem was not of concern in radical cations, as the enolization of o-alkyl phenyl ketone radical cations is exothermic by at least lOkcalmol", because the ionization energies of the o-quinoid enols are much lower than those of the aromatic ketones, as illustrated in Figure 4.1 for the example of o-methylbenzaldehyde. 

The photocyclization of o-alkoxy phenyl ketones to yield benzofuranols (57 and 58) represents one of the earliest example of 8-H-abstraction from the lowest n, n triplet Wagner et al. [18] have provided detailed photokinetic data studying the photocyclization of a variety of o-alkoxyphenyl ketones 56, and have revealed that quantum efficiency for cyclization for 56d was the lowest (0.023) and that for 56f the highest (1.00). The diastereoselectivity for cyclization of 56 was found to be higher in benzene and lower in polar solvents. From the estimated kH values (0.6-25 x 106 s 1), it was inferred that the low rate constant for 56e (8 x 106 s ) compared to that for 56g (25 x 106s 1) i s due to the alkyl chain in the alkoxy groups that points away from the o-carbonyl moiety in the most populated equilibrium conformations (Table 8.1). 

The thermolysis of o-azidostyrenes gives good yields of indoles. By this method 2-alkyl, 2-aryl and the relatively inaccessible 2-acylindoles have been prepared. (o-Azidostyryl) phenyl ketone (159) yielded 71% of 2-benzoylindole (160) Another indole synthesis utilizing... 

Since the rearrangement of benzoylalkyl radicals is unrelated to the production of resinous materials (instead of the anticipated dimers) in the acetyl peroxide - alkyl phenyl ketone reactions, we must look elsewhere for an explanation. Once we come to this conclusion the fact that acetophenone is isoelec-tronic with o-methylstyrene immediately becomes significant. That is, radical additions to the carbonyl oxygen of phenyl ketones will be facilitated by resonance stabilization of the adduct, just as is the case with a-methylstyrene or styrene, i.e. 

Various diorganozinc compounds (ZnR2 R = Me, Et, Pr, Pr1, Buc, Ph) reacted with o-quinones by two mechanisms, namely (i) a single-electron transfer from ZnR2 to the quinone to yield, after hydrolysis, alkyl(phenyl)oxyphenols, and (ii) a polar 1,2- and 1,4-addition of ZnR2 similar to those of conjugated ketones.201 Diorganozinc compounds with low ionization potentials favor a polar mechanism. 

Similar effects are also seen with enolates of simple ketones. For isopropyl phenyl ketone, the inclusion of one equivalent of 12-crown-4 in a DME solution of the lithium enolate changes the C/O-alkylation ratio from 1.2 1 to 1 3, with methyl sulfate as the alkylating agent.50 With methyl iodide as the alkylating agent, C-alkylation is strongly favored with or without 12-crown-4. 

A convenient route to 2-alkylthio-4-alkyl-4-hydroxy-5,6-dihydro-4/7-l,3-thiazine derivatives 176 is the reaction of A-alkyldithiocarbamates with a,/3-unsaturated ketones in the presence of boron trifluoride etherate at 0°C (Scheme 15) <2002HAC377>. The predominant diastereomer displayed a m-relationship between the hydroxyl group and the C-4 substituent. Subsequent dehydration led to two isomeric products 177 and 178 with an equilibrium mixture resulting in a ratio of 94 6 in the case of 2-benzylthio-4-hydroxy-4-methyl-5,6-dihydro-4/7-l,3-thiazine. 2-Phenyl-4-alkyl-4-hydroxy-5,6-dihydro-4/7-l,3-thiazine derivatives are similarly prepared by reacting thio-benzamide with o ,/3-unsaturated ketones at room temperature <2002EJP307>. 

Lithium enolates of phenyl esters (28) react with aldehydes or ketones to give O-lithiated phenyl 3-hydroxyalkanoates (29) which undergo spontaneous intramolecular cyclization to P-lactones (30) (95JOC758), Also, lithium enolates are used in the synthesis of 3-[l-(dialkylamino)alkyl]()-lactoncs (94JOC7994), which are precursors for a-oxo-P-lactones. 

Alkylation of ketones. Ketones are readily alkylated in the a-position on reaction with alkyl halides in the presence of 50% aqueous sodium hydroxide and catalytic amounts of benzyltriethylammonium chloride.19 The catalytic effect of the salt is particularly marked in the case of weakly active alkyl halides. Thus the reaction o phenylacetone with n-butyl bromide in the absence of catalyst gives 3-phenyl-2-heptanone in 5 % yield the yield is 90 % in the presence of the catalyst. Highest yields are obtained with ketones bearing an aromatic substituent at the a-CH2 group. 

The rearrangement reaction of a variety of alkyl phenyl ethers over a dealumi-nated HY zeolite has been shown to involve both intramolecular and intermolecular processes to afford phenol, (alkoxyalkyl)benzenes and alkylphenols as the main products. o-Benzylphenol has been obtained as the exclusive product in the rearrangement of benzyl phenyl ether in the presence of montmorillonite. The mechanism for a novel zeolite /3-catalysed rearrangement of alkoxybenzyl allyl ethers to aldehydes and ketones has been investigated by the use of cross-over reactions and deuterium labelling. The reaction was found to be mainly intramolecular and has been described as a nucleophilic attack of the double bond on the electrophilic benzylic carbon of the ether-Lewis acid complex, followed by a... 

Table 9.6. O versus C Alkylation for Phenyl Ketones in DMSO...

Complexes of lithium aluminium hydride with l,4 3,6-dianhydro- and 1,3 4,6-di-O-benzylidene-D-mannitol, each of which contains a two-fold axis of symmetry, have been used to achieve asymmetric reductions of some alkyl aryl and dialkyl ketones e.g. methyl or ethyl phenyl ketone and 3,3-dimethylbutan-2-one). All reductions with lithium l,4 3,6-dianhydro-D-mannitolatodihydridoaluminate(iii), using a 2 1 molecular ratio of ketone to reducing agent, gave the 5-enantiomer of the secondary alcohol preferentially (selectivity 1.1—5.3 %), whereas those of alkyl aryl ketones and dialkyl ketones gave more of the 5- and R-alcohols, respectively, when lithium l,3 4,6-di-0-benzylidene-D-mannitolatodihydridoaluminate(iii) was used. 

The a-methyltoluene-2,o -sultam auxiliary is also displaced by a variety of dilithiated alkyl phenyl sulfones. This unique procedure provides direct access to synthetically useful fi-o o sul-fones which may he further functionalized or simply subjected to reductive desulfonation to give alkyl ketones. A particularly striking use of this method is the preparation of p-oxo sulfone 8, a key intermediate in a concise synthesis of (—)-semicorole (eq 5). Remarkably, the MeCLi2S02Ph reagent attacks selectively the C(4)-imide C=0 group in preference to the C(6)-ester C=0 group and no epimerization occurs at C(3) or C(F). 

Figure 9.12. O- versus C-alkylation of isopropyl phenyl ketone. (See Jackman, L. M. Lange, B. C. J. Am. Chem. Soc., 1981,103, 4494.)...

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