1976 1893Chemistry of Adamantane. Part 1X.l I ,2-Difunctional Adamantanes ;Synthesis and Reactions of Protoadamantane-4-spiro-oxiranBy Jiban K. Chakrabarti,’ Terrence M. Hotten, David M. Rackham, and David E. Tupper, Lilly ResearchCentre Limited, Erl Wood Manor, Windlesham, Surrey GU20 6PHThe synthesis of protoadamantane-4-spiro-oxiran {octahydrospiro2,5-methano-l H-indene-7,2’-oxiran} and itsisomerisation to protoadamantane-4-carbaldehyde are described. Electrophilic cleavage of the oxiran ring withsimultaneous rearrangement gives 1.2-difunctional adamantane derivatives. Reactions of lithium carbenoids,from benzylidyne chloride and benzylidene bromide, with protoadamantan-4-one mainly lead to protoadamantan-4-yl phenyl ketone. 4-Phenylprotoadamantan-4-01s on treatment with acid preferentially undergo eliminationto give 4-phenylprotoadamantene.THE recent discovery of certain 1,2-disubstitutedadamantane derivatives possessing anti-depressant andanti-Parkinson properties encouraged us to exploreconvenient methods for the synthesis of w-(2-substitutedl-adamanty1)alkylamines. We have previously de-scribed the preparation of such adamantylethyl and1 Pai-t VIII, J.K. Chakrabarti, T. M. Hotten and D. E.2 J. ICH*OCH,) in the 13C n.m.r.spectrum.Similarly, the reaction in ethanol produced2-ethoxy-l-adamantylmethanol (13), in high yield, alsocharacterised as its acetate. The shift reagent Eu(fod),revealed the magnetic nonequivalence of the CH,=OHprotons in the methoxy-alcohol (12) as in the cases of2-hydroxy-l-adamantylmethanol (4) (see Experimentalsection) and 2-(2-hydro~y-l-adamantyl)ethanol.~ How-ever, the corresponding signal in the case of the ethoxy-alcohol (13) remained a singlet at all concentrations ofthe shift reagent.The oxiran (1) underwent a Ritter reaction withacetonitrile and sulphuric acid to give a mixture of therearrangement products N- (l-hydroxymethyl-2-adaman-t yl) acetamide ( 14) and 2-methyl- l0aH-adamant ano 2,1-d l ,310xazine (l5), presumably formed by intramole-cular quenching of a nitrilium intermediate.A smallamount (ca. 1) of the cyclic sulphate, adamantano-2,1-d 1,3,2dioxathian 2,2-dioxide (16) was also iso-lated by chromatography. This became the majorproduct a t higher temperatures (ca. 50 “C).In view of our requirement for certain (substitutedl-adamantyl) phenyl ketones, we investigated thereaction of the lithium carbenoid generated from benzyl-* A. F. Cockerill and D. M. Rackham, Tetrahedron Letters,1070, 5153.elimination reaction of the chloro-oxiran (17) may haveoccurred in a concerted manner as indicated. Thecrude product from the reaction of the carbenoid withprotoadamantan-4-one, on treatment with phosphoruspentabromide-phosphorus tribromide, yielded 5-bromo-protoadamantan-4-yl phenyl ketone (20) after aqueouswork-up.This could be derived by addition of HBrto protoadamant-4-en-4-yl phenyl ketone. However,2-bromo-l-adamantyl phenyl ketone (24) was preparedby the reaction of the acid chloride of the acid (10) withdiphen ylcadmium.Since the chlorine attached to the postulated oxiran(17) seems to facilitate the elimination reaction, we exam-ined the reaction of the carbenoid derived from benzyl-idene bromide and n-butyl-lithiumgb with protoadamant-an-4-one. The desired phenyloxiran could not beisolated, and only 20 of the elimination product (19)was isolated by chromatography.The reactive carb-enoid appeared to have been generated by preferentialabstraction of the benzylic proton during lithiationrather than by halogen-lithium exchange.gb The reac-tion of the ylide derived from dimethylbenzylsulphoniumbromide and potassium t-butoxide lo with protoadamant-an-4-one did not result in 3’-phenylprotoadamantane-4-spiro-oxiran.0 (a) 0. M. Nefedov, V. I. Shiryaev, Zhur. obshchei. Khim.,1967, 37, 1233; (b) G. Cainelli, N, Tangari, and A. U. Ronchi,Tetrahedron, 1972, 28, 3009.lo M. J. Hatch, J . Org. Chem., 1969, 34, 21331976 1897The mixture of epimeric alcohols (21) obtained byaddition of phenyl-lithium or phenylmagnesium bromideto protoadamantan-4-one, on attempted rearrangementwith 5~-hydrochloric acid at room temperature, easilyunderwent dehydration leading to 4-phenylproto-adamant-4-ene (22) (Scheme 6).The n.m.r. spectrumshowed a double doublet at 6 6.45 (J5,6 ca. 7.5, J5,3 ca.1.8 Hz) for the olefinic proton. These values aresimilar to those reported4 for the vinylic proton of 4-cliloroprotoadamant-4-ene. The mass spectrum is simi-lar t o that of the parent alcohol (M+ 210 = 228 - 18).The product was extracted with carbon tetrachloride andthe extract was washed with water, dried, and evaporatedunder vacuum to give an oil (16.3 g), which was distilled at70-80 "C and 1.5 mmHg to yield a white waxy solid (12.8 g),m.p. 62-64"; vmx. 3 020, 2 960-2 840, 1 290, 1 270, and1255 cm-l (Found: C, 80.3; H, 9.7; 0, 10.0.CllHl,Orequires C, 80.4; H, 9.8; 0, 9.7).The above experiment, when carried out at a highertemperature (80-90 "C), afforded a mixture of products.This was chromatographed (elution with methylenechloride) to produce only a small amount of the oxiran (1)(1 ) and protoadamantane-4-carbaldehyde (3) (26).Ph Ph121)SCHEME 6The alcohol mixture is extremely sensitive to elimin-ation by acids. 4-Phenylprotoadamant-4-ene was alsothe main product of attempted separation of the epimerson silica gel. Elution with methylene chloride gave asmall amount (ca. 5) of the expected rearrangedproduct, l-phenyladamantan-2-01 (23). The elimin-ation was also effected when (21) was heated with aceticanhydride.Treatment of protoadamantan-4-one with potassiumcyanide and sulphuric acid gave the cyanohydrin.Noacid-catalysed rearrangement of the cyanohydrin couldbe effected. Prolonged treatment with 50 aqueousacid mainly caused disproportionation to protoadamant-an-4-one.ESPERIXENTAL3T.p.s were determined with a Kofler hot-stage apparatus.J3.p.s were recorded from short-path distillation carried outwith a Biichi Kugelrohr apparatus. Unless otherwisestated i.r. spectra were measured for potassium bromide discswith a Perkin-Elmer 457 instrument, lH n.m.r. spectra forsolutions ir, deuteriochloroform (Me,Si as internal reference)with a Varian A-60A spectrometer, and 13C n.m.r. spectra(at 22.63 hfHz under both broad-band and off-resonancecontinuous wave decoupling conditions) with a BrukerWH90 instrument. Mass spectra were obtained with anLKB-9000s spectrometer (ionising beam energy 20 eV).G.1.c.was conducted with a 1.2 SE3O-GCQ columnprogrammcd. from 150 to 250 "C. Unless mentioned other-wise the Lying- agent used was magnesium sulphate andcolumn cliromatography was carried out with Sorbsil M60grade silica gel.Protondamawtu~ze-4-s~i~o-oxiran (1) .-To a solution ofprotoadainantan-4-one l1 (15.1 g, 0.1 mol) and trimethyl-sulphoniuni iodide (31 g, 0.15 mol) in dry dimethyl sulph-oxide (200 inl) was added potassium t-butoxide (14 g) undera stream of nitrogen (the outlet was connected to a trapcontaining chromic acid t o destroy the dimethyl sulphideformed). The mixture was stirred at 50-55 "C for 18 h,cooled to ca.10 "C and poured onto ice-water (200 ml).Subsequent elution with ethyl acetate gave l-hydroxyunethyl-adamantan-2-one (6) (33), m.p. 91-97', v,, (CHCI,)3 560 (OH) and 1 700 cm-l (GO), 6 3.33 (2 H, s, CH,-OH),2.92 (1 H, m, OH, exchanged in D,O), and 1.13-2.48 (13 H,m, skeletal) (Found: C, 73.4; H, 9.2; 0, 17.6. CllH,,O,requires C, 73.3; H, 8.95; 0, 17.8); oxime, m.p. 149-150" (from carbon tetrachloride) (Found: C, 67.5; H,8.95; N, 6.9; 0, 16.6. CllH1,NO, requires C, 67.3; H,9.25; N, 7.1; 0, 16.3).2-Hydroxy-l-adarnantylnzethanol (4) .-The oxiran (1)(7.0 g, 0.043 mol) was dissolved in dioxan (150 ml) andwater (20 ml). The solution was cooled to ca. 10 "C and 10aqueous sulphuric acid (2 ml) was added with stirring.Themixture was left at room temperature overnight. Most ofthe dioxan was removed slowly under vacuum at 50 "C andwater was added to the residue simultaneously untilcrystallisation of the product was complete. The crystalswere collected and dried at 50 "C under vacuum (yield 7.3 g),m.p. 172-174" (from di-isopropyl ether-n-hexane), vmax.3 400-3 100 cm-l, 6 (CC1,) 3.77 (1 H, CH-OH), 3.28 (2 H,CH,*OH), 4.2 (2 H, 2 OH, exchanged in D,O), and 1.0-2.3(13 H, m, skeletal). Addition of Eu(fod), revealed the non-equivalence of the CH,.OH protons, also observed in therelated 2-( 2-hydroxy- l-adamantyl)ethan~l.~ Europium in-duced shift gradients (relative to CHOH) were: 1.0 (CHOH),0.98, 0.67 (CH,OH), 0.92 (skeletal methylene proton atC-8 or C-9).The 13C n.m.r. spectrum showed, 6 78.4(d, CH*OH), 73.3 (t, CH,*OH), 38.7, 37.6, 37.1, 36.2, 35.2,33.1, 30.5, 27.7, and 27.7 (nine skeletal carbons). The massspectrum showedmle 180 (M - 2), 164 (M - 18), 157 (M -31, CH,OH), 146 (M - 36), 133, 93, and 91 (Found: C,72.2; H, 9.67; 0, 17.3. CllHl,O, requires C, 72.5; H,9.95; 0, 17.6).Reaction of Protoadamantane-4-spiro-oxiran with 2 ~ -Sulphuric Acid in Ethanol.-The oxiran ( 1 ) (16.3 g) inethanol (50 ml) and Z~-sulphuric acid (10 ml) was refluxedfor 2 h. The solution overnight deposited a solid, which wasfiltered off and dried under vacuum at 60 OC. Crystallis-ation from methanol gave 2-(protoadanzantan-4-yl) adamant-ano2,l-d1,3dioxan (5) (3.6 g), m.p. 216-218', vmX. 2 940,2 860, 1460, 1170, 1140, 1110, 1095, 1055, and 102811 W.H. W. Lunn, J . Chsm. SOC. (C), 1970, 2124J.C.S. Perkin Icm-l, 6~ 3.47 (1 H, m, )CH*O*), 4.44 (d, -O-CH*O, J ca.6.5 Hz), 3.46 and 3.26 (2 H, non-equivalent CH,, J ca. 9.5Hz), and 1.1-2.6 (28 H, complex m, aliphatic), aa (C,D,)106.3 (d, O*CH*O) 83.3 (d, S H O O ) , 77.3 (t, CH,*O), and41.5-28.6; (skeletal), mle 328 (M+), 310 (M - IS), 193(M - 135), 165, 164, and 147 (Found: C, 80.7; H, 9.6;0, 10.1.The mother liquor was evaporated to dryness (12.1 g).Elution from a column with 0-50 methanol in methylenechloride gave 2-hydroxy- l-adamantylmethanol (4) (7 g),m.p. 168-171" (from di-isopropyl ether-n-hexane).Reaction of Z-(Protoadamantan-4-yl) adamantano2,l-d- 1,3dioxan with Acetic Anhydride and Concentrated SulphuricAcid.-A suspension of the adamantanodioxan (5) (0.1 g)in acetic anhydride (5 ml) was treated with concentratedsulphuric acid (2 drops) at room temperature.The solutionwas stirred for 6 h, poured onto a mixture of ice and 2 ~ -sodium hydroxide, and extracted with methylene chloride.The extract was washed with water, dried, and evaporated toan oil (0.08 g). The product was analysed by g.1.c.-massspectrometry. The main component (43 by peak height),on the basis of its mass spectrum m/e 223 (M+ - l), 206,(M - 18), 181 (M - 43, CH,CO), 164 (M - SO), and 151(M - 73, CH,O,CCH,) was identified as 2-hydroxy-l-adamantylmethyl acetate. The minor component (17by peak height) showed mle 264 (M+ - 2), 222 (M - 44),193 (M - 73, CH,O,CCH,), 179, 162, 151, and 134, suggest-ing that i t was 2-acetoxy- l-adamantylmethyl acetate.A solution of the crude product from the above reactionin dioxan (5 ml) and 20 sodium hydroxide (5 ml) wasrefluxed for 2 h.The mixture was diluted with water andextracted with methylene chloride. The extract waswashed with water, dried, and evaporated to an oil. Analy-sis of the product by g.1.c.-mass spectrometry showed themajor component to be 2-hydroxy- l-adamantylmethanolProtoadamantane-4-carbaldehyde (3) .-Boron trifluoride-ether complex (0.5 ml) was added to a solution of theoxiran (1) (0.1 g, 0.000 6 mol) in dry benzene (10 ml) in aseparating funnel, The mixture was shaken, set aside for2 min, washed with water, dried, and evaporated undervacuum to give a waxy solid (ca.0.1 g), vwx. 2 705 and 1 725cm-1, 6 9.81 and 9.73 (1 H, CHO), in the ratio 1 : 3 for thetwo epimers.The oxiran (1) (1.0 g) and Sorbsil M60 silica gel (1.0 g)in dry methylene chloride (10 ml) were stirred at roomtemperature for 72 h. The silica gel was filtered off andwashed with chloroform and the solvent was removed fromthe combined filtrate and washings to give an oil (0.8 g),vmx. 2 705 and 1 725 cm-1 containing 40 of the aldehyde(3), 6 (CCl,) 9.71 and 9.65 (1 H, CHO, in the ratio 1 : 3),40 unchanged oxiran (l), 6 2.68 (2 H, s, CH,*O; endo-isomer), and 20 of an unidentified product. The oil waspurified by column chromatography (elution with methylenechloride); distillation at 50 "C and 1 mmHg gave thealdehyde, vmax.2 705 and 1725 cm-l (Found: C, 80.2; H,10.0; 0, 9.9. C,,H,,OrequiresC, 80.4; H, 9.8; 0, 9.7);2,4-dinitrophenylhydvazone, m.p. 181-183" (from ethanol),v,, 3 280, 1 510, and 1 330 cm-l,6 2.65-3.04 (1 H, m, H-4),7.55 and 7.69 (2 d in the ratio 1 : 4 due to two forms of-CH=N J ca. 4 Hz), 7.92 (1 H, d, aryl H-6), 8.32 (1 H, dd,aryl H-5), 9.06 (1 H, d, aryl H-3), (Jy,5 2.5, J6,6 9.8 Hz),10.96 (1 H, s, NH), and 1.15-2.65 (14 H, m, skeletal)(Found: C, 59.4; H, 5.9; N, 16.2. C,,H,,W,O, requiresC, 59.3; H, 5.85; N, 16.3), oxime, m.p. 87-90' (fromC22H3202 requires C, 80.4; H, 9.8; 0, 9.8).(4)-carbon tetrachloride-n-hexane), vmx 3 260 and 1 660 cni-1,6 7.46 and 7.50 (2 d in the ratio 1 : 9 due to two forms of-CH=N-, J ca.5.5 Hz), 8.80 (1 H, s, N-OH, exchanged inD,O), and 1.2-2.9 (15 H, ni, skeletal) (Found: C, 73.9;H, 9.85; N, 7.9; 0, 9.2. C11H17N0 requires C, 73.7; H,9.55; N, 7.8; 0, 8.9).2-Bromo-l-adamantylmethanol (9) .-To a cooled (ca.10 "C) solution of the oxiran (1) (1.0 g, 0.006 mol) in glacialacetic acid (10 ml) was added 5576 hydrogen bromide inacetic acid (10 ml). The mixture was stirred for 3 h a troom temperature, diluted with water, and extracted withchloroform. The extract was washed with dilute sodiumhydrogen carbonate solution and water, dried, and evapor-ated under vacuum to give an oil. Column chromato-graphy (elution with methylene chloride) afforded theproduct (0.45 g, 30), m.p. 138' (from n-hexane), vmaX3 500br 1035, and 735 cm-l, 6 4.65 (m, CHBr), 3.19 and3.52 (2 H, CH,*OH), and 1.0-2.5 (13 H, skeletal + 1 H,OH, exchanged with D,O) (Found: C, 54.2; H, 7.1; Br,32.4; 0, 6.8; Cl,H17Br0 requires C, 53.9; H, 7.0; Br,32.6; 0, 6.5).2-Ethoxy- l-adamantylmethanol ( 13) .-Boron trifluoride-ether complex (freshly distilled; 1 ml) was added undernitrogen to a solution of the oxiran (1) (0.48 g, 0.003 mol) inabsolute ethanol (20 ml), cooled in ice.The mixture wasstirred at room temperature for 2-3 h, then diluted withwater, and the product was extracted into ether. Theextract was washed with water, dried, and evaporated undervacuum to give an oil (0.5 g). Distillation at 120 "C and1 mmHg gave an oil (0.4 g), vmX (neat) 3 400, 2 980-2 920,1100, 1040, and 1020 cm-l, 6 (CCl,) 3.3-3.8 (3 H, m,CH*O*CH,), 1.22 (3 H, t , CH,), 3.18 (2 H, CH,-OH), 2.83(1 H, m, OH, exchanged in D,O), and 1.0-2.4 (13 H, m,skeletal) Eu(fod),-induced shift gradients : 1.0 (CHOEt),2.10 (CH,*OH), 1.64 (skeletal methylene proton at C-8 orC-9), 0.52 (OCH,*CH,), and 0.49 (OCH,CH,) ; the CH,OHsignal appeared as a singlet at all europium concentrations,m/e 210 (M+), 192, 179, 164, and 135 (Found: C, 74.4;H, 10.5; 0, 15.1.C,,H,,O, requires C, 74.3; H, 10.5;0, 15.2). The alcohol (13) (0.1 g) was acetylated (aceticanhydride-pyridine) to give the acetate as an oil, which wasdistilled at 150 'C and 0.1-0.2 mmHg; vmx. (neat) 1745cm-1, 6 (CCl,) 3.23 (1 H, CH-OEt) 3.63 and 3.87 (non-equivalent CH,, J ca. 10 f 1 Hz), 3.25-3.55 (2 H, m,m, skeletal) Eu(fod), induced shift gradients: 1.0 (CHOC,-H5), 2.95 (CH,*O-CO), 0.87 (skeletal methylene proton atC-8 or C-9), 0.56 (OCH,*CH,), 0.22 (OCH,*CH,), and 3.00(Ac) (Found: C, 71.6; H, 9.8; 0, 18.8.C15H,requiresC, 71.4; H, 9.6; 0, 19.0). A similar reaction of theoxiran in methanol gave 2-methoxy- l-adamantylmethanol(12) as an oil, b.p. 130-135" at 0.1 mmHg, 6 (CCl,) 3.25(1 H, CH-OMe), 3.17 (2 H, s, CH,-OH), 3.30 (3 H, s, OMe),2.40 (1 H, OH, exchanged in D,O), and 1.0-2.4 (13 H, m,skeletal) Eu(fod), induced shift gradients : 1.0 (CH-OMe),2.36 and 2.17 (CH,-OH), 1.69 (skeletal methylene protonat C-8 or C-9), and 0.47 (OMe) ; the enhanced shifts for thehydroxymethylene protons indicate that co-ordination isfavoured at this site rather than at the CH*OMe function,60 87.8 (d, CH-OMe), 73.1 (t, CH,*OH), 55.4 (9, OCH,), and39.0, 37.7, 37.3, 35.7, 33.6, 30.2, 29.1, 27.5, and 27.2 (nineskeletal carbons), m/e 196 (M+), 178, 181, 165, and 135(Found: C, 73.6; H, 10.25; 0, 16.1.C,,H,,O, requiresC, 73.4; H, 10.25; 0, 16.3).Ritter Reaction of Protoadamantane-4-s+iro-oxiran withCH,*O), 1.97 (3 H, S , Ac), 1.15 (3H, t, CH,), 1.1-2.1 (13 H1976 1899Acetonitrile.-The oxiran (1) (1.64 g, 0.01 mol) was added t oa solution of concentrated sulphuric acid (15 ml) in aceto-nitrile (40 ml) at 5 "C. The mixture was stirred for 3 h at25 "C, poured onto ice-water, and extracted with chloroform.The extract was washed with saturated sodium hydrogencarbonate solution and water, dried, and evaporated t o awaxy solid.This was chromatographed elution withchloroform containing ethanol (0-20y0 v/v) t o give twofractions: (a) (0.02 g, l), adarnantano2,1-d1,3,2-dioxathian 2,2-dioxide (16), v,,, 1385 and 1 190 cm-l(SO,), 6 4.85 (1 H, CHoO), 3.92 and 4.40 (2 H, AB,d, CH,*O,J ca. 11 Hz), and 0.5-2.8 (13 H, m, skeletal), m/e 244 (M+),164, and 146 (M - 98, H,SO,) (Found: C, 54.7; H, 6.5;0, 26.0; S, 13.2. CI,HI6O,S requires C, 54.2; H, 6.6;0, 26.2; S, 13.1); and (b) (0.2 g), identified by n.m.r. as amixture of 2-methyl-lOaH-adamantano2, l-d 1,3oxazine(15) S 3.9 (1 H, -CH-IS=), 2.95 (2 H, S , CH,*O), 1.9 (3 H, S,Me), and 0.8-2.2 (13 H, m), m/e 205 (M+) 163 ( M - 42)and X-(l-hydroxymethyl-2-adamantyl)acetanide (14)63.9 (1 H,CH*N), 2.80 and 3.17 (2 H, AB,d, CH,, J ca.11Hz), ca. 4 ( 1 H, OH), and 0.8-2.2 (m, 13 H). Fractionalshortpath distillation at 230 "C and 0.1 mmHg gave analy-tically pure product (14) (Found: C, 69.6; H, 9.25; N, 6.0.C,,H,,NO, requires C, 69.9; H, 9.5; N, 6.3).2-Oxoadarnantane-l-carboxylic Acid (1 1) .-To a stirredsolution of 3-hydroxy- l-adamantylmethanol (4) ( 10.0 g,0.055 mol) in reagent grade acetone (200 ml), Jones reagent50 ml of a solution containing chromic oxide (13.4 g) andconcentrated sulphuric acid (1 1.5 ml) was added dropwiseover 20 min. The mixture was stirred for 2 h and thenmethanol (50 nil) was added to destroy the excess of oxidant ;the mixture was then diluted with water, and extractedwith chloroform.The organic phase was washed withwater, dried, and evaporated to a white semi-solid. Crystal-lisation from carbon tetrachloride gave the pure product(5.8 g), m.p. 167-169", vmBx 3 500-2 000, 1715, and 1695cm-l, 6 10.9 ( 1 H, C0,H) and 1.8-2.8 (13 H, skeletal)(Found: C, 68.3; H, 7.45; 0, 24.8. C,,H1,O3 requires C,6S.O; H, 7.25; 0, 24.7). The oxiran (1) (2.0 g), 0.012niol) was similarly oxidised to give the oxo-acid (11) (1.4 g),as was 1-hydroxymethyladaniantan-2-one (6).2-B~oznoadamantane- l-carboxylic Acid ( 10) .-2-Bromo- 1-adamantylniethanol (9) (2 g , 0.008 mol) was oxidised asabove to give the acid (10) (2.06 g, 97), m.p. 160", 6 4.83(1 1-3, CHBr), 9.55 (1 H, CO,H), and 1.5-2.5 (13H, skeletal)(Found: C, 50.6; H, 5.95; Br, 30.7; 0, 12.5.C,,H,,BrO,requires C, 50.8; H, 6.2; Br, 30.7; 0, 12.3).2-Bromo-l-adamantyl PkeTzyl Ketone (24) .-2-Bromo-adamantane-l-carboxylic acid (10) (2.92 g, 0.001 1 mol) wasrefluxed with thionyl chloride (8.6 ml) for 30 min. Theexcess of reagent was removed and the crude acid chloridev,. (ncat) 1 795 cm-l was dried (KOH), dissolved in drybenzene (20 ml), and added dropwise t o a solution of di-phenylcadmium from phenyl-lithium (1 2 ml of 2~-solutionin benzene-ether) and cadmium chloride (2.57 g) 12. Themixture was refluxed for 35 min, cooled in ice, and hydrolysedwith cold 20 sulphuric acid. The product was extractedwith carbon tetrachloride ; the extracts were washed withsodium hydrogen carbonate solution, dried, and evaporatedto kave an oil which was crystallised from methanol t oyicld the ketone (24) (0.7 g, YO), m.p.57", vmax. (Nujol)1 675 cm-l (GO), 8 (CCl,) 5.05 (1 H, m, CHBr), 7.48 (5 H, m,Ph), and 1.4-2.75 (13 H, m) (Found: C, 64.0; H, 5.85;Br, 25.2; 0, 5.2. C,,H,,BrO requires C, 63.7; H, 6.0;Br, 25.0; 0, 5.0).Reaction of Protoadaunantan-4-one with BenzylidyneChloride and n-Butyl-lithiurn.-l?rotoadamantan-4-one (1.5g, 0.01 mol) and benzylidyne chloride (2.85 ml, 0.02 mol)were stirred in dry tetrahydrofuran (25 ml) under nitrogenat -70 "C. To this a solution of ca. 1.4~-n-butyl-lithiumin n-hexane (14.6 ml, 0.02 mol) in dry tetrahydrofuran (20 ml)was added slowly over 1 h. The solution was stirred at-70 "C for another 1 h, then evaporated under vacuum t oleave an oil, which was partitioned between chloroform andwater.The organic phase was dried and evaporated t o anoil, which was dissolved in aqueous dioxan at 0 "C and madejust acidic with 2~-sulphuric acid. The mixture was stirredovernight, diluted with water, and extracted with chloro-form. The extract was washed with dilute sodium hydro-gen carbonate solution and water, dried, and evaporated toan oil. Short-path distillation gave two fractions : (a)$votoadamant-4-en-4-y1 phenyl ketone (19), b.p. 100 "C at1 mmHg (0.45 g, 20y0), m.p. 73" (from n-hexane), vmaX (neat)1 650 cm-1 (C=O), 6 (CCl,) 6.92 (1 H, dd, H-5, J3,5 ca. 1.8,J5.6 ca. 8.2 Hz) (this allylic coupling was removed by irradi-ation at the frequency of H-3), 3.42 (1 H, m, H-3), 7.2-7.5(3 H, m, aryl H), 7.5-7.7 (2 H, m, aryl H), and 0.8-2.8(11 H, m, skeletal) (Found: C , 85.5; H, 7.85; 0, 7.0.Cl,HI,O requires C, 85.7; H, 7.6; 0, 6.7); and (b)2-hydroxy-l-adamantyl phenyl ketone (18), b.p.ca. 200 "Cat 1 mmHg (0.05 g), 81 pure by g.l.c., rn/e 256 (M'), 238,and 135, 6 (CCl,) 4.18 (1 H, CH-OH), 3.35 (1 H, OH, ex-changed in D,O), 7.26-7.70 ( 5 H, m, Ph), and 1.2-2.5(13 H, m, skeletal).The crude product from a similar reaction of protoadamant-an-4-one and benzylidyne chloride, as described above, wasdissolved in phosphorus tribromide (5 ml) at 0 "C, phos-phorus pentabromide (4.2 g, 0.01 mol) was added, and themixture was stirred at room temperature overnight, pouredonto ice, and extracted with carbon tetrachloride.Theextract was washed with water, dried, and evaporated andthe residue in carbon tetrachloride was chromatographed,(elution with n-hexane containing an increasing proportionof carbon tetrachloride). The major component wascrystallised from methanol to give 5-bromoprotoadarnantan-4-ylphenyl Ketone (20) (1.15 g, 37y0), m.p. go", vmaX 1 695 cm-f(GO), m/e 320/318 (M+) and 239 (M - Br), 8 (CC1,) 3.92(1 H, dd, H-4, J4,5 ca. 9.0, J3,, ca. 1.5 Hz), 4.87 (1 H, dd,H-5, J5,g ca. 1.5 Hz), 7.3-7.6 (3 H, m, aryl H), 7.85-8.15(2 H, m, aryl H), and 1.2-2.7 (12 H, m, skeletal) (Found:C, 63.7; H, 5.75; Br, 25.3. C,,H,,BrO requires C, 64.0;H, 6.0; Br, 25.0).Reaction of Protoadamantan-4-one with BenzylideneBromide and n-Butyl-lithiurn.-Protoadamantan-4-one ( 1.5g, 0.01 mol) and benzylidene bromide (3.3 ml, 0.02 mol)were treated with n-butyl-lithium as described above.Themixture was stirred for 20 h, poured onto ice, and extractedwith carbon tetrachloride. The extract was chromato-graphed (elution with methylene chloride) to give the olefin(19) (0.44 g, 19).4-Phenylprotoadamantan-4-01 (2 1) .-To a solution ofprotoadamantan-4-one (1.5 g, 0.01 mol) in dry benzene (15ml) was added dropwise, under nitrogen, a 2~-solution ofphenyl-lithium (5 ml, 0.01 mol) in benzene-ether (7 : 3; 20ml). The mixture was heated under reflux for 2 h, thencooled and 30 ammonium chloride solution (20 ml) wasadded. The organic phase was separated, washed withwater, dried, and evaporated under vacuum t o give an oil(2.3 g).Short-path distillation at 150 "C and 0.2 mmHgla J. Cason, Chem. Rev., 1947, 40, 221900 J.C.S. Perkin Iproduced a waxy solid (2.0 g), vmx (neat) 3 400 cm-1 (OH),6 (CC1,) 1.47 (1 H, s, OH exchanged with D,O), 7.1-7.55(5 H, m, Ph), and 1.1-2.85 (14 H, m, skeletal), mle 228(M+), 210 (M - 18), 195, 168, 167, 155, 91, and 77 (Found:C, 83.9; H, 9.0; 0, 6.9. C16H2,0 requires C, 84.1; H,8.85; 0, 7.0).A similar yield of the same product was obtained whenphenylmagnesium bromide was used. Separation of themixture of 8x0- and endo-epimers by chromatography wasattempted. Elution with methylene chloride produced twofractions: (i) (major) an oil (50), distilled at 150 "C and0.1 mmHg to give 4-phenyZprotoadamant-4-ene (22), vmaX.(neat) 1628 cm-l (C=C), 6 (CCl,) 6.45 (1 H, dd, H-5), 3.10(1 H, H-3) (J5,6 ca.7.5, J5,3 ca. 1.8 Hz), 6.9-7.5 ( 5 H, m,Ph), and 1.1-2.7 (11 H, m) (Found: C, 91.1; H, 8.55.Cl,H1, requires C, 91.4; H, 8.65); (ii) (minor) a wax(5) characterised as 1-phenyladamantan-2-01 (23), v,,,3 400 cm-l (OH), 6 (CCl,) 3.85 (1 H, m, CH-OH), 7.0-7.4(6 H, m, Ph), and 1.0-2.7 14 H, m, skeletal and OH(exchanged in D,O).4-Phenylprotoadamant-4-ene (22) .-A solution of 4-phenylprotoadamantan-4-01 (21) (2.1 g) in acetic anhydride(20 ml) was heated on a steam-bath for 8 h, poured ontoice, and extracted with diethyl ether. The extracts werewashed with water, dried, and evaporated to an oil (1.6 g).Chromatography (elution with methylene chloride) gave theolefin (22) (0.9 g, 47).4-Hydroxyprotoadarna?ztane-4-ca~bonitrile.-A solution ofprotoadamantan-4-one (7.8 g, 0.05 mol) in ethanol (50 nil)was stirred with a solution of potassium cyanide (5.1 g,0.075 mol) in water (50 ml). The vessel was fitted with anitrogen inlet, a dropping funnel, a pH electrode, and agas outlet passing through alkaline iron(I1) sulphate solution.Aqueous sulphuric acid (20 ml; containing 2.25 ml ofconc. H,SO,) was added dropwise over 30 min with thetemperature kept below 20 "C. The mixture was allowedto attain room temperature and stirred for 18 h. The pHwas adjusted to 3.6 to destroy any residual hydrogen cyanideand the solution was purged with nitrogen. The ethanolwas removed by vacuum distillation, and the residue dilutedwith water and extracted with chloroform. The extractwas washed with water, dried, and evaporated to a yellowgum, which was chromatographed (elution with methyienechloride) to give unchanged protoadamantanone (0.6 g) andthe nitrile (5.4 g, 59), m.p. 149-151" (from n-hexane),vmaX. (Nujol) 3 400 (OH) and 2 240 cm-l ( E N ) , 6 (CDC1,-CCl,) 1.2-2.9 (14 H, m, alkyl) and 3.7 (5, OH, exchangedwith D,O) (Found: C, 74.8; H, 8.8; N, 7.9; 0, 8.9.C,,H15NOrequires C, 74.5; H, 8.55; N, 7.9; 0, 9.0).We thank Professor J. E. Baldwin, MassachusettsInstitute of Technology, for discussions, Mr. D. N. B.Mallen for g.1.c.-mass spectrometric analyses, Mr. R. C.Harden for i.r. and n.m.r. spectra, and Mr. G. Maciak formicroanalyses.6/134 Received, 21st January, 197610 Copyright 1976 by The Chemical Societ
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