Sn2 Displacements of Sulfonates

SCHEME 6.11 Halogenation reactions via displacement at primary centers. 

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Most functional group conversions abxmdantly used on carbohydrate derivatives are also compatible with thioglycosides, e.g. SN2-displacements of sulfonates [37], azo transfer [38], and deoxygenation by tributyltin hydride reduction of o-carbonyl carbamates [39]. During oxidations care has to be taken so not to obtain the sulfoxide derivative (if that is not desired). DMSO and also PDC-mediated oxidations can usually be performed without problems [40]. 

Thioethers are prepared mainly by Williamson-type Sn2 displacements of RS and R X or R OSOjAr (aryl sulfonates). RS" is formed from the acidic thiol RSH, with NaOH as the base. 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

Until the introduction of triflate or imidazylate esters in carbohydrates, SN2-displacements of carbohydrate sulfonates with charged nucleophiles in certain positions of hexopyranose orfuranose derivatives were not possible, or gave low yields of substituted products owing to the predominance of elimination or rearrangement reactions [6,22,32,33]. 

The foregoing method of preparation of sugar thiocyanates109,110 by Sn2 displacement of a sulfonyloxy group has been reported by many workers.111 143 Displacement of sugar sulfonate groups by various nucleo-... 

Copper-mediated Sn2 displacement of enantiomerically pure allylic mesyloxy vinyl sulfoxides occurs with high yields and stereoselectivities.11 The S 2 reactions of structurally related mesyloxy sulfides and sulfones with organocuprates have also been examined. 

Hart assembled olefin 109 convergently from benzyl bromide 106 by taking advantage of the Ramberg-Backlund reaction.59 As depicted below, the Sn2 displacement of benzyl bromide 106 with thiol 107 led to sulfide 108. Oxidation of 108 to the sulfone, followed by the Myers modification delivered alkene 109, an intermediate for the synthesis of C-aryl glycosides related to chrysomycins. 

The nucleophilicity of 02 - toward primary alkyl halides (Scheme 10) results in an Sn2 displacement of halide ion from the carbon center. The normal reactivity order, benzyl > primary > secondary > tertiary, and leaving group order, I > Br > OTs > Cl, are observed, as are the expected stereoselectivity and inversion at the carbon center. In DMF, the final product is the dialkyl peroxide. The peroxy radical (ROO-), which is produced in the primary step and has been detected by spin trapping,is an oxidant that is readily reduced by 02 - to form the peroxy anion (ROO ). Because the latter can oxygenate Me2SO to its sulfone, the main product in this solvent is the alcohol (ROH) rather than the dialkyl peroxide. 

The displacement of sulfonate groups by halide ions (Q, Br , I ) readily yields the corresponding haloalkanes, particularly with primary and secondary systems, in which Sn2 reactivity is good. In addition, however, alkyl sulfonates allow replacement of the hydroxy... 

The use of tetra-n-butylammonium fluoride (54) in an aprotic solvent such as acetonitrile may be more advantageous. Foster and colleagues (19, 37) have effected an SN2 type of reaction using this reagent in the conversion of l,2 5,6-di-0-isopropylidene-3-0-p-tolylsulfonyl-D-allofura-nose into the C-3 epimeric fluorodeoxy derivative. Note that whereas potassium fluoride is ineffective in displacing secondary sulfonate esters in sugars, tetra-n-butylammonium fluoride is capable of effecting a displacement with Walden inversion even in a furanose drivative. 

The aziridine aldehyde 56 undergoes a facile Baylis-Hillman reaction with methyl or ethyl acrylate, acrylonitrile, methyl vinyl ketone, and vinyl sulfone [60]. The adducts 57 were obtained as mixtures of syn- and anfz-diastereomers. The synthetic utility of the Baylis-Hillman adducts was also investigated. With acetic anhydride in pyridine an SN2 -type substitution of the initially formed allylic acetate by an acetoxy group takes place to give product 58. Nucleophilic reactions of this product with, e. g., morpholine, thiol/Et3N, or sodium azide in DMSO resulted in an apparent displacement of the acetoxy group. Tentatively, this result may be explained by invoking the initial formation of an ionic intermediate 59, which is then followed by the reaction with the nucleophile as shown in Scheme 43. 

A simple chemical approach to aminosugars is to use Sn2 displacement by ammonia of a suitable leaving group, such as a tosylate (toluene jc-sulfonate, see Section 7.13.1). This process can be made selective for position 6, since the less-hindered primary alcohol group is more readily esterified than the secondary alcohols. 

Okamoto and co-workers noted that N-phenylhydroxylamine gave predominately diphenylamine on treatment with benzene in TFA but mostly 4-aminobiphenyl and 2-aminobiphenyl in the stronger acid trifluoromethane-sulfonic acid (TFSA). Similar results were obtained if benzene was replaced by toluene or anisole. The authors suggested that the reaction in TFA proceeded through O-protonated hydroxylamine either via a direct Sn2 displacement on N by the aromatic nucleophile or via attack of the aromatic compound on the N of a nitrenium ion. In TFSA they favored a mechanism in which the diprotonated hydroxylamine lost water to generate an iminium-benzenium dication (11, Scheme 5), a protonated nitrenium ion. " This... 

Since the pioneering work of Karl Freudenberg on displacements of carbohydrate p-toluene-sulfonates [1-5], bimolecular nucleophilic substitutions became one of the most employed and useful reactions in carbohydrate chemistry. Indeed SN2-type reactions have allowed the introduction of a variety of heteroatoms (halogens, N-, O-, S-) into carbohydrates, and the resulting compounds have been used in many synthetic and biological contexts [6],... 

The imidazole-l-sulfonate (imidazylate, lmz) group was a designed leaving group for Sn2 displacement reactions by virtue of its inherent structure [68]. It represents a different notion of reactivity because, in addition to the inherent sulfonate-type character, its reactivity can be enhanced by remote activation involving a nitrogen atom (Scheme 5). 

Tosylate and mesylate displacements at C(2) of a-glycosides are very slow owing to unfavourable dipolar interactions in the SN2 transition state. Both polar bonds of the transition state are inclined at an angle of about 30° to permanent dipoles of the C(l)—0(1) and C(l)—0(5) bonds. Displacement of C(2) sulfonates of p-glycosides is much more facile because, in this case, the transition state experiences only one unfavourable dipolar interaction of the C(l)—0(1) bond.12d,e... 

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