Abstracts

Article

Cohalogenation of Limonene, Carvomenthene and Related Unsaturated Monoterpenic Alcohols

Antonio M. Sanseverino, Flavia M. da Silva, Joel Jones Jr* and Marcio C. S. de Mattos*

Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, CP 68545, 21945-970, Rio de Janeiro - RJ, Brazil

Introduction

Electrophilic halogenation of alkenes to produce vicinal dihaloalkanes is a well-known reaction in organic chemistry¹. A proposed mechanism for it goes through a p complex among alkene and halogen, followed by decomposition to a bridged halonium ion intermediate and then a nucleophilic opening by the halide ion². 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 obtained². 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·H₂O and other metal salts⁴ or by 2 mol equiv. of iodine in place of the metal salt⁵. Thus, using this simple methodology, iodohydrins^4,6 and b-iodoethers⁵ 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 p 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 iodine⁷ (Scheme 2). As iodine is formed from CuI₂, 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.

Herein we communicate our results on the cohalogenation of limonene, carvomenthene and related unsaturated monoterpenic alcohols, namely carveols, a-terpineol, and perillyl alcohol⁸.

Results and Discussion

The reaction of (R)-limonene (1) with iodine in aqueous dioxane in the presence of Cu(OAc)₂·H₂O 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 NaBH₄ 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 Na₂CO₃ 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-epoxycarvomenthene¹¹ (6) in 59 % yield. Scheme 3 summarizes all results.

The characterization of 3 and 6 were made by comparison of their spectral data with those previously reported^10,11 and by the ¹³C NMR values of chemical shift for the g-carbon of the epoxides and the parent alkenes, assuming that there is no significant difference if the epoxide ring is trans to the g-carbon hydrogen¹² (see Figure 1).

The results on the cohalogenation of limonene are important because electrophilic additions to it lack stereo and chemoselectivity¹³. 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-epoxides¹⁴, useful intermediates in synthesis of natural products¹⁵. Although the separation of both cis- and trans-1,2-epoxylimonene can be achieved by careful spinning-band distillation¹⁶, 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 isomers¹⁰ or reaction of limonene with NBS/H₂O followed by base treatment¹⁷. Moreover, trans-1,2-epoxylimonene is more reactive than cis and so it is selectively opened on nucleophilic additions to the mixture of cis- and trans-1,2-epoxylimonene¹⁸.

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 p complex anti to the isopropenyl (or isopropyl) group, followed by its decomposition to the iodonium ion and an antiperiplanar opening by an axial¹⁹ nucleophilic attack of water on the tertiary carbon to produce the trans-diaxial iodohydrin. Stereospecific formation of epoxides by base promoted cyclisation of halohydrins is vastly described in the literature²⁰.

The above results led us to investigate the extension of this methodology of cohalogenation with unsaturated monoterpenic alcohols, as a possible route of cyclofunctionalization²¹ to produce functionalized bicyclic ethers.

The reaction of (5R)-carveols 7 (1:1 mixture of cis 7a and trans 7b isomers by HRGC) with I₂/H₂O/Cu(OAc)₂·H ₂O for 5 h led to an iodopinol derivative (8)²² and an iodohydrin (9)²³, as shown in Scheme 5.

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, trans-isomer (7b) was slowly and incompletely converted to the iodohydrin 9 among other unidentified products. The structure of 8 was determined by ¹H and ¹³C NMR 1D and 2D NMR techniques²⁴ (COSY, HMQC, and HMBC) and its relative stereochemistry was established with the aid of NOESY experiment that showed the cross signals shown in Figure 2²⁵.

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 attack²⁶ and the p complex of I₂ 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 cis-carveol 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)-a-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 structure of 11 was determined by ¹H NMR (that showed a sharp signal of a tertiary hydroxyl group upon changing the solvent from CDCl₃ to DMSO-d₆) along with ¹H and ¹³C NMR 1D and 2D techniques²⁴, assuming the most stable conformation being a bridged chair form²⁸. NOESY experiment showed the cross signals shown in Figure 3²⁵.

The formation of the dihydropinol derivative 11 by the cohalogenation methodology is an attractive alternative to the thallium(III)-induced cyclization of a-terpineol²⁹.

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 b-iodoether intermediate 12 (detected by MS in the reaction media³⁰). This kind of intermediate easily rearranges through a bridged oxonium ion (13) to dihydropinol derivatives³¹. Regiospecific opening of the oxonium ion by H₂O produced 11 in two further steps.

Reaction of (S)-perillyl alcohol (14) with I₂/H₂O/Cu(OAc)₂·H ₂O was not completed after several hours and produced the diastereomeric iodohydrins 15 predominantly along with diiodohydrin³²16 (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 seven-membered 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. I₂ in the place of cupric acetate⁵.

In summary, cohalogenation of limonene and carvomenthene with I₂/Cu(OAc)₂·H₂ O in aqueous dioxane produce stereospecifically iodohydrins which upon base treatment are converted to the respective epoxides. On the other hand, when the cohalogenation is applied to related unsaturated monoterpenic alcohols, the nature of products is highly dependent on the structure of substrates. Thus, iodohydrins and bicyclic ethers are produced from inter-or intramolecular reactions, respectively.

Experimental

(R)-Limonene {+ 118.7 (neat)} and (S)-a-terpineol {- 76.0 (c 1.0, CHCl₃)} were purchased from Dierberger, (5R)-carveols {- 108.1 (c 1.1, CHCl₃), ca. 1:1 mixture of cis- and trans-isomers} and (S)-perillyl alcool {- 91.0 (c 1.0, CHCl₃)} were purchased from Aldrich.

(R)-Carvomenthene {+ 78.5 (c 2.0, CHCl₃)} was prepared in 98 % yield (> 99 % purity) by catalytic hydrogenation of (R)-limonene, as described by Jackman et al.³³

Infrared (IR) spectra were recorded on a Perkin Elmer 1600 series FTIR (film in NaCl pellets). Analyses by HRGC were performed on a HP-5890-II gas chromatograph with FID by using a RTX-5 silica capillary column and H₂ (flow-rate 50 cm/s) as carrier gas. Mass spectra (MS) were obtained on a Hewlett-Packard HP 5896-A (column: SE-54) or on a Hewlett-Packard HP 5937 (column: OV-1) HRGC-MS spectrometers using electron impact (70 eV). ¹H (300 MHz) and ¹³C (75 MHz) NMR spectra were acquired on a Bruker spectrometer for CDCl₃ solutions with TMS as internal standard. Polarimetric analyses were performed on a Jasco DIP 370 polarimeter.

(1S,2S,4R)-2-Iodo-4-isopropenyl-1-methylcyclohexanol (2)

To a stirred solution of (R)-limonene (1.36 g, 10.00 mmol) and Cu(OAc)₂·H₂O (1.00 g, 5.00 mmol) in dioxane (22 ml) and water (3 ml), was added I₂ (1.90 g, 7.50 mmol) in small lots at rt. After 4 h, Cu₂I₂ was filtered off and CHCl₃ (30 ml) was added to the filtrate. The resulting solution was treated with a suspension of NaBH₄ (1 g) in EtOH (50 ml) and then washed with water (3 ´ 20 ml). The organic layer was dried (Na₂SO₄) 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 %). + 103.5 (c 2.0, CHCl₃). ¹H NMR (CDCl₃): d 1.00-2.00 (m, 7H), 1.37 (s, 3H), 1.44 (s, 3H), 2.85 (br s, 1H), 4.46 (d, 1H, J 8.5 Hz), 5.12 (br s, 1H) ppm. ¹³C NMR (CDCl₃): d 21.3 (CH₃), 26.1 (CH₂), 30.5 (CH₃), 33.5 (CH₂), 37.4 (CH₂), 40.0 (CH), 43.1 (CH), 70.4 (C), 109.4 (CH₂), 148.2 (C) ppm. MS: m/z (%): 280 (M⁺, 1), 153 (42), 135 (62), 107 (46), 93 (50), 71 (58), 43 (100).

trans-1,2-Epoxy-(R)-limonene (3)

The crude iodohydrin 2 (2.30 g, 8.21 mmol) was treated with Na₂CO₃ (1.59 g, 15.00 mmol) in water (40 ml) and ethanol (10 ml). After stirring for 24 h at rt the reaction mixture was extracted with ether (3 x 10 ml) and the organic phase dried (Na₂SO₄). The solvent was evaporated in a rotatory evaporator at reduced pressure and the residue purified by column chromatography (SiO₂, hexane, chloroform) to give epoxide 3 (0.74 g, 4.87 mmol, 59 %). + 78.0 (c 1.0, CHCl₃). IR: n_max 3072, 2960, 2920, 2860, 1637, 1437, 1373, 920, 890, 838 cm^-1. ¹H NMR (CDCl₃): d 1.31-1.43 (m, 2H), 1.34 (s, 3H), 1.68 (s, 3H), 1.65-1.77 (m, 2H), 1.80-1.95 (m, 1H), 2.00-2.10 (m, 2H), 2.99 (d, 1 H, J 5.38 Hz), 4.66 (br s, 2 H) ppm. ¹³C NMR (CDCl₃): d 18.1 (CH₃), 20.2 (CH₃), 23.1 (CH₂), 30.0 (CH₂), 30.8 (CH₂), 40.8 (CH), 53.4 (C), 57.5 (CH), 109.1 (CH₂), 149.2 (C) ppm. MS: m/z (%):152 (M^+•, 2), 137 (4), 123 (5), 108 (42), 94 (62), 67 (62), 43 (100).

(1S,2S,4R)-2-Iodo-4-isopropyl-1-methylcyclohexanol (5)

(R)-Carvomenthene (1.38 g, 10.00 mmol) used instead of (R)-limonene, other reagents and conditions being as described for 2 above. After all, it was obtained 2.43 g (8.62 mmol, 86 %) of crude 5, along with recovered carvomenthene (8 %). + 64.3 (c 2.0, CHCl₃). ¹H NMR (CDCl₃): d 0.90-2.02 (m, 8H), 1.37 (s, 3H), 1.40 (s, 3H), 1.41 (s, 3H), 2.85 (br s, 1H), 4.40 (br s, 1H) ppm. ¹³C NMR (CDCl₃): d 20.1 (CH₃), 20.2 (CH₃), 24.6 (CH₂), 30.9 (CH₃), 31.6 (CH), 33.5 (CH₂), 36.5 (CH₂), 39.5 (CH), 43.1 (CH), 71.5 (C) ppm. MS: m/z (%): 267 (M^+• - Me, 2), 249 (2), 155 (75), 137 (80), 95 (71), 93 (50), 81 (90), 43 (100).

trans-Epoxy-(R)-carvomenthene (6)

The crude iodohydrin 5 (2.43 g, 8.62 mmol) was treated as described for 3 above to give epoxide 6 (0.78 g, 5.06 mmol, 59 %). + 42.9 (c 1.0, CHCl₃). ¹H NMR (CDCl₃): d 0.84 (d, 6H), 1.30-1.34 (m, 1H), 1.31 (s, 3H), 1.37-1.40 (m, 2H), 1.53-1.62 (m, 2H), 1.70 (m, 2H), 1.98 (m, 1H), 2.98 (d, 1 H, J 5.37 Hz) ppm. ¹³C NMR (CDCl₃): d 19.2 (CH₃), 19.5 (CH₃), 22.4 (CH₃), 23.0 (CH₂), 27.7 (CH₂), 30.8 (CH₂), 32.1 (CH), 39.1 (CH), 57.7 (C), 59.5 (CH) ppm. MS: m/z (%): 154 (M^+•, 5), 139 (20), 125 (12), 111 (50), 95 (10), 83 (20), 69 (40), 43 (100).

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·H₂O (1.00 g, 5.00 mmol) in dioxane (10 ml) and water (2 ml), was added I₂ (0.95 g, 3.75 mmol) in small portions at rt. After 16 h (1 h for carveols), the reaction media was filtered and CHCl₃ (15 ml) was added to the filtrate. The resulting solution was washed with a saturated solution of Na₂SO₃ (3 x 10 ml), the organic layer dried (Na₂SO₄) 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 CH₂Cl₂ as eluent.

(1R,5R,6S)-2,6-dimethyl-6-iodomethyl-7-oxabicyclo[3.2.1]-oct -2-ene (8)

It was obtained 1.18 g [4.24 mmol, 85 % from (5R)-cis-carveol]. - 17.8 (c 1.0, CHCl₃). ¹H NMR (CDCl₃): d 1.45 (s, 3H), 1.72 (m, 3H), 1.94 (d, 1H, J 10.74 Hz), 2.34 (m, 3H), 2.52 (m, 1H), 3.36 (dd, 2H, J 22.61 Hz, 9.69 Hz), 4.15 (d, 1H, J 4.41 Hz), 5.26 (m, 1H) ppm. ¹³C NMR (CDCl₃): d 14.2 (CH₂), 17.9 (CH₃), 27.9 (CH₃), 29.7 (CH₂), 35.1 (CH₂), 40.7 (CH), 77.6 (CH), 84.1 (C), 120.7 (CH), 139.8 (C) ppm.

(1S,2S,5S)-2,6,6-trimethyl-7-oxabicyclo[3.2.1]-octan-2-ol (11)

It was obtained 0.38 g (2.24 mmol, 45 % from (S)-a-terpineol). + 25.6 (c 10.0, CHCl₃). ¹H NMR (CDCl₃): d 1.23 (s, 3H), 1.24 (s, 3H), 1,38 (s, 3H), 1.43 (m, 2H), 1.66 (m, 2H), 1.84 (m, 2H), 2.17 (m, 2H), 3.81 (d, 1H, J 5.37 Hz) ppm. ¹H NMR (DMSO-D₆): d 1.13 (s, 3H), 1.21 (s, 3H), 1.37 (s, 3H), 1.43 (m, 1H), 1.74 (m, 3H), 1.88 (m, 1H), 2.05 (m, 1H), 2.25 (d, 1H, J 11.55 Hz), 3.68 (d, 1H, J 6.33 Hz), 4.45 (s, 1H) ppm. ¹³C NMR (CDCl₃): d 23.5 (CH₃), 24.3 (CH₂), 28.7 (CH₃), 30.2 (CH₃), 31.9 (CH₂), 33.1 (CH₂), 41.3 (CH), 72.1 (C), 82.3 (C), 82.5 (CH) ppm. MS: m/z (%) 170 (M^+•, 5), 155 (2), 137 (1), 126 (23), 111 (10), 109 (16), 97 (18), 83 (10), 71 (45), 43 (100), 69 (27).

(1'S, 2RS)-2-(4'-hydromethyl-3'-cyclohexenyl)-1-iodo-2-propanol (15)

It was obtained 0.22 g [0.74 mmol, diastereoisomeric mixture, 15 % from (S)-perillyl alcohol]. - 32.1 (c 0.7, CHCl₃). IR: n_max 3363, 1674, 1642, 1191, 1029 cm^-1. ¹H NMR: d 1.25 (d, J 6.08 Hz), 1.82 (m), 2.15 (m), 3.45 (m), 4.05 (br s), 5.70 (m) ppm. ¹³C NMR: d 21.70 (CH₃), 22.7 (CH₂), 23.1 (CH₂), 23.3 (CH₂), 23.5 (CH₃), 24.1 (CH₂), 25.9 (CH₂), 26.3 (CH₂), 26.4 (CH₂), 26.6 (CH₂), 42.2 (CH), 42.6 (CH), 66.9 (CH2), 67.0 (CH2), 72.1 (C), 72.2 (C), 121.5 (CH), 122.2 (CH), 137.3 (C), 137.9 (C) ppm. MS: m/z (%) 278 (M^+•- H₂O, 4), 220 (2), 185 (63), 169 (8), 151 (18), 133 (65), 93 (75), 79 (100), 43 (37).

Acknowledgments

We thank CNPq and PADCT for financial support of this work. AMS, FMS, and JJJ thank CNPq for fellowships. We also thank Carlos R. Kaiser, Rosane A.S. San Gil, and Cristiane P. S. Chaves for the NMR spectra and Claudia Moraes de Rezende for mass analyses.

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Received: September 17, 1999

Dedicated to our teacher and mentor W. Bruce Kover, who taught us to find the beauty of each reaction.

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