5-Fluoro 5 -thioethers

Treatment of thioethers with xenon difluoride, or a-chloro thioethers with potassium fluoride/crown ether, had been reported to give a-fluoro thioethers. McCarthy and... 

We applied the McCarthy DAST procedure to the sulfoxides 9a (see Scheme 2) derived by selective oxidation of 2, 3 -di-0-acetyl-5 -S-phenyl-5 -thioadenosine (8a) [ 1 equivalent MCPBA (3-chloroperoxybenzoic acid)/-40 C], but observed minimal conversion to the desired a-fluoro thioethers. The major product was the deoxygenated thioether precursor 8a. Addition of zinc(II) iodide as catalyst resulted in rapid deoxygenation of 9a to give 8a. Facile deoxygenation of sulfoxides to thioethers had been reported with sodium iodide and boron trifluoride etherate, so we investigated other Lewis acid systems that did not contain iodide. 

Several compounds were examined for concentration-dependent inactivation of AdoHcy hydrolase from beef liver (Table 1), and candidates were selected for evaluation of time-dependent inactivation (Table 2). The 5 -a-fluoro thioethers 10a, 10b, and 10c were quite potent inactivators. However, it was observed that lOa-c were unstable in the buffer test solutions, and other compounds were formed (HPLC) soon after the samples were dissolved. H NMR peaks at 6 9.8 and -11.7 (DMSO-de) were present after 10a was allowed to stand in aqueous solution. The first peak was stable upon addition of D2O, but the second peak at 5 11.7 rapidly disappeared upon D2O exchange. This is consistent with chemical hydrolysis of the 5 -a-fluoro thioethers 10 to give the epimoic 4 -carbaldehyde 28, hydroxy enol etho 29, and aldehyde dihydrate 30 products (see Scheme 4). 

Since 7b was not an inhibitor and apparently was not oxidized to its 3 -keto intermediate, it is unlikely that 5 -fIuoro derivatives of 7b (i.e., the active 10b) would be alternative substrates. It is more probable that the 10b diastereomers undergo chemical hydrolysis to an active species. This is consistent with the facile hydrolysis of 10b to give an active species and the absence of formation of this species from the chemically stable 18. Specific inhibition by a species derived from adenosine 5 -a-fluoro thioethers rather than nonspecific inhibition by fluoride, thiophenol, or generic nucleoside 5 -aldehyde products is supported by lack of inhibition with the uridine analope of 10b. 

Slight differences in inhibitory concentrations and rates of inactivation of AdoHcy hydrolase were observed between diastereomer-enriched samples of the 4-chlorophenylthio compounds 10c (Table 2) and larger differences relative to the 4-methoxyphenylthio analogues 10b were found. Current studies indicate that different rates and/or mechanisms of chemical hydrolysis of the a-fluoro thioethers can account for these differences. 

J.R. McCarthy, NP. Peet, ME, LeToumeau, and M. Inbasekaran, (Diethylamino)sulfur trifluoride in organic synthesis. 2. The transformation of sulfoxides to a-fluoro thioethers, J, Am, Chem, Soc, 107 735 (1985). 

S.F. Wnuk and M.J. Robins, Antimony(III) chloride exerts potent catalysis of the conversion of sulfoxides to a-fluoro thioethers with (diethylamino)sulfur trifluoride, J, Org, Chem, 55 4757 (1990). 

Intramolecular cyclization of 2-lithiobenzyl-2-halophenyl amines, ethers, and thioethers—Synthesis of phenanthridine, dibenzopyran, and dibenzothiopyran derivatives Having demonstrated the efficiency of this methodology for the preparation of indole derivatives, we prepared the 2-fluoro-phenyl ether and thioether 22 a, b to study their potential as substrates that could afford oxygen and sulfur heterocycles. However, treatment of 22 a, b with fBuLi afforded, after... 

Besides processes (1) and (2), the reader should be aware that nucleophilic attacks on alkynes are treated in other chapters of this book, dealing with rearrangements, cyclizations, polyacetylenes, cyclic acetylenes and perhaps others. A number of publications overlap with ours in different ways and at different levels -. They treat individual alkynes or families " , e.g. acetylene, diacetylenes , acetylene dicarboxylic esters haloacetylenes , alkynyl ethers and thioethers > ynamines , fluoro-alkynes ethynyl ketpnes , nitroalkynes , etc. synthetic targets, e.g. pyrazoles , if-l,2,3-triazoles , isothiazoles , indolizines S etc. reagents, e.g. nitrones , lithium aluminium hydride , heterocyclic A -oxides - , azomethine ylids - , tertiary phosphorus compounds , miscellaneous dipolar nucleophiles - , etc. The reader will appreciate that all of these constitute alternate entries into our subject. 

The electrochemical behavior of dithioacetals under fluorination conditions (DME-Et N 3HF, divided cell, Pt electrodes) deserves attention. Anodic oxidation of 2,2-disubstituted 1,3-dithianes and thioacetals of ketones produced the corresponding geminal fluoro compounds, while thioacetals of aromatic and aliphatic aldehydes afforded geminal difluoro- and monofluoro thioethers, respectively [147] (see Chapter 26). 

Reaction of thioethers with one equivalent of NF-reagent results in the formation of a-fluorothioethers via a fluoro-Pummerer rearrangement [199] (Scheme 2.90). With appropriate excesses a-fluorosulfoxides and sulfones are obtained [200]. The thiophenyl group can also be used as a subsequently removable directing function for site-selective fluorination of natural products [201]. 

Claisen rearrangement. On contrary, thioethers 226 and 227 synthesized by the reaction of the corresponding furan or thiophene with allyl mercaptane are thermally stable and no evidence of thio-Claisen rearrangement of these compounds was found. ° The fluorine atom of 2-fluoro-3-trifluoromethylfurans and thiophenes can be replaced upon nucleophilic substitution with benzyl alcohols. Compounds 228 are susceptible to [1,3]- and [l,5]-benzyl group migration. " ... 

A series of high molecular weight poly(thioether ketone)s (M = 55,000-100,000), eg, (24) and (25), have successfully been prepared from bis(4-mercaptophenyl) ether (4,4 -dimercaptodiphenyl ether) or bis(4-mercaptophenyl) sulfide (4,4 -dimercaptodiphenyl sulfide) by reaction with a series of ketone-activated aromatic fluoro-compoimds in the presence of anhydrous K2CO3. The polymers are amorphous and soluble in common organic solvents. They show TgS from 154 to 251°C and excellent thermal stability [temperatures of 5% weight loss (Tds) even above 500°C] (65). 

Deoxy-5 -(cyclopropylmethylthlo)adenosine (70) has been prepared from 5 -chloroadenosine,l23 and there has been a further report on the synthesis of 5 -(fluoromethylthio)adenosine (71), formed with the 5 -fluoro-5 -methylthio compound discussed last year (see Vol.22, p. 212) from reaction of the 5 -methylsulphinyl derivative with DAST. Thioether (71) is a potent inhibitor of methylthioadenoslne phosphorylase.i24 An oxidation-reduction... 

Fluorination at C5 of nucleoside 5 -thioethers with DAST/antimony(III) chloride or xenon difluoride to give 5 -S-aryl-5 -fluoro-5 -thiouridines, J, Org, Chem. 56 6878 (1991). 

A variety of discotics can be prepared from the tetrabromopyrene 59 as shown in Scheme 4.17. Thus, the Suzuki coupling between 59 and commercially available methoxyphenylboronic acid or 1-fluorophenylboronic acid yields tefiaphenyl derivatives 64 and 67, respectively. Demethylation of 64 with HBr yields 1,3,6,8-tetrakis(4-hydroxyphenyl)-pyrene 65 which can be alkylated with different alkyl halides to tetraethers 66. Similarly, esterification of the tetraphenol with acid chloride or benzoic acid affords tetraesters 66 (R = COR) or benzoate 66 (R = CORiR), respectively [111]. Replacement of fluoro atoms with alkylthiolates generates nonmesomorphic tetra-thioethers of pyrene 68. 

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