Mesylates, fluorination

Reactions of ar>l or alkyl bis(siloxy)isopropyl ethers with tetrabutyl-ammoninm fluoride-mesyl fluoride reagent lead to replacement of one siloxy group by fluorine and dehydrosiloxylation, providing an efficient access to fluoroisopropenyl ethers, which are useful as specific building blocks in drug design The reactions proceed via the intermediate allyl methanesulfonates [30, 31] (equation 23)... 

In contrast to phosphorus esters, sulfur esters are usually cleaved at the carbon-oxygen bond with carbon-fluorine bond formation Cleavage of esteri nf methanesulfonic acid, p-toluenesidfonic acid, and especially trifluoromethane-sulfonic acid (tnflic acid) by fluoride ion is the most widely used method for the conversion of hydroxy compounds to fluoro derivatives Potassium fluoride, triethylamine trihydrofluoride, and tetrabutylammonium fluoride are common sources of the fluoride ion For the cleavage of a variety of alkyl mesylates and tosylates with potassium fluoride, polyethylene glycol 400 is a solvent of choice, the yields are limited by solvolysis of the leaving group by the solvent, but this phenomenon is controlled by bulky substituents, either in the sulfonic acid part or in the alcohol part of the ester [42] (equation 29)... 

Gemcitabine (Gemzar ) is prepared from the 2,2-difluoro-2-deoxyribose, itself available by the addition of the Reformatsky reagent of ethyl bromodifluoroace-tate on the (R)-2,3-0-isopropylidene glyceraldehyde. The condensation of the corresponding mesylate with di(trimethylsilyloxy)pyrimidine provides gemcitabine [93]. The control of the stereoselectivity of the Reformatsky reaction is difficult (Fig. 30) [95]. Other approaches involving the fluorination of D-pyranoses have been proposed (Fig. 31) [96]. 

Synthesis of the thymidine derivative relies on the older two-step insertion of fluorine. Thus, the hydroxyl group in 3 -deoxythymidine benzoate (51-1) is first converted to the mesylate (51-2). Reaction with potassium fluoride in hydrogen fluoride replaces the mesylate by fluorine (51-3). The fact that this reaction, as that above, proceeds with retention of the configuration mles out simple displacement as the mechanism for this transform. The presence of the methyl group at position 5 negates the need for the chlorination step. Saponification then affords the antiviral agent alovudine (51-4) [52]. 

Propargylic mesylates such as fluorine-substituted derivative 265 react with PhZnCl in the presence of Pd(PPh3)4 (5 mol%) in THF at 0°C within 2 h to provide the anti-Si 2 product in excellent yield and complete transfer of the stereochemistry leading to the allene 266 (Scheme 78). Copper(I) catalyzed allylic substitutions with functionalized diorganozincs proceed with high 8 2 selectivity. Thus, the reaction of the chiral allylic phosphate 267 with 3-carbethoxypropylzinc iodide in the presence of CuCN 2LiCl (2 equivalents) furnishes the awf/-Sjv2 substitution product 268 in 68% yield. By the addition of w-BuLi (1.2 equivalents) and TMSCl (1.5 equivalents), the bicyclic enone 269 is obtained in 75% yield and 93% ee (Scheme 79) . 

Treatment of some mesylated N,N-diallylamino sugars with triethylamine tnhydrofluoride results m the fluorination and regioselective transfer of the mtro gen atom to give, after platinum-catalyzed reductive deallylation, 2,3-ammo-fluorodeoxysugars A mechanism involving aziridimum ions has been proposed [44] (equation 32)... 

The iodo derivative is a useful intermediate for the preparation of a wide variety of different types of compounds. Primary mesyl esters also react with sodium iodide in acetone, but the selectivity of this cleavage is less because of the greater reactivity of secondary mesyl esters. oa( ) Methyl 2,3,4-tri-0-acetyl-6-0-mesyl-a-D-glucopyranoside is converted into methyl 2,3,4,6-tetra-O-acetyl-a-D-glucopyranoside with acetic anhydride and potassium acetate. Replacements of a primary mesyloxy group with fluorine by use of potassium fluoride in methanol,106 with chlorine by use of lithium chloride,102 and with pyridine to form a pyri-dinium deoxy derivative,106 have been reported. Primary tosyloxy groups have been replaced by hydrogen,106 by thiocyanate,107 and by... 

Fluorine-18 labelled BD 1304, a high affinity and specific ligand for the sigma receptor90 92, has been obtained93 using [18F]fluoride from the amine bis-mesylate precursor (equation 41). 

Other good leaving groups have also been used. Many tosylates and mesylates were replaced with fluorine when KF in polyethylene glycol was employed50. Such a reaction was a key step for making various fluoroprostaglandins (equation 29)51. 

The synthesis of y-fluoroalkylated allylic alcohols and amines like 51 starting with chiral fluorinated allylic mesylates 50 has also been reported (Eq. 3) [134]. In this case, the regiochemistry of the addition is controlled by the substrate and the addition of the nucleophile occurs distal to the fluorinated alkyl chain. 

The SLibstitiilion of an inorganic ester group, such as /t-toluenesulfonate (tosylate), methanesul-I onate (mesylate), trifluoromethancsulfonate (triflate), cyclic sulfate, etc., by fluorine is one of the most important methods for the introduction of fluorine into aliphatic molecules. It is an indirect method for the substitution of a hydroxy group with a fluorine. By using an in situ esterification, e.g, with trifluoromethancsulfonyl fluoride, and fluorination, c.g. with tetrabutyl-ammonium fluoride, it also provides a one-pot reaction for realizing this reaction. 

Due to the relatively forcing reaction conditions, i.e. severe heating in strongly polar media, that are usually applied in potassium fluoride fluorinations. several attempts have been made to find mild and efficient methods to fluorinate with metal fluorides. l-(Mesyloxy)octane is converted into 1-fluorooetane in high yield with aqueous potassium fluoride in the presence of catalytic amounts of tributyldecylphosphonium bromide. Similarly, (m-fluoropropoxy)ni-trobenzenes are obtained in good yield from the corresponding mesylates with potassium fluo-... 

Allylic and benzylic alcohols have been converted into the corresponding fluorides in a one-pot reaction via in situ tosylation with tosyl fluoride and fluorination with lithium fluoride or in situ mesylation with mesyl fluoride and fluorination with cesium fluoride in the presence of crown ethers, respectively. 

A recent improvement in the method was achieved by using formamidc as solvent for the fluorination of mesylates 1. ... 

The preparation of fluorinated carbohydrates via nucleophilic displacement of the. sulfonate group of the corresponding sulfonates by fluoride is a well-known rcaction " however, potassium fluoride, which was used to prepare the first alkyl fluoride type of sugar derivative, has been progressively replaced by the alkylamine fluorides (.see Section 1.1.4.2.1.2.). The substitution of relatively unhindered primary mesylates or tosylates in cxocyclic positions of carbo-... 

Triethylamine trishydrofluoridc is commercially available and is readily prepared by mixing stoichiometric amounts of triethylamine and hydrogen fluoride with cooling. It was recently shown that with this reagent, at least in some cases, fluorinations of mesylates or triflates can be performed with results similar to those using the more expensive tris(dimethylamino)suiro-nium difluorotrimethylsilicate [TASF(Me)]. For example, 1 gives 2 in 87% yield with triethylamine trishydrofluoride compared to 80% with TASF(Mc). 

However, displacement of sulphur ester groups such as tosylate [183], mesylate [184] and triflate [185] groups are of much greater synthetic importance. These excellent leaving groups are readily displaced by an active source of fluoride ion this process represents an efficient method for the overall transformation of hydroxyl groups to fluorinated derivatives (Figure 3.33). 

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