Regio-and stereo-selective coupling reactions of heteroarylalkyl propargyl ethers with electrophiles

Treatment of heteroarylalkyl propargyl ethers with n-BuLi affords relatively stable α− and α ’-carbanions. Deprotonation performed in the presence of electrophiles leads to heteroaryl-substituted propargylic ethers and hydroxyalkylpropargylic ethers, containing new stereogenic centers. When the same reactions were carried out in the presence of an external chiral ligand, fairly good asymmetric induction was observed


Introduction
Carbanions α− to an aza-heterocycle are known to be relatively stable. 1 More interesting in synthetic organic chemistry are those carbanions which possess a further electron-withdrawing group.α-Chlorocarbenoids, prepared by deprotonation of the corresponding α-chloro-heteroarylalkanes, have been widely exploited as key intermediates in the synthesis of oxiranes 2 and aziridines.2c,3 Less studied as synthetic intermediates are those hetero-substituted carbenoids which possess in their framework an oxygen, 4,5 a nitrogen, or a sulfur atom other than in the heterocycle.

Results and Discussion
The heteroarylalkyl propargyl ethers 1--5, prepared as reported, 4 were treated with n-BuLi in THF at -78°C, in the presence of various electrophiles (Scheme 1).The resulting lithiated species coupled efficiently with the electrophile; the outcome of the coupling reaction depending upon the heterocyclic group linked to the ether.The incoming electrophile goes to the α-carbon in the case of benzothiazolyl ethers, and to the α'-carbon atom with pyridyl-, thiazolyl-, and oxazolinyl ethers.Such a trend parallels the 1,2-and 2,3-Wittig rearrangements, which occur when the propargylic heteroaryl ethers are deprotonated in the absence of the external electrophile.Indeed, as anticipated in a previous paper, the deprotonation of 2-(but-2ynyloxymethyl)benzothiazole 1 with n-BuLi in THF at -78°C, followed by the addition of iodomethane, afforded the 2-[1-(but-2-ynyloxy)ethyl]benzothiazole 1a. 4 Thus proving that the carbanion generation takes place at the α-carbon atom, immediately trapped by the CH 3 I (Table 1: Entry 1).
Compounds reported in a previous paper 4 and listed in this Scheme only for comparison purposes.
Comparable results were obtained when the substrate 1 was deprotonated in the presence of different electrophiles, such as trimethylchlorosilane, allyl bromide, or benzyl chloride (entries 4, 5, and 6).The isolated reaction products were, again, coupling products at the α-carbon atom.Similarly, treatment of 2 with n-BuLi in the presence of CH 3 I provided the α-carbonatommethylated compound 2a as the sole reaction product (80% yield, entry 7).In contrast, treatment of 2-(3-phenylprop-2-ynyloxy-methyl)pyridine 3 with n-BuLi in the presence of CH 3 I afforded the methylation product 3a, arising from the deprotonation at the α'-carbon atom (entry 8), together with the [1,2]-Wittig rearrangement product. 4Similarly, deprotonation-methylation of 4 produced the methylation product 4a, arising again from the deprotonation at the α'-carbon atom (55% yield, entry 9), together with the [1,2]-Wittig rearrangement product.The deprotonationmethylation combination of 4,4-dimethyl-2-[1-(3-phenylprop-2-ynyloxy)ethyl]-4,5-dihydro-1,3oxazole 5 afforded compound 5a (60% yield, entry 10) as the sole reaction product, arising from the deprotonation at the α'-carbon atom.The consideration that the deprotonation-alkylation sequence of the above propargylic ethers provides products with new stereogenic centres prompted us to investigate a possible asymmetric induction by using an external chiral ligand.The coupling reaction of the substrate 1 with iodomethane was then carried out in the presence of (−)-sparteine as the external chiral ligand, in n-hexane and toluene (entries 2 and 3).A reasonable level of enantioselection was observed, and this seemed to be remarkably dependent upon the solvent used.In n-hexane, low enantioselectivity (ee = 14, entry 2) was observed; in toluene the methylated product 1a was isolated with a good enantiomeric enrichment (ee = 60; entry 3), according to the results reported for asymmetric [2,3]-Wittig rearrangements of crotyl furfuryl ethers. 12Encouraged by these findings, we performed several coupling reactions of substrate 1 with various symmetric ketones, obtaining hydroxypropargylic ethers as the only reaction products (Scheme 2). 1e-1l Coupling reaction of 2-(but-2-ynyloxymethyl)benzothiazole, 1, with symmetrical ketones.
In order to check the asymmetric induction in more detail, each reaction was performed in three different solvents: THF, n-hexane and toluene, in the presence of (−)-sparteine.The presence of the external chiral ligand usually lowered the yield of the coupling product.No enantioselection was observed in THF, and the lack of stereoselection could be ascribed to the THF's co-ordinating power, which probably prevents the generation of chiral co-ordinated intermediate involving the lithiated species and (−)-sparteine.In n-hexane, and especially in toluene, the (−)-sparteine allowed the formation of a chiral co-ordinated anion leading, by coupling with the corresponding ketone, to hydroxypropargylic ethers with remarkable enantiomeric enrichments (Table 1 In conclusion, we have shown that heteroarylalkyl propargyl ethers, deprotonated at the αcarbon atom or at the α'-carbon atom, depending on the stabilizing group of the carbanionic center, undergo a coupling reaction with a number of different electrophiles.Using this protocol, more complicated organic structures can be synthesized, such as compounds containing alkyl-or alcoholic functions.The carbanion complexation by an external chiral ligand leads to enantiomerically enriched mixtures (ee = 64).The option of freeing the acyl groups masked by the heterocycles (benzothiazole, thiazole, oxazoline) and the presence in their framework of various functions, makes them good intermediates for polyfunctional compounds such as heteroaryl hydroxy aldehydes which are of synthetic interest.

Experimental Section
General Procedures.n-BuLi was a commercial solution in hexanes (Aldrich) and was titrated with N-pivaloyl-o-toluidine prior to use. 13  reagents were performed under nitrogen in oven-dried glassware using syringe/septum cap techniques.
General procedure for the coupling reactions of heteroarylalkyl propargyl ethers with alkyl halides 1a and 3a were prepared as reported. 4The synthesis of the compound 1a was performed also in the presence of (−)-sparteine (2 mmol) in n-hexane and toluene as solvent, following the same reported procedure. 4

Table 1 .
Coupling reactions of heteroarylalkyl propargyl ethers with electrophiles ).The enantiomeric enrichments were measured, for almost all the reactions, by HPLC analyses (more details are given in the Experimental Section).The entries 18−19, 25−26) was measured by 1 H NMR analyses, calculating the integral's ratio of the two different broad signals given by the enantiomeric protons (δ = 5.30 and 5.22 for 1g, δ = 6.50 and 5.60 for 1l) distinguished by adding Eu(tfc) 3 as chiral NMR shift reagent.When cyclohexanone was used as the electrophile (entry 23) neither HPLC, nor the 1 H NMR technique allowed us to measure any enantiomeric enrichment of 1i.