Alkylation reactions Methylation, Propargylation

Assembly of the subunits began with the Nozaki-Kishi coupling reaction of iodoacetylene 13 and aldehyde 12, in the presence of CrCl2/NiCl2, to provide propargylic alcohol 23, with 3 1 dr at C7 (Scheme 3). The four-step conversion to bromide 24 was followed by the enolate alkylation of methyl ketone 14. 

The general synthetic scheme employing the reaction of 2-halo-substituted hetero-cyclics with the appropriate acetylenes in the presence of palladium catalyst affords the 2-alkyne-substituted heterocyclics, l-(2-benzothiazol)-2-phenylethyne was used followed by N-alkylation with methyl or propargyl triflate produces l-[2-(N-propargyl-benzothiazolium)]-2-phenylethyne. 

In a second approach, the (S)-proline derivative was used as the alkyne precursor in the click reaction. A propargyl subunit was introduced at the 4-hydroxy position of a diprotected frans hydroxy proline 39 by means of Williamson ether synthesis. Click reaction with an alkyl azide furnished the triazole 41 in good yield. This product was transformed into the desired 1,2,3-triazolium ionic liquid tagged (S)-proline catalyst 44 by means of an analogous methylation, salt metathesis and a final removal of the protecting groups (Scheme 9) (Shah, Khan et al. 2009). 

The reaction of methyl propargylate (propiolate) with benzylimidazole and its 2-alkyl and aryl derivatives in acetonitrile leads to the formation of the methyl esters of 3-fran -(l-benzimidazolyl)acrylic acid 106a and 107a, b, whereas the reaction with benzimidazole in methanol leads exclusively to the corresponding cis isomer 106b in the absence of the solvent, the treatment of benzimidazole with methyl propiolate gives a mixture of compounds 106a, b, and pyrrolo[l,2-a]ben-zimidazole 108 (Fig. 3.5). At the same time, the 2-isopropyl, 2-phenyl, and 2-benzyl derivatives of benzimidazole in reaction with methyl propiolate without a solvent form the pyrrolo[l,2-a]quinoxalines 114 and 115 (Scheme 3.35) (Acheson and Verlander 1973). 

The beneficial effect of added phosphine on the chemo- and stereoselectivity of the Sn2 substitution of propargyl oxiranes is demonstrated in the reaction of substrate 27 with lithium dimethylcyanocuprate in diethyl ether (Scheme 2.9). In the absence of the phosphine ligand, reduction of the substrate prevailed and attempts to shift the product ratio in favor of 29 by addition of methyl iodide (which should alkylate the presumable intermediate 24 [8k]) had almost no effect. In contrast, the desired substitution product 29 was formed with good chemo- and anti-stereoselectivity when tri-n-butylphosphine was present in the reaction mixture [25, 31]. Interestingly, this effect is strongly solvent dependent, since a complex product mixture was formed when THF was used instead of diethyl ether. With sulfur-containing copper sources such as copper bromide-dimethyl sulfide complex or copper 2-thiophenecarboxylate, however, addition of the phosphine caused the opposite effect, i.e. exclusive formation of the reduced allene 28. Hence the course and outcome of the SN2 substitution show a rather complex dependence on the reaction partners and conditions, which needs to be further elucidated. 

The analogue, t-butyl methyl iminodicarboxylate 25, is obtained by the reaction of methanol with t-butyl oxamate (24) in the presence of lead tetraacetate. Its stable non-hygroscopic potassium salt is converted into alkyl derivatives 26 by the action of alkyl halides such as butyl bromide, allyl bromide, propargyl bromide and ethyl bromoacetate. The products are hydrolysed by trifluoroacetic acid to salts of primary amines, whereas... 

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