Cohalogenation of Limonene , Carvomenthene and Related Unsaturated Monoterpenic Alcohols

A coalogenação de ( R)-limoneno e ( R)-carvomenteno com I 2/H2O/Cu(OAc)2·H2O em dioxano aquoso seguida por tratamento em meio básico produz estereoespecificamente os transepóxidos correspondentes. Já essa mesma metodologia de coalogenação aplicada a álcoois monoterpênicos insaturados estruturalmente relacionados produz derivados do pinol [a partir de (5R)-cis-carveol e ( S)-α-terpineol] ou então iodoidrinas [a partir de ( S)-álcool perílico e (5 R)trans-carveol].


Introduction
Electrophilic halogenation of alkenes to produce vicinal dihaloalkanes is a well-known reaction in organic chemistry 1 .A proposed mechanism for it goes through a π complex among alkene and halogen, followed by decomposition to a bridged halonium ion intermediate and then a nucleophilic opening by the halide ion 2 .However, when the halogenation of the alkene is carried out in a nucleophilic solvent (water, alcohols, carboxylic acids, nitriles, etc), a competition between the halide ion and the solvent for opening of the halonium ion can occur and difunctionalized products are obtained 2 .This process, termed 'cohalogenation', proved to be useful for diverse synthetic applications 2,3 (Scheme 1).
Recently, we published an efficient coiodination of simple alkenes with oxygenated nucleophiles promoted by Cu(OAc) 2 •H 2 O and other metal salts 4 or by 2 mol equiv. of iodine in place of the metal salt 5 .Thus, using this simple methodology, iodohydrins 4,6 and β-iodoethers 5 were effectively prepared in good yields and high purity when the iodination of alkenes was performed in water or alcohols, respectively.
The role of the metal salt or of the second equivalent of iodine in the coiodination reactions is to decompose the π complex formed among alkene and iodine to the bridged iodonium ion 5,7 .In the case of Cu(OAc) 2 , cupric iodide is formed followed by disproportionation to cuprous iodide and iodine 7 (Scheme 2).As iodine is formed from CuI 2 , less than 1 mol equiv. of it is required for these reactions.On the other hand, in the absence of the metal salt (or without excess iodine), low conversion and poor yields of products are observed 4,7 .

Results and Discussion
The reaction of (R)-limonene (1) with iodine in aque-X2 C C S: nucleophilic solvent X: halogen ous dioxane in the presence of Cu(OAc) 2 •H 2 O was carried out at room temperature (rt) stirring together 1 mol equiv. of 1, 0.5 mol equiv. of Cu(II) salt and addition of 0.75 mol equiv. of iodine.After NaBH 4 reduction of the remaining excess of iodine and work up, HRGC (high-resolution gas chromatography) analysis of the crude material showed the unstable iodohydrin 2 (82 %) along with recovered substrate (ca.15 %).Several attempts to purify 2 were unsuccessful and only dark products and intense gas evolution were obtained.Treatment of 2 with Na 2 CO 3 in aqueous ethanol produced pure trans-1,2-epoxylimonene 9,10 (3) in 59 % isolated yield.Catalytic hydrogenation of (R)-limonene to (R)-carvomenthene (4) and similar cohalogenation led to the iodohydrin 5 in 86 % crude yield (ca. 8 % recovered substrate).Base treatment of 5 produced trans-epoxycarvomenthene 11  (6) in 59 % yield.Scheme 3 summarizes all results.and chemoselectivity 13 .The trans-epoxides were obtained stereospecifically and usual oxidation (peracids and related oxidants) of limonene and carvomenthene produced both a 1:1 mixture of cis-and trans-epoxides 14 , useful intermediates in synthesis of natural products 15 .Although the separation of both cis-and trans-1,2epoxylimonene can be achieved by careful spinning-band distillation 16 , this is a difficult and slow task and more practical methods of obtaining the pure trans-epoxide involve selective chemical transformation of the 1:1 mixture of isomers 10 or reaction of limonene with NBS/H 2 O followed by base treatment 17 .Moreover, trans-1,2epoxylimonene is more reactive than cis and so it is selectively opened on nucleophilic additions to the mixture of cis-and trans-1,2-epoxylimonene 18 .
A proposed mechanistic scheme (Scheme 4) for the stereospecific formation of the iodohydrin 2 derived from limonene (and the analogue 5 from carvomenthene) assumes a π complex anti to the isopropenyl (or isopropyl) group, followed by its decomposition to the iodonium ion and an antiperiplanar opening by an axial 19 nucleophilic attack of water on the tertiary carbon to produce the transdiaxial iodohydrin.Stereospecific formation of epoxides by base promoted cyclisation of halohydrins is vastly described in the literature 20  The characterization of 3 and 6 were made by comparison of their spectral data with those previously reported 10,11 and by the 13 C NMR values of chemical shift for the γ-carbon of the epoxides and the parent alkenes, assuming that there is no significant difference if the epoxide ring is trans to the γ-carbon hydrogen 12 (see Figure 1).
The results on the cohalogenation of limonene are important because electrophilic additions to it lack stereo The above results led us to investigate the extension of this methodology of cohalogenation with unsaturated monoterpenic alcohols, as a possible route of cyclofunctionalization 21 to produce functionalized bicyclic ethers.
The structure of 11 was determined by 1 H NMR (that showed a sharp signal of a tertiary hydroxyl group upon changing the solvent from CDCl 3 to DMSO-d 6 ) along with 1 H and 13 C NMR 1D and 2D techniques 24 , assuming the most stable conformation being a bridged chair form 28 .NOESY experiment showed the cross signals shown in Figure 3 25    Control experiments showed that cis-carveol (7a) was completely converted to 8 (85 % isolated yield based on 7a) in 1 h while 7b was unchangeable.After that, transisomer (7b) was slowly and incompletely converted to the iodohydrin 9 among other unidentified products.The structure of 8 was determined by 1 H and 13 C NMR 1D and 2D NMR techniques 24 (COSY, HMQC, and HMBC) and its relative stereochemistry was established with the aid of NOESY experiment that showed the cross signals shown in Figure 2 25 .These results contrast with those obtained for limonene and carvomenthene, where the reaction occurred at the trisubstituted double bond.In the case of carveols, probably due to electronic reasons, the allylic hydroxyl group deactivates the trisubstituted double bond to an electrophilic attack 26 and the π complex of I 2 is formed with the disubstituted double bond.Furthermore, the relative position of the hydroxyl is crucial to the nature of the products.When the hydroxyl is cis to the isopropenyl group (as in ciscarveol 7a) it can open the iodonium ion producing the iodo-bicyclic ether 8. On the other hand, if the hydroxyl is trans to isopropenyl (trans-carveol 7b), this intramolecular process is less favorable and water in the media slowly opens the iodonium ion producing the iodohydrin 9 (Scheme 6).
The reaction of (S)-α-terpineol (10) with iodine and water in the presence of cupric acetate led predominantly to trans-4-hydroxy-dihydropinol (11) 27 along with some unidentified minor products.From the reaction mixture, 11 was isolated in 45 % yield after radial chromatography (Scheme 7).The formation of the dihydropinol derivative 11 by the cohalogenation methodology is an attractive alternative to the thallium(III)-induced cyclization of α-terpineol 29 .
A proposed mechanistic scheme (Scheme 8) for the rationalization of the hydroxy-dihydropinol 11 could be the formation of an iodonium ion (similar in the case of limonene and carvomenthene) followed by intramolecular opening to the unstable β-iodoether intermediate 12 (detected by MS in the reaction media 30 ).This kind of intermediate easily rearranges through a bridged oxonium ion (13) to dihydropinol derivatives 31 .Regiospecific opening of the oxonium ion by H 2 O produced 11 in two further steps.
Reaction of (S)-perillyl alcohol ( 14) with I 2 /H 2 O/ Cu(OAc) 2 •H 2 O was not completed after several hours and produced the diastereomeric iodohydrins 15 predominantly along with diiodohydrin 32 16 (ca.18:1 by HRGC) and several others minor products (epoxides, iodo-triols, etc) -Scheme 9. From this reaction mixture, 15 (a diastereomeric mixture) was isolated in 15 % yield after radial chromatography.Once more, no bicyclic products were formed because it would be necessary a bridgehead unsaturated sevenmembered cyclic transition state.Attempts to improve the yield of 15, lower the subproducts or increase the consumption of perillyl alcohol were unsuccessful.No significative changes in the crude reaction mixture were observed in HRGC analysis when the cohalogenation was performed with 2 mol equiv.I 2 in the place of cupric acetate 5 .
To a stirred solution of (R)-limonene (1.36 g, 10.00 mmol) and Cu(OAc) 2 •H 2 O (1.00 g, 5.00 mmol) in dioxane (22 ml) and water (3 ml), was added I 2 (1.90 g, 7.50 mmol) in small lots at rt.After 4 h, Cu 2 I 2 was filtered off and CHCl 3 (30 ml) was added to the filtrate.The resulting solution was treated with a suspension of NaBH 4 (1 g) in EtOH (50 ml) and then washed with water (3 × 20 ml).The organic layer was dried (Na 2 SO 4 ) and filtered through a small silica gel column.The solvent was evaporated in a rotatory evaporator at reduced pressure and low heating to produce crude 2 (2.30 g, 8.21 mmol, 82 %), along with recovered limonene (15 %).

Typical procedure for the cohalogenation of unsaturated monoterpenic alcohols
To a stirred a solution of appropriated unsaturated monoterpenic alcohol (5.00 mmol) and Cu(OAc) 2 •H 2 O (1.00 g, 5.00 mmol) in dioxane (10 ml) and water (2 ml), was added I 2 (0.95 g, 3.75 mmol) in small portions at rt.After 16 h (1 h for carveols), the reaction media was filtered and CHCl 3 (15 ml) was added to the filtrate.The resulting solution was washed with a saturated solution of Na 2 SO 3 (3 × 10 ml), the organic layer dried (Na 2 SO 4 ) and filtered through a small silica gel column.The solvent was removed under reduced pressure and low heating and the crude product purified by radial chromatography using CH 2 Cl 2 as eluent.

Figure 2 .
Figure 2. Essential NOE observed in NOESY spectra for determination of relative stereochemistry of 8.