Anti addition reactions nucleophilic substitution

This scheme represents an alkyne-bromine complex as an intermediate in all alkyne brominations. This is analogous to the case of alkenes. The complex may dissociate to a inyl cation when the cation is sufficiently stable, as is the case when there is an aryl substituent. It may collapse to a bridged bromonium ion or undergo reaction with a nucleophile. The latta is the dominant reaction for alkyl-substituted alkynes and leads to stereospecific anti addition. Reactions proceeding through vinyl cations are expected to be nonstereospecific. 

Overall the stereospecificity of this method is the same as that observed m per oxy acid oxidation of alkenes Substituents that are cis to each other m the alkene remain CIS m the epoxide This is because formation of the bromohydrm involves anti addition and the ensuing intramolecular nucleophilic substitution reaction takes place with mver Sion of configuration at the carbon that bears the halide leaving group... 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

Markovnikov s rule is also usually followed where bromonium ions or other three-membered rings are intermediates. This means that in these cases attack by W must resemble the SnI rather than the Sn2 mechanism (see p. 461), though the overall stereospecific anti addition in these reactions means that the nucleophilic substitution step is taking place with inversion of configuration. 

Scheme 2.2 illustrates several examples of the Mukaiyama aldol reaction. Entries 1 to 3 are cases of addition reactions with silyl enol ethers as the nucleophile and TiCl4 as the Lewis acid. Entry 2 demonstrates steric approach control with respect to the silyl enol ether, but in this case the relative configuration of the hydroxyl group was not assigned. Entry 4 shows a fully substituted silyl enol ether. The favored product places the larger C(2) substituent syn to the hydroxy group. Entry 5 uses a silyl ketene thioacetal. This reaction proceeds through an open TS and favors the anti product. 

As indicated under section 2.2. the overall result is the same as that of an insertion reaction, the difference being that insertion gives rise to a yw-addition and nucleophilic attack to an anri-addition. Sometimes the two reaction types are called inner sphere and outer sphere attack. There is ample proof for the anti fashion the organic fragment can be freed from the complex by treatment with protic acids and the organic product can be analysed [19], Appropriately substituted alkenes will show the syn or anti fashion of the addition. The addition reaction of this type is the key-step in the Wacker-type processes catalysed by palladium. 

The same result can be achieved in one step with m-chloroperoxybenzoic acid and water.719 Overall anti addition can also be achieved by the method of Prevost. In this method the olefin is treated with iodine and silver benzoate in a 1 2 molar ratio. The initial addition is anti and results in a 3-halo benzoate (71). These can be isolated, and this represents a method of addition of IOCOPh. However, under the normal reaction conditions, the iodine is replaced by a second PhCOO group. This is a nucleophilic substitution reaction, and it operates by the neighboring-group mechanism (p. 308), so the groups are still anti ... 

Most of the types of cyclofunctionalization reaction discussed in this chapter have been shown to result in stereospecific anti addition across the ir-bond. This result suggests that the important intermediates are ir-complexes (B) or onium ions (C) rather than carbocations (E). In the case of cyclofunctionalization with some electrophiles, such as phenylselenenyl chloride, it has been shown that the formation of addition products such as (D) occurs faster than the cyclization.4 Stereospecific trans addition in these reactions then requires conversion to intermediates (B) or (C) before nucleophilic attack, since nucleophilic attack on intermediate (D) and substitution of X with inversion would result in syn addition. Thus, in the discussions below, intermediates (B) and/or (C) are considered to be the key... 

Well before the wide use of organoselenium compounds in chemistry, it was discovered that electrophilic selenium compounds of the type RSeX add stereospecifically to alkenes.45 Since that time this reaction has been an important tool in the portfolio of organic chemists and has been used even for the construction of complex molecules. Comprehensive reviews on this chemistry have appeared46-49 and in recent times the synthesis of chiral selenium electrophiles and their application in asymmetric synthesis has emerged. As shown in Scheme 1, the addition reactions of selenium electrophiles to alkenes are stereospecific anti additions. They involve the initial formation of seleniranium ion intermediates 1 which are immediately opened in the presence of nucleophiles. External nucleophiles lead to the formation of addition products 2. The addition to unsymmetrically substituted alkenes follows the thermodynamically favored Markovnikov orientation. The seleniranium ion intermediates of alkenes with internal nucleophiles such as 3 will be attacked intramolecularly to yield cyclic products 4 and 5 via either an endo or an exo pathway. Depending on the reaction conditions, the formation of the seleniranium ions can be reversible. 

Dideoxynucleosides show potent anti-retroviral activity against HIV-specific reverse transcriptase80-83. In particular, 2, 3 -dideoxy-3 -C-cyano-2 -substituted thymidine derivatives (33 A and 33 B) with a free 5 -hydroxy function (R1 = H) are potential inhibitors of the HIV-reverse transcriptase-promoted c-DNA synthesis. As these compounds have yet to be prepared by another method, the 3 -ene-nitrile 3284 was subjected to conjugate addition reactions with ammonia, primary amines, secondary amines and carbon nucleophiles. Most of these nucleophilic amine addition reactions give either the trans-isomer 33 A as the sole product (e.g., reaction with pyrrolidine, piperidine, morpholine), or as the major product along with the c/s-isomer (e.g., reaction with methylamine, benzylamine), except for the reaction with ammonia where the cts-isomer 33B is formed as the major product84. 

Kobayashi et al. found that lanthanide triflates were excellent catalysts for activation of C-N double bonds —activation by other Lewis acids required more than stoichiometric amounts of the acids. Examples were aza Diels-Alder reactions, the Man-nich-type reaction of A-(a-aminoalkyl)benzotriazoles with silyl enol ethers, the 1,3-dipolar cycloaddition of nitrones to alkenes, the 1,2-cycloaddition of diazoesters to imines, and the nucleophilic addition reactions to imines [24], These reactions are efficiently catalyzed by Yb(OTf)3. The arylimines reacted with Danishefsky s diene to give the dihydropyridones (Eq. 14) [25,26], The arylimines acted as the azadienes when reacted with cyclopentadiene, vinyl ethers or vinyl thioethers, providing the tet-rahydroquinolines (Eq. 15). Silyl enol ethers derived from esters, ketones, and thio-esters reacted with N-(a-aminoalkyl)benzotriazoles to give the /5-amino carbonyl compounds (Eq. 16) [27]. The diastereoselectivity was independent of the geometry of the silyl enol ethers, and favored the anti products. Nitrones, prepared in situ from aldehydes and N-substituted hydroxylamines, added to alkenes to afford isoxazoli-dines (Eq. 17) [28]. Addition of diazoesters to imines afforded CK-aziridines as the major products (Eq. 18) [29]. In all the reactions the imines could be generated in situ and the three-component coupling reactions proceeded smoothly in one pot. 

The mercurinium ion is attacked by the nucleophilic solvent—water, in the present case— to yield the addition product. This attack is back-side (unless prevented by some structural feature) and the net result is anti addition, as in the addition of halogens (Sec. 7.12). Attack is thus of the Sn2 type yet the orientation of addition shows that the nucleophile becomes attached to the more highly substituted carbon— as though there were a free carbonium ion intermediate. As we shall see (Sec. 17.15), the transition state in reactions of such unstable three-membered rings has much SnI character. 

Nucleophilic substitution at an allylic substrate under S 2 conditions may proceed via nucleophilic attack at the y-carbon, especially when substitution at the a-carbon sterically impedes the normal 8 2 reaction. These S 2 reactions with cyclohexenyl systems generally proceed via an anti addition of the nucleophile to the double bond, as depicted below (best overlap of participating... 

In 2007, Jorgensen and coworkers also reported the anti-Michael reaction of the cyclic P-ketoesters 53 with the sulfone group-substituted acrylonitrile 54 under PTC conditions (52 (6mol%), CHC13, aq Cs2C03 or K3P04) [15]. As depicted in Scheme 9.18, the sulfone group of the acceptor directed the nucleophile and then is removed to afford the anti-Michael (a-addition Morita-Baylis-Hillman-like) adducts 55 in variable yields (42-90%) and ee values (60-94% ee) (Scheme 9.18). 

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