Synthesis and Some Transformations of (–)-Carveol

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ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 6, pp. 810–814. © Pleiades Publishing, Ltd., 2009. Original Russian Text © R.F. Valeev, N.S. Vostrikov, M.S. Miftakhov, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 6, pp. 828–831. Synthesis and Some Transformations of (–)-Carveol R. F. Valeev, N. S. Vostrikov, and M. S. Miftakhov Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences, pr. Oktyabrya 71, Ufa, 450054 Bashkorto

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   ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 6, pp. 810–814. © Pleiades Publishing, Ltd., 2009.Original Russian Text © R.F. Valeev, N.S. Vostrikov, M.S. Miftakhov, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 6, pp. 828–831. 810 Synthesis and Some Transformations of (–)-Carveol R. F. Valeev, N. S. Vostrikov, and M. S. Miftakhov  Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences, pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russiae-mail:   bioreg@anrb.ru   Received March 17, 2008 Abstract  —Reduction of the oxo group in (–)-carvone with LiAlH 4 , NaBH 4 , and ( i -Bu) 2 AlH was performed. Itwas found that the reduction with the system CeCl 3   ·   7   H 2 O–NaBH 4 in methanol at 20°C is the most practical procedure for the synthesis of (–)-carveol. Solvolysis of (–)-carvyl methanesulfonate gave products of S  N 2 andS  N 2 ′ replacement of the methylsulfonyloxy group, the latter slightly prevailing. Overman rearrangement of (–)-carveol resulted in the formation of the corresponding trichloroacetamide derivative, and intramolecular iodoetherification of the title compound afforded 6-iodomethyl-2,6-dimethyl-7-oxabicyclo[3.2.1]oct-2-ene. Commercially available and cheap monoterpene(  R )-(–)-carvone ( I ) is widely used in organic synthesisas chiral template [1–5]. In the present work weexamined some aspects of selective transformations of (–)-carvone into building blocks that are more suitablefor subsequent target-oriented syntheses. Initially, we planned to obtain (–)-carveol ( II ) by reduction of  I  with lithium tetrahydridoaluminate in diethyl ether at –78°C [6]. According to the GLC data, the purity of compound II synthesized in this way was 95%, and theconcentration of minor (–)-carveol ( III ) reached 5%.The best results (from the viewpoint of stereoselec-tivity) were obtained using Luche’s reagent (NaBH 4  – CeCl 3   ·   7   H 2 O) [7]. In this case, the reduction of (–)-carvone ( I ) in methanol at room temperature gave(–)-carveol ( II ) in 90% yield, and its purity was 98%(after chromatographic purification on silica gel; cf.[8–10]) (Scheme 1). In the reduction of  I with Luche’sreagent in THF the yield of (–)- II was 96%, and thereduction with ( i -Bu) 2 AlH in CH 2 Cl 2 at –78°C gave80% of (–)- II . From the preparative viewpoint, it isconvenient to perform reduction of (–)- I in methanolwith subsequent purification of the product by vacuumdistillation, although in this case the yield of (–)- II issomewhat lower (~80%).We made an attempt to convert (–)-carveol ( II ) intoits enantiomer. The known procedure for the trans-formation of (–)- II into (+)- II includes initial prepara-tion of epoxy derivative, mesylation, and reductivefragmentation of methanesulfonate IV with “dissolvedmetal” (Scheme 2). The yield of (+)-carveol (+)- II inthe latter step was moderate (57%) [11]. We trieda shorter way of converting carveol enantiomers intoeach other via solvolysis of allylic methanesulfonates,which follows S  N 2 ′ mechanism. For this purpose,(–)-carveol ( II ) was treated with methanesulfonylchloride in the presence of triethylamine, and methane-sulfonate V thus obtained was heated for 1 h at 60°C ina mixture of DMSO and 10% aqueous sodium hydrox-ide (1   :   1 by volume). The subsequent chromatographic purification on silica gel gave pure (according to theGLC data) carveol ( III , [ α ] D20 = +17 o ).In our case, the initial (–)-carveol ( II ) had [ α ] D20 = –25.4° {published data: [ α ] D20 = –25.8 [6], –23.9 [12], –23.0 ( c = 5.6, EtOH, ee 100%) [11]}; (–)- III : [ α ] D20 = –213.8 [12]. Obviously, the observed optical rotationof solvolysis product III results from the presence of a small excess of enantiomeric (+)-carveol ( III ) whichis formed according to the S  N 2 ′ mechanism. Takinginto account that racemization is hardly probable under the above conditions (alkaline medium), (–)-carveol( III ) is likely to be formed via S  N 2 substitution of the DOI: 10.1134/S1070428009060025 MeOCH 2 Me I MeHOCH 2 Me II +MeHOCH 2 Me III Scheme 1.  SYNTHESIS AND SOME TRANSFORMATIONS OF (–)-CARVEOL RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009 811 Scheme 2. (–)- II MsOCH 2 Me IV OMeCH 2 Me(+)- II MeOHMsOCH 2 Me V MeCH 2 Me(+)- III MeOHOH  – >98%+CH 2 Me(–)- III MeHOMeSO 2 Cl, Et 3 N Scheme 3. (–)- II OCH 2 Me VI MeCl 3 CCN, DBUCH 2 Cl 2 , 0°CCl 3 CNHXylene,  Δ HNCH 2 Me VII MeCCl 3 O methylsulfonyloxy group in (–)-( V ) by hydroxy group.We can conclude that the solvolysis of methanesulfo-nate V is not regioselective and that it follows both possible paths, S  N 2 and S  N 2 ′ , though each of these paths is stereoselective [only (+)- or (–)-carveol ( III ) isformed].With a view to obtain nitrogen-containing chiral building blocks, (–)-carveol ( II ) was subjected toOverman rearrangement [13]. Treatment of (–)- II withtrichloroacetonitrile in methylene chloride in the pres-ence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at0°C gave trichloroacetimidate VI which was convertedinto trichloroacetamide VII by heating in boilingxylene (Scheme 3). It is known that this [3,3]-sigma-tropic rearrangement is suprafacial and stereospecific.(–)-Carveol ( II ) was then subjected to intramolec-ular iodoetherification. cis Arrangement of the isopro- penyl and hydroxy groups in its molecule favorediodine-initiated intramolecular cyclization with prefer-ential formation of sterically less hindered bicyclic product VIII (Scheme 4). Minor stereoisomer  IX wasformed in trace amounts (3–5%) and was detected bydownfield signals from the C 6 Me group in the 13 C NMR spectrum.Thus we proposed a highly stereoselective and practical procedure for the reduction of (–)-carvone to(–)-carveol using the system NaBH 4  –CeCl 3   ·   7   H 2 O andstudied solvolysis of the corresponding methanesul-fonate. (–)-Carveol ( II ) was converted into  N  -carvyl-trichloroacetamide via Overman rearrangement, andintramolecular iodoetherification of (–)- II gave iodo-methyl-substituted bicyclic ether.EXPERIMENTALThe IR spectra were recorded on a UR-20 spec-trometer from samples prepared as thin films. The 1 Hand 13 C NMR spectra were measured on a Bruker AM-300 instrument at 300 and 75.47 MHz, respectively,using CDCl 3 as solvent and tetramethylsilane as in-ternal reference. Thin-layer chromatography was per-formed on Silufol plates. The optical rotations weremeasured on a Perkin–Elmer 241 MS polarimeter. The purity of the initial compounds was checked by GLCon a Chrom 5 chromatograph. Reduction of (  R )-(–)-carvone with LiAlH 4 . A so-lution of 5 g (33 mmol) of (  R )-(–)-carvone in 10 mlof diethyl ether was added dropwise to a suspension of   RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009 VALEEV et al. 812 Scheme 4. (–)- II I 2 , NaHCO 3 MeCN, 0°COMeCH 2 IMe VIII +OCH 2 IMeMe IX 0.32 g (8.3 mmol) of LiAlH 4 in 30 ml of diethyl ether under stirring at –78°C in a stream of argon. The mix-ture was stirred for ~1.5 h until the initial ketonedisappeared (TLC). Excess LiAlH 4 was decomposed by carefully adding 10% sulfuric acid at 0°C to pH ~7.The organic phase was separated, the aqueous phasewas extracted with ethyl acetate (3   ×   15 ml), and theextracts were combined with the organic phase,washed with a solution of sodium chloride, dried over MgSO 4 , and evaporated. The residue was purified bycolumn chromatography on silica gel using ethylacetate–petroleum ether (1   :   3) as eluent. We isolated4.8 g (95%) of a mixture of stereoisomers (–)- II and(–) -III at a ratio of 95   :   5 (according to the GLC data).Light yellow oily liquid, [ α ] D20 = –25.4° ( c = 2.1,EtOH); published data [6]: [ α ] D20 = –25.8° (ee 97%). (1  R ,5  R )-5-Isopropenyl-2-methylcyclohex-2-en-1-ol   (II).   IR    spectrum,  ν , cm  –1 : 3331 (OH), 3082 (=C–H),1645 (C=C). 1 H NMR spectrum, δ , ppm: 1.47–1.52 m(1H, 6-H), 1.72 s (3H, CH 3 ), 1.74 d (3H, CH 3 ,  J  =2 Hz), 1.85–2.30 m (5H, 4-H, 5-H, 6-H, OH), 4.17 br.s(1H, 1-H), 4.71 s (2H, =CH 2 ), 5.44 m (1H, 3-H). Reduction of (–)-carvone (I) with NaBH 4  –CeCl 3   ·   7   H 2 O . a . Sodium tetrahydridoborate, 0.025 g(0.67 mmol), was added at 20°C to a solution of 0.1 g(0.67 mmol) of (–)-carvone ( I ) and 0.25 g (0.67 mmol)of CeCl 3   ·   7   H 2 O in 10 ml of methanol. The mixture wasstirred for 5 min, 20 ml of diethyl ether and 20 ml of water were added, the organic layer was separated, andthe aqueous layer was extracted with diethyl ether (3   ×   10 ml). The extracts were combined with theorganic phase, dried over Na 2 SO 4 , and filtered. Thefiltrate was concentrated under reduced pressure, andthe residue was subjected to column chromatographyon silica gel using ethyl acetate–petroleum ether (1   :   5)to isolate 0.09 g (90%) of (–)-carveol ( II ). b . Likewise, the reduction of (–)- I with CeCl 3   ·   7   H 2 O–NaBH 4 in THF at 0°C gave 90% of (–)- II witha purity of 98% (according to the GLC data). Reduction of (–)-carvone (I) with ( i  -Bu) 2 AlH.  A solution of 2.7 mmol of ( i- Bu) 2 AlH in 5 ml of an-hydrous methylene chloride was added dropwise under stirring to a solution of 0.1 g (0.67 mmol) of (–)- I  in 20 ml of anhydrous methylene chloride, cooled to –70°C. The mixture was stirred for 1 h at that tem- perature, 0.17 ml of water was slowly added dropwise,the mixture was allowed to warm up to 25°C, the sol-vent was distilled off under reduced pressure, and the powder-like residue was extracted with hot methanol(3   ×   10 ml). The extract was evaporated, and the resi-due was dried with benzene (azeotropic distillation).We thus isolated 0.08 g (80%) of a mixture of stereo-isomers (–)- II and (–)- III at a ratio of 4   :   1 (accordingto the 1 H NMR data). 5-Isopropenyl-2-methylcyclohex-2-en-1-ol (III).  Carvyl methanesulfonate ( IV ), 0.7 g (4.6 mmol), wasadded under stirring to 40 ml of a 1   :   1 mixture of DMSO with 5% aqueous sodium hydroxide. The mix-ture was stirred for 5 h at room temperature (until theinitial compound disappeared according to the TLCdata), neutralized with 5% hydrochloric acid, andextracted with methylene chloride (3   ×   20 ml). Theextracts were combined, dried over MgSO 4 , and evap-orated. After removal of DMSO under reduced pres-sure, the residue was subjected to column chromatog-raphy on silica gel using ethyl acetate–petroleum ether (1   :   3) as eluent to isolate 0.45 g (99%) of compound III as a mixture of enantiomers, [ α ] D20 = +17.2° ( c =0.85, EtOH). IR spectrum,  ν , cm  –1 : 3334 (OH), 3082,1645. 1 H NMR spectrum, δ , ppm: 1.58–1.62 m (1H,6-H), 1.76 s (3H, CH 3 ), 1.82 s (3H, CH 3 ), 1.92–1.97 m(3H, 4-H, 6-H), 2.13–2.34 m (2H, 5-H, OH), 4.04 m(1H, 1-H), 4.74–4.76 m (2H, =CH 2 ), 5.59–5.61 m(1H, 3-H). 13 C NMR spectrum, δ C , ppm: 20.85 (CH 3 ),20.91 (CH 3 ), 30.99 (C 4 ), 35.23 (C 5 ), 36.71 (C 6 ),68.64 (C 1 ), 109.06 (=CH 2 ), 125.47 (C 3 ), 134.22 (C 2 ),149.15 ( C =CH 2 ). (1  R ,5  R )-5-Isopropenyl-2-methylcyclohex-2-en-1-yl methanesulfonate (V). Triethylamine, 1.3 g(13 mmol), was added under stirring in a stream of argon to a solution of 1.0 g (6.6 mmol) of (–)-carveol( II ) prepared as described above (method a ) in 20 mlof methylene chloride. The mixture was stirred for 15 min, a solution of 1.5 g (13 mmol) of methanesul-fonyl chloride in 15 ml of methylene chloride was  SYNTHESIS AND SOME TRANSFORMATIONS OF (–)-CARVEOL RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009 813slowly added dropwise, and the mixture was stirred for 4 h at 40°C, cooled, and neutralized to pH ~7 with 3%hydrochloric acid. The organic phase was separated,and the aqueous phase was extracted with methylenechloride (3   ×   10 ml). The extracts were combined withthe organic phase, dried over MgSO 4 , and evaporated,and the residue was purified by chromatography onsilica gel using ethyl acetate–petroleum ether (1   :   5) aseluent. Yield 0.9 g (60%), light yellow oily liquid,[ α ] D20 = –57.5° ( c = 1.7, EtOH). IR spectrum,  ν , cm  –1 :3082, 1645, 1440 (SO 2 ), 1379 (S–CH 3 ). 1 H NMR spec-trum, δ , ppm: 1.56 m (1H, 6-H), 1.76 s (3H, CH 3 ),1.83 s (3H, CH 3 ), 1.94–2.25 m (4H, 4-H, 5-H, 6-H),2.15 s (3H, SO 2 CH 3 ), 4.74 br.s (3H, =CH 2 , 1-H), 5.52– 5.54 m (1H, 3-H). 13 C NMR spectrum, δ C , ppm: 20.93(CH 3 ), 21.07 (CH 3 ), 30.76 (C 4 ), 34.86 (C 5 andSO 2 CH 3 ), 37.14 (C 6 ), 60.67 (C 1 ), 109.26 (=CH 2 ),126.53 (C 3 ), 133.15 (C 2 ), 148.45 ( C =CH 2 ). 2,2,2-Trichloro-1-[(1  R ,5  R )-5-isopropenyl-2-methylcyclohexen-2-en-1-yloxy]ethan-1-imine (VI).  (–)-Carveol ( II ), 1 g (6.6 mmol), was dissolved in20 ml of methylene chloride, 2 g (13 mmol) of DBUwas added under stirring, the mixture was stirred for 15 min, and a solution of 1.9 g (13 mmol) of trichloro-acetonitrile in 10 ml of methylene chloride was care-fully added dropwise. The mixture was stirred for 6 hat room temperature until the initial compound disap- peared (TLC), 10 ml of a saturated aqueous solution of ammonium chloride was added, the organic phase wasseparated, and the aqueous phase was extracted withmethylene chloride (3   ×   15 ml). The extracts were com- bined with the organic phase, washed with a solutionof sodium chloride, dried over MgSO 4 , and evaporat-ed, and the residue was purified by column chromatog-raphy on silica gel using ethyl acetate–petroleum ether (1   :   5) as eluent. Yield 1.45 g (74%), light yellowliquid, [ α ] D20 = –19.4° ( c = 1.25, EtOH). IR spectrum,  ν ,cm  –1 : 3323 (N–H), 3082, 1680 (C=N), 1645. 1 H NMR spectrum, δ , ppm: 1.26–1.43 m (1H, 6-H), 1.73 s (3H,CH 3 ), 1.76 s (3H, CH 3 ), 1.81 m (1H, 6-H), 1.94– 2.40 m (3H, 4-H, 5-H), 4.74 s (2H, =CH 2 ), 4.78 m(1H, 1-H), 5.62–5.64 m (1H, 3-H), 8.28 s (1H, NH). 13 C    NMR    spectrum   (acetone- d  6 ), δ C , ppm: 20.58 (CH 3 ),20.78 (CH 3 ), 29.41 (C 4 ), 29.67 (C 6 ), 35.97 (C 5 ), 75.86(C 1 ), 108.67 (CCl 3 ), 108.86 (=CH 2 ), 123.98 (C 3 ),133.97 (C 2 ), 150.03 ( C =CH 2 ), 162.50 (C=NH). 2,2,2-Trichloro-  N  -[(1  S  ,5  S  )-5-isopropenyl-2-methylcyclohex-2-en-1-yl)acetamide (VII). A solu-tion of 1 g (3.37 mmol) of compound VI in 25 ml of xylene was heated for 7 h under reflux. When theinitial compound disappeared, the solvent was re-moved under reduced pressure, and the residue was purified by column chromatography on silica gel usingethyl acetate–petroleum ether (1   :   10) as eluent. Yield0.6 g (60%), colorless crystals, mp 90–90.5°C, [ α ] D20 = –38.8° ( c = 4.3, MeOH). IR spectrum,  ν , cm  –1 : 3298(NH), 1692. 1 H NMR spectrum, δ , ppm: 1.60–1.65 m(1H, 6-H), 1.69 s (3H, CH 3 ), 1.76 s (3H, CH 3 ), 2.04 m(1H, 6-H), 2.13–2.33 m (3H, 4-H, 5-H), 4.52 m (1H,1-H), 4.76 s (1H, =CH 2 ), 4.79 s (1H, =CH 2 ), 5.64– 5.68 m (1H, 3-H), 6.68 br.s (1H, NH). 13 C NMR spec-trum, δ C , ppm: 19.64 (CH 3 ), 21.14 (CH 3 ), 30.13 (C 4 ),34.02 (C 6 ), 39.25 (C 5 ), 51.34 (C 1 ), 92.88 (CCl 3 ),109.87 (=CH 2 ), 125.96 (C 3 ), 132.03 (C 2 ), 148.42( C =CH 2 ), 161.49 (C=O). (1  R ,5  R ,6  S  )-6-Iodomethyl-2,6-dimethyl-7-oxabi-cyclo[3.2.1]oct-2-ene (VIII). A solution of 0.5 g(3.3 mmol) of (–)-carveol ( II ) in 20 ml of acetonitrilewas cooled to 0°C, 0.55 g (6.6 mmol) of NaHCO 3 wasadded in one portion under stirring, the mixture wasstirred for 15 min, and 0.84 g (3.3 mmol) of crystallineiodine was added. The mixture was stirred for 2 h atroom temperature (until the initial compound disap- peared according to the TLC data) and evaporated,15 ml of a saturated solution of Na 2 S 2 O 3 was added tothe residue, and the mixture was extracted with ethylacetate (3   ×   10 ml). The extracts were combined, driedover MgSO 4 , and evaporated, and the residue was purified by column chromatography on silica gel usingethyl acetate–petroleum ether (1   :   10) as eluent. Yield0.66 g (73%), light yellow liquid, [ α ] D20 = –17.5° ( c =5.0, EtOH). IR spectrum:  ν 1088 cm  –1 (C–O–C). 1 H NMR spectrum, δ , ppm: 1.45 s (3H, CH 3 ), 1.50 m(1H, 8-H), 1.70–1.72 m (3H, CH 3 ), 1.91–1.95 m (1H,8-H), 2.23–2.38 m (2H, 4-H, 5-H), 2.49–2.50 (1H,4-H), 3.32 s (1H, CH 2 I), 3.36 s (1H, CH 2 I), 4.13– 4.15 m (1H, 1-H), 5.25–5.27 m (1H, 3-H). 13 C NMR spectrum, δ C , ppm: 14.22 (CH 2 I), 21.41 (CH 3 ), 27.94(CH 3 ), 29.76 (C 4 ), 35.10 (C 8 ), 40.77 (C 5 ), 77.53 (C 1 ),84.03 (C 6 ), 120.72 (C 3 ), 139.80 (C 2 ).This study was performed under financial support by the Federal Science and Innovation Agency and bythe Council for Grants at the President of the RussianFederation (project no. NSh-1725.2008.3).REFERENCES 1. Srikrishna, A., Reddy, T.J., and Kumar, P.P., Chem.Commun ., 1996, p. 1369.2. Brabander, J., Kulkarni, B.A., Jarcia-Lopez, R., andVardewalle, M., Tetrahedron: Asymmetry , 1997, vol. 8, p. 1721.
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