1977 2433Synthesis of 4,4a-5,6,7,8- Hexahydro-5P- hydroxy-4ap,8a-dimethylnaph-thalen-2(3H)-one, a Versatile Intermediate for Sesquiterpene SynthesisBy Michiharu Kato, Hiroshi Kurihara, Hiroshi Kosugi, Masataka Watanabe, Shigeru Asuka. and AkiraYoshikoshi, Chemical Research Institute of Non-aqueous Solutions, Tohoku University, Sendai 980, JapanTwo routes have been examined from 5~-acetoxy-4,4a,5,6,7,8-hexahydro-4a~-methylnaphthalen-2(3~) -one (1 0)to 4,4a,5,6,7,8-hexahydro-5~-hydroxy-4ap.8a-dimethylnaphthalen-2(3~)-one (1 ), a key intermediate for thesynthesis of some types of sesquiterpenoid. The route shown in Scheme 2 is preferable to that in Scheme 1(although the former is slightlythe more lengthy), giving compound (1) in ca. 48 overall yield from (1 0).THE title compound (1) is potentially a versatile key in-termediate for the synthesis of some representative typesof sesquiterpene.Compound (2a) would be obtainable on/I/// t(4)QH(7) (8) (9)saturation of the olefinic double bond followed by intro-duction of an isopropyl carbon unit at the ketone func-tion. Selinane (3) or guaiane (4) sesquiterpenes could bederived from (2a) on removal of the hydroxy-group or bysolvolytic rearrangement after conversion of the hydroxy-group into an appropriate leaving group such as sulphon-ates as in (2b), respectively. In fact, some guaianeM. Kato, H. Kosugi, and A. Yoshikoshi, Chem. Comm.,1970, 185.M. Kato, H. Kosugi, and A. Yoshikoshi, Chem. Comm.,1970, 934.sesquiterpenoids bulnesol (7), kessane (8), and globu-lo1 (9) have been synthesised from compound (1). Onthe other hand, fission of the peripheral (2,3-) or central(5,lO-) bond would lead to elemane (5) or germacrane (6)sesquiterpenes.Previously we reported the synthesis of the hydroxy-octalone (1) by the route shown in Scheme 1 from theacetoxy-octalone (lo), readily available from theWieland-Pvliescher ketone via a known pr~cedure.~ Wedescribe here the details of this synthesis of (1) and animproved route (Scheme 2).The unstable enol ether (11) was prepared from (10)according to Burn’s pr~cedure,~ i.e.by reaction with tri-ethyl orthoformate and a catalytic amount of toluene-$-sulphonic acid in dioxan (Scheme 1). The crude enolether was successively treated with the Vilsmeier reagent(Me,N-CHO-POCl, or Me,N*CHO-COCl,) , lithium alu-minium hydride, and then methyl iodide to obtain theammonium salt (14) v i a the iminium salt (12) and theamine (13).None of compounds (12)-(14) was suffi-ciently stable for analytically pure material to be ob-tained, although they were characterised spectroscopic-ally. Reductive cleavage of the carbon-nitrogen bond in(14) was performed with Raney nickel. This reaction,however, was capricious ; it gave the hydroxy-octalone(1) in good yield in some cases after acidic hydrolysis ofthe resultant enol ether (15) (which was also unstable),but complex mixtures were produced in other cases, andoptimum conditions for this reaction were not established.The poor reproducibility might be ascribed to high sensi-tivity of the reaction to the activity of the Kaney nickelused, or to impurities in the substrate which deactivatedthe Raney nickel, or to both.An equatorial orient-ation of the newly formed methyl group in (1) was ascer-tained from the coupling constant (1.8 Hz 6, of the olefinicJ . A. Marshall and J. A. Ruth, J . Org. Chem., 1974,39, 1971. * C. B. Boyce and J. S. Whitehurst, J . Chem. Soc., 1960, 2680.D. Burn, Tetrahedron, 1964, 20, 597.6 H. J . Ringold, J . Amer. Chem. Soc., 1963, 85, 16992434 J.C.S. Perkin IlH n.m.r. doublet. The best result obtained from reduc-tive cleavage of the ammonium salt (14) was an overallyield of the hydroxy-octalone (1) from (10) of ca. 60.sodium acetate, and reduction of the product with boro-hydride afforded the corresponding alcohol (17).Thisacid- and heat-sensitive alcohol was immediately treatedwith acetic acid at room temperature to -achieve dehydra-tion, affording the dienone (18) in .high yield. Theoily octalone (19) was then obtained by partial hydrogen-ation over palladium-barium sulphate. As expected,the secondary methyl group in (19) was axial, as was(1 0) (11) CH=N Me2CL' evidenced by the singlet nature of the olefinic proton(12) n.m.r. signal. To epimerise the axial secondary methylgroup to an equatorial one, the acetoxy-octalone (19)was treated with toluene-@-sulphonic acid in benzene;however the product was contaminated with an unidenti-fied by-product which was difficult to remove on a pre-In an improved procedure, the crystal-line acetal (20) was prepared, and deacetalised afterOEt OEt recryst allisation.The resultant acetoxy-oct alone (2 1)was hydrolysed with potassium carbonate giving the(15) hydroxy-octalone (1). The final product was also derivedin a similar overall yield from (20) by reduction withlithium aluminium hydride of the acetal (ZO), and hydro-lysis of the resultant hydroxy-octalin (22).By Scheme 2, the hydroxy-octalone (1) was preparedfrom (10) in ca. 48 over-all yield.AcO / / i i = Apt / /OEt +A- ( 1 ) parative scale. qJ+ @; mOEt CH2NMe2 CH2 N Me3I'(13) ( 1 4 )SCHEME 1 i, (EtO),CH-TsOH; ii, Vilsineier reagent; iii,LiAlH,; iv, MeI; v, Raney Ni; vi, H,SO,-H,OAlthough the foregoing route to (1) was relatively ex-peditious, the obstacle in the reductive cleavage of (14)could not be circumvented. We then turned to another EXPERIMENTAL1.r.spectra were taken with a Hitachi EPI-32 spectro-photometer, and n.m.r. spectra with a JEOL C-60-HLspectrometer (60 MHz) for solutions in CDC1, unless other-wise stated. Tetramethylsilane was used as an internalstandard and coupling constants are given in Hz.5P-A cetoxy-2-ethoxy-3,4,4a, 5,6,7-hexahydro-4ap-methyl-naphthalene ( 1 1) .-Ethyl orthoformate (33 ml, ca. 0.2 mol)and toluene-psulphonic acid (600 mg) were added to asolution of the acetoxy-octalone (10) (48 g, 0.216 mol) indry dioxan (200 ml), and the mixture was stirred a t roomAcO temperature for 3 h. Pyridine (15 ml) was added, and themixture was poured into ice-water and extracted withether.The extract was washed with water and brine, and Q-LA@;Ap3 dried. a glassy Removal mass (52.2 of g), the vmaX, solvent (film) 1 left 735, the 1 653, enol 1 ether 620, 1 (ll), 245,and 1 030 cm-l, 6 (CCl,) 1.01 (3 H, s), 1.14 (3 H, t, -1 7), 1.89AcO(12)/ / LOE tCHO CH20H(17) (16)(18) (19) (20)(22)(3 H, s ) , 3.70 (2 H, q, J 7), 4.5-4.8 (1 H, m, AcOCH), and4.97 (2 H, in, =CH).Although analytically pure material could not be ob-tained, the crude product was sufficiently pure to be used inthe next step (as shown by g.1.c.).8- Diwzethylaminomethyl- 2-ethoxy-5P- Jzydroxy- 3,4,4a, 5,6,7-hexahydro-4ap-methylnaphthalene ( 13) .-A solution of di-methylformamide (22 g, 0.3 mol) in dry dichlorometliane(100 ml) was added to a stirred solution of phosgene * '(22 g,0.22 mol) in the same solvent (100 ml) in an ice-bath.TheVilsmeier reagent was precipitated as a solid with evolutionof carbon dioxide. A solution of the enol ether (11) (40 8,0.16 mol) in the same solvent (100 ml) was added dropwise,giving a red solution immediately. After stirring for 3 h,SCHEME 2 i, NaOAc-H,O; ii, NaBH,; iii, HOA~-H,O; iv, the solvent was removed in vacua a t room temperature toH,-Pd(BaS0,); v, (CH,OH),-TsOH; vi, Me,CO-TsOH; leave a viscous deep red oil. A solution of the oil in dryvii, K,CO,-MeOH; viii, LiAlH,; ix, HC1-H,O tetrahydrofuran (500 ml) was added dropwise to a stirredsuspension of lithium aluminium hydride (8.0 g) in dryether (400 ml) under nitrogen, and the mixture was stirredchloride, see later.route (Scheme ')* The formy' ether (16) was Ob-hydrolysis of the crude iminium salt (12) with aqueoustained as in high Yield On * More reproducible results were obtained with phosphory1977a t room temperature for 12 11.The excess of reagent was de-composed with wet ether and then with a small quantity ofwater. Work-up gave the crude tertiary amine (13) (32.9 g)as a pale yellow oil, v,. (film) 3 400, 1 643, and 1 615 cm-l,6 1.00 (3 H, s), 1.30 (3 H, t, J 7), 2.20 (6 H, s, NMe,), 3.85(2 H, q, J 7), and 5.62 (1 H, s, =CH).Attempts to obtain a pure sample were unsuccessful.8-Dimethylaminou~ethyl-2-ethoxy-5~-hydroxy-3,4,4a, 5,6,7-hexahydro-4ap-methylnaphthalene Methiodide ( 14) .--Methyliodide (14 ml, ca.0.22 mol) was added to a stirred solutionof the crude amine (13) (25.0 g) in dry ethanol (100 ml) in anice-bath, and stirring was continued at room temperaturefor several h. A small quantity of dry ether was added,and the mixture was stirred for an additional few min. Theprecipitate was collected by filtration, washed with dryether several times, and then dried in vacuo to yield theammonium salt (14) as a hygroscopic powder (39 g), n1.p.200 "C (decomp.), vmax. (KBr) 3 400, 1 630, and 1 600w cm-l.Attempts to obtain an analytically pure sample were un-successful.naphthaZen-2(3H)-one (1) .-The best result for the reductivecleavage of the ammonium salt (14) was obtained as follows.A suspension of (14) (12 g) and Raney nickel (W-2; 100 g)in dry ethanol (250 ml) was saturated with hydrogen at roomtemperature, and the mixture was refluxed for 3 h withstirring.After filtration, the solution was concentrated invacuo leaving an oil, which was extracted with ether severaltimes. The combined extracts were evaporated to give thecrude hydroxy-enol ether (15) (5.2 g) as an oil, vnlSx. (film)3400, 1645, and 1620 cm-l, 6 0.93 (3 H, s,) 1.58 (3 H, s),3.40 (1 H, t, J 9, CHOH), and 5.23 (1 H, s, X H ) .The crude (15) was dissolved in 2N-sulphuric acid (15 inl)and ethanol (30 ml), and stirred a t room temperature for12 h. The mixture was concentrated in vacuo, and the resi-due was added to water and extracted with dichloromethane.Work-up gave an oil, which was filtered through a shortsilica gel column in ether. Removal of the solvent from thefiltrate left the hydroxy-octalone (1) (4.0 g) as an oil, b.p.135 "C (bath temp.) a t 0.2 mmHg, v,,,.(film) 3 400, 1 660,and I610 cm-l, 6 1.07 (3 H, d, J 6), 1.20 (3 H, s ) , 3.07 (1 H,s, OH), 3.45 (1 H, q, J 6, CHOH), and 5.81 (1 H, d, J 1.8).A sample for analysis was obtained by evaporative distill-ation in vacuo (Found: C, 74.0; H, 9.7. C1,H1,O, requiresC , 74.2; H, 9.3).5P-A cetoxy- 2-ethoxy- 8- formyl- 3,4,4a, 5,6,7-hexahydro-4ap-methylnafihthalene ( 16) .-To prepare the Vilsmeier reagent,phosphoryl chloride (2.58 ml, ca. 33.9 mmol) was addeddropwise to purified dimethylformamide (7.56 nil, ca. 109mmol) with stirring under nitrogen in an ice-bath.Afterthe exothermic reaction had subsided, a solution of thefreshly prepared enol ether (1 1) (6.32 g, 30 mmol) in dimethyl-formamide (20 ml) .was added dropwise. The mixture wasthen stirred a t room temperature for 4 h and poured into alarge excess of saturated aqueous sodium acetate in an ice-bath. The precipitate was collected by filtration, washedwith cold water, and dried in vacuo a t room temperature,giving the crude formyl enol ether (16) (6.50 g). Recrystid-Lisation from dichloromethane gave pale yellow needles, m.p.126-127 OC, vlllAX. (KBr) 1 728, 1 645, 1 605, and 1 572 cm-l,8 1.20 (3 H, s), 1.37 (3 H, t, J 7), 1.5-2.8 (8 H, m), 2.10 (3H,s,Ac),3.96(2H,q, J7),4.80(1H,m,AcOCH),6.37(lH,j,=CH), and 10.25 (1 H, s, CHO) (Found: C, 69.0; H, 7.7.21sH,20, requires C, 69.0; H, 8.0).5P-A cetoxy-4,4a, 5,6,7,8-hexaJzydro-4a~-rethyl-8-methylene-4,4a,5,6,7, 8-Hexahydro-5P-hydroxy-4a/iI, 8cc-dirnethyl-nuphthalen-2( 3H)-one ( 18) .--Sodium boroliydride (1 87 mg,3.62 mmol) was added to a stirred solution of the forniylenol ether (16) (3.3 g, 12 mniol) in ethanol (25 ml) in an ice-bath, and stirring was continued for a further 30 min.Themixture was allowed to warm to room temperature over 1 11,poured into ice-water, and extracted with dichloromethane.The combined extracts were washed with brine and dried.Removal of the solvent gave the alcohol (17) (3.22 g) as anoil, vnYJx. (film) 3 400, 1 730, 1 645, and 1 618 cm-l, 6 1.03 (3 H,s), 1.33 (3 H, s, J 7), 1.5-2.6 (9 H, m), 2.05 (3 H, s), 3.85 (2H, q, J 7),4.15 (2 H, q, CH,OH), 4.77br (1 H, t, AcOCH),and 5.54 (1 H, s, =CH).This alcohol was sensitive to heat and acid, and decomposedeven on a silica gel t.1.c.plate. Since the n.m.r. spectrum,however, indicated it to be almost homogeneous, the crudeproduct was used without purification in the next step.The alcohol (4.81 g, ca. 17.2 mmol) was dissolved inaqueous acetic acid (800/, ; 20 ml), and, after stirring a t roomtemperature for 3 h, the mixture was poured into ice-water.The product was extracted with ether, and the extract waswashed successively with water, aqueous sodium hydrogencarbonate, and brine, and dried. Evaporation left an oil,which crystallised. Recrystallisation from ether-lightpetroleum (10 : 1) gave the pure dienone (18) (3.45 g, 870/,) aspale yellow needles, m.p.58.5-59.5 OC, vInrtx-. (KBr) 1 750,1680, 1 6 3 0 ~ ) and 1608wcm-l, 6 1.20 (3H, s ) , 1.5-2.7 (8H,m), 2.07 (3H, s ) , 4.85 (1 H, dd, J 10.5 and 5.3, AcOCH), 5.05and 5.18 (each 1 H, s, C=CH,), and 6.02 (1 H, s, =CH) (Found:C, 71.4; H, 7.9. C14H1803 requires C, 71.8; H, 7.77;).5P-Acetoxy-3,4,4a,5,6,7-hexahydro-4au,8-dimethylna$h-thnlen-2( 1H)-one Ethylene Acetal (20) .-The dienone (18)(2.73 g, 11.7 mmol) was hydrogenated over 5 palladium-barium sulphate (560 mg) in ethyl acetate (35 ml) underatmospheric pressure. After absorption of 0.95 equiv. ofhydrogen, the catalyst was filtered off, and the filtrateevaporated in vacuo to give a viscous oil.Although theproduct was contaminated by a by-product, the main pro-duct was the 8P-methyloctalone (19), as shown by spectraldata: v,,,. (film) 1 735, 1 673, and 1 615 cm-l, 6 2.08 (3 H, s),4.70 (1 H, m, AcOCH), and 5.86 (ca. 1 H, s, =CH).A mixture of the above octalone, ethylene glycol (5 ml),toluene-$-sulphonic acid ( 15 mg) , and benzene was a,zeotropi-cally refluxed for 12 h (Dean-Stark water separator). Themixture was then diluted with water and extracted withether. The extract was successively washed with aqueoussodium hydrogen carbonate, water, and brine, and thendried. Removal of the solvent left a crystalline residue,which was recrystallised from ether-light petroleum (10 : 1)to give needles of (20) (2.49 g, 76y0), m.p. 116-117 "C, vmBx.(KRr) 1730 cm-l, 6 1.13 (3 H, s), 1.63 (3 H, s), 1.3-2.8 (10H, m), 2.05 (3 H, s), 3.96 (4 H, s, OCH,CH,O), and 4.85 (1 H,t, AcOCH) (Found: C, 68.8; H, 8.9.Cl,H,,04 requires C,Attenifitad Direct Epimerisation of the Octalone (19) .-Asolution of the 8P-methyloctalone (19) (198 mg), obtained onhydrogenation of the dienone (18) as described above, and acatalytic amount of toluene-$-sulphonic acid in benzene wasrefluxed under nitrogen overnight. Water was added, andthe product was extracted with ether. The extract waswashed, dried, and evaporated to leave an oil, which waspassed through a short silica gel column in ether. The eluategave an oil (185 mg) on concentration. Spectral data andg.1.c. showed that this was the acetoxy-octalone (21) con-taminated by an unidentified product (< 10).Attemptedseparation on a preparative scale was unsuccessful.68.5; H, 8.6)The Hydroxy-octale (1) from the Acetoxy-acetal (20) viathe A cetoxy-octalone (21) .-A solution of the acetoxy-acetal(20) (280 mg, 1 mmol) and a catalytic amount of toluene-p-sulphonic acid in acetone (30 ml) was refluxed overnight andthen poured into water. The product was extracted withether, and the extract was washed and dried. The residualoil obtained on evaporation was passed through a short silicagel column in ether, affording the acetoxy-octalone (21) (200mg) as an oil, vmax. (film) 1 730, 1 670, 1 610, 1 235, and 1 030cm-l, 6 1.10 ( 3 H, d, J 6), 1.30 (3 H, s ) , 2.05 (3 H, s ) , 4.70 ( 1H, m, AcOCH), and 5.85 (1 H, d, J 1.8, =CH).Potassium carbonate (120 mg) was added to a solution ofthe above acetoxy-octalone (146 mg, 0.62 mmol) in meth-anol (2 ml) , and the mixture was stirred at room temperaturefor 2 h under nitrogen.It was then diluted with water andextracted with ether. The extract was washed with waterand brine, and dried. Removal of the solvent left the hy-droxy-octalone (1) (86 mg, 61). The product was homo-geneous in t.1.c. and identified by i.r.J.C.S. Perkin IThe Hydroxy-octalone ( I) jrom the A cetoxy-acetal (20) viathe Hydroxy-ncetal (22) .-The acetoxy-acetal (20) (1 77 mg,0.63 mmol) dissolved in dry ether (2 ml was added drop-wise to a stirred suspension of lithium aluminium hydride(15 mg, 0.40 mmol) in the same solvent (1 ml) in an ice-bathunder nitrogen. After stirring for an additional 30 min a troom temperature, water was added and the mixture wasfiltered. The filtrate was washed and dried. Evaporationleft the hydroxy-acetal (22) (130 mg) as an oil, v,, (film)3 400 cm-l, 6 1.07 (3 H, s ) , 1.62 (3 H, s), 3.50 ( I H, m, CHOH),and 3.97 (4 H, s, OCH,CH,O).A solution of the above hydroxy-acetal (81 mg) in meth-anol (6 ml) containing iv-hydrochloric acid ( 1 ml) was re-fluxed for 2 h and then diluted with water. The productwas extracted with ether, washed, and then dried. Re-moval of the solvent gave the hydroxy-octalone ( 1) (54 mg,71) as an oil, homogeneous on t.1.c. and identified by i.r.and n.m.r. spectra.7/671 Received, 22nd April, 1977
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