Side-chain reactions alkylation

Side-chain anionic alkylation reactions with aromatic compounds take place when cataly2ed with strong basic catalysts, like Na—K (228). The yield is 83% when o-xylene reacts with butadiene... 

Chlorine molecules are cleaved at high temperatures by photoinduced radical formation. By this means, a gas/liquid reaction can be performed in the side chain of alkyl aromatics quite selectively. The electrophilic ring substitution, instead, is favored using Lewis catalysts in polar solvents at low temperature. 

The Selectivity Relationship was shown to be applicable for substitution in the meta and para positions of toluene (Section II). The fine adherence of the -methyl group to a linear free-energy relationship (Fig. 37) is apparently typical of the behavior of the other alkyl substituents, as illustrated for the p-ethyl, p-i-propyl, and p-t-butyl groups (Figs. 38-40). Indeed, the data for electrophilic substitution in toluene are better correlated by a linear relationship than are the data for ordinary side-chain reactions of p-tolyl derivatives (Stock and Brown, 1959a). In the Extended Selectivity Treatment (Fig. 25) the side-chain reactions show a slightly greater scatter from the correlation line than the aromatic substitution reactions. 

A material such as Na°/NaY catalyzes the aldol condensation of acetone, to form mesityl oxide and eventually isophorone. Another strong base catalyzed reaction is the side chain alkylation of toluene with ethylene. In contrast with acid catalysis, side chain reaction is strongly preferred over ring alkylation. With a Na°/NaX in the gas phase at 473 K, toluene reacts to give n-propylbenzene (66%) and the dialkylated product, 3-phenylpentane (32%) (41). 

Alkylation and acylation of pteridinones, pteridinethiones and pteridinamines have been considered in Section 7.3.1.4.3. as either (or both) ring nitrogen and side-chain reactions can occur. 

Geometrical constraints associated with intramolecular hydrogen transfer reactions can also be exploited to accomplish side chain reactions of amino acid derivatives, in some cases via radicals that would not be formed through inter-molecular processes. Photolytic reactions of A -phthaloyl and A -halo amino acid derivatives have been used in this manner [8, 37]. For example, the chloroamides 38 and 40 reacted to give the corresponding alkyl chlorides 39 and 41. In these reactions, the regioselectivity of chlorination is determined by the preference for intramolecular... 

On account of their increased ease of substitution, alkylphenols readily afford side-chains containing alkyl substituents having oxy, oxo or aikoxycarbonyl groups as shown by the examples given in Table 6.5 (refs.74-78). Frequently these reactions have been mediated by titanium tetrachloride or even by a phenoxymagnesium halide. 

However, another type of reactions of benzene derivatives was studied by in-situ IR spectroscopy as well, viz. the side-chain alkylation of alkylbenzenes, for instance of toluene, over basic zeolite catalysts such as M -X zeolites (M=Na, K, Rb, Cs) [901,902]. The intermediate conversion of methanol to formaldehyde turned out to be crucial for the side-chain alkylation as well as a strong polarization of the methyl group of toluene, the preferential adsorption of toluene, and a sufficient basicity, i.e., base strength of the catalyst. Related to these IR studies of side-chain alkylation of toluene were in-situ IR spectroscopic investigations of the decomposition of methanol over basic zeolites (M+-X, M =Na+, K+, Rb, Cs+ Na-ZSM-5 and Cs-ZSM-5 [903]). It was shown that over weakly basic zeolites (Na-ZSM-5, Cs-ZSM-5) dimethyl ether was formed from methanol, whereas over more strongly basic X-type zeolites formaldehyde was produced, which is an indispensable intermediate for the side-chain reaction (vide supra). 

Reactions via 2-pyridone dianions Side chain a-alkylation... 

The substitution reactions of aromatic rings and the reactions of the side chains of alkyl-and alkenylbenzenes, when taken together, offer us a powerful set of reactions for organic synthesis. By using these reactions skillfully, we shall be able to synthesize a large number of benzene derivatives. 

Patterson and Fried [139] inserted the a-side chain by alkylation of a cyclo-pentatone enol ether. Intermediate (127) was first obtained by reaction of cyclopent-2-enone with an organocopper reagent followed by formation of the silyl enol ether and the a-chain then added by alkylation of 127 with c/s-7-bromooct-5-enoate, thus leading to ( )-l l-deoxy-PGE2 methyl ester. 

When stirred in toluene under oxygen with solid potassium hydroxide and PEGMe, 4-nitrotoluene couples to the bibenzyl and styrene products. This coupling does not proceed by a direct reaction of the 4-nitrobenzyl radicals. Sonication increases the conversion rate and yield and more importantly, leads to a different chemical evolution with the formation of 4-nitrobenzoic acid. This sonochemical switching cannot be fully interpreted in the absence of accurate kinetic measurements. Oxidation of the side chain in alkyl aromatics was studied... 

The solid mixture of KMnOa and CUSO4 continuous to be a popular reagent system for oxidation of secondary alcohols to corresponding ketones the reaction works well under the assistance of ultra sound (eq 32). The reagent can even be used for oxidation of side chains in alkyl aromatic compounds to the corresponding ketones under solvent-free conditions (eq 33). ... 

Hydrodealkylation— This reaction removes alkyl side chains lirom alkyl-aromatic hydrocarbons, and adds hydrogen—used in the production of naphthalene from methyl naphthalene and benzene fixrm toluene. 

It has been tentatively suggested that one mechanism underlies the Willgerodt reaction and the Kindler modification of it. A labile intermediate is first formed which has a carbon—carbon bond in the side chain. The scheme is indicated below it postulates a series of steps involving the addition of ammonia or amine (R = H or alkyl), elimination of water, re addition and eUmination of ammonia or amine until the unsaturation appears at the end of the chain then an irreversible oxidation between sulphur and the nitrogen compound may occur to produce a thioamide. 

Classical syntheses of steroids consist of the stepwise formation of the four rings with or without angular alkyl groups and the final construction of the C-17 side-chain. The most common reactions have been described in chapter 1, e.g. Diels-AIder (p. 85) and Michael additions (p. 

Lewis acids such as zinc triflate[16] and BF3[17] have been used to effect the reaction of indole with jV-proiected aziridine-2-carboxylate esters. These alkylations by aziridines constitute a potential method for the enantioselective introduction of tryptophan side-chains in a single step. (See Chapter 13 for other methods of synthesis of tryptophans.)... 

The percentage of cyclohexylation is given in Fig. 1-20. (411,412). Hydrogen abstraction from the alkyl side-chain produces, in addition, secondary products resulting from the dimerization of thiazolylalkyl radicals or from their reaction with cyclohexyl radicals (Scheme 68) (411). 

The reactivity of alkylthiazoles possessing a functional group linked to the side-chain is discussed here neither in detail nor exhaustively since it is analogous to that of classical aliphatic and aromatic compounds. These reactions are essentially of a synthetic nature. In fact, the cyclization methods discussed in Chapter II lead to thiazoles possessing functional groups on the alkyl chain if the aliphatic compounds to be cyclized, carrying the substituent on what will become the alkyl side chain, are available. If this is not the case, another functional substituent can be introduced on the side-chain by cyclization and can then be converted to the desired substituent by a classical reaction. 

Benzene with no alkyl side chain and no benzyhc hydrogens undergoes a different reaction under these conditions Oxidation of the ring occurs to convert benzene to its epoxide... 

Reactions Involving Alkyl and Alkenyl Side Chains in Arenes and Arene Derivatives... 

A primary or secondary alkyl side chain on an aromatic ring is converted to a carboxyl group by reaction with a strong oxidizing agent such as potassium permanga nate or chromic acid... 

Acylated Corticoids. The corticoid side-chain of (30) was converted iato the cycHc ortho ester (96) by reaction with a lower alkyl ortho ester RC(OR )2 iu benzene solution ia the presence of i ra-toluenesulfonic acid (88). Acid hydrolysis of the product at room temperature led to the formation of the 17-monoesters (97) ia nearly quantitative yield. The 17-monoesters (97) underwent acyl migration to the 21-monoesters (98) on careful heating with. In this way, prednisolone 17a,21-methylorthovalerate was converted quantitatively iato prednisolone 17-valerate, which is a very active antiinflammatory agent (89). The iatermediate ortho esters also are active. Thus, 17a,21-(l -methoxy)-pentyhdenedioxy-l,4-pregnadiene-liP-ol-3,20-dione [(96), R = CH3, R = C Hg] is at least 70 times more potent than prednisolone (89). The above conversions... 

Tocotrienols differ from tocopherols by the presence of three isolated double bonds in the branched alkyl side chain. Oxidation of tocopherol leads to ring opening and the formation of tocoquinones that show an intense red color. This species is a significant contributor to color quaUty problems in oils that have been abused. Tocopherols function as natural antioxidants (qv). An important factor in their activity is their slow reaction rate with oxygen relative to combination with other free radicals (11). 

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