Benzylic and Allylic Halides

Benzyl and ally I halides are both easily reduced hy transfer of an electron (Table 2.Si. They are also reactive in both S 2 reactions (comparable in methyl and 30 to over 100 limes faster than I ) and Sy I (between 2 and 3 in rale) 7 9. They might, therefore, he expected to read readily wiili Grignard reagents by any of the ihrce iiiechauisms under consideration, and. in fact, they arc generally more reactive iltan alkyl halides. 

Support for a SET mechanism also comes from C lDNP observations in the reactions of /-BuMgX with allyl and bcn/yl bromides 7Sa. II is stated (but without details) that the polarization indie,lies a mechanism involving geminate radical pans, as expected in eq. (2.b. A study of the reaction of HlMeBr with p-CICVHjCH Br led to similar conclusions, though the emphasis was on exchanee and disproportionation lather than cnuplim 9I.  

An oxygen or sulfur siihsiituictl on a earbneaiioiiie cemei gieatly stabilizes the species by tesonanee  

An oxygen or sulfur also stabilizes an adjacent radical, so a SHT mechanism with a radical intermediate might he tin alternative. An estimate of the radical stabilization may be made by comparison of the primary ( II bond dissociation energies of propane (100 heal/mol) and dimethyl 

When we see that one of the reactants is an acid, we know we should start by protonating the other reactant. We need to protonate it at the position that allows the most stable carbo-cation to be formed. Therefore, we protonate the CH2 group because that forms a tertiary allylic carbocation with a positive charge that is shared by three carbons as a result of electron delocalization. A 1,2-methyl shift results in a carbocation with the desired carbon skeleton. Loss of a proton gives the final product. 

Now use the strategy you have just learned to solve Problem 8. 

Benzylic and aUylic halides readily undergo E2 reactions, because the new double bond in the product is relatively stable, and therefore easily formed, since it is conjugated with a benzene ring or with a double bond. 

Benzylic halides and allylic halides also undergo El reactions, because they form relatively stable carbocations. 

If the two resonance contributors are not mirror images, as they are in the preceding example, two dienes will be formed. 

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Lithiation at C2 can also be the starting point for 2-arylatioii or vinylation. The lithiated indoles can be converted to stannanes or zinc reagents which can undergo Pd-catalysed coupling with aryl, vinyl, benzyl and allyl halides or sulfonates. The mechanism of the coupling reaction involves formation of a disubstituted palladium intermediate by a combination of ligand exchange and oxidative addition. Phosphine catalysts and salts are often important reaction components. 

Benzylic, allylic and propargylic positions enhance the cathodic cleavage rate of C— heteroatom bonds as, for example, in the reduction of benzylic and allylic halides or alcohols56. Similar activated sulphones, due to their acidity, are in a class apart. Figure 8 shows the similitude between the cathodic behaviour of an allylic sulphone and its isomer, i.e., the corresponding vinylic sulphone when the electrolyses are run in an aprotic solvent. However, in the presence of an excess of proton donor, discrepancies appear. 

Alkenylboranes (R2C=CHBZ2 Z — various groups) couple in high yields with vinylic, alkynyl, aryl, benzylic, and allylic halides in the presence of tetra-kis(triphenylphosphine)palladium, Pd(PPh3)4, and a base to give R C CHR. 9-Alkyl-9-BBN compounds (p. 1013) also couple with vinylic and aryl halides " as well as with a-halo ketones, nitriles, and esters.Aryl halides couple with ArB(IR2 ) species with a palladium catalyst. ... 

Palladium complexes also catalyze the carbonylation of halides. Aryl (see 13-13), vinylic, benzylic, and allylic halides (especially iodides) can be converted to carboxylic esters with CO, an alcohol or alkoxide, and a palladium complex. Similar reactivity was reported with vinyl triflates. Use of an amine instead of the alcohol or alkoxide leads to an amide. Reaction with an amine, AJBN, CO, and a tetraalkyltin catalyst also leads to an amide. Similar reaction with an alcohol, under Xe irradiation, leads to the ester. Benzylic and allylic halides were converted to carboxylic acids electrocatalytically, with CO and a cobalt imine complex. Vinylic halides were similarly converted with CO and nickel cyanide, under phase-transfer conditions. ... 

Alkylation also occurs with benzylic and allylic halides Abood. N.A. Nosal, R. Tetrahedron Lett., 1994, 35, 3669... 

C-Alkylations of l,4-dihydro-27/-pyrazino[2,l-A]quinazoline-3,6-diones at positions C-l and CM were studied in detail. Compounds of type 57 could be alkylated diastereoselectively at C-l, owing to the geometry of the piperazine ring, which is locked in a flat boat conformation with the R4 or R1 substituent in a pseudoaxial position to avoid steric interaction with the nearly coplanar C(6)-carbonyl group. Alkylation of 57 (R2 = Me, Bn, R4 = Me) in the presence of lithium hexamethyldisilazide (LHMDS) with benzyl and allyl halides resulted, under kinetic control, in the 1,4-trans-diastereomer 59 as the major product, with retention of the stereocenter at CM (Scheme 5). 

More reactive electrophiles, such as benzyl and allyl halides, as well as a- or 3-halo-carbonyl compounds, react smoothly with amines, often even at room temperature. Support-bound chloro- and bromoacetamides, for instance, react cleanly with a wide range of aliphatic and aromatic amines to yield glycine derivatives (Entries 1-4, Table 10.2 [22-32]). This reaction is usually conducted in DMSO at room temperature (2-12 h), but for sensitive amines DMF or NMP might offer milder reaction conditions (Entry 3, Table 10.2). Higher yields can often be obtained by increasing the reaction temperature and the concentration of the amine. 

Selective reduction of t-alkyl halides. The ate complex of B-butyl-9-BBN with n-BuLi selectively reduces tertiary alkyl halides to hydrocarbons in high yield without effect on primary or secondary halides. It does not reduce aryl or vinyl halfdes, but does reduce benzyl and allyl halides. The reduction involves a carbonium ion, and thus can proceed with Wagner-Meerwein rearrangements in certain systems. 

Coupling of alkyl halides (cf. 8,111).1 (-Alkyl, benzylic, and allylic halides form symmetrical dimers in about 85-95% yield when treated with CrCI,.5 The dimerization involves monoalkylchromium(lll) complexes followed by a radical reaction. Crosscoupling of these same halides is also possible, but yields are lower (40-90%). 

Selective reduction of halides.1 Thecomplexl reduces tertiary halides to alkanes without attack on primary or secondary halides. It is more selective than organotin hydrides. Benzylic and allyl halides are also reduced easily. The reagent reduces a mixture of the halides 2 mainly to trims-3 thus, a partial inversion oftonfiguration is... 

A major breakthrough in the use of Nobin as an asymmetric phase-transfer catalyst came when Belokon and coworkers applied it to the alkylation of glycine-derived nickel(II) complex 11a under the conditions shown in Scheme 8.13 [25], Representative results are given in Table 8.1, which illustrate that benzylic and allylic halides react very rapidly and highly enantioselectively to produce a-amino acids. Intrigu-ingly, in this case (R)-Nobin catalyzes the formation of (R)-amino acids, which is the opposite enantioselectivity to that observed for the alkylation of alanine derivative 16b [21,24],... 

Buu-Hoi, N. P. Demerseman, P. Zinc chloride-catalyzed benzylations of phenols and naphthols./. Org. Chem. 1955, 20, 1129—1134. Curtin, D. Y. Crawford, R. J. Wilhelm, M. Factors controlling position of alkylation of alkali metal salts of phenols, benzyl and allyl halides./. Am. Chem. Soc. 1958, 80, 1391— 1397. 

The method is less successful with benzylic and allylic halides, and problems of selectivity with these substrates have been overcome in the past via an initial substitution with lithium butyltelluride the organolithium is then formed cleanly from the telluride 135 or 136 (which need not be isolated) by tellurium-lithium exchange.112... 

The lithium salts of acyclic secondary amines 92 can be conveniently transformed into the corresponding carbamoyllithiums 89 at —78 °C. Under these reaction conditions they react with trialkyltin chlorides to give carbamoyl stannanes 93 (Scheme 24)98. In the case of benzyl and allyl halides, an alkylation can occur affording products 94. However, when trialkylsilyl chlorides were used as electrophiles no carbamoyl silanes could be detected.. V-Alkyl thiocarbamates 95 can be prepared by reaction of the same intermediates 89 with sulfur followed by. S -alkylation at 0°C (Scheme 24)". 

Chromate and dichromate are capable of displacing halide from benzylic and allylic halides. Oxidation with dichromate has been performed under traditional conditions (equation 37) with the aqueous sodium salt, or with a quaternary ammonium salt in an aptotic solvent (equation 38). Of the two procedures the first would seem to be preferable from the point of view of simplicity and safety. 

Alkyl halides, including bcnzylic and allylic halides, do not react with trimethyl(trifluoro-methyl)silane. even with molar amounts of tetrabutylammonium fluoride. A convenient method has been developed for the perfluoroalkylation of organic (aryl, vinyl, benzyl and allyl) halides, e.g. formation of 1. using a mixture of trialky (perfluoroalkyl)silane/potas-sium fluoride/copper in dimethylformamide. Under these conditions perfluoroalkylcopper RpCu reagents are produced in situ. 

Deprotonation of tricarbonyl(isoprene)iron generates anion (249) which will react with organic electrophiles, such as aldehydes, and alkyl, benzyl, and allyl halides, to give alkylated products (equation 61). The anion is unstable above -30 °C and apparently rearranges to the trimethylenemethane anion (250). 

Reduction of halides. Benzylic and allylic halides are dimerized in good yield by the complex of copper metal and cyclohexylisonitrile (Wurtz reaction). Secondary halides are dimerized in low yield, and primary halides do not react. The system is less active than Cu(I) salts and resembles potassium graphite. 

This reaction has been extended to a similar alkylation with more reactive primary and secondary alkyl halides, such as benzylic and allylic halides. For this purpose the milder Lewis acid zinc bromide is generally preferable to titanium(IV) chloride as catalyst. ... 

Oxidation of alkyl halides. This reagent oxidizes benzyl and allyl halides to the corresponding carbonyl compounds in high yield. Secondary alkyl bromides afiord ketones in good yield, but primary alkyl bromides are oxidized in low yield to aldehydes. ... 

Both benzyl and allyl halides are rapidly hydrogenolyzed. Cleavage can be achieved selectively in the presence of aryl and alkyl halides. Double bond isomerization can often prevent any stereoselectivity in allylic cleavages. 

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