Scope, applications and limitations

After Grignard reagents were found to be the best nucleophiles for the synthesis of diaryl sulfides from cationic imidazolium sulfides, as shown in the previous Chapter 3.5.1 for 99 and 129, a library of 28 diaryl sulfides was synthesized (Scheme 92). The concentration of the utilized Grignard reagents was determined by titration before usage following established protocols.^[270] For less reactive reagents and reactants, an excess of up to 2.9 equivalents of the organomagnesium reagent was used. In cases of cationic imidazolium sulfides possessed

94 protic functional groups like carboxylic acids, additional equivalents of the organometallic nucleophile were added (e. g. 87).

Studies revealed that more electron-rich und therefore more nucleophilic Grignard reagents gave higher yields of the desired aryl sulfides. Thus, para-methoxyphenylmagnesium bromide afforded arylsulfide 161 in 94% yield, whereas the utilization of corresponding fluoro- and cyano-containing Grignards resulted in formation of 162 and 163 in 67% and 78% yield, respectively.

With the optimized reaction conditions in hand also more sophisticated diaryl sulfides with menthol (165 and 187) or sugar (169) motifs were accessible in yields of 89%, 51% and 53%, respectively. For the introduction of para-cyanophenyl (163) and bromopyridyl (172) motifs, the applied Grignard reagents were obtained by a LiCl-mediated Br/Mg exchange reaction, as reported by the group of Knochel and coworkers.^[271]

In other cases, e. g. for the synthesis of benzothiazole- (170), dichloropyridine- (173) and quinolone-containing (166) thioethers, Grignard reagents were prepared by deprotonation of the corresponding heterocycle with 2,2,6,6-tetramethylpiperidinylmagnesium chloride in the presence of lithium chloride (TMPMgCl LiCl) following the protocol of Knochel and coworkers.^[272] In case of the furylpyrrolyl sulfide 167 it could be shown that also lithiumorganic reagents can be utilized as nucleophiles. In contrast to the observation of the group of N. Kuhn who reported the nucleophilic substitution of SMe^- at the C2 atom of the imidazolium motif of 2-(methylthio)imidazolium salts with methyl lithium, the utilized furyllithium organyl selectively substituted the NHC under formation of the desired aryl sulfide 167.^[273]

However, different metalalkynyl reagents (metal = Mg, Zn, Li) were not reactive enough to form alkyne sulfides 177, and sterically demanding Grignard reagents (e. g. mesitylmagnesium bromide) gave only traces of the desired product 178. Unfortunately, the utilization of thiophenyl- and allylmagnesium bromide resulted in complex reaction mixtures.

95

Scheme 92: Scope of diaryl sulfides.

96 In several cases (compounds 168, 87, 175, 170, 163 and 162) X-ray crystallography confirmed the expected connectivity of the obtained sulfides. The representative crystal structure of 168

& 87 can be seen in Figure 23.

Figure 23: Molecular structure of compound of 168 and 170 Non-acidic hydrogen atoms and solvent molecules are omitted for clarity. Thermal ellipsoids are drawn at 50% probability level.

After several diaryl sulfides were successfully synthesized it could be shown, that alkyl aryl and alkenyl aryl sulfides were also accessible by the developed methodology with yields up to 93% (Scheme 93). From the synthetic point of view, the introduction of alkenyl groups as in compounds 193, 195, 196 and 200 is of immense interest, because they are potential precursors for the formation of new C=C double bonds by alkene metathesis reaction.^[80]

Additionally, double bonds can be functionalized by bromination^[274], epoxidation^[275], aziridination^[276] and other chemical transformations^[277] to allow the selective introduction of new functional groups into a structure. As already discussed above in the case of diaryl sulfide synthesis, also lithiumorganic nucleophiles like sec- or tert-butyllithium can be utilized for the synthesis of the desired alkyl aryl sulfide 197 and 192.

97

Scheme 93: Scope of alkyl and alkenyl aryl sulfides.

In addition to the mono-sulfenylations of N-phenylpyrrole resulting in thioethers 161 to 164 already described above (see Scheme 92), also the twofold sulfenylated species 88 was accessible by stepwise transformation of 161 with an overall yield of 61% (Scheme 94).

Scheme 94: Synthesis of twofold sulfenylated N-phenylpyrrole 88 via imidazolium salt 201.

98 Having the established protocol for the sulfenylation of arenes and heteroarenes in hand, the potential of the methodology was demonstrated in the synthesis of the compound 87, which is the precursor of the compound 151 (Scheme 95, A). Studies of R. Silvestri et al. have shown that 151 is a potent inhibitor of tubulin assembly and therefore a potential candidate for the treatment of cancer.^[11,12] Upon sulfenylation of the indole derivative 203, the corresponding imidazolium chloride 117 precipitated from the reaction mixture and was obtained in good yield of 79%, as already shown in Scheme 85. Subsequent reaction of 117 with an excess of phenylmagnesium bromide gave access to precursor 87, whereas lowering the quantity of Grignard reagent to 3.5 equivalents decreased the yield significantly to 35% (Scheme 95, B).

Attempts to obtain the tubulin inhibitor 151 starting from ethyl ester 204 failed, since the reaction of nearly quantitatively isolated intermediate 118 with Grignard reagent resulted in the formation of several by-products, most probably due to the reaction of the ester functionality with the Grignard reagent. Noteworthy, the sulfenylation of 190 with an overall yield of 49%

starting is superior to the sulfenylation step in the work of R. Silvestri cited above, who reported a lower yield of 35% for the sulfenylation of 204 utilizing N-thiophenylsuccinimide and equimolar amounts of boron trifluoride diethyl etherate.^[11]

Scheme 95: A: Approach to potent inhibitor of tubulin assembly 151 by esterfication of precursor 87; B:

Preparation of precursor 1141 and attempted synthesis of 151.

99 The connectivity of the obtained imidazolium salts 117, 118 and of compound 87 was verified by X-ray diffraction of single crystals (Figure 24).

Figure 24: Molecular structure of imidazolium salts 117 and 118 and precursor 87 in the crystal. Non-acidic hydrogen atoms, anions and solvent molecules are omitted for clarity. Thermal ellipsoids are drawn at 50%

probability level.

100