Positional selectivity alkylation

Shape selective catalysts, such as ZeoHtes of the H-ZSM-5 type, are capable of directing alkyl groups preferentially to the para position (18). The ratio of the catalyst to the substrate also plays a role ia controlling the regiochemistry of the alkylations. For example, selective alkylation of anilines at the para position is achieved usiag alkylatiag ageats and AlCl ia equimolar ratio (19). 

In 1957 a procedure was described that selectively alkylated phenol in the ortho position (7). This approach, using aluminum catalysis, made a variety of 2,6-dialkylphenols accessible. The mechanism proposed for this ortho alkylation is outlined as follows ... 

Other limitations of the reaction are related to the regioselectivity of the aryl radical addition to double bond, which is mainly determined by steric and radical delocalization effects. Thus, methyl vinyl ketone gives the best results, and lower yields are observed when bulky substituents are present in the e-position of the alkene. However, the method represents complete positional selectivity because only the g-adduct radicals give reductive arylation products whereas the a-adduct radicals add to diazonium salts, because of the different nucleophilic character of the alkyl radical adduct. ... 

Table 10.9. Substrate and Position Selectivity in Friedel-Crafts Alkylation Reactions...

One other feature of the data in Table 10.10 is worthy of further comment Notice that alkyl substituted acylium ions exhibit a smaller ortho para ratio than the various arpyl systems. If steric factors were dominating the position selectivity, one would expect the opposite result A possible explanation for this feature of the data could be that the aryl compounds are reacting via free acylium ions, whereas the alkyl systems may involve more bulky acyl chloride-catalyst complexes. 

Low substrate selectivity accompanying high positional selectivity was also found in isopropylation of a range of alkyl and halogenobenzenes by /-propyl bromide or propene in nitromethane, tetramethylene sulphone, sulphur dioxide, or carbon disulphide, as indicated by the relative rates in Table 86. The toluene benzene reactivity ratio was measured under a wide range of conditions, and varied with /-propyl bromide (at 25 °C) from 1.41 (aluminium chloride-sulphur... 

In addition to DBT and BT, strain A11-2 could utilize methyl, dimethyl, and trimethyl DBTs as sulfur sources. The desulfurization of asymmetric alkylated DBTs was assessed to understand the sulfur specificity of this organism. It was shown to desulfurize several asymmetric alkyl DBTs up to C3-DBTs. It was shown that the rates of desulfurization depended on not only the position of alkyl substitution but also the number and length of alkyl substitution. An attempt was made to co-relate the data based on a molecular shape parameter. Selectivity of this organism was compared with R. erythropolis KA2-5-1 and, although clear differences were observed, the parameter fitting was not perfect. Two Paenibacillus strains, Paenibacillus sp. A11-1 and All-2, were patented [87] and were deposited as PERM BP-6025 and PERM BP-6026 in 1996 [122,123],... 

The addition to a double bond is observed in aromatic substrates where the reaction is assisted by chelation. The initial success of such reactions was achieved with the double alkylation of phenol with ethene (Equation (2)).1 This reaction occurs at the or/ -positions selectively by using an orthometallated ruthenium phosphate complex 1. 

A major limitation of these alkylation reactions has been the regiospecificity and/or need for directing groups of the nucleophile. MacMillan has overcome this and expanded the scope of the reaction to include alkene nucleophiles by using trifluoroborate salts (Scheme 18) [87]. This approach enables alkylation of the 2-position of indoles, complimenting the 3-selective alkylation shown in Scheme 16. One equivalent of hydrogen fluoride was found to be necessary in the reaction in order to sequester the boron trifluoride generated. 

Since aprotio sites in the zeolites under study were generated via ion exchange of protons inside crystal volume, the aprotio sites formed are also situated inside crystals. In connection with this, a position selectivity of primary alkylation must be influenced by structural restrictions which are put on the ti nsition state by ZSM-5 type zeolite. Hence, as follows from refs.[6,7], para-isomer must be a primary product of alkylation. Taking into account these ideas,the schemes of the main routes of investigated reactions are accepted (Jigs. 1,2). As seen from the schemes, the pathways of both reactions are practically the same. The only difference is that in the case of ethylbenzene alkylation proceeds... 

Alkylation at the 2-position can be achieved by formation of the anion with sodium hydride in 1,2-dimethoxyethane (DME) at 0°C followed by reaction with an alkyl halide at room temperature. Alternatively, selective alkylation at C-4 Involves sequential treatment with sodium hydride (at 10°C) and butyllithlum in DME (at -40°C) to form the dianion, followed by kinetic alkylation with an alkyl halide (or carbonyl compound). ... 

An improved procedure for the selective alkylation of 2,4-quinazolinediones at the 1-position via the 2,4-bistri-methylsilyloxy derivatives has been developed <20030PD700>. This procedure enabled a large-scale synthesis of the aldose reductase inhibitor FK366 28 from the bistrimethylsilyloxy quinazoline 27 (Scheme 2). 

With 2,4-dimethyl-pyridine and -quinoline it is possible to achieve selective alkylation or acylation at either position. Although it might be expected that the greater acidity of... 

Dewar,120 as well as Brown and Olah, respectively, raised the importance of initial n complexing of aromatics in alkylations.109121 Relevant information was derived from both substrate selectivities (usually determined in competitive alkylations of benzene and toluene, or other alkylbenzenes), and from positional selectivities in the alkylation of substituted benzenes. Olah realized that with reactive alkylating agents substrate and positional selectivities are determined in two separate steps. 

Regiocontrol in these useful reactions is achieved by a careful selection of alkylation or acylation reagent, base, nucleophile, solvent, and reaction temperature. Reactions of oxyazolium salts are useful for regioselective introduction of substituents both at ring positions and at lateral positions. The alkylation or acylation followed by reaction with nucleophile, base, or... 

Selective alkylation of the y position of a,/3-unsaturated esters, aldehydes, or ketones can be achieved if a sterically demanding Lewis acid is used to coordinate to the carbonyl group and inhibit a-alkylation by steric shielding [123, 125, 126] (Scheme 5.11). This method not only results in high regioselectivity but also enables highly stereoselective aldol-type additions to be performed in good yields, even with sensitive substrates, such as a,/3-unsaturated aldehydes [126]. Thus, when two dia-stereotopic y positions are available, the addition of a bulky aluminum phenolate leads to the clean formation of the Z-alkene (second and third examples, Scheme 5.11). 

Comparison of results from the gas-phase proton-induced unimolecular isomerization of (R)- -d -3-(p-fluorophcnyl )bulanc (11) with the positional selectivity of the corresponding gas-phase bimolecular arene alkylation confirms the presence of non-covalent j-type intermediates and their important role in determining the intramolecular selectivity of gas-phase electrophilic aromatic substitutions.20... 

The ruthenium-catalyzed addition of C-H bonds in aromatic ketones to olefins can be applied to a variety of ketones, for example acetophenones, naphthyl ketones, and heteroaromatic ketones. Representative examples are shown in the Table 1. Terminal olefins such as vinylsilanes, allylsilanes, styrenes, tert-butylethy-lene, and 1-hexene are applicable to this C-H/olefin coupling reaction. Some internal olefins, for example cyclopentene and norbornene are effective in this alkylation. The reaction of 2-acetonaphthone 1 provides the 1-alkylation product 2 selectively. Alkylations of heteroaromatic ketones such as acyl thiophenes 3, acyl furans, and acyl pyrroles proceed with high yields. In the reaction of di- and tri-substitued aromatic ketones such as 4, which have two different ortho positions, C-C bond formation occurs at the less congested ortho position. Interestingly, in the reaction of m-methoxy- and m-fluoroacetophenones C-C bond formation occurs at the congested ortho position (2 -position). 

Hydroxypyridines are readily alkylated under a variety of conditions. Mitsunobu reaction with alcohols occurs selectively at oxygen in the presence of PPh3 and DEAD in THF at room temperature <2003TL725>. The 3-hydroxy group may be selectively alkylated in the presence of aliphatic hydroxyl groups. Pyridine 104 is alkylated at the aromatic position with dodecyl bromide in the presence of potassium carbonate in DMF at 95 °C <20030BC644> (Equation 70). 

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