Nucleophilic substitution of allylic halides

Nucleophilic substitutions of allylic halides provide much of the experimental evidence on which our understanding of allylic carbocations rests. This evidence includes both rate and product studies. 

FIGURE 9.22 (a) Nucleophilic substitution of allylic halides. The crossed arrows mean that... 

It is clear that during nucleophilic reactions of allylic halides carrying one EWG various other reaction pathways can occur in addition to MIRC reactions, e.g. addition, substitution, rearrangement and eliminationFor example, reaction of ethyl 4-bromocrotonate (273) with sodium ethoxide in ethanol only affords minor amounts of the 2-ethoxycyclopropane carboxylate (274) in addition to the substitution (276) and the addition-substitution (275) product (equation 83). Nevertheless, a cyclopropane... 

The palladium(0)-catalysed nucleophilic substitution of allylic acetates, carbonates or halides, also known as the Tsuji-Trost reaction, is a powerful procedure for the formation of C—C, C—O and C—N bonds. One of the early impressive examples, where this transformation had been combined with a pallada-ene reaction, was developed by Oppolzer and Gaudin [126], Although, in general, the Tsuji-Trost reaction can be combined with other palladium-catalysed transformations, there are only a few examples where it is combined with a Mizoroki-Heck transformation. 

Nucleophilic substitutions of allylic functional groups (allyl esters, ethers, alcohols, halides, fluorosilanes, etc.) are efficiently catalyzed by palladium derivatives a very electrophilic jr-allyl palladium being formed as an intermediate. 

FIGURE 9.45 Substitution of allylic halides by oxygen nucleophiles. 

Allylic amination of allyl halides can also be achieved using lithium and potassium bis(trimethylsilyl)amides [34] and potassium 1,1,3,3-tetramethyldisilazide [35] as the nucleophiles. It has been found that for the reaction of alkyl-substituted allyl chlorides using lithium bis(trimethylsilyl)amides as the nucleophile the allylic amination proceeds smoothly in a SN2 fashion to give /V,Af-disilylamines in high yields when silver(I) iodide was used as an additive. Other metal complexes such as copper ) iodide and other silver(I) salts can also be used as additives for the reaction. 

Substitution reactions of allylic halides show diverse character according to the reagent and the position of the allylic system. In buffered aqueous solutions the 3 a- and 3 3-chloro-A -compounds 7) and (8), and also the 4/5-chloro-AS-(10) and 6ji -chloro-A4 compounds (ii) clearly react through common allylic cations (9 and 12, respectively). The product patterns are what one would expect from nucleophilic attack upon these cations by water, accompanied in the case of the C<3) C(4)-C(5) cation (9) by proton abstraction to give a diene. This cation exhibits no preference for either 3 a- or 3jS-attack of the nucleophile but the C(4>-C(5) C(6) cation 12) is attacked... 

In most cases, treatment of allylic halides containing one ASG with a nucleophile does not result in formation of electrophilic cyclopropanes (MIRC product) instead, other reaction pathways are followed, e.g. addition, substitution, rearrangement and elimination reactions.However, with certain alkenes or nucleophiles or under the appropriate conditions a conjugate addition-nucleophilic substitution pathway is favored, resulting in cyclopropanes substituted with one ASG. Representative examples are compiled in Tables 20 and 21 where organometallic compounds or active methylene compounds are used as the nucleophilic species in combination with allyl bromides containing an ester or a sulfone as ASG. 

Leaving groups in the Tsuji-Trost reaction include acetates, halides, ethers, carbonates, sulfones, carbamates, epoxides, and phosphates. Reviews (a) Tsuji, J. In Handbook of Organopalladium Chemistry for Organic Synthesis, Negishi, E. deMeijere, A., Eds. Wiley-lnterscience New York, 2002 Vol II, Palladium-Catalyzed Nucleophile Substitution Involving Allyl Palladium, Propargyl-palladium and Related Derivatives, pp. 1669-1687. (b) Frost C. G. Howarth, J. Williams, J. M. J. Tetrahedron Asymmetry 1992, 3, 1089-1122. 

Oxidative addition of unsaturated halides is also believed to involve co-ordination prior to C—X cleavage in other cases. Allyl chloride reacts 10 times faster with [IrCl(CO)(PMe2Ph)2] than Mel, a larger factor than expected for normal nucleophilic substitution of these compounds. A modified 5- 2 mechanism is proposed with somewhat different routes in MeOH and C H to account for the different isomers formed as shown in Scheme 8. 

Another interesting application of allyl halides in Pd-catalyzed allylic alkylations utilizes substituted 1-alkenylcyclopropyl chlorides (Scheme 12.38). These allylic chlorides, as well as the more reactive, analogous tosylates, react with soft nucleophiles, such as malonates, in a highly regioselective manner [17d,e, 72]. The attack at the ii-allylpalladium intermediate takes place preferentially at the allylic position distal to the cyclopropyl substituent, providing access to a variety of synthetically useful methylenecydopropane derivatives. 

Again, the double-headed arrow indicates that the actual state of the ion is between the two resonance forms. Attack by an electron-rich nucleophile may occur at either of the two positive carbons, making allyl halides more susceptible to nucleophilic substitution of the halogen than ordinary alkyl halides. 

The Tsuji-Trost reaction is the palladinum-catalyzed substitution of allylic leaving groups by carbon nucleophiles. The nucleophile can be carbon-, nitrogen-, or oxygen- based compounds such as alcohols, enolates, phenols, and enamines, and the leaving group can be a halide or an acetate. This emerged as a powerful procedure for the formation of C—C, C—O and C—N bonds. The reaction, also known as Trost allylation or allylic alkylation, was named after Jiro Tsuij, who first reported the method in 1965 [42], and Barry Trost, who introduced an asymmetric version in 1973 [43]. 

Nucleophilic Substitution on Alkyl Halides by Heteroatoms. A number of more or less activated alkyl halides, such as benzyl halides and allyl halides, undergo substitution reactions mediated by AgBp4 in the presence of a heteroatom nucleophile. For example, treatment of pentamethylcyclopentadienyl bromide with AgBp4 in the presence of a nucleophile gives the corresponding substituted product (eq 2). Thiols, amines, and alcohols have been used as nucleophiles. ... 

---