Substitution reactions neighboring group participation

Furthermore, a neighboring group participation of a phenylthio function is observed in the Lewis acid-catalyzed nucleophilic substitution reaction of various P-nitrosulfides. Because the P-nitrosulfides are readily available, by the Michael addition of thiols to nitroalkenes (see Michael addition Chapter 4), this reaction is very useful. The P-nitrosulfides are prepared stereoselectively, and the reaction proceeds in a stereo-specific way (retention of configuration) as shown in Eqs. 31-34.35... 

Under more basic conditions, a-elimination predominates and insertion of the carbene 40 to the solvent gives racemic 22. Non-basic and poorly nucleophilic conditions allow neighboring group participation to form the rearranged substitution product 23 with complete chirality transfer. The participation can be considered as an intramolecular nucleophilic substitution, and does occur only when it is preferable to the external reactions. Under slightly basic conditions with bases in HFIP, participation is allowed, and the weak base can react with the more electrophilic vinylic cation 21 (but not with the iodonium ion 19). A suitably controlled basicity can result in the formation of cycloalkyne 39, which is symmetrical and leads to racemization. These reactivities are illustrated in Scheme 6. 

Neighboring group participation effects appear to play a crucial role in the nucleophilic substitution of chlorine in Michael adducts of 1-R, 2-R, 3-X. Thus, this substitution proceeds very easily in any of the adducts formed with an electron rich nitrogen, sulfur and oxygen Michael donor. For the adducts of nitrogen nucleophiles, the facile substitution of the chlorine has been suggested to occur via formation of intermediate aziridinium ions 103 [8] (Scheme 32), and this postulate was later supported by isolation of azaspiropentane derivatives under appropriate conditions in several reactions (see Sect. 3.2.2) [11b, 53,56]. It is most likely that alkylthio substituents in adducts of type 85 participate in the same way to first form spirocyclopropane-annelated thiiranium ion intermediates which are subsequently opened by attack of the incoming nucleophile. 

The preparation of norbomadiene-fused thiophene (17) involved a double-Wittig reaction of 1,2-dione 15 with the bis-ylide derived from phosphonium salt 16 <99BCSJ1597>. The effect of the fused heteroaromatic ring of 17 (neighboring group participation) on electrophilic substitution of the norbomadiene ring was examined. 

As shown by the relative rates of methanolysis of thioethers PhS(CH2)nCl (Scheme 4.50), the same substrate can react with or without neighboring-group participation, depending on the nucleophile and on the reaction conditions. Under conditions which favor bimolecular substitution, anchimeric assistance by neighboring groups is observed only rarely. 

Fig. 6.4.1A,B. Proposed mechanism of lignin thioacidolysis A Substitution at C B Substitution at Cp, then at Cy via a neighboring group participation reaction...

There are a number of synthetically important applications, involving these heterocycles, as unstable intermediates, which are reviewed here. These applications feature the ability of selenium to be readily extruded from seleniranes and selenirenes, neighboring group participation by / -Se to control the stereochemistry of nucleophilic substitution reactions, and facile, chemoselective replacement of Se by H in radical-induced reactions. 

The effect of a heteroatom 0 to the oxirane ring has been studied in the reaction of monosubstituted oxiranes 131 and benzylamine. If X = 0, the reaction occurs via the transition state 132 with neighbouring-group participation. Neighboring-group participation has similarly been observed in the reactions of mono- and tri-substituted oxiranes and )3-substituted primary amines. The product ratio of the aminoalcohols formed from the reactions of a-vinyloxiranes and primary amines depends on the geometry of the oxirane.Base-catalyzed addition of oxiranes to oximes leads not only to 0-alkyl but to A -alkyl derivatives (Eq, 319). ... 

Neighboring group participation involving acylamino or acyloxy groups is common in nucleophilic substitution. For example, in the reaction of methyl 4,6-0-benzylidene-2-deoxy-2-benzoylamino-3-O-mesyl-a-D-altro-pyranoside 8 with NaOEt, no 3-0-ethoxy-mannoside derivative was obtained. Instead, oxazoline 9 and epimine 10 were identified in this reaction (O Scheme 5) [12]. This results from the l,2-tra 5 -diaxial relationship between the leaving... 

Neighboring group participation is also another important factor for predicting the reactivity of secondary hydroxyl groups, particularly at the C-2 position. Under basic conditions, the C-2 hydroxyl tends to be more acidic than the C-3 hydroxyl and this may be advantageously exploited in certain cases such as partial benzylation under phase-transfer catalysis. The latter reaction conditions also contribute to the relatively good selectivity for substitution at a primary hydroxyl group in preference to a secondary one at either C-3 or C-4. 

Primary and secondary kinetic isotope effects are of general importance in the study of neighboring group participation. Isotopic substitution a to the incipient carbo-cation produces a secondary isotope effect whereas 0 and y substituents may give rise to both primary and secondary effects. For example, if the rate determining step of a solvolytic reaction involves a hydrogen shift or elimination, primary deuterium isotope effects are clearly implicated. 

One concern applicable to all aspects of organic chemistry is the question of the stereochemical outcome of reactions. In the case of C-glycosides, since no anomeric effect exists, the stereochemistry is completely dictated by stereoelectronic effects. Additionally, it should be noted that neighboring group participation is not a predominant factor. The major consequence of these observations is that axially (a) substituted C-glycosides are far more accessible than the corresponding equatorial (p) isomers. 

It is in this sense that cyclic sulfates are superior to epoxides. Further examples of double displacement reactions of cyclic sulfates are cited vide infra). In the absence of neighboring group participation, a -substituted ethylene sulfate may undergo an elimination reaction to furnish olefin. For example, when a cyclic sulfate was treated with sodium naphthalide in TFIF, only alkene 127 was obtained (90SL479) [Eq. (28)]. 

A special case is the observed substitution with retention as the result of the reaction of N(6)-phenylsulfonyl-4° 8° -diiodo-2-oxa-6-aza-adamantane 54) with silver acetate in acetic acid during 9 hrs at 60°, which yielded 4° -acetoxy-8 -iodo-adamantane 55 (20% relative to reacted 54) and 4° 8° l-diacetoxy-ada-mantane 56 (66% relative to reacted 54). Because of the reduced basicity of N(6) by the sulfone group this reaction will not be classified as one involving normal neighboring group participation (2.1.5.2.) . 

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