Highly Regioselective Addition of Allylic Zinc Halides and Various Zinc Enolates to [1.1.1]Propellane

Abstract We report a range of highly regioselective openings of [1.1.1]propellane with various allylic zinc halides, as well as zinc enolates of ketones, esters and nitriles. The resulting zincated bicyclopentanes (BCPs) were trapped with a range of electrophiles including acyl chlorides, sulfonothioates, hydroxylamino benzoates, tosyl cyanide as well as aryl and allyl halides, generating highly functionalized BCP‐derivatives. The unusually high regioselectivity of these reactions has been rationalized using DFT calculations. A bioisostere of the synthetic opioid pethidine was prepared in 95 % yield in one step using this method.

Theaddition of organozinc halides to [1.1.1]propellane (1) has not yet been reported. Indeed, we have observed that alkyl-, aryl-and benzylzinc halides were not able to react with [1.1.1]propellane (1)even under harsh conditions (100 8 8C, up to 60 h). Since allylic zinc halides (7)d isplay an enhanced reactivity due to am ore polar carbon-zinc bond, [19] we envisioned that they could add to [1.1.1]propellane (1), allowing the formation of zincated BCPs of type 8 (Scheme 3). Subsequent trapping with various electrophiles (E-Y) would then provide double functionalized BCPs of type 9.Asimilar reactivity would be expected for zinc enolates generated from ketones (10)a nd esters (11), [20] leading to zincated BCPs of type 12 or 13,w hich after electrophilic trapping would generate functionalized BCPs of type 14 and 15.Herein, we report these highly regioselective reactions,aswell as atheoretical rationalization of their high selectivity and as traightforward one step synthesis of the BCP-bioisostere 6 of the synthetic opioid pethidine (Scheme 1).
Next, we turned our attention to zinc enolates.Initially,we treated ketones of type 16 with an equimolar amount of LDA (17)a tÀ78 8 8C, followed by the same amount of ZnCl 2 .T he resulting zinc enolates added smoothly to [1.1.1]propellane (1,0 .5-2 h, 0 8 8C, Scheme 8). However,t he newly generated zincated BCPs were mostly protonated before they could be trapped with electrophiles,p robably due to the competitive deprotonation of the acidic protons in a-position to the carbonyl group.T his problem was solved by using 2equivalents of LDAf or 1equivalent of the ketone,f ollowed by transmetalation with ZnCl 2 (2.3 equiv), presumably leading to mixed zinc enolates coordinated with NiPr 2 (10). The zincated BCPs of type 12 that resulted from the addition of these amidozinc enolates to [1.1.1]propellane (1,0.5-2 h, 0 8 8C, Scheme 8) were apparently much less prone to protonation compared to the standard zincated BCPs. [30] Alternatively,the additional amide might also deprotonate the ketone products, thus removing the acidic protons.P ossible trapping reactions included protonation (14 a, 14 g), copper-catalyzed allylations (14 b, 14 f, 14 h, 14 i), ap alladium-catalyzed Negishi crosscoupling (14 c), an acylation (14 d)and acyanation performed with tosyl cyanide (14 e). Theo verall yield of the sequence including enolate addition and electrophilic trapping was 46-88 %. In the case of cyclohexyl acetone and dihydro-b-ionone aregioselective enolate formation was achieved and only the products 14 f and 14 g,inwhich the BCP unit is attached to the terminal methyl groups,w ere obtained in 67-71 %y ield. Moreover,t he sterically hindered isobutyrophenone was added to 1,l eading to the BCP-derivative 14 h in 86 %y ield.
Thereaction with cyclohex-2-en-1-one led to the formation of the expected cyclohexenone derivative 14 i in 75 %yield.
Finally,t he a-deprotonation of nitriles (19 a-19 c, 2.0 equiv) with LDA(17,2.1 equiv) followed by atransmetalation with ZnCl 2 (2.5 equiv) led to the formation of nitrilestabilized carbanions of type 20, [33] which added to [1.1.1]propellane (1)within 1-6 hat258 8C. Theresulting zincated BCPs of type 21 were then submitted to ac opper-catalyzed allylation with allyl bromide (2.5 equiv,S cheme 10). This protocol was used to prepare BCP-derivatives of cyclohexanecarbonitrile (22 a)a nd 2-phenylpropanenitrile (22 b)i n 51-96 %y ield. When using 1-cyanocyclohexene as as tarting material, the BCP 22 c was isolated in 96 %yield. This can be explained due to ar earrangement after the initial deprotonation in the allylic position, resulting in the formation of the most stabilized anion. [34] With this optimized procedure,w eh ave carried out the synthesis of the BCP-analogue of the synthetic opioid pethidine [8] (24,S cheme 11). Thed eprotonation of commercially available ethyl 1-methylpiperidine-4-carboxylate (23, 2.0 equiv) with LDA( 17,2 .1 equiv) proceeded smoothly within 30 min at À78 8 8Ci nT HF.A fter the addition of ZnCl 2 (2.5 equiv) the resulting zinc enolate was reacted with [1.1.1]propellane (1,1.0 equiv) at 0 8 8Cfor 2h.T he generated zincated BCP was trapped through the addition of asaturated aqueous solution of NH 4 Cl. Thec rude mixture was purified using column chromatography,a ffording the pethidine analogue 6 in 95 %yield on a1.5 mmol scale in asingle step.The structure of the isolated product was confirmed by X-ray analysis. [35] In order to rationalize the exquisite regioselectivity observed in transformations with unsymmetrically substituted allylic zinc species,t heoretical calculations have been performed for the reaction of propellane (1)w ith prenylzinc bromide complexed with lithium chloride (7d), whose sole reaction product is the BCP 9k (Scheme 6). Following effectively the same protocol used in earlier studies of organozinc reagents, [36] free energies in THF solution have been calculated at the SMD(THF)/B2PLYP/def2-TZVPP level of theory (see SI for further details). Calculations start from the cubic cluster 25 assembled from 2equivalents of LiCl, ZnBr 2 , [37] and prenylzinc bromide (7k). Complexation of propellane to one of the zinc centres in 25 displaces one of the cluster bromide atoms and generates the adduct 26 in am ildly exergonic first step.F ormation of the adduct 26 is accompanied by am inor degree of charge transfer from the propellane unit to the cluster 25 by 0.11e,b ut leads to practically no change of the propellane structure itself. [38] Backside attack of the prenyl side chain at the bound propellane unit through the transition state 27 then carries the system over to the product side,whose ultimate end point is the cubic cluster 28 located À42.7 kJ mol À1 lower than the separate reactants (for additional transient intermediates on the way to the product 28 see SI). That the barrier for this reaction amounts to only 52 kJ mol À1 demonstrates the intrinsic flexibility of the salt cluster that thus acts as at emplate for the reacting organozinc/propellane units.A s can readily be seen from the 3D presentation of the transition state 27 in Figure 1, formation of the CÀZn bond is almost

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Research Articles 20238 www.angewandte.org complete at r(C-Zn) = 205 pm, while formation of the C À C bond between the propellane and prenyl units is still underway with r(CÀC) = 203 pm. From the almost perfect alignment of both reacting bonds along the propellane axis it is also apparent, that the cluster template exerts practically no external strain onto the reacting fragments.T he overall reaction cycle is completed by salt metathesis of the product cluster 28 with one equivalent of the prenylzinc reagent 7d, yielding the starting cluster 25 and the product organozinc species 8d (Scheme 12). This reaction is almost thermoneutral at DG 298 = À2.5 kJ mol À1 .The activation of propellane (1) by other cluster designs or through other activation modes has also been studied, but all of these variations are energetically less favourable than the reaction pathway shown in Scheme 12 (see SI). This includes the reaction with ac luster containing the regioisomeric form of prenylzinc bromide,i n which the zinc is located at the tertiary carbon atom. Forthis cluster the calculated reaction barrier was 43.6 kJ mol À1 higher than the one detailed in Scheme 12. Therefore,t he high regioselectivity can be attributed to akinetic selectivity. Good energetics have been found for the reaction of propellane with ar adical version of the cluster 25 (lacking ab romine atom). However,t his reaction pathway suffers from the lack of aw ell-defined step for the initial radical formation. Areaction pathway starting with the coordination of [1.1.1]propellane to lithium instead of zinc resulted in ar eaction barrier that was 82.5 kJ mol À1 higher than the one detailed in Scheme 12.

Conclusion
We have reported arange of new regioselective openings of [1.1.1]propellane (1)w ith various allylic zinc halides,a s well as zinc enolates of ketones,e sters and nitriles.T he resulting zincated BCPs were trapped with ar ange of electrophiles,i ncluding acyl chlorides,a ryl and allyl halides as well as sulfonothioates,hydroxylamino benzoates and tosyl cyanide,g enerating new highly functionalized BCP derivatives.R emarkably,t he opening of [1.1.1]propellane (1)w ith unsymmetrical allylic zinc reagents proceeds via ac omplete allylic rearrangement. This behaviour was rationalized by DFT-calculations,w hich showed that the allylic rearrangement proceeds via ac yclic transition state (27)i nvolving ZnBr 2 ,L iCl, the allylic zinc halide and [1.1.1]propellane. Furthermore,w eh ave demonstrated the utility of our procedure by preparing ab ioisostere of the synthetic opioid pethidine in 95 %yield in as ingle step.