Substitution, SN2

Sn2 substitution using organocopper reagents is an efficient method for the synthesis of 3-substituted olefins. In the synthesis of farnesyl diphosphate analogues (43, 45) as potential inhibitors of the enzyme protein-farnesyl transferase, for example, organocopper methodology was compared with the Stifle reaction [33] and the Suzuki reaction [34], frequently used in the coupling of vinyl triflates with 

In a total synthesis of cdc25A protein phosphatase inhibitor dysidiolide (46) [37], substitution on an sp carbon center by vinyl cuprate was used to accom- 

Cleavage of aziridines has been employed in the asymmetric total synthesis of pancratistatin 57 [47], a compound that is the object of considerable attention thanks to its broad spectrum of antineoplastic activities [48]. The chemistry of vinylaziridines has for the most part been confined to their use in rearrangement sequences resulting in functionalized pyrrolines. Hence, because of the lack of data concerning the ring-opening of vinylaziridines with carbon nucleophiles, 

9 Copper-Mediated Synthesis of Natural and Unnatural Products 

5 Copper-Mediated Synthesis of Natarai and Unnatarai Products 

Epoxide ring-opening with transfer of an sp carbon moiety was applied in a short synthesis [44] of eicosanoid 56 [45], rdevant in marine prostanoid biosynthesis (Sdieme 9.13). Homoallyl alcohol 55 was obtained in good yidd from 54 by use of a cyano-Gilman alkenylcuprate [46]. 

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A) Sn2 substitution at the allylic alcohol with hydrobromic acid followed by reaction with the requisite secondary amine, or... 

Neither fonnic acid nor water is very nucleophilic, and so Sn2 substitution is suppressed. The relative rates of hydrolysis of a group of alkyl bromides under these conditions are presented in Table 8.5. 

Secondary and tertiary alkyl halides are not suitable, because they react with alkoxide bases by E2 elimination rather than by Sn2 substitution. Whether the alkoxide base is primary, secondary, or tertiary is much less important than the nature of the alkyl halide. Thus benzyl isopropyl ether is prepared in high yield from benzyl chloride, a primary chloride that is incapable of undergoing elimination, and sodium isopropoxide ... 

The Sn2 substitution competes with the elimination, but a bond to hydrogen is not cleaved in the substitution. 

Nucleophilic displacement reactions One of the most common reactions in organic synthesis is the nucleophilic displacement reaction. The first attempt at a nucleophilic substitution reaction in a molten salt was carried out by Ford and co-workers [47, 48, 49]. FFere, the rates of reaction between halide ion (in the form of its tri-ethylammonium salt) and methyl tosylate in the molten salt triethylhexylammoni-um triethylhexylborate were studied (Scheme 5.1-20) and compared with similar reactions in dimethylformamide (DMF) and methanol. The reaction rates in the molten salt appeared to be intermediate in rate between methanol and DMF (a dipolar aprotic solvent loiown to accelerate Sn2 substitution reactions). 

A similar salt effect is observed in the reaction of propargylic epoxides67. RMgBr in diethyl ether in the presence of 5% CuBr PBu, gave an anti-SN2 substitution product, whereas RMgCl in diethyl ether/pentane in the presence of 5% copper(I) bromide and chlorotrimethylsilane (1 equivalent) afforded a syn-SN2 substitution product (Table 3). 

Visualisation of a chemieal reaetion as a single event is sometimes unconsciously encouraged by the language that we use. For example, this extract placed alongside a mechanistic representation of an Sn2 substitution reaetion from a popular textbook is similar to that in many others ... 

Entries 3 to 6 are examples of ester enolate alkylations. These reactions show stereoselectivity consistent with cyclic TSs in which the hydrogen is eclipsed with the enolate and the larger substituent is pseudoequatorial. Entries 4 and 5 involve SN2 substitutions of allylic halides. The formation of the six- and five-membered rings, respectively, is the result of ring size preferences with 5 > 7 and 6 > 8. In Entry 4, reaction occurs through a chairlike TS with the tertiary C(5) substituent controlling the conformation. The cyclic TS results in a trans relationship between the ester and vinylic substituents. 

Organomagnesium and organolithium compounds are strongly basic and nucleophilic. Despite their potential to react as nucleophiles in SN2 substitution reactions, this reaction is of limited utility in synthesis. One limitation on alkylation reactions is competition from electron transfer processes, which can lead to radical reactions. Methyl and other primary iodides usually give the best results in alkylation reactions. 

Secondary bromides and tosylates react with inversion of stereochemistry, as in the classical SN2 substitution reaction.24 Alkyl iodides, however, lead to racemized product. Aryl and alkenyl halides are reactive, even though the direct displacement mechanism is not feasible. For these halides, the overall mechanism probably consists of two steps an oxidative addition to the metal, after which the oxidation state of the copper is +3, followed by combination of two of the groups from the copper. This process, which is very common for transition metal intermediates, is called reductive elimination. The [R 2Cu] species is linear and the oxidative addition takes place perpendicular to this moiety, generating a T-shaped structure. The reductive elimination occurs between adjacent R and R groups, accounting for the absence of R — R coupling product. 

Similar results were obtained using n-BuMgBr-CuCN and tertiary allylic acetates, although under these conditions there is competition from SN2 substitution with primary acetates.33 The stereoselectivity is reversed with a hydroxy group, indicating a switch to a chelated TS. 

Those complexes which have four or five of the possible coordination sites filled, see Fig. 1, can form weak bonds (addition complexes) in the fifth and sixth positions. It is known that PtClI- will bind to methionine, imidazole and amines in such a fifth position, but very weakly. Such weak sites also offer initial positions of attack in an Sn2 substitution of say PtClI-, see below. 

E. Dynamical Model for Sn2 Substitution and Central Barrier Recrossing. 152... 

These reactions comprise nucleophilic SN2 substitutions, -eliminations, and nucleophilic additions to carbonyl compounds or activated double bonds, etc. They involve the reactivity of anionic species Nu associated with counterions M+ to form ion-pairs with several possible structures [52] (Scheme 3.4). 

Supercritical water (SCW) presents a unique combination of aqueous and non-aqueous character, thus being able to replace an organic solvent in certain kinds of chemical synthesis. In order to allow for a better understanding of the particular properties of SCW and of its influence on the rate of chemical reactions, molecular dynamics computer simulations were used to determine the free energy of the SN2 substitution reaction of Cl- and CH3C1 in SCW as a function of the reaction coordinate [216]. The free energy surface of this reaction was compared with that for the gas-phase and ambient water (AW) [248], In the gas phase, an ion-dipole complex and a symmetric transition... 

FIGURE 23.5 Profiles of different local reactivity descriptors (electrophilic attack) along the path of the gas phase SN2 substitution F + CH3—Fb —> Fa—CH3 + Fb. Profiles of energy and bond order are also shown. (Reprinted from Chattaraj, P.K. and Roy, D.R., J. Phys. Chem. A, 110, 11401, 2006. With permission.)... 

FIGURE 2.10 Differentiation of SN1 (substitution nucleophilic unimolecular, first order) and SN2 (substitution nucleophilic bimolecular, second order) reactions. 

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