Unusual rearrangement of dihalocyclopropanes

Dihalocyclopropanation of the double bond of some olefins, leading to dihalocyclopropanes, offered an opportunity to perform their rearrangement to dihalomethylvinyl with Hiyama type reagents, in presence of cationic system such as Cr/Cr. The chain elongation of alkenes via the gem-dihalocyclopropanes produced α,β-unsaturated aldehydes and acids.


Introduction
Dihalocyclopropanes are interesting starting materials to attempt some rearrangements.When attached to cyclic structures with an endocyclic-double-bond, the extension of the cycle takes place, usually with help of the phase transfer catalyst [1,2].Conversely, the formation of allene is expected for some exocyclic double bond originated dihalocyclopropanes [3].We recently have reported on Eliel's-reagentsinduced reactions of dihalocyclopropane lactones, and demonstrated the formation of allenic derivatives (dihalo, monohalo and fully reduced) from exocyclic methylenes [4,5] with Hiyama reagents in situ formed (Cr +2 /Cr +3 H − , DMF) [6].
This family of Lewis acid reagents, consisting of a pair of cations, is necessary to perform this rearrangement.During this reaction, the reduction of dihaloallene takes place because of both the formation in situ of Cr +2 cation and presence of the hydride ion.
We studied the behavior of the endocyclic double bond with the dihalocyclopropanes attached to a cyclic structure.When reacted with Hiyama reagent, new rearrangement products were observed with low yield.The structure, of these products displayed the dihalomethylvinyl moiety (Scheme 1).
This functional group is a potential precursor of α, β-unsaturated aldehydes or acids.Faced with what is a potentially new rearrangement, it was necessary to compare it to similar reactions involving either carbene addition, Lewis-acid-induced rearrangement, synthesis of α, β-unsaturated carbonyl compounds and, the Hiyama reaction.Closely related reactions included Reimer-Teimann, Doering-Laflamme, Ciamician-Dennstedt, retro-Griffin and Hiyama-Heatchock reactions, most of which are performed on the aromatic compounds [7][8][9][10][11].Finally, from a mechanistic standpoint, the obtention of dihalomethylvinyl from dihalocyclopropane should follow one electron mechanism rearrangement pathway suggested by Wang [12].
We examined over twenty dihalocyclopropanes of which only three cyclohexene (1) and dihydropyrane (2) both of which are endocyclic, as well as limonene (4), which is not only endocyclic, but has a second exo double bond on a terminal methylene, react along the new dihalocyclopropane-dihalomethylvinyl direction with a reasonable yield (Scheme 2).
Subsequently, some other Lewis acids able to produce two neighboring oxidation states such as Ce +3 or Sm +2 as well as with Cr +3 alone (without hydride), were applied to 6, 7, 8 and 16 dichlorocyclopropane adduct rearrangement.The post-reaction mixtures were examined using NMR and GC-MS.The most interesting results were obtained for both Cr +2 experiments (Scheme 3).
In the presence of Cr +3 (Aldrich Chemicals, CrCl 3 ) none of the rearrangement products were observed (Table 1).
This confirms, that the formation of allene from the spiro dihalocyclopropane takes place, and the rearrangement does not stop on the dihalomethylvinyle step.
The dihalocyclopropanation of limonene (4) gives three different derivatives, separated by column chromatography (Al 2 O 3 , basic), resulting from the addition of cyclopropane moieties to, either one of the two (endocyclic or terminal methylene) or to both double bonds.The NMR spectrum of the tetrachloro derivative of limonene 7,7-dichloro-4-(2,2-dichloro-1-methylcyclopropyl)-1-  16), obtained with total yield of 41% from 4, displayed 1.95 and 2.18 ppm signals corresponding to H2 and to the methylene at H8, the characteristic protonated cyclopropane carbon in C-13 NMR resonated at 25.2, C2 and 20.4,C8 ppm and the GC-MS spectrum confirm the structure (Fig. 4).
Molecular modelling of 16 of the two isomeric structures showed lower energy for cis isomer 16 (17 kcal/mol, Fig. 7).From the GC-MS this ratio (cis/trans) was evaluated 95 : 5, the 16cis had a shorter retention time.
The two other dihalocyclopropane derivatives 17 and 18, obtained in 3 : 1 ratio, respectively (total yield of 47%), displayed cyclopropane only on the endocyclic double bond and only on the methylene double bond of the other.The NMR characteristic features witnessing their differences are in particular proton and carbon signals of two double bond systems with two olefinic methylene protons and one cyclopropane methylene in the spectrum of 18 and one proton on the endocyclic double bond (H2 at 5.39 ppm) and methelyne cyclopropane proton at 1.95 ppm for H8 and the GC-MS spectrum confirm the structures (Fig. 5a, b and c).The tetrachloro limonene derivative 16 produced under the Hiyama Cr +2 in situ reagent, yielded 5% of allene-aldehyde mixture products, while the mixture dichloro derivatives 17 and 18 (3 : 1) gave a small yield of allene-aldehyde mixture at ca 1%.These compounds were identified by proton and carbon-13 NMR, and confirmed by mass spectrometry.
The allene-aldehyde 19 was observed in both rearrangements of 16 with Cr +2 produced in situ and with commercial Cr +2 , but the dihalocyclopropane unsaturated aldehyde 20 was observed only with Cr +2 produced in situ (Scheme 4).
Of the two possible orientations of the dichlorocyclopropane moiety of 17 toward the α-isopropenyl group of the natural 4, the most stable is that whose isoprenyl is oriented trans (dichlorocyclopropane 17 trans).Molecular modelling of the two isomeric structures showed lower energy for trans isomer 17 (9.3kcal/mol, Figs 8 and 9).The rearrangement on mixture of 17 and 18, was also being tested, according to Hiyama Cr +2 in situ formation condition.The compound 17 rearranges to aldehyde, and the isomer 18 produces monochloro allenic product in 3% of total yield.Commercial Cr +2 does not lead to any considerable rearrangement results.
Finally, we tested the dihalocyclopropanation of cubebene ( 5) and observed the formation of the dichlorocyclopropane derivative (21) in the α-position (Scheme 5).The NMR spectrum shows that the proton of double bond in 5 at 5.00 ppm, is shifted to 2.31 ppm which confirms the formation of a second cyclopropane ring.The GC-MS spectra showed a molecular ion at m/z = 286 corresponding to dihalocyclopropane cubebene (21), with the characteristic isotopic two chlorine pattern (Fig. 6).Three C-13   signals provide at 46.6 at 37.4 and 67.5 respectively, are additional confirmation of the structure, assigned to C1, C2 and C16.Despite the successful transformation of cubebene (5) into the dihalocyclopropane derivative 21 (with 87% of total yield from proton NMR spectrum), the tentative rearrangement of this highly crowded molecule failed (Fig. 10).

Conclusion
This preliminary report on the rearrangement of dihalocyclopropane derivatives of several compounds promoted by Hiyama Cr +2 /Cr +3 system confirmed the formation of new dihalomethylvinyl intermediate product further hydrolyzed to the α, β-unsaturated aldehyde and acid.Although, the yield of this reaction is small and the total yield of transformation of starting material does not exceed 40%, this reaction is apparently new.In particular, the difference between this reaction and the Makosza extended dihalocarbocyclic compound is striking.The relative efficiency of the synthese of α, β-unsaturated aldehyde with Cr +2 created in situ and α, β-unsaturated acid with commercial Cr +2 , could be related to the purity of the reagent and a higher ratio of Cr +2 /Cr +3 generated by the in situ route.
The major dihalomethylvinyl product, 9 or 22 were observed with a maximum of 15% for both dihalocyclopropanes 6 and 7.The simultaneous presence of Cr +2 /Cr +3 resulting from the reduction of Cr +3 /H − seems to be necessary to obtain this rearrangement.
The rearrangement of some dihalocyclopropane derivatives of natural product could be a simple way to introduce aldehyde or acid functions on to these molecules.
More were is in progress in order to specify the influence of the neighboring group of varying different electronic effects on the direction of this rearrangement, in particular, the effect of electron-withdrawing groups placed near the dihalocyclopropane substrate site.

General procedure of synthesis of dihalocyclopropane
In 500 ml round-bottomed flask, a NaOH 50% solution (15 g of hydroxide/15 ml of water) was prepared (ice bath), 25 ml of chloroform with 1 g of catalyst tributylammonium chloride (TEBA) were added to the NaOH solution, finally 10 ml of the substrate 1 (same volume for 2, 3 and 4) except 5 was added, and the mixture was stirred for 2 h, (24 h for 4 and 5) at room temperature.The reaction was controlled with TLC, then after the addition of water extracted with CH 2 Cl 2 and the products were purified via the chromatography column on silica gel (basic alumina for 4).

General procedure of the rearrangement with Cr +2 in situ
A solution of 0.5 g of chromium chloride (III) and 0.6 g of LiAlH 4 with 5 ml of THF were mixed in a 50 ml round-bottomed flask, and stirred for 30 minutes.The changing color from violet to green indicated the formation of Cr +2 .The solvent was replaced with 8 ml of DMF and 0.1 g of the dihalocyclopropane adduct were added at room temperature.The mixture was stirred for 24 h.After the hydrolytic workup (10 ml of water and 10 ml of hexane-ether (1 : 1) mixture) the sample analyzed via the GC-MS.

General procedure of the rearrangement with Cr +2 (commercial)
A solution of 0.5 of chromium chloride (II) and 0.1 g of the dihalocyclopropane adduct with 8 ml of DMF were mixed, in a 50 ml round-bottomed flask, and stirred for 24 h at room temperature.After the usual workup (10 ml of water and 10 ml of hexane-ether (1 : 1) mixture) the sample was analyzed via the GC-MS.
Molecular modeling calculations were done with help of Hyperchem TM 6.03 (©2000 Hypercube, Inc.).All spectral material (H-1, C-13, 1D, 2D NMR, GC-MS, EI and CI) for compounds of this paper are available on request from the corresponding author (C.K. Jankowski) at the e-mail address of the Université de Moncton.

Fig. 4 .
Fig. 4. GC-MS of double adduct 16.M + = 300, M + -(CH 2 -CCl2) = 204, M + -(CH 2 -CCl2), Cl = 169 (100%), M + -Cl-CCl2-CH3-C2H2 = 141.methylbicyclo[4.1.0]heptane(16), obtained with total yield of 41% from 4, displayed 1.95 and 2.18 ppm signals corresponding to H2 and to the methylene at H8, the characteristic protonated cyclopropane carbon in C-13 NMR resonated at 25.2, C2 and 20.4,C8 ppm and the GC-MS spectrum confirm the structure (Fig.4).Molecular modelling of 16 of the two isomeric structures showed lower energy for cis isomer 16 (17 kcal/mol, Fig.7).From the GC-MS this ratio (cis/trans) was evaluated 95 : 5, the 16cis had a shorter retention time.The two other dihalocyclopropane derivatives 17 and 18, obtained in 3 : 1 ratio, respectively (total yield of 47%), displayed cyclopropane only on the endocyclic double bond and only on the methylene double bond of the other.The NMR characteristic features witnessing their differences are in particular proton and carbon signals of two double bond systems with two olefinic methylene protons and one cyclopropane methylene in the spectrum of 18 and one proton on the endocyclic double bond (H2 at 5.39 ppm) and methelyne cyclopropane proton at 1.95 ppm for H8 and the GC-MS spectrum confirm the structures (Fig.5a, b and c).The tetrachloro limonene derivative 16 produced under the Hiyama Cr +2 in situ reagent, yielded 5% of allene-aldehyde mixture products, while the mixture dichloro derivatives 17 and 18 (3 : 1) gave a small yield of allene-aldehyde mixture at ca 1%.These compounds were identified by proton and carbon-13 NMR, and confirmed by mass spectrometry.The allene-aldehyde 19 was observed in both rearrangements of 16 with Cr +2 produced in situ and with commercial Cr +2 , but the dihalocyclopropane unsaturated aldehyde 20 was observed only with Cr +2 produced in situ (Scheme 4).Of the two possible orientations of the dichlorocyclopropane moiety of 17 toward the α-isopropenyl group of the natural 4, the most stable is that whose isoprenyl is oriented trans (dichlorocyclopropane 17 trans).Molecular modelling of the two isomeric structures showed lower energy for trans isomer 17 (9.3kcal/mol, Figs8 and 9).

Table 1
Efficiencies of dihalocyclopropanes rearrangement of 6 * * Efficiency is reported on the basis of dihalocyclopropane derivative consumed.

Table 2
Efficiencies of dihalocyclopropanes rearrangement of 7 * * Efficiency is reported on the basis of dihalocyclopropane derivative consumed.