Ionic liquids accelerating cycloaddition between 1-aryl-2-halocyclopropenes and furan

Treatment of a series of 1-aryl-2,2-dihalocyclopropanes with t -BuOK at -10 ºC gave the corresponding 1-aryl-2-halocyclopropenes, which react with furan in a RTIL to give a fair good yield of the [4+2]-cycloadducts with more than 90% of the exo -isomer. The imidazolium type ionic liquids are able to accelerate this cycloaddition process with high steric selectivity. Neither pyrrole nor thiophene undergoes the cycloaddition with cyclopropene to form the [4+2]- cycloadduct. 1-Aryl-3,3-difluoro-2-halocyclopropenes are inert towards furan even at a temperature higher than 100 ºC.


Introduction
Cyclopropene has attracted the attention of both theoretical and experimental chemists due to its special place as the simplest small ring with a double bond. 1 It contains 27.7 Kcal/mol of olefinic strain energy and 55.2 Kcal/mol of strain energy 1 with a short double bond of 1.296 Å 2 ; therefore it is expected to be a highly reactive molecule.Unsubstituted cyclopropene 1 is a potentially explosive gas and is oligomerizing rapidly via ene reactions. 3In contrast to 1, the substituted cyclopropenes, which are stabilized by the substituent, are stable enough to be utilized as a dienophile.The cycloaddition of cyclopropenes have been studied in some extent. 4The reactivity of dienes toward cyclopropene and the steric selectivity strongly depend on the nature of the diene and the substituent on the cyclopropene.Although cycloadditions using heterocycles as diene have been widely applied to prepare some potential pharmaceutical derivatives, 5 the cycloaddition between phenylcyclopropene and furan is less successful.5a Room-temperature ionic liquids (RTIL) provide a solvent environment that is quite different from any other available solvent at room temperature.With their unique character, the RTIL may induce solvent effects on a wide range of processes.A chloroloaluminate ionic liquid is able to reverse the steric selectivity in the reaction of cyclopentadiene with methyl methacrylate from an exo-adduct in a common organic solvent to an endo-adduct. 6Such a phenomenon is also observed in the reaction of cyclopentadiene with ethyl acrylate in an imidazolium system. 7This may be rationalized by the "polarity" of the RTIL which is able to stabilize the more polar (endo) activated complex. 8Herein, we like to report the cycloaddition of 1-aryl-2halocyclopropenes (X=Br 2, Cl 3) and furan, pyrrole or thiophene effected by a RTIL.

Results and Discussion
Compound 2 always decomposes to form either allene or acetylene in the presence of either strong base or at elevated reaction temperature. 91-Bromo-2-phenylcyclopropene has been prepared from the reaction of 1-phenyl-1,2,2-tribromocyclopropane and MeLi at -45 ºC or even lower to avoid the ring opening reaction. 5In this study, compounds 2, 3 were prepared from the reaction of 1-aryl-2,2-dihalocyclopropanes with t-BuOK in hexane at -10 ºC for 4h.(Scheme 1) The formation of 2, 3 is monitored using GC-MS analysis.(Figure 1).Compounds 2, 3 prepared from this reaction are used without purification.The reactions of compound 2, 3 and a large excess of furan (1 : 10) were conducted within a sealed system at 30 ºC for 12 h due to the thermal instability of cyclopropenes and the lower boiling point of furan (bp.31-33 ºC).Flash chromatography afforded a mixture and the ratio of exo-and endo-isomer was estimated according to the peak areas obtained from the GC-MS analysis.(Figure 2) In general, the molecular ions of those adducts appear with either a very low abundance or absence of the molecular ion along with the fragments of [M-29] + and [XC12H11] + as common ions.Due to the low yields of the endo-isomers, only the exo-isomers were isolated for characterization (Table 1).The chemical shifts of C6-H and C7-H and the coupling constant between them were obtained via the treatment according to the non-first order coupling system. 1 H NMR spectroscopy appeared to be particularly informative in the compounds 4, 5 because one of the cyclopropyl protons appeared consistently at a much lower field than the other.The signal associated with the proton anti to the oxygen atom was found at 1.56~1.63ppm, while the syn proton appeared between 2.63 and 2.70 ppm.This difference may conceivably be attributed to the diamagnetic anisotropy of the oxygen atom, which causes a decrease in the shielding of the syn proton relative to the anti proton. 10This interpretation is in agreement with the formation of the exo isomer at the expense of the endo form due to the lack of a favorable secondary orbital interaction (SOI) in the transition state 11 as well as the potential congestion between the cyclopropyl proton and the furan ring in the transition state for the formation of the endo-isomer.This result led to a contradiction to the conclusion from the reactions of cyclopropene and furan by Apeloig, 12 "the parent cyclopropene and 1,2-disubstituted cyclopropenes are expected to yield endo-adducts exclusively or predominantly.3,3-Gem-disubstituted cyclopropenes are predicted to yield exo-adducts."The competition between decomposition and cycloaddition of arylcyclopropenes 2, 3 and furan resulted in very poor yields of the cycloadducts in common organic solvents or in a solventless system.In this study, we found that the yields of the cycloaddition products can be improved by adding imidazolium type ionic liquids, i.e. 1-hexyl-3-methylimidazolium ([hmin] + ) and 1-methyl-3-octylimidazolium ([omin] + ) salts.The reaction rates are also accelerated by the presence of ionic liquids in 50 volume % or less.However, when more ionic liquids are used, a more difficult chromatographic separation needs to be performed.Normally, the reaction rate can be enhanced by the presence of 25 vol% of RTIL (entry 2).The distribution of the exo-isomer is not much affected by the used RTIL.The RTIL bearing a longer R group leads to better yields (entries 3, 5 vs. entries 4, 6); the type of anion doesn't affect the yields (entries 3, 4 vs. entries 5,  6).This different result on the steric selectivity might be due to the bulky aryl ring on the cyclopropene ring creating a congestion effect in the transition state.A less polar cyclopropene leads to a less polar transition state which will poorly interact with a highly polar RTIL.
The extension of this reaction to their gem-difluorocyclopropene 8 analogues failed.Although, the compounds 8 are relatively thermally stable and allowed us to carry out the reaction at temperatures higher than 100 o C, this reaction resulted in the recovery of starting material.This might be due to the fact that the cyclopropene ring of compound 8 possesses aromaticity.This is deduced from the calculated and observed bond length and dipole moment of the gem-difluorocyclopropene, consistent with the delocalization of electron density via a negative hyperconjugation from the π-bond into the C-F σ* orbital. 13Neither pyrrole nor thiophene undergoes the [4+2]-cycloaddition with compound 2.
The simulated thermal dynamic data from MN2 and AM1/MOPAC are also used to explain the selectivity in this system.The heats of formation of exo-and endo-isomer of 5a and 7a are -18.25 and -12.49Kcal/mole with activation energies of 19.55 and 20.55 Kcal/mole, respectively.The distance between the oxygen atom and the hydrogen of the cyclopropane of 5a and 7a ranged from 2.359 to 2.527Å and 2.382 to 2.541 Å, respectively, (Figure 1).While the sum of the van der Waal radii of hydrogen and oxygen atoms are ranging from 2.500 to 2.700Å. 14The simulated thermodynamic data suggested that the heat of formation is responsible for the high exo-selectivity.From the same simulation, the results for gem-difluorocyclopropene adduct 8 reveal a heat of formation of -0.588 and 0.65Kcal/mole with activation energies of 23.66 and 25.26 Kcal/mol for exo-and endo-isomer respectively, while the distance between the oxygen atom and the fluorine atom range from 2.500 to 2.672Å and 2.537 to 2.703 Å for exoand endo-adduct, respectively, which are very close to van der Waal's radii (2.75Å). 15The low heat of formation of adduct 8 indicates its instability that is responsible for slowing down the cycloaddition between gem-difluorocyclopropene and furan.

Conclusions
The thermal unstable compounds1-aryl-2-halocyclopropenes 2, 3 readily undergo cycloaddition with furan in the presence of a RTIL to yield the exo-isomers as the main products.The possible congestion between an aryl ring of cyclopropene and the oxygen of furan might prohibit the formation of the endo-isomer.

Experimental Section
General. 1 H NMR and 13 C NMR spectra were recorded at 400, 100 MHz on Bruker Advance-400, respectively, at ambient temperature.Chemical shifts for samples in CDCl3 solution are reported in δ units relative to TMS ( 1 H and 13 C).Mass spectra were obtained from GC/MS (Fisons 8000 series coupled with Finnigan MD-800) at an ionization potential of 70 eV.High resolution mass spectra were determined using a JEOL JMX SX/SX 102A mass spectrometer at the Instrumental Analytic Center at National Chung-Hsing University.IR spectra were recorded of a film on KBr plate with a Perkin-Elmer System 2000 FT-IR spectrometer.Elemental analyses were performed at the Instrumental Analytic Center at National Chung-Hsing University.Melting points were measured on a Yanaco MP-J3 micro melting apparatus and are uncorrected.2,2-Difluorostyrenes were prepared from the corresponding aldehyde and ClCF2CO2Na in the presence of triphenylphosphine in a diglyme solution at 180 ºC. 16-Aryl-2,2-dihalocyclopropanes were prepared from the reaction of styrene and CHX3 (X= Br, Cl) in hexanes solution with the presence of t-BuOK. 171-Aryl-2-halocyclopropenes (2, 3) were prepared by a dehydrohalogenation of 1-aryl-2,2-dihalocyclopropanes using t-BuOK at 0 ºC. 18ompounds 2, 3 were isolated as a hexanes solution which was used without purification.Their concentration was estimated by GLC analysis.1-Aryl-3,3-difluoro-2-halocyclopropenes were prepared from 2,2-difluorostyrene, CHCl3, and NaOH in the presence of a phase transfer reagent. 19he structural elucidation of adducts (4, 5) were simplified using 2D NMR experiments (COSY, HSQC, and HMBC), in addition to the standard analysis listed.

Computational details
All of the calculations described above were performed using Gaussian 98. 20 Computations were carried out at the restricted Hartree-Fock (RHF), 21 and Density Functional Theory (DFT).DFT calculations used the hybrid B3LYP functional and triple zeta 6-311++G** basis sets. 22MN2 and AM1/MOPAC were simulated by using Chem Office 2004, Chem 3D ultra 8.0 ed..

Figure 3 .
Figure 3. Possible distance between oxygen atom and either hydrogen or fluorine atoms obtained from calculation using MN2 and AM1/MOPAC. method

Table 1 .
Results of the Diels-Alder addition of 1-aryl-2-halocyclopropene and furan in a RTIL a