C-Alkylation selective

A new perspective for safe and highly selective mono-N-and mono-C-alkylations Selective Mono-Methylation of Arylacetoni-triles and Methyl Arylacetates by Dimethylcarbonate... 

Studying alkylations, we developed a series of selective ionic alkylating agents. Although Meerwein s trialkyloxonium and dialkoxycar-benium salts are widely used as transfer alkylating agents, they lack selectivity and generally are incapable of C-alkylation. 

Selectivity, Steering of reaction directions by the type of catalyst cation, eg, O- vs C-alkylation (7), substitution vs dibalocarbene addition (8), as weU as enantioselective alkylations by optical active catalysts (9) have been achieved in some systems. Extensive development is necessary, however, to generate satisfactorily large effects. 

C-alkylation of secondary and tertiary aromatic amines by hexafluoroacetone or methyl trifluoropyruvate is performed under mild conditions [172] (equation 147) The reaction of phenylhydrazme with hexafluoroacetone leads selectively to the product of the C-hydroxyalkylation at the ortho position of the aromatic ring The change from the para orientation characteristic for anilines is apparently a consequence of a cyclic transition state arising from the initial N hydroxy alky lation at the primary amino group [173] (equation 148)... 

The selectivity 3,0 is strongly dependent on the Mg content (Fig. 4). It increases with Mg concentrations up to 7 5%, passing through a maximum of S3.0 = 0.65. 3-methyl catechol becomes the main product at low conversion. It is worthwhile to note that only the relative formation of guaiacol and 3-methyl catechol are affected by the percentage of Mg added to alumina, 0-alkylation is reduced in favour of C-alkylation, but the ring methylation stays preferentially ortho-selective. 

The solvent can also affect regioselectivity. Consider O- vs C-alkylation of phenoxide ion with allyl chloride or bromide. In water, with allyl chloride the O- to C-alkylation ratio is 49 41 with phenol as a solvent it is 22 78 with methanol, dimethylformamide, and dioxane 100% O-alkylation is achieved. The selective solvation of the more electronegative O by the more protic solvents perhaps leads to some C-alkylations. 

By decreasing the GHSV values, the selectivity dramatically decreased due to the presence of the side-reaction of C-alkylation on the aromatic ring, giving rise to relevant amounts of 3-MC and a not-fully-identified methyl-MDB derivative (however, the 3-methyl isomer is the most probable candidate). Lastly, the lowest GHSV value was conducive to the condensation of PYC, with a formation of heavy by-products, a dramatic decrease of C-balance, and resulting catalyst deactivation. 

The effect of HMPA on the reactivity of cyclopentanone enolate has been examined.44 This enolate is primarily a dimer, even in the presence of excess HMPA, but the reactivity increases by a factor of 7500 for a tenfold excess of HMPA at -50° C. The kinetics of the reaction with CH3I are consistent with the dimer being the active nucleophile. It should be kept in mind that the reactivity of regio- and stereoisomeric enolates may be different and the alkylation product ratio may not reflect the enolate composition. This issue was studied with 2-heptanone.45 Although kinetic deprotonation in THF favors the 1-enolate, a nearly equal mixture of C(l) and C(3) alkylation was observed. The inclusion of HMPA improved the C(l) selectivity to 11 1 and also markedly accelerated the rate of the reaction. These results are presumably due to increased reactivity and less competition from enolate isomerization in the presence of HMPA. 

Owing to the predominance of the less-substituted enamine, alkylations occur primarily at the less-substituted a-carbon. Synthetic advantage can be taken of this selectivity to prepare 2,6-disubstituted cyclohexanones. The iminium ions resulting from C-alkylation are hydrolyzed in the workup procedure. 

Mg/Me (Me=Al, Fe) mixed oxides prepared from hydrotalcite precursors were compared in the gas-phase m-cresol methylation in order to find out a relationship between catalytic activity and physico-chemical properties. It was found that the regio-selectivity in the methylation is considerably affected by the surface acid-basic properties of the catalysts. The co-existence of Lewis acid sites and basic sites leads to an enhancement of the selectivity to the product of ortho-C-alkylation with respect to the sole presence of basic sites. This derives from the combination of two effects, (i) The H+-abstraction properties of the basic site lead to the generation of the phenolate anion, (ii) The coordinative properties of Lewis acid sites, through their interaction with the aromatic ring, make the mesomeric effect less efficient, with predominance of the inductive effect of the -O species in directing the regio-selectivity of the C-methylation into the ortho position. 

Selectivity parameters can be used to compare the catalytic performance of the different catalysts, and to find relationships between catalysts performance and physico-chemical features. Specifically, the following parameters were chosen (a) the O/C-methylation ratio, that is the ratio between the selectivity to 3-MA and that to 2,3-DMP+2,5-DMP+3,4-DMP (b) the ortho/para-C-alkylation ratio, that is the ratio between the selectivity to 2,3-DMP+2,5-DMP and the selectivity to 3,4-DMP (c) the 2,5-DMP/2,3-DMP selectivity ratio. Table 2 compares these parameters for MgO, Mg/Al/O and Mg/Fe/O catalysts. Data were reported at 30% m-cresol conversion, thus under conditions of negligible consecutive reactions. In this way it is possible to compare the ratio of the sole parallel... 

The present work deals with the study of the liquid phase phenol alkylation by (-butanol over the three types of catalysts derived from MWW-precursor MCM-22, MCM-36 and ITQ-2. It was assumed that by pillaring and/or delamination the contribution of acid sites located on the hemicages will increase and it could be evidenced during the alkylation of phenol by (-butanol, process involving large reaction intermediates and products which are difficult to be accommodated within sinusoidal channels. The reaction pathway involves many parallel and/or successive steps, the main reactions being O-alkylation and C-alkylation. The catalytic activity and selectivity of these materials are discussed. A general scheme of the process is proposed on the basis of the structural and acidic features of the catalysts. 

Another problem with the reaction of phenols with aziridines is the selectivity between O-alkylation vs C-alkylation. A recent report has identified that the use of (ArO)3B selects for C-alkylation <06OL2627>. Most of the examples reported in this paper showed less than 5% of the O-alkylation product. What is interesting about this report is the stereochemistry of the product. While the mechanism is not known, the product is formally an SNl type product. Generally less than 5% was the product of inversion of configuration (the Sn2 product). In addition to the A-tosyl, both the A-Cbz and A-Dpp aziridines gave excellent yields of aziridine-opened product. 

Pyridones were studied for N- and C-alkylation reactions by de la Hoz et al. [100] as already mentioned for 1,2,4 triazoles, the selectivity of the alkylation is highly dependent on the activation technique (microwave or conventional heating). 

Selective C-alkylation of the Na[CH(N02)SC>2Ph] salt with l-chloro-3-iodo-propane (Eq. 2) followed by cyclization of product (39b) was documented (70). 

Alkylation of P-dicarbonyl compounds and p-keto esters occurs preferentially on the carbon atom, whereas acylation produces the 0-acyl derivatives (see Chapter 3). There are indications that C- and 0-alkylated products are produced with simple haloalkanes and benzyl halides, but only C-alkylated derivatives are formed with propargyl and allyl halides [e.g. 90]. Di-C-alkylation frequently occurs and it has been reported that the use of tetra-alkylammonium 2-oxopyrrolidinyl salts are more effective catalysts (in place of aqueous sodium hydroxide and quaternary ammonium salt) for selective (-90%) mono-C-alkylation of p-dicarbonyl compounds [91]. 

C). The substrate is deprotonated [pK(PhCH2COOMe) 22.7] and trapped by an alkyliodide (—78°C). This procedure leads selectively to mono a-alkylation (81-99%) [103]. Selective monoalkylation of 8-diketones in 70 to 95% yield was obtained by a similar procedure, and only in a few cases (bulky secondary alkylhalides) were the O-alkylated substrate found as a side product. Tetraalky-lammonium counter cations were necessary in stabilizing the enolate Na+ counter cations did not give selective C-alkylation [104]. 

Nieuwstad, Klapwijk, and van Bekkum (105) have added to the knowledge of aromatic hydrogenation by their study of the influence of alkyl substituents in the 1 and 2 positions of naphthalene on the rate. Tetrahydro-naphthalenes were the products of hydrogenation over palladium at 80°C. The selectivity of the reaction was also followed and expressed as the ratio of the rate constants for the saturation of the unsubstituted and substituted rings, respectively. Steric effects play an important role, and, beside steric hindrance by the bulky substituents, steric acceleration also has been observed, the latter being caused by a release of the strain between the 1-alkyl group and hydrogen in position 8. 

---