Benzylic halides, reactivity

Pyrroles do not react with alkyl halides in a simple fashion polyalkylated products are obtained from reaction with methyl iodide at elevated temperatures and also from the more reactive allyl and benzyl halides under milder conditions in the presence of weak bases. Alkylation of pyrrole Grignard reagents gives mainly 2-alkylated pyrroles whereas N-alkylated pyrroles are obtained by alkylation of pyrrole alkali-metal salts in ionizing solvents. 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

This method is particularly applicable to the more reactive benzyl halides which are easily hydrolyzed in the aqueous media usually employed for the metathetical reaction with alkali cyanides. For example, anisyl chloride treated with sodium cyanide in aqueous dioxane gives, as a by-product, 5-10% of anisyl alcohol as determined by infrared analysis. The use of anhydrous acetone not only prevents hydrolysis to the alcohol but also decreases the formation of isonitriles. This method was also applied successfully by the submitters to the preparation of -chlo-rophenylacetonitrile in 74% yield. 

Primary benzylic halides are ideal substrates for Sn2 reactions because they are very reactive toward good nucleophiles and cannot undergo competing elimination. 

A fundamental problem in the alkylation of enamines, which is inherent in the bidentate system, is the competition between the desired carbon alkylation and attack at the nitrogen. With unactivated alkyl halides (3,267), this becomes especially serious with the enamines derived fromcycloheptan-one, cyclooctanone, cyclononanone, and enamines derived from aldehydes. Increasing amounts of carbon alkylation are found with the more reactive allyl and benzyl halides (268-273). However, with allyl halides one also observes increasing amounts of dialkylation of enamines. 

Differences in solubility of the reactants may for example be utilized as follows. Sodium iodide is much more soluble in acetone than are sodium chloride or sodium bromide. Upon treatment of an alkyl chloride or bromide with sodium iodide in acetone, the newly formed sodium chloride or bromide precipitates from the solution and is thus removed from equilibrium. Alkyl iodides can be conveniently prepared in good yields by this route. Alkyl bromides are more reactive as the corresponding chlorides. Of high reactivity are a-halogen ketones, a-halogen carboxylic acids and their derivatives, as well as allyl and benzyl halides. 

Notes, (a) The alkylating agent must be reactive, i.e. a methyl, ethyl, ally] or benzyl halide. 

Poly (ethylene oxide) macromonomers72 761 are made in a similar way, as the alkoxide end group is reactive enough towards benzylic halides. With methacryloyl chloride, side reactions are involved. It is better to first protonate the PEO, and then to have it react with methacryloyl chloride in the presence of some triethyl amine. One can also react co-hydroxy polyethylene oxide) with methacryloyl imidazole, or with methacrylic acid in the presence of dicyclohexyl carbodiimide (DCCf)77). 

Alkylation of enamines requires relatively reactive alkylating agents for good results. Methyl iodide, allyl and benzyl halides, a-halo esters, a-halo ethers, and a-halo ketones are the most successful alkylating agents. The use of enamines for selective alkylation has largely been supplanted by the methods for kinetic enolate formation described in Section 1.2. 

Grignard reagents are somewhat less reactive toward alkylation but can be of synthetic value, especially when methyl, allyl, or benzyl halides are involved. 

Hindered lithium dialkylamides can generate aryl-substituted carbenes from benzyl halides.162 Reaction of a,a-dichlorotoluene or a,a-dibromotoluene with potassium r-butoxide in the presence of 18-crown-6 generates the corresponding a-halophenylcarbene.163 The relative reactivity data for carbenes generated under these latter conditions suggest that they are free. The potassium cation would be expected to be strongly solvated by the crown ether and it is evidently not involved in the carbene-generating step. 

The relative reactivity of Friedel-Crafts catalysts has not been described in a quantitative way, but comparative studies using a series of benzyl halides has resulted in the qualitative groupings shown in Table 11.1. Proper choice of catalyst can minimize subsequent product equilibrations. 

Thus the Sjvl reactivity of allyl and benzyl halides has already been referred to, and the particular effectiveness of the lone pair on the oxygen atom above is reflected in the fact that MeOCH2Cl is solvolysed at least 1014 times faster than CH3CI. 

The reduction of transition metal halides with Li has been recently extended by Boudjouk and coworkers for Ullman coupling (benzyl halide to bibenzyl) by Cu or Ni, using a low intensity cleaning bath (5J.). Ultrasound dramatically decreased the time required for complete reduction of the metal halides ( 12 h without, <40 minutes with ultrasound). The subsequent reactivity of the Cu or Ni powders was also substantially enhanced by ultrasonic irradiation. This allowed significant increases in the yield of bibenzyl (especially for Ni) at lower temperatures, compared to simple stirring. 

Figure 4.35 Benzyl halides and halomustards can be used as crosslinking agents reactive toward sulfhydryl groups.

Serine esters can be O-alkylated without concomitant A -alkylation, when the amino group is protected as its trityl derivative. The reaction is generally high yielding under relatively mild conditions [33], particularly with the more reactive allyl and benzyl halides. 

Using a procedure analogous to 8.4.1.A, the benzyl halide is replaced by a simple bromo-or chloroalkane (1.5 mmol) and the two-phase system is stirred at room temperature for 12 h. The reactive iodoalkane (4.5 mmol) is then added and the reaction mixture is stirred for a further 5 h. The unsymmetrical ketone is isolated as described in 8.4.I.A. 

As the supported glycol catalysts worked better in promoting reactions in a single solvent system, we explored the direct carbonylation of benzyl halides using an alcohol solvent, base, and cobalt carbonyl. Our initial experiments concentrated on the reaction of benzyl bromide at room temperature and one atmosphere carbon monoxide. We chose sodium hydroxide as the base, methanol as the solvent, and looked at the product distribution. We were interested in the selectivity to ester and the reactivity of this system. The results are given in Table III. 

Kinetic studies have been carried out for reactions of triphenylphosphine with substituted benzyl halides in various two-phase organic solvent-water media. The effects of water, agitation, organic solvent, reactant and temperature were investigated. The order of relative reactivity for solvents was CHCI3 > CH2CI2 CeHe. 

A variety of alkyl halides have been reduced at room temperature, including benzyl halides, primary, secondary and tertiary alkyl halides. The reaction times depend on the halide, and vary between 20min (benzyl bromide, 0.5 mol% 28) up to several days (iodopentane, fluoropentane). The reactivity of alkyl halides decreases in the order R—Br > R—Cl > R—1 when reductions are performed in separate flasks. Several mechanistic details of the reaction have been uncovered by in situ monitoring of the reaction by NMR spectroscopy. The precatalyst 28 appeared to be activated by a rapid reduction of the coordinated acetone to PrO—SiEt3 and concomitant coordination of an alkyl halide (H Scheme 12.11). This complex represents a resting state that is in equilibrium with a o-silane... 

However, with the more reactive chlorine, chlorination can occur at either position, though the major product is the benzylic halide. Benzylic bromina-tion is also efficiently achieved by the use of N-bromosuccinimide as the halogenating species. 

The difference in the reactivity of benzylic versus aromatic halogens makes it possible to reduce the former ones preferentially. Lithium aluminum hydride replaced only the benzylic bromine by hydrogen in 2-bromomethyl-3-chloro-naphthalene (yield 75%) [540]. Sodium borohydride in diglyme reduces, as a rule, benzylic halides but not aromatic halides (except for some iodo derivatives) [505, 541]. Lithium aluminum hydride hydrogenolyzes benzyl halides and aryl bromides and iodides. Aryl chlorides and especially fluorides are quite resistant [540,542], However, in polyfluorinated aromatics, because of the very low electron density of the ring, even fluorine was replaced by hydrogen using lithium aluminum hydride [543]. 

This new method was attempted since the a-chloro-N-nitrosamines seem to possess reactivity similar to that of benzyl halides. The compounds synthesized so far are listed in Table 8. 

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