Asymmetric synthesis of cyclopropanes by reaction of (2 E, S S )-(+)-4,4-diethoxy-2-[(4-methylphenyl)sulfinyl]but-2-enenitrile and 2-methoxyfuran

The reaction of 2-methoxyfuran with the 2-sulfinylacrylonitrile 1 provides a route to the asymmetric synthesis of cyclopropanes. Problems associated with the separation of the two formed diastereoisomers and the epimerization observed in desulfinylation reactions are described.


Introduction
The stereoselective construction of optically pure functionalized cyclopropanes is a matter of great interest 1 since these structural moieties are present in many natural and unnatural products exhibiting significant biological activities. 2 Additionally, cyclopropanes can be used as chiral three-carbon building blocks 3 for synthesizing other more complex substances due to the chemical versatility of this small rings. 4Particularly, sulfinyl substituted cyclopropanes are of synthetic interest because several sulfur mediated ring opening reactions have been developed. 5he described methods for the asymmetric synthesis of functionalized sulfinylcyclopropanes are based on a stereoselective Michael addition of nucleophiles to enantiomerically enriched vinyl sulfoxides followed by ring closure of the initial Michael adduct.1a, 6 In this field, we have recently reported the reaction of some sulfur ylides with 2-sulfinylbutenolides. 7These reactions provide bicyclic sulfinylcyclopropanes in highly stereoselective way, but the attempts to eliminate the sulfinyl group by reductive desulfurization were unfruitful.Much easier was the hydrogenolysis of the C-S bond from monocyclic sulfinylcyclopropanes resulting in the pyrolysis of sulfonylpyrazolines. 8 This observation suggested the convenience of using acyclic vinyl sulfoxide as electrophiles in their cyclopropanation reactions with nucleophiles.In this context, we were interested in the reported nucleophilic behavior of 2-methoxyfuran when it is confronted with good Michael acceptors to yield racemic cyclopropanes according to a Michael induced ring closure cyclopropanation. 9On this basis we reasoned that reactions using properly activated chiral vinyl sulfoxides as electrophiles and 2-methoxyfuran as nucleophile could provide a new entry to the synthesis of optically active cyclopropanes.With the aim of exploring the scope of this method we chose (2E,SS)-(+)-4,4-diethoxy-2-[(4-methylphenyl)sulfinyl]but-2enenitrile (1) as the starting sulfoxide, because of its acyclic structure as well as our interest in the chemical behavior of sulfinylacrylonitriles. 10 Moreover, the stereoselectivity control this sulfoxide had shown in Diels-Alder reactions with cyclopentadiene, 10e suggested it could be analogously efficient in reactions with nucleophiles.In this paper we report the results obtained in the study of their reactions with 2-methoxyfuran under different conditions, as well as some transformations providing desulfinylated cyclopropane derivatives.Details concerning the configurational assignment of the resulting adducts and a mechanistic proposal explaining the stereochemical results are also presented.

Results and Discussion
The starting optically pure (2E,SS)-(+)-4,4-diethoxy-2-[(4-methylphenyl)sulfinyl]-but-2enenitrile (1) was obtained following a previously described synthetic route.10e The results obtained in reactions of 2-methoxyfuran with diethylacetal 1 using CH 2 Cl 2 , CH 3 CN or CH 3 NO 2 as solvents, under thermal and catalytic conditions, are collected in Table 1.All reactions were performed at 25ºC.Only two of the eight possible adducts were formed in all cases.We first carried out the reaction of 1 with an excess of 2-methoxyfuran (6 equiv.) in CH 2 Cl 2 for 24 h and obtained an inseparable mixture of sulfinylcyclopropanes 2a and 2b in 80:20 ratio (41 % yield after flash chromatography, entry 1).The use of more polar solvents such as CH 3 CN (entry 2) or CH 3 NO 2 (entry 3) slightly decreases the stereoselectivity.The reaction time is significantly lower in CH 3 NO 2 .The addition of Eu(fod) 3 increases the reactivity only in CH 3 CN (entry 5), but the stereoselectivity is significantly decreased in all the solvents (entries 4, 5, and 7).The best yield was obtained in CH 3 CN under Eu(fod) 3 catalysis without using an excess of the diene (70%, entry 6) and the resulting 60:40 mixture of 2a/2b has been used for further explorations.In CH 3 NO 2 , decreasing of the excess of diene did not have the same influence (entry 8).The use of ZnBr 2 as catalyst produces the inversion of the diastereofacial selectivity (entries 9-11) but the yields were very low due to the formation of decomposition products.As we could not separate diastereoisomers 2a and 2b, in order to assign the configuration of the obtained cyclopropanes, the 60:40 mixture of 2a and 2b was oxidized with m-CPBA (Scheme 1).The signals corresponding to only one sulfone 3 could be detected in the 1 H NMR spectrum of the reaction crude.It means that the oxidation of the diastereomeric sulfoxides 2a and 2b yields enantiomeric sulfones 3a and 3b (thus exhibiting the same 1 H NMR spectrum).Therefore we can conclude that 2a and 2b differ in the configuration of their three chiral carbons (they have the same configuration at the sulfinyl sulfur).Then, we established from NMR studies mainly by the two-dimensional NOESY spectrum, that both, 2a and 2b, have a cis-relationship between their cyclopropanic protons as well as between the olefinic proton at C-3 and the acetalic one. 11It restricted the structural possibilities for 2a and 2b to those indicated in Table 1.The absolute configuration of 2a was unequivocally established by chemical correlation with hydrazone 4a (Scheme 1) whose X-ray crystallographic analysis is presented in Fig. 1.This correlation was made by hydrolysis of the mixture of 2a and 2b with an excess of 98% formic acid, which affords a 60:40 mixture of the corresponding cyclopropylaldehydes, which could not be separated.The treatment of this mixture with 2,4-dinitrophenylhydrazine in aqueous acetic acid gave a 60:40 mixture of 2,4-dinitrophenylhydrazones 4a and 4b, from which the major diasteroisomeric hydrazone 4a was obtained in a pure form by fractional crystallization from CH 2 Cl 2 -hexane.The absolute configuration of 4a was established as 1'S, 2'R, 3'S, SS by X-ray diffraction analysis 12 (an ORTEP-type view of 4a is depicted in Fig. 1).Consequently this must also be the configuration of 2a and therefore the 1'R, 2'S, 3'R, SS configuration must be assigned to 2b.
The stereochemistry of the cyclopropanation reaction must be defined in the first step (Michael-type reaction) giving zwitterionic intermediates A' and B' which undergo ring closure through stereoselective intramolecular nucleophilic substitution with simultaneous opening of the heterocyclic ring affording 2a and 2b, respectively 9 (Scheme 2).The stereoselectivity under different conditions can be rationalized taking into account a sterically favored approach of 2-methoxyfuran to vinyl sulfoxide 1 from the less hindered face which supports the lone electron pair at the sulfur atom.The presumably most stable conformations around the C-S bond for vinyl sulfoxides must be A and B, with the sulfinyl oxygen adopting the s-cis and s-trans arrangement with respect to the double bond.Rotamer A should be slightly favored from electrostatic grounds (dipolar repulsion of the CN and SO bonds) and therefore, the compound resulting in the approach of the nucleophile to the less hindered face of the A conformation (bottom face in Scheme 2) must be the major one.Two possible transition states can be postulated: TS I and TS III differing at the nucleophilic atom adopting the antiperiplanar relationship with respect to the electrophilic C=C (C and O, respectively), being the first one the most stable.It would explain the formation of A' and therefore 2a as the major isomer.The compound resulting from the evolution of TS III is not observed in the reaction.The attack of the nucleophile to conformation B would result in the formation of 2b through TS II and the intermediate B'.The fact that the observed de decreases in a more polar solvent could be a consequence of their influence on the composition of the conformational equilibrium around the C-S bond (A rotamer is less polar than B rotamer) and the inversion of the stereoselectivity produced by the addition of Eu(fod) 3 could be explained by assuming that its association with the sulfinyl oxygen (the presumably most basic center at the substrate) destabilize TSI more than TSII (Scheme 2).Finally, the desulfinylation of 2a and 2b was investigated.Reductive desulfinylation was attempted with several reagents, namely, Raney nickel, sodium or aluminum amalgam, samarium iodide and Zn/NH 4 Cl.In all cases, these reactions were unsuccessful.However, desulfinylation of a 60:40 mixture of 2a and 2b was carried out with 5 equiv. of EtMgBr 13 in THF at -78ºC and trapping of the resulting Grignard intermediate (C) with an excess of saturated ammonium chloride solution.Purification by flash column chromatography gave a 60:40 mixture of diastereoisomeric cyclopropanes 5 and 6 which suggests that desulfinylation has not taken place with complete stereoselectivity (Scheme 3), but with epimerization at the carbon supporting the sulfur function, thus yielding C and C' in a 60:40 mixture (Scheme 3) which was subsequently protonated.On preparative thin-layer chromatography the 60:40 mixture of cyclopropanes 5 and 6 could be separated.The cis arrangement of the three protons at cyclopropane 5 was unequivocally established by NOESY studies.The NOESY spectrum of 5 showed proximity between H-1', H-2' and H-3' (Scheme 3).Afterwards we performed the capture of the Grignard intermediates C and C' (generated with 5 equiv. of EtMgBr) with iodomethane (7 equiv.)affording a 1:1 mixture of cyclopropane 5 and methylcyclopropane 7, both obtained as a 60:40 mixture of their enantiomers as it could be established by 1 H NMR by using Yb(hfc) 3 as chiral shift reagent.The NOESY spectrum of 7 showed the methyl group at C-2' close in the space to H-1'and H-3'.The use of larger amounts of MeI does not increase the proportion of 7 in the mixture.These results suggest that only the intermediate C evolves in the methylation process, which takes place with retention of the configuration.The lack of reactivity of C' could be due to steric reasons (the substituents at the C-1 and C-3 are oriented toward the approach direction of the electrophile).

Scheme 3
In conclusion, we have demonstrated that 2-methoxyfuran acts as a nucleophile in its reaction with 2-sulfinylacrylonitrile 1 providing a new access to the asymmetric synthesis of cyclopropanes.The 2-sulfinylacrylonitrile 1 reacts with moderated selectivity yielding a mixture of two diastereoisomers whose separation is not possible, which restricts the usefulness of the reaction.The search of new vinylsulfoxides able to evolve in a more stereoselective way is in progress.

Experimental Section
General Procedures.All moisture sensitive reactions were carried out in a flame dried glassware under argon atmosphere and monitored by TLC.Flash chromatography was performed with silica gel 60 (230-400 mesh ASTM).Melting points were determined in a Culatti melting point apparatus in open capillary tubes and are uncorrected.The optical rotations were measured at room temperature (20-23 ºC) using a Perkin-Elmer 343 polarimeter (concentration in g/100 mL).The IR spectra were recorded in a Nicolet-5SX spectrophotometer.The NMR spectra were determined in CDCl 3 solutions unless otherwise indicated at 300 and 75.5 MHz for 1 H and 13 C-NMR, respectively.Chemical shifts (δ) are reported in ppm and J values are given in hertz.
Mass spectra were measured at 70 eV and 190ºC.All described compounds were over 97% pure by NMR analysis.

Table 1 .
Reactions of 1 with 2-methoxyfuran at 25˚C b Mixture

of 2a and 2b after flash chromatography.
c Not determined.d Obtained with variable amounts of unknown impurities.