Diastereoselective addition of heteroatom nucleophiles to ethyl 2-(diethoxymethyl)cycloprop-2-ene-1-carboxylate

We report a simple and straightforward route to hetero-functionalized cyclopropanes by addition of heteroatom nucleophiles to ethyl 2-(diethoxymethyl)cycloprop-2-ene-1-carboxylate. The resulting donor–acceptor substituted cyclopropane are useful synthetic intermediates owing to their high functionalization. Particular emphasis is placed in the stereochemical outcome of this reaction.


Introduction
Cyclopropenation of alkynes by diazocarbonyl compounds, promoted by copper or rhodium (II) catalysts, has been extensively studied. 1 Rhodium (II) carboxylates and carboxamides have been found the most effective cyclopropenation catalysts, although the yields depend on the nature of the alkyne substituents. 2This reaction offers a direct entry to highly functionalized cyclopropenes, 3 a very attractive class of strained rings that can be transformed into a wide variety of compounds because of its high reactivity. 4In the intramolecular version, the reaction of rhodium carbene complexes onto alkynes yields vinyl carbenoids that can be trapped in situ. 5

Scheme 1
Cyclopropenyl esters are very useful synthetic intermediates, readily available by slow addition of alkyl diazoacetates to an excess of the appropriate alkyne in the presence of a catalytic amount of rhodium acetate. 2 Following this general procedure, ethyl 2-(diethoxymethyl)cycloprop-2-ene-1-carboxylate (1) was prepared in 72% yield by reaction of propionaldehyde diethyl acetal (2) with ethyl diazoacetate (Scheme 2), using dirhodium(II) tetraacetate as catalyst.The cyclopropene 1 was purified by column chromatography and could be kept in the freezer under nitrogen for several days.The enantioselective cyclopropenation of propionaldehyde diethyl acetal (2) with methyl diazoacetate, using Rh 2 (5S-MEPY) 4 as chiral catalyst, has been described previously, in 42% yield. 11In a more recent paper, this reaction has been optimized by increasing the addition time and the reagent ratio.With the cyclopropene 1 in hand we have examined the addition of heteroatom nucleophiles (Table 1).For this purpose, we chose thioalkoxides (entries 1-4), selenides (entries 5, 6), and alkoxides.Of the three species studied, thioalkoxides and selenides were found to be more suitable nucleophiles for the desired reaction.We attribute this result to their softer nucleophilicity and to the higher stability of the resulting cyclopropanes.As an example, when we attempted the reaction of cyclopropene 1 with sodium ethoxide in ethanol, the corresponding addition product was detected and isolated in very low yield (12%).The same reaction with sodium methoxide in methanol provided the addition plus transesterification compound in 14% yield.A substantial amount of starting material was recovered in both cases.
The reactions proceeded under very mild conditions, at room temperature, using one equivalent of nucleophile.Acetonitrile was found to be the best solvent for thioalkoxides (entries 1-4) and DMF for selenides (entries 5 and 6).In all cases, a mixture of diastereomeric cyclopropanes 3 and 4 was obtained (Table 1).We were not able to separate the diastereomers by column chromatography, but they could be separated by HPLC.The relative configuration of cyclopropanes 3 and 4 was established by NMR spectroscopy, the assignment of the resonances being achieved through a combination of COSY and HMBC experiments.The stereochemistry of the cyclopropane ring was assigned from the observed coupling constants.The cyclopropane 5 (Figure 1) was isolated as the major compound, in 36 % yield.
The stereoselectivity obtained in the formation of major isomers could be rationalized by assuming attack of the heteroatom nucleophile from the less sterically hindered side, transto the alkoxycarbonyl group.For the small XR groups (entries 1-3), the subsequent protonation could occur from the bottom side, yielding the cyclopropanes 3a-3c as major isomers.Bulkier groups (entries 4-6) should direct protonation from the top face, giving compounds 4d-4f.
Although yields are moderate (Table 1), all the attempts to increase them were unsuccessful after an extensive search for optimal conditions.In most cases, no reaction was observed at 0 ºC.Heating of the reactions to 40 ºC led to decomposition of the cyclopropene 1.The use of a twofold molar excess of sodium thioalkoxide did not modify the yield.For the same nucleophile type, we have observed that the yield decreases with the size of the R group (Table 1).In fact, when we tried the reaction with the sterically hindered sodium salt of 1methyl-5-mercaptotetrazole, no addition was observed.With sodium methylselenide (entry 5), the yield of the resulting cyclopropenes 3e, 4e was lower than expected, owing to some instability detected during purification.Although the cyclopropanes 3, 4 were stable and could be purified by chromatography, they were kept in the freezer under nitrogen to avoid slow decomposition.It is known that donor-acceptor substituted cyclopropanes are particularly unstable substrates, and they are prone to rapid ring-opening reactions. 13he reaction of ethyl 2-mercaptoacetate (entry 3) with cyclopropene 1 using sodium hydride as base (1.1 equiv.)provided the cyclopropane 3c only in 25% yield.This is due to the presence of the unexpected regioisomer 5 (Figure 1), which was isolated in 36% yield.Although the mechanism of formation of the cyclopropane 5 is unclear, its formation could be explained in terms of a process that involves partial isomerization of the double bond under the reaction conditions, and subsequent Michael addition.We attribute this competitive reaction to the lower nucleophilicity of ethyl 2-mercaptoacetate.The relative configuration of the cyclopropane 5 was determined by NMR spectroscopy through a combination of COSY, HSQC and HMBC experiments.1D-and 2D-NOESY experiments were carried out to determine the relative disposition of the substituents in the cyclopropane ring.The key NOE for determining the relative configuration is shown in Figure 2. The existence of a NOE between H-4 and H-3a, although no NOEs were detected between H-4 and H-3b or between H-4 and H-1, demonstrates that H-4 and H-3a are on the same side of the ring.

Conclusions
In summary, we have shown that 3-hetero-substituted 2-(diethoxymethyl)cyclopropane-1carboxylates can be obtained easily, using a simple and convenient methodology, by addition of heteroatom nucleophiles to the readily available ethyl 2-(diethoxymethyl)cycloprop-2-ene-1carboxylate.Although yields were moderate, all reactions proceeded with high selectivity with a common transnucleophilic addition.The relative configuration of the third stereogenic center formed can be reversed by modifying the size of the nucleophile.

Figure 2 .
Figure 2. Minimum energy conformation of 5 (MMFF force field) showing the key NOE interaction.Ethyl groups are omitted for clarity.

Table 1 .
Addition bDetermined by 1 H-NMR.c 13l solvents and reagents were purchased from commercial sources and used without further purification.All reactions were carried out under a positive pressure of nitrogen.RT denotes room temperature.Analytical TLC was performed on Merck TLC glass plates precoated with F 254 silica gel 60.Silica gel 60 (Merck, 230-400 mesh) was used for flash chromatography.IR spectra were obtained on a Nicolet 510 P-FT.1H-and13C-NMR spectra were recorded on Bruker Avance 200 and 500 spectrometers as noted below.Chemical shifts are expressed as δ values (ppm) relative to internal TMS (0 ppm).Absolute-value COSY, phasesensitive HSQC, and HMBC spectra were acquired using gradient-selection techniques.1D-NOESY experiments were carried out with the selective 1D-double-pulse field gradient spin echo module using a mixing time of 500 ms.2D-NOESY experiments were also performed with the same mixing time.Data were processed using the XWINNMR Bruker program on a Silicon Graphics computer.