Alkyl halides sterically hindered

Alkylative esterification of carboxylic acids with alkyl halides are effected by action with TMG (1) [65]. An ester is given by the TMG (1) mediated reaction of y-hydroxy-a,p-unsaturated carboxylic acid with methyl iodide without lactone formation after isomerization [65a]. Barton s base effectively works in the alkylation of sterically hindered carboxylic acid [3]. Ethanolysis of the acetate of tertiary alcohol occurred easily in 86% yield in the presence of BTMG (2) [66] (Scheme 4.24). 

Tertiary alkyl halides are so sterically hindered to nucleophilic attack that the pres ence of any anionic Lewis base favors elimination Usually substitution predominates over elimination m tertiary alkyl halides only when anionic Lewis bases are absent In the solvolysis of the tertiary bromide 2 bromo 2 methylbutane for example the ratio of substitution to elimination is 64 36 m pure ethanol but falls to 1 99 m the presence of 2 M sodium ethoxide... 

The alternative synthetic route using the sodium salt of benzyl alcohol and an isopropyl halide would be much less effective because of increased competition from elimination as the alkyl halide becomes more sterically hindered... 

Halide ions may attack 5-substituted thiiranium ions at three sites the sulfur atom (Section 5.06.3.4.5), a ring carbon atom or an 5-alkyl carbon atom. In the highly sterically hindered salt (46) attack occurs only on sulfur (Scheme 62) or the S-methyl group (Scheme 89). The demethylation of (46) by bromide and chloride ion is the only example of attack on the carbon atom of the sulfur substituent in any thiiranium salt (78CC630). Iodide and fluoride ion (the latter in the presence of a crown ether) prefer to attack the sulfur atom of (46). cis-l-Methyl-2,3-di-t-butylthiiranium fluorosulfonate, despite being somewhat hindered, nevertheless is attacked at a ring carbon atom by chloride and bromide ions. The trans isomer could not be prepared its behavior to nucleophiles is therefore unknown (74JA3146). 

The preparation of esters can be classified into two main categories (1) carboxy-late activation with a good leaving group and (2) nucleophilic displacement of a caiboxylate on an alkyl halide or sulfonate. The latter approach is generally not suitable for the preparation of esters if the halide or tosylate is sterically hindered, but there has been some success with simple secondaiy halides and tosylates (ROTs, DMF, K2CO3, 69-93% yield). ... 

The equatorial orientation of the newly introduced alkyl group may be controlled in both (3) and (6) by stereoelectronic and steric factors. The attack of the enolate anions (2) and (5) by the alkyl halide proceeds in a plane that is perpendicular to the plane of the enolate system. Products result from attack at the less hindered a- or -face, respectively... 

Because the new carbon-carbon bond is formed by an SN2-type reaction the alkyl halide must not be sterically hindered. Methyl and primary alkyl halides work best secondary alkyl halides give lower yields. Tertiary alkyl halides fail, reacting only by elimination, not substitution. 

If the alkyl halide contains more than one, equally reactive C-halogen centers, these will generally react each with one aromatic substrate molecule. For example dichloromethane reacts with benzene to give diphenylmethane, and chloroform will give triphenylmethane. The reaction of tetrachloromethane with benzene however stops with the formation of triphenyl chloromethane 7 (trityl chloride), because further reaction is sterically hindered ... 

The first SN2 reaction variable to look at is the structure of the substrate. Because the S, j2 transition state involves partial bond formation between the incoming nucleophile and the alkyl halide carbon atom, it seems reasonable that a hindered, bulky substrate should prevent easy approach of the nucleophile, making bond formation difficult. In other words, the transition state for reaction of a sterically hindered alkvl halide, whose carbon atom is "shielded" from approach of the incoming nucleophile, is higher in energy... 

Polk et al. reported27 that PET fibers could be hydrolyzed with 5% aqueous sodium hydroxide at 80°C in the presence of trioctylmethylammonium bromide in 60 min to obtain terephthalic acid in 93% yield. The results of catalytic depolymerization of PET without agitation are listed in Table 10.1. The results of catalytic depolymerization of PET with agitation are listed in Table 10.2. As expected, agitation shortened the time required for 100% conversion. Results (Table 10.1) for the quaternary salts with a halide counterion were promising. Phenyltrimethylammonium chloride (PTMAC) was chosen to ascertain whether steric effects would hinder catalytic activity. Bulky alkyl groups of the quaternary ammonium compounds were expected to hinder close approach of the catalyst to the somewhat hidden carbonyl groups of the fiber structure. The results indicate that steric hindrance is not a problem for PET hydrolysis under this set of conditions since the depolymerization results were substantially lower for PTMAC than for die more sterically hindered quaternary salts. 

With the exception of intramolecular amination reactions, all of the early aryl halide aminations were catalyzed by palladium complexes containing the sterically hindered P(o-tol)3. In papers published back-to-back in 1996, amination chemistry catalyzed by palladium complexes of DPPF and BINAP was reported.36,37 These catalysts allowed for the coupling of aryl bromides and iodides with primary alkyl amines, cyclic secondary amines, and anilines. 

Several syntheses of l,3-dioxoperhydropyrrolo[l,2-c]imidazoles have been developed using different strategies. a-Substituted bicyclic proline hydantoins were prepared by alkylation of aldimines 135 of resin-bound amino acids with a,tu-dihaloalkanes and intramolecular displacement of the halide to generate cr-substituted prolines 136 and homologs (Scheme 18). After formation of resin-bound ureas 137 by reaction of these sterically hindered secondary amines with isocyanates, base-catalyzed cyclization/cleavage yielded the desired hydantoin products <2005TL3131>. 

Solid-liquid phase systems with no added solvent produce esters in high yield [e.g. 2, 3] and are particularly Useful when using less reactive alkyl halides [e.g. 15], for the preparation of sterically hindered esters [16], or where other basic sites within the molecule are susceptible to alkylation, e.g. anthranilic acid is converted into the esters with minimal A-alkylation and pyridine carboxylic acids do no undergo quat-emization [17]. Excellent yields of the esters in very short reaction times (2-7 minutes) are also obtained when the two-phase system is subjected to microwave irradiation [18]. Direct reaction of the carboxylic acids with 1,2-dichloroethane under reflux yields the chloroethyl ester [19], although generally higher yields of the esters are obtained under microwave conditions [20]. 

The main advantages of preparation of hydroxylamines through Af-alkylation of other hydroxylamines are versatility and predictable stereochemical outcome that allow the introduction of the hydroxyamino group at advanced stages of multistep syntheses. The use of nucleophilic displacement is however problematic for sterically hindered alkyl halides and sulfonates. Apart from several examples mentioned below, alkylation of hydroxylamines with tertiary alkyl halides does not take place. 

Intermolecular reactions of hydroxylamines with secondary alkyl halides and mesylates proceed slower than with alkyl triflates and may not provide sufficiently good yield and/or stereoselectivity. A nseful alternative for these reactions is application of more reactive anions of 0-alkylhydroxamic acids or 0-alkoxysulfonamides ° like 12 (equation 8) as nucleophiles. The resulting Af,0-disubstituted hydroxamic acids or their sulfamide analogs of type 13 can be readily hydrolyzed to the corresponding hydroxylamines. The same strategy is also helpful for synthesis of hydroxylamines from sterically hindered triflates and from chiral alcohols (e.g. 14) through a Mitsunobu reaction (equation 9). 

Carbanion-enolates are nucleophiles that react with alkyl halides (or sulfonates) by typical S 2 reactions, Carbanion-enolates are best formed using lithium diisopropylamide (lda), (r-Pr)2N Li, in tetrahydrofuran. This base is very strong and converts all the substrate to the anion. Furthermore, it is too sterically hindered to react with RX. 

Typical synthetic procedures include the reaction of alkyl halides with the silver salts of carboxylic acids, the reaction of carboxylate anions in alkali with an excess of a dialkyl sulphate, (especially dimethyl sulphate), and heating tertiary184 or quaternary ammonium salts of carboxylic acids. These routes are particularly valuable for the preparation of esters of seriously sterically hindered acids. For example, Fuson et al.iK made the methyl ester of 2,4,6-triethylbenzoic acid by heating the tetramethyl ammonium salt to 200-250°C, viz. 

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