1,5-Hydride shifts in acyclic systems containing alpha;beta;-unsaturated ketones andp-methoxyphenyl groups

摘要

394 J.C.S. Perkin II ,5-Hydride Shifts in Acyclic Systems Containing ap-Unsaturated Ketonesand p-Methoxyphenyl GroupsBy Robert S. Atkinson and Richard H. Green, Department of Chemistry, University of Leicester, LeicesterAcid-catalysed rearrangement of 8- (p-hydroxyphenyl) oct-3-en-2-one (4) to 2- (p- hydroxyphenyl)cyclohexyl Jmethyl ketone (1 0) is shown to involve an intramolecular hydride shift by deuterium labelling : a similar rearrange-ment is observed for 8- (p-hydroxyphenyl) -5.5-dimethyIoct-3-en-2-one (3) and its aromatic methyl ether (2) butno analogous products could be isolated from 7-(pmethoxyphenyl) hept-3-en-2-one (1 8) or 7,7-bis-(p-methoxy-phenyl) hept-3-en-2-one (1 9) under the same reaction conditions.LE1 7 R HINTRAMOLECULAR 1,n (n 2) hydride transfer is a com-mon reaction in medium ring and certain polycyclicsystems.l It is likely that there is an optimum distancebetween transfer source and terminus in such compounds.The importance, if any, of stereoelectronic factors, whichare known to be important in 1,2-hydride shifts has notbeen assessed.2For acyclic systems, l,.rz (n 2) hydride shifts are less1 A.C. Cope, M. M. Martin, and M. A. McKervey, Quart. Rev.,1966, 20, 119; P. T. Lansbury, J. B. Bieber, F. D. Saeva, andK. R. Fountain, J . Amer. Chem. SOL, 1969, 91, 399; R. K. Hilland R. M. Carlson, ibid., 1965, 87, 2772, reference 4; L. StChelin,J. Lhomme, and G. Ourisson, ibid., 1971, 93, 1650.common,3 but the functionality present in the chain mayencourage population of those conformations necessaryfor such shifts to occur.This is exemplified in the caseof (1) from decomposition of the aromatic diazonium saltwhere the constraint imposed by the benzene ring andcarbonyl group enables intramolecular hydride shift to2 P. v. R. Schleyer, L. K. Rf. Lam, D. J. Raber, J. L. Fry,M. A. McKervey, J. R. Alford, B. D. Cuddy, V. G. Keizer, H. W.Geluk, and J. L. M. A. Schlatmann, J . Amer. Chem. SOC., 1970,92, 5246.3 J. L. Fry and G. J. Karabatsos, in lsquo; Carbonium Ions,rsquo; vol.11, eds. G. A. Olah and P. v. R. Schleyer, Wiley-Interscience,New York, 1970; Q. Branca and D. -4rigoni, Chimia, 1969, 25,1891974 395compete with external water for the reactive phenylcation.4( 1 )The present paper is concerned with an acid-catalysedrearrangement of a@-unsaturated ketones (2)-(4) whichis shown to involve a 1,5-hydride shift.5For the synthesis of (2), the route shown in Scheme 1was followed.Ar Ar Ar0(6) R=Me( 7 ) R=HAr Ar ArC H,O H CHOAr=p - MeOC6H, ( 2 )SCHEME I Reagents: i, Wolff-Kishner, Me,SO,, ii, EtOH-HfLiAlH, ; iii, CrO, ; iv, Ph36CH*COMeWolff-Kishner reduction of (5) was accompanied bypartial demethylation of the aromatic methyl ether.Re-methylation using dimethyl sulphate-potassiumhydroxide gave the expected acid together with a neutralproduct (8).Elemental analysis and the mass spec-trum showed that this latter product contained twonitrogen atoms and the n.m.r. spectrum suggested thatone of these nitrogen atoms bore a methyl group asshown by the presence of a three-proton singlet at T 6.75.The available spectroscopic evidence supports the N-methyldiazepinone structure (6) for this neutral product.The parent diazepinone (7) was obtained in 51 yieldby heating the keto-acid (5) and hydrazine under lessvigorous conditions (see Experimental section) and wasconverted into the N-methyl derivative (6) with dimethylsulphate and sodium hydroxide.Diazepinones of thistype have recently been obtained by cyclisation of aroylacid chlorides, aroyl acids, and aroyl esters with hydra-zine.6Ketone (2) showed the expected spectroscopic featureswith the double bond in the trans-configuration (n.m.r.).Attempts to cleave the aromatic methyl ether withhydrobromic acid-acetic acid were thwarted by re-arrangement (see below).The phenolic ketones (3) and (4) were obtained, asshown in Scheme 2.Alkylation of the crystallineT. Cohen, C. H. McMullen, and K. Smith, J . Aruzev. Chem.R. S. Atkinson, Chem. Comm., 1969, 735.Soc., 1968, 90, 6866.tosylate (8) derived from the corresponding alcohol (seeScheme l), with the sodium salt of ethyl acetoacetategave the required C-alkylation product in 38 yield,the major product being the O-alkylated material.Although cleavage of the ethoxycarbonyl and aromaticmethyl ether groups proceeded in good yield, aP-unsatur-ation was introduced in only 31 yield by the bromina-tion-dehydrobromination sequence. The oily cr p-un-saturated ketone showed the anticipated spectroscopicproperties and formed a crystalline 3,5-dinitrobenzoate.A similar procedure provided the aP-unsaturated ketone(4), both the alkylation (51) and the bromination-dehydrobromination (40) steps giving better yields.Again, (4) was adjudged pure by spectroscopy and wasc haract erised by its crystalline $-nitro benzoat e.Heating the aP-unsaturated ketones (3) and (4) withboron trifluoride-ether complex in benzene gave thecrystalline ketones (9) and (10) in 77 and 63 yield,respectively. In the n.m.r.spectrum of (9) the geminalmethyl groups appear as two distinct singlets, and bothAr Ar Ar( 8 ) R=MeAr lsquo;C02E tAr tiiUrsquo;0 bsol; RR( 3 ) R=Me A r = p- Me0 C,H,( 4 ) R=H A amp;-HOC~H,SCHEME 2 Reagents: i, TsC1; ii, MeCO*CH.CO,Et; iii, HC1-HOAc ; iv, HBr-HOAc ; v, CuBr,-CHCl,-EtOAc, LiBr-Liz-(9) and (10) show a two-proton multiplet at 7 ca. 7.2.A sample identical with (10) was obtained by copper(1)chloride-catalysed addition of p-methoxyphenylmag-nesium bromide to l-acetylcyclohexene followed bydemethylation of the intermediate ketone (1 1) withhydrobromic acid-acetic acid.The stereochemistryof (4) is assumed to be trans since it was recovered un-changed after treatment with base.lsquo;The conversion of (3) into (9) was also effected by otheracid catalysts including toluene-p-sulphonic acid, andhydrobromic acid-acetic acid but the yield was inferiorto that obtained with boron trifluoride-ether complex-benzene. Rearrangement of the aromatic methyl etherC.-G. Wermuth and J.- J.Koenig, ,4 ngew. Chem. Internat.Edn., 1972, 11, 162; I. Sataty, Tetrahedron, 1972, 28, 2307;J.- J. Koenig and C.-G. Wermuth. Tetrahedron Letters, 1973, 603.H. E. Zimmerman, J . Amer. Chem. SOC., 1957, 79, 6554.COS-DM396 J.C.S. Perkin Iap-unsaturated ketones (14) and (4) was treated withboron trifluoride-ether. Analysis of the resultantmixture by mass spectrometry showed that, at most, 6of the reaction was proceeding by intermolecular hydridetransfer.Our attempts to effect the rearrangement aftermodifying the present system have not met with success.Treatment of 7- ($-met hoxyphenyl) hept-3-en-one (1 8)with perchloric acid, toluene-P-sulphonic acid, trifluoro-acetic acid, and hydrobromic acid-acetic acid gave eitherunchanged starting material or mixtures of high mole-cular weight compounds.No homogeneous product wasisolated from attempts to rearrange 7,7-bis-(+-methoxy-phenyl)hept-3-en-Z-one (19), synthesised from (20) by aroute similar to that outlined in Scheme (1). Similarly,(2) to the ketone (12) was accomplished using 70 per-chloric acid in 43 yield. Methylation of the phenolicketone (9) with dimet hyl sulphate-pot assium carbonategave a sample identical with this $-methoxyphenylketone (12).21 2(9 1 R L M ~ , R=H(10) R=H , R_=HA reasonable mechanism for this rearrangement,illustrated for the case of (4) (Scheme 3) includes a 1,5-hydride shift within the molecule, assisted by co-ordination of the boron trifluoride to the carbonyl oxygenand the stability of the resulting anisylic carbonium ion(13)SCHEME 3To test this mechanism, the 8,8-2H.J-ap-unsaturatedketone (14) has been prepared by catalytic exchange ofthe anisylic protons in (15) in the presence of deuteriumfollowed by the bromination-dehydrobrominationsequence. Mass spectral analysis indicated the composi-tion of (14) to be 92 2H, and 8 2H, and n.m.r.showedthe anisylic location of the deuterium in (14) with thedisappearance of the triplet at T 7.47. Examination ofthe mass spectrum * of the product (17), obtained aftertreatment with boron trifluoride-ether, revealed that theprobable location of the transferred deuterium corre-sponded to that required by a 1,5-hydride shift. Themajor peaks in the spectrum were found at m/e 134, 109,108 (base peak), and 107, and may all be accommodatedby postulating an initial homolysis of the substitutedcarbon-carbon bond (Scheme 4).Part of the intensityof the m/e 108 peak is therefore a result of its compoundnature. The fragmentation (b) includes, in effect, areversal of the formation of ketone (10) from the ap-unsaturated ketone (4). To show the intramolecularityof the hydride shift, a mixture of di- and non-deuteriated* The mass spectra of phenyl substituted ap-unsaturatedketones analogous to (2) and (18) have been discussed in detailby Djerassi in ref. 8* +OH4-OH+OH1* +OHcy co c H 3(DIH1"+OH+OH 2 m / e 134+ *0m / e 108 (109) m / e 107 (108)SCHEME 4the ap-unsaturated ester (21) on treatment with hydro-bromic acid-acetic acid gave the unrearranged phenolicacid (22) with no detectable rearrangement products.Assuming that a final ring closure of the dipolar speciesanalogous to (13) (Scheme 3) would proceed readily, a1,4-hydride shift seems less favourable than a 1,5-shiftin the system in hand.This conclusion is in agreementwith recent n.m.r. studies which indicate that 1,4-R. J. Liedtke, A. F. Gerrard, J. Diekman, and C. Djerassi,J. Org. Chem., 1972, 37, 7761974 397hydride shifts have higher energies of activation than1,5- (or 1,3-) shift^.^A t C H.CH,CHi C H = C H-COCH,IR(18) R=H(19) R=ArOR'Ar=p-MeOC,H,/ OR2EXPERIMENTALM.p.s were determined with a Kofler hot-stage apparatus.The i.r.spectra of crystalline compounds were determined asNujol mulls and of other compounds as thin films. N.m.r.spectra were measured with a Varian A60A or T60 andmass spectra with A.E.I. MS902 or MS9 spectrometers.The alumina used was Spence type ' H ' and Kieselgelrefers to Kieselgel G (Merck). For the para-substitutedaromatic ring, the AA'BB' signals in the n.m.r. spectra aredenoted by the position of the four main peaks.Synthesis of the ap- Unsaturated Ketone (2) .-4-($-Anisoy1)-3,3-dimethylbutyric acid (5) was prepared by the methodpreviously reported .loThe keto-acid (5)(10 g) was heated under reflux for 0.5 h with hydrazinehydrate (7-2 g; 95y0), potassium hydroxide (7 g), andethylene glycol (50 ml). The mixture was then distilledtill the vapour temperature reached 195", then heatedunder reflux for 4 h.After cooling, the solution was pouredinto water, acidified, and extracted with ethyl acetate.The organic layer was washed with water, evaporated, theresidual oil dissolved in ethanol (100 ml), and the ethanolicsolution heated under reflux while dimethyl sulphate(10.1 ml) and sodium hydroxide (56-5 ml; 10 solution)were added simultaneously. After heating under refluxfor 4 h the solvent was distilled off up to a temperature of96O, the residual solution cooled, and extracted with ether.From this ether extract the diazepinone (6) was isolated(see below). The aqueous layer after ether extraction wasacidified and further extracted with ether, and the etherlayer dried and evaporated t o give 5-(p-methoxy$henyl)-3,3-dimethylpentanoic acid (8.3 g, 88 from the keto-acid) asneedles (from ethyl acetate-light petroleum), m.p.80-81"(Found: C, 71.05; H, 8.6. Camp;f,@, requires C, 71.15; H,8.55y0), vmx. 2680s,br and 1690s cm-l; 't (CDCl,) 8.90 (s,Meamp;), 8-65-8-15 (m, 4-H,), 7.70 (s, 2-H,), 7-65-7-20 (m,5-H,), 6.20 (s, OCH,), 3-30, 3.15, 3.00, and 2-85 (4 x ArH),and 1.54 (s, C0,H).M. Saunders and J. J. Stofko, J . Amer. Chem. SOC., 1973, 95,252.WoZffKishner reduction of acid (5).lo R. S. Atkinson, J . Chem. SOC. ( C ) , 1971, 784.In a separate experiment, a sample of the crude acid(280 mg) obtained after evaporation of the ethyl acetateextract above, was esterified with boiling ethanol (10 ml)containing dry hydrogen chloride gas overnight.The bulkof the ethanol was removed, chloroform was added, and theorganic layer was washed with sodium hydrogen carbonatesolution and water, dried, and evaporated. T.1.c. examina-tion of the residual oil showed the presence of two productsRF 0.8 and 0-3 in benzene-ethyl acetate (10 : 1). Chroma-tography of the mixture over Kieselgel using benzene-ethylacetate (15 : 1) gave ethyE 5-(p-methoxyphenyl)-3,3-dirhethyZ-pentanoate (145 mg) as a mobile liquid, b.p. (bulb-tube;bath temp.) 140-144" a t 1 mmHg (Found: C, 72.4; H,9.35. C1,H,,O3 requires C, 72.7; H, 9.15y0), v- 1730scm-l; z (CCl,) 8-96 (s, Me,C), 8-77 (t, J 7 Hz, CH,CH,),8.67-8-27 (m, 4-H,), 7.81 (s, 2-13,), 7.67-7-31 (m, S-H,),6.28 (s, OCH,), 5-92 (q, J 7 Hz, CH,CH,), and 3.38, 3-24,3-06, and 2-92 (4 x ArH).Further elution with benzene-ethyl acetate (5 : 1) gave the slower running spot on t.1.c.(120 mg). Distillation afforded ethyl 5-(p-hydroxyphenyZ)-3,3-dimethylpentanoate as an oil, b.p. (bulb-tube; bathtemp.) 150-155" a t 1 mmHg (Found: C, 71.65; H, 8.65.C15HzZO3 requires C, 71-95; H, 8.85Y0), v- 3465m, 1726s,and 1710s cm-l; z (CDCl,) 8.93 (s, Meamp;), 8.73 (t, J 7 Hz,CH,CH,), 8.63-8-22 (m, 4-H,), 7.71 (s, 2-H,), 7-62-7.26(m, 5-H,), 5.84 (q, J 7 Hz, CH,CH,), and 3-32, 3-18, 3.02,and 2.88 (4 x ArH).Reduction of the foregoing ester (100 mg) with excess oflithium aluminium hydride in ether (20 ml) gave 5-(p-hydroxy$henyZ)-3,3-dimethylpentan- 1-01 (74 mg, 84) asblades (from ethyl acetate), m.p.120~5-121deg; (Found: C,75.05; H, 9.35. C13H200, requires C, 74-95; H, 9.70).5- (p-Methoxyphenyl) -3,3-dimethyZpentan- 1-01. The acid(5) (2.6 g) was esterified by heating under reflux with ethanolcontaining hydrogen chloride overnight. The crude esterwas reduced with excess of lithium aluminium hydride inether for 2 h a t room temperature. After destroying excessof hydride with ethyl acetate and then water, removal ofsolvent gave the alcohol, b.p. (bulb-tube; bath temp.)145-150" a t 1 mniHg, as an oil (2.2 g, 84) (Found: C,75.25; H, 9-7. C14H2,Oz requires C, 75.65; H, 9.95), v-3440br cm-l; T (CDCl,) 9-02 (s, Me,C), 8.72-8-26 (m, 2-H,and 4-H,), 8.43 (t, J 7.5 Hz, OH), 7-69-7.32 (m, 5-H,), 6-30(t, J 7-5 Hz, 1-H,), 6-24 (s, OCH,), and 3-30, 3-15, 2.98, and2.84 (4 x ArH).5- (p-Methoxyphenyl) -3,3-dimethylpentanaZ.Chromiumtrioxide (12.75 g) was added in portions to a mixture offreshly dried pyridine (21 ml; distilled from calciumhydride) and dichloromethane (140 ml) with stirring.11After 20 min, the foregoing alcohol (1.5 g) dissolved indichloromethane (20 ml) was added, the mixture stirred for1 min a t room temperature then the dichloromethane wasdecanted from the precipitated chromium salts which werefurther washed with dichloromethane by decantation. Thecombined organic solutions were washed successively withsodium hydroxide ( 2 ~ ) , dilute hydrochloric acid ( 2 ~ ) ,sodium carbonate, and sodium chloride solution. Removalof the solvent gave the aldehyde as a pale yellow oil (1.2 g,79) which was used directly in the following steps; vmz2740w and 1720s cm-l; z (CCl,) 8-95 (s, Meamp;), 8.8-8.2 (m,4-H,), 7.80 (d, J 3 Hz, 2-H,), 7-70-7.30 (m, 5-H,), 6-35(s, OCH,), 3-40, 3-25, 3.10, and 2-95 (4 x ArH), and 0-50br(lH, t, CHO).l1 R.Ratcliffe and R. Rodehorst, J . Org. Chem., 1970, 35.4000398 J.C.S. Perkin I8- (p-Methoxyphenyl)-6,6-dzmethyloct-3-en-2-one (2). Acet-onyltriphenylphosphonium chloride (2.4 g) and sodiumcarbonate (0.8 g) were dissolved in a mixture of water (7 ml)and tetrahydrofuran (15 ml) and stirred a t room tempera-ture for 0.5 h. The foregoing aldehyde (1.2 g) dissolved intetrahydrofuran (8 ml) was quickly added and the mixtureheated under reflux overnight, under nitrogen.After cool-ing, the mixture was poured into water and extracted withether, and the extracts were washed with sodium chloridesolution, dried, and evaporated. Trituration of the residualbrown oil with light petroleum ( x 4 ) and removal of the lightpetroleum yielded an oil (1.3 g) which was purified bychromatography over Kieselgel eluting with benzene-ethylacetate ( 3 : 1). Distillation gave the up-unsaturated ketone( 2 ) as an oil (0.95 g, 67y0), b.p. (bulb-tube; bath temp.)173-175" a t 0.2 mmHg (Found: C, 78.2; H, 9.25. Cl,H,,-0, requires C, 78.4; H, 9.3y0), vmX. 1670s and 1625 cm-1;'i (CC1,) 9-05 (s, Me,C), 8-75-8-3 (m, 7-H,), 7.80 (s, MeCO),8-0-7.2 (m, 5-H, and 8-H,), 6-25 (s, OCH,), 5.95 (d, J 16Hz, 3-H), and 3-30, 3.15, 3.00, and 2.85 (6H, 4 x ArHsuperimposed on 4-H) .Ethyl 7-(p-Methoxy~henyZ)-5,5-dimethylhept-2-enoate (21).-Triethylphosphonoacetate (3.86 g) in dry tetrahydrofuran(50 ml) was added dropwise to a stirred suspension of sodiumhydride (0.20 g) in dry tetrahydrofuran (25 ml) and stirringwas continued for 16 h a t room temperature.The aldehydeprepared above (2.2 g) in dry tetrahydrofuran (50 ml) wasthen added dropwise and the mixture stirred for 0.75 hbefore pouring into water and extracting with ether. Theether layer was washed with water, dried, and evaporatedto yield a yellow oil (2.8 g). Chromatography over Kiesel-gel, eluting with benzene, followed by distillation gave theap-unsaturated ester (21) (2.0 g, 69) as an oil, b.p. (bulb-tube; bath temp.) 170-180" a t 0.1 mmHg (Found: C,74.2; H, 8.75.C18H2,O3 requires C, 74.45; H, 9.05);vmaZ 1720s and 1650m cm-l; 7 (CCl,) 9-00 (s, Meamp;), 8-91-8.2 (m, 6-H,), 8.75 (t, J 7 Hz, CH,CH,), 7.9 (d, J 8 Hz, 4-H,),7.7-7.3 (ni, 7-H,), 6.25 (s, OCH,), 5.9 (4, J 7 Hz, CH,CH,),4.3 (d, J 16 Hz, 2-H), and 3.45, 3.30, 3.15, and 3-00 (5H,4 x ArH superimposed on 3-H).Isolation of 2,4,5,6-Tetrahydro-7- (p-methoxyphenyl) -2,5,5-trimethyl- 1,2-diazepin-3-one ( 6 ) .-Wolff-Kishner reductionto the keto-acid ( 5 ) followed by re-methylation with di-inethyl sulphate and sodium hydroxide was carried out asdescribed above. The ether extracts obtained from thebasic solution were dried and evaporated to yield a colourlessoil which was purified by chromatography over silica.Elution with ethyl acetate and crystallisation from ethylacetate-light petroleum gave the N-methyldiazepinone ( 6 ) ascubes, m.p.77-78" 8 from the keto-acid ( 5 ) (Found:C, 69.05; H, 7 . 8 ; N, 10.55. C,,H,,N,O, requires: C,69.2; H, 7.75; N , 10-75), vmE 1645s and 1 6 1 h crn-1;-T (CDCl,) 8.90 (s, Me,C), 7-90 (s, 4-H,), 7.40 (s, amp;euro;I,), 6-75(s, NCH,), 6.20 (s, OCH,), and 3.25, 3-10, 2.35, and 2.20(4 x ArH) .The parent diazepinone ( 7 ) was obtained by the followingprocedure: the acid ( 5 ) ( 1 g) was dissolved in ethanol (100ml), hydrazine hydrate (1.3 ml; 95) was added, and themixture heated under reflux for 2 h. Potassium carbonate( 3 g ) was then added followed by dimethyl sulphate (1.2 g),and the mixture was heated under reflux for a further 3 hthen stirred overnight.The mixture was poured into water ex-tracted withether, and the extracts were dried and evaporatedto yield 2,4,5,6-tetrahydro-7- (p-methoxyphenyl) -5,5-dimetJzyZ-1,2-diaze$in-3-one ( 7 ) as a white solid (500 mg, 51) whichcrystallised as needles (from ethanol), m.p. 180-181"(Found: C, 68.1; H, 7-45; N, 11.3. ClpHl,N,O, requiresC, 68.25; H, 7.35; N, 11.30/,), y,, 3180w, 3060w, ancl1645s cni-l; T (CDCI,) 8.80 (s, hle,C), 7.70 (s, 4-H,), 7-20(s, 6-H,), 6-05 (s, OCH,), 2-55 (s, NH), and 3.00, 2.85, 2-10.and 1.95 ( 4 x ArH). The diazepinone ( 7 ) was convertedinto its N-methyl derivative (6) on treatment with dimethylsulphate-potassium hydroxide.Synthesis of 8- (p-Hy droxypheizyl) - 6,6-dimet hyloct- 3-en- 2-one ( 3 ) .-5-(p-Methoxyphenyl)-3,3-dimethylpentan- 1-01(8-85 g) in ice-cold pyridine (50 ml) was treated with toluene-p-sulphonyl chloride (8.9 g) and the mixture stirred a t 0"for 5 h.The oil obtained on pouring the mixture into ice-water solidified on standing. Crystallisation from ethanolgave 5- (p-methoxyphenyl) -6,6-dimetl1yloctyl tosylate asblades (9-2 g, 61y0), n1.p. 39-41" (Found: C, 66-95; H,7-35. C,,H,,O,S requires C, 67.0; H, 7.5), 7 (CDC1,)9-07 (s, Me,C), 8.79-8.44 (m, 4-H,), 8-35 (t, J 7-5 Hz, 2-H,),7-76-7-38 (m, ti-amp;), 7.57 (s, CH,Ar), 6.22 (s, OCH,), 5.88(t, J 7-5 Hz, CH,OTs), 3.29, 3.14, 3-03, and 2.89 (C,H,OMe),and 2.75, 2.62, 2.27, and 2-13 (MeC,H,).Ethyl 2-A cetyl-7- (p-methoxyphenyl) -5,5-dimethylheptanoate.Ethanol (50 ml) containing sodium ( 0 4 1 g) was treated withethyl acetoacetate (3.46 g) and then in portions with theforegoing tosylate (9.1 g ) and the mixture heated underreflux for 6 h with vigorous magnetic stirring.The cooledmixture was acidified with acetic acid, the bulk of thealcohol removed under reduced pressure, and the residueextracted with ethyl acetate and water. After washing theorganic layer with sodium hydrogen carbonate and waterand then evaporating, the oil obtained was chromatographedover Kieselgel (250 g) eluting with benzene-ethyl acetate(20 : 1). 1.r. examination of the first fraction eluted ( 3 g)suggested this was the 0-alkylated product. Further elutiongave the (3-Fzeto-ester (3.1 g, 38) as a mobile oil, b.p.(bulb-tube; bath temp.) 180-185" a t 0.1 mmHg (Found :C, 71-95; H, 9.2.C,,H,,O, requires C, 71-8; H, 9.05y0),vmX. 1743s and 1716s cm-l; 7 (CCl,) 0.05 (s, Me,C), 8.73(t, J 7.5 Hz, CN,CH,), 8-96-7.97 (in, 3-H,, 4-H,, and6-H,), 7-87 (s, CH,CO), 7.74-7.35 (m, 7-H,), 6.85 (t, J 7Hz, 2-H), 6.28 (s, OCH,), 5-85 (q, J 7.5 Hz, CH,CH,), and3-42, 3.27, 3.08, and 2.94 ( 4 x ArH).8-(p-MethoxyphenyZ)-6,6-divnethyloctan-2-one. The fore-going P-keto-ester (2 g) was heated under reflux with glacialacetic acid (26 ml), concentrated hydrochloric acid (2-3 ml),and water ( 2 ml) for 3.5 h. After removal of the bulk of theacetic acid under reduced pressure, the residue was neutral-ised with sodium carbonate and extracted with chloroform.The chloroform extract was washed with water, dried, andevaporated, and distillation of the residue gave the ketone(1.15 g, 73) as an oil, b.p.(bulb-tube; bath temp.) 170-174" a t 2 mmHg (Found: C, 77.6; H, 10.2. C,,H,,O,requires C, 77-8; H, 10-0), v- 1711s cm-l; -T (CCl,)9.07 (s, Me,C), 8.95-8.3 (m, 4-H,, 5-H,, and 7-H,), 7.97(s, CH,CO), 7-89-7.36 (m, 3-H, and 8-H,), 6.28 (s, OCH,),and 3.43, 3.27, 3.08, and 2-94 (4 x ArH).8- (p-Hydroxyphenyl) -6,6-dimethyloctan-2-one. The fore-going ketone (500 mg), glacial acetic acid (5-5 ml), andhydrobromic acid (1.2 ml; 48) were heated under refluxfor 1 h. The bulk of the solvent was removed under reducedpressure, the residue dissolved in chloroform, and thechloroform layer washed with sodium hydrogen carbonateand water, dried, and evaporated.Distillation gave thephenolic ketone (380 mg, SOY0) as a glass, b.p. (bulb-tube;bath temp.) 175-180" a t 1 mmHg (Found: C, 77.0; H19749.5. C16H2,02 requires C, 77-35; H, 9-75y0), vmx. 3446mand 1702s cm-l; T (CC1,) 9-07 (s, Meamp;), 8.85-8.36 (ni,4-H,, 5-H,, and 7-H,), 7-88 (s, CH,CO), 7.79-7-38 (m, 3-H,and 8-H,), 4-14br ( s , OH), and 3.47, 3.32, 3-17, and 3-02(4 x ArH).8-(p-Hydrox~~Phenyl)-G, O-dimethyloct-3-en-2-one (3). Thephenolic ketone above (1.14 g) was heated under reflux for0.5 h with copper(I1) bromide (2-05 g) in chloroform (6 ml)and ethyl acetate (6 ml) with magnetic stirring. Afterstirring for a further 0.5 h a t room temperature, the whitecopper(1) bromide was separated, washed well with chloro-form, and the chloroform layer was washed with sodiumhydrogen carbonate, water, dried, and evaporated.Theresidual oil was heated under reflux with lithium bromide(2.4 g) and lithium carbonate (2.4 g) in dimethylformamide(6 ml) with vigorous magnetic stirring for 1-5 h. Benzenewas added to the cooled mixture and the bulk of the di-methylformaniide and inorganic salts were removed bywashing ( x 3) with water. Drying of the benzene solutionand evaporation yielded an oil which was chromatographedover Kieselgel using benzene-ethyl acetate (5 : 1 ) . Thea$-unsaturated ketone (3) (350 mg, 31) was obtained as aviscous oil, b.p. 175-182" a t 1 mmHg, vax; 3410m, 1660s,and 1620s cm-l; T (CCl,-CHCl,, 10: 1) 9-03 (s, I!vle,C),8.80-8.38 (m, 7-H,), 8.0-7.4 (m, 5-H, and 8-H,), 7-80(s, CH,CO), 3-98 (d, J 16 Hz, 3-H), 3.6br (s, OH), and 3.5-3.0 (4 x ArH superimposed on m, 4-H) ; T (after treatmentwith 1 drop CF,CO,H) 7.85 (d, J 7.5, 5-H,) visible, OH re-moved; m/e 246, 161, 125, and 107 (11, 16, 12, and looyo),m* 105.4 (246 -+ 161).The 3,5-dinitrobenzoate was pre-pared, using 3,5-dinitrobenzoyl chloride in pyridine, asplates, m.p. 80-84" (from ethanol) (Found: M+,440.158301. C,,H,,N,O, requires M , 440458358).Synthesis of 8- (p-Hydroxyphenyl) oct-3-en-2-one (4) .-5-(p-Methoxypheny1)pentan-1-01 was prepared from 4-(fi-anisoyl) butyric acid by Wolff-Kishner reduction 12 withre-methylation of the phenol as described for (ti), followedby esterification and lithium aluminium hydride reduction.It was converted into the title a@-unsaturated ketone by asequence of reactions analogous to those described for thepreparation of (3).The crude oily tosylate was useddirectly to alkylate ethyl acetoacetate ; ethyl 2-acetyZ-7-(p-nzethoxyfihenyl) heptanoate was obtained (51 yo) as a mobileoil, b.p. (bulb-tube; bath temp.) 170-177" a t 1 mmHg(Found: C, 70-35; H, 8.75. C,,H,,O, requires C, 70.55; H,8.55), vmX. 1736s and 1712s cm-l; T (CCl,) 8.74 (t, J 7 Hz,CH3CH,), 8.87-8.02 (m, 3-H,, 4-H,, 5-H,, and 6-H,), 7-88(3.26 (s, OCH,), 5.87 (q, J 7 Hz, CH,CH2), and 3.41, 3.26,3-09, and 2.95 (4 x ArH).Hydrolysis of the above @-keto-ester gave 8-(p-methoxy-9henyZ)octan-Z-one (76) as an oil, b.p.(bulb-tube; bathtemp.) 160-165" a t 1 mmHg (Found: C, 77-16; H, 9.6.C,,H,,O, requires C, 76.9; H, 9.45), vmx. 1711s cm-1;7 (CCl,) 8-9-8-21 (m, CH,,), 7-98 (s, CH,CO), 7.71 and7-50 (2 overlapping t, J 7 and 6.5 Hz, 3-H, and 8-H,,respectively), 6.28 ( s , OCH,), and 3.40, 3-25, 3.09, and 2.95(4 x ArH).Further hydrolysis of the aromatic methyl ether waseffected by heating the ketone above (1 g) with glacial aceticacid (11 ml) and hydrobromic acid (2-5 ml; 48) underreflux. Approximately half the solvent was evaporated offunder reduced pressure and the residue diluted with water.The solid obtained was separated and crystallised fromchloroform-light petroleum to give 8- (p-hydroxyphenyl) -(s, CH,CO), 7.50 (t, J 6.5 Hz, Y-H,), 6.79 (t, J 7 Hz, 2-H),octan-2-one (15) (0.75 g, ?go/,) as prisms, m.p.67-68'(Found: C, 76-05; H, 8.85. C,,H,,,O, requires C, 76.3; H,9.15y0), vmx. 3480s and 1707s cm-1; T (CDCl,) 8.95-8.22(m, CH,,), 7-85 (s, CH,CO), 7.59 (t, J Hz, 3-H,) overlapping7.49 (t, J 6.5 Hz, 8-H2), 4.69br (s, OH), and 3-34, 3-18, 3-05.and 2.92 (4 x ArH); m/e 220, 120, 107, and 43 (24, 33, 100,and 20), m* 65.5 (220- 120)8,8-2H,-8-(p-HydroxyfihenyZ)octan-2-one (16) .-The fore-going phenol ( 1 g) in ethyl acetate (20 ml) was shaken withpalladium-charcoal (200 mg; loo/,) for 3 h in an atmosphereof deuterium, the deuterium being renewed three times.After separation of the catalyst, the ethyl acetate wasremoved and the residue crystallised from chloroform-lightpetroleum.The n.m.r. spectrum shows the disappearanceof the triplet a t 7 7.49; m/e 222, 121, 109, and 43 (22, 27, 100,and 28).Bromination-dehydrobromination of the phenolic ketonegave 8-(p-hydroxyphenyE)oct-3-en-2-one (4) (40) as an oil,b.p. (bulb-tube; bath temp.) 167-172" a t 1 mmHg, vmaL3400m,br and 1666s cm-l; T (CDC1,) 8.65-8.15 (m, 6-Hzand 7-H,), 8.03-8.63 (m, 5-H,), 7-77 (s, CH,CO), 7-47 (t,J 6-5 Hz, 8-H,), 4.33 (s, OH), 3.97 (dt, J 16 and 1.2 Hz,3-H), and 3.34, 3-19, 3.06, and 2-92 (4 x ArH superimposedon 4-H), m/e 218, 160, 133, 120, and 107 (23, 13, 23, 13, andlooyo), m* 117.4 (218- 160) and 52-5 (218 + 109).A crystalline p-nitrobenzoate was obtained with p-nitro-benzoyl chloride and pyridine and crystallised from meth-anol as pale yellow prisms, m.p.96-97.5" (Found: Mf,367.139969. C21H,1N0, requires M , 367441962).Likewise 8, 8-2H-8- (P-hydroxyphenyl)oct-3-en-2-one ( 14)was obtained from the dideuteriated phenol (16). Then.ni.r. spectrum of the pure product showed the absence ofthe triplet a t z 7.47 ; m/e 220, 109, and 43 (37, 100, and 23).A crystalline dideuteriated p-nitrobenzoate was obtained(Found : M+, 369.154298. CZlH,,D,NO, requires M ,369.154517).Rearrangement of the a@- Unsaturated Ketone (3) wzth BoronTri~~oride-Ether.-The a@-unsaturated ketone (3) (1 10 mg)was heated under reflux with benzene (9 mU and borontrifluoride-ether (9 ml) for 1.25 h. After cooling, the mix-ture was added cautiously to sodium hydrogen carbonatesolution and the benzene layer was washed with water, dried,and evaporated.Chromatography of the residue over silicain benzene-ethyl acetate (5 : 1) gave 2-(p-hydroxyphenyl)-4,4-dimethyZcycZohexyZ methyZ ketone (9) (70 mg, 63) asneedles (from chloroform-light petroleum), m.p. 130-131"(Found: C, 77-9; H , 8.9. C,,H,,O, requires C, 78.0; H,9.0), vwx. 3310m and 1687s cm-l; T (CDCl,) 9.2 and 8.96(2s, Me,C), 8.9-8-1 (m, 3-H,, 5-H,, and 6-H,), 8-05 (s,CH,CO), 7.6-7.0 (m, l-H and 2-H), and 3-35, 3-20, 3.03,and 2.88 (4 x ArH) ; m/e 246, 161, 107, and 43 (83, 100, 92,and 72), m* 105.4 (246- 161).Rearrangement of 8-(p-Methoxyphe+zyZ)-6,6-dimethyZoct-3-en-2-one with Perchloric A cid.-The ap-unsaturated ketone(2) (135 mg) was dissolved in perchloric acid (5 ml; 70)and stirred a t room temperature for 2 h.Cautious additionof the red reaction mixture to sodium carbonate solution andextraction with benzene followed by washing of the benzenesolution, drying, and evaporating gave a brown oil (65 mg).Chromatography over Kieselgel, eluting with benzene, anddistillation yielded 2-(p-methoxyphenyl)-4,4-dimethylcyclo-hexyl methyl ketone (12) (58 mg, 43y0), b.p. (bulb-tube, bathtemp.) 200-210" a t 3 mmHg (Found: C, 78.5; H, 9-15.1* D. Papa, E. Schwenk, and H. Hankin, J. Amer. Chem. Soc.,1947, 69, 3018400 J.C.S. Perkin ICi,H,,O, requires C, 78.4; H, 9-3), v,.- 1710s cm-1;T (CCl,) 9.05 and 8.94 (2s, Me,C), 8.9-8-0 (m, 3-H,, 5-H2,and 6-H,), 8.15 (s, CH,CO), 7-4-6.8 (m, l-H and 2-H), 6-20(s, OCH,), and 3-30, 3-15, 2-95, and 2-80 (4 x ArH). Theforegoing methyl ether was identical with a sample preparedby methylation of the phenol (9) with dimethyl sulphate andpotassium carbonate in acetone.2-(p-HydroxyphenyZ)cycZohexyZ Methyl Ketone (10) .-Theap-unsaturated ketone (4) (53 mg) was heated under refluxfor 2 h with boron trifluoride-ether (2.5 ml) in benzene (2-5ml).After cooling the reaction mixture was addedcautiously to sodium hydrogen carbonate solution, morebenzene was added, and the benzene layer was washed withwater, dried, and evaporated. A yellow oil remained whichsolidified on standing. Recrystallisation (from benzene)gave the Ketone (10) (30 mg) as flat white needles. A furtherquantity (11 mg, total 41 mg, 77) of product was obtainedafter filtering the residues through alumina in ethyl acetate-ethanol (1 : 1).An analytical sample was prepared bysublimation (142' a t 1 mmHg) as white rods, m.p. 158.5-159.5' (Found: C, 77.0; H, 8-15. C1,HI8O, requires C,77.05; H, 8-3), vmX. 3340s and 1688s cm-l; T (CDC1,)8.85-7-91 (m, CHJ,), 8.14 (s, CH,CO), 7-49-7.13 (m,1-H and 2-H), 3-55br (s, OH), and 3.44, 3-29, 3-08, and 2-94(4 x ArH); m/e 218, 160, 133, and 107 (61, 24, 50, andlooyo), I* 117.4 (218 ---t 160) and 52.6 (218 -+ 107).Treatment of S, 8-2HJ-8- (p-Hydroxyphenyl) oct-3-en- 2-onewith Boron Trifluoride-Ether.-The procedure above wasrepeated using the deuteriated +unsaturated ketone ( 14).Mass spectral analysis showed the product was 2,6-,H2-2-(p-hydroxypheny1)cyclohexyl methyl ketone (17), m/e 220,134, 109, 108, 107, and 43 (87, 56, 33, 100, 40, and 65).Repetition of the foregoing two experiments using a 3 : 2mixture of non-deuteriated (4) and dideuteriated (14) aP-unsaturated ketones gave a product containing a t most a 6excess of monodeuteriated product ketone (from analysis ofthe m/e 218, 219, and 220 peaks in the mass spectrum).A sample of the phenolic ketone (10) was synthesised bythe following procedure: the Grignard reagent from p-methoxyphenyl bromide (4.61 g) was prepared by heatingunder reflux for 0.5 h with magnesium (1 g) in ether (50 ml)under a nitrogen atmosphere.Dry tetrahydrofuran (90 ml)was added and ca. 70 ml of solution distilled off.Copper(1) chloride (200 mg) was added followed by 1-acetylcyclohexene (3.05 g) in dry tetrahydrofuran (25 ml)dropwise, with vigorous magnetic stirring of the solutionat room temperature.After stirring for 20 min, a saturatedsolution of ammonium chloride was added and the solutionextracted with ether. The ether layer was washed withsodium thiosulphate solution and water, dried, and evap-orated. A yellow oil was obtained which was chromato-graphed over silica using benzene. A waxy white solid wasfirst eluted followed by 2-(p-methoxy~he.rzyZ)cycZohexyZ methylketone (11) (3 g, 52y0), b.p. 140-145O a t 0.2 mmHg (Found:C, 77.45; H, 8.45. C1,H,,O2 requires C, 77.55; H, 8.7y0),vmx 1706s cm-l; T (CCl,) 8.65-7-92 (m, CH,,), 8.35 (s,CH,CO), 7.41-6.96 (m, l-H and 2-H), 6.28 (s, OCH,), and3.38, 3.23, 3-03, and 2-88 (4 x ArH).This methyl ether(130 mg) was heated under reflux with glacial acetic acid(2.2 ml) and hydrobromic acid (0.45 ml; 48). Someacetic acid was evaporated off under reduced pressure, theresidue was diluted with water, and a solid separated.Crystallisation from benzene gave a sample of the ketone(10) (80 mg, 65) identical with that isolated previously.Attempted Rearrangement of Ethyl 7-(p-Methoxyphenyl)-5,5-dinzethyZhept-2-enoate (2 1) with Hydrobromic Acid-Acetic Acid.-The ester (21) (202 mg) was heated underreflux with hydrobromic acid (2 ml; 48) and glacialacetic acid (2 ml). After cooling, the mixture was addedcarefully to sodium hydrogen carbonate solution andextracted twice with dichloromethane. The basic aqueoussolution was acidified with concentrated hydrochloric acidand re-extracted twice with dichloromethane.This extractwas dried, evaporated, and the residue crystallised fromethyl acetate-light petroleum to give 7- (p-hydroxyphenyl) -5,5-dimethyZhept-2-enoic acid (22) as plates, m.p. 130-132'(94 mg, 54) (Found: C, 72-3; H, 7-95. C1,HZ0O3 re-quires C, 72-55; H, 8.1), vmx. 3170m,br, 1685s, and1635m cm-l; T (CF,CO,H) 8.90 (s, Me,C), 8.69-8.15 (m,6-H,), 7.85-7-1 (m, 4-H, and 7-H,), 3-95 (d, J 15 Hz, 2-H),3.15, 3-00, 2-90, and 2.75 (4 x ArH), and 2-57 (dt, J 15 andSynthesis of EthyZ 6-(p-Methoxy$henyZ)hex-enoate and7- (p-Methoxyphenyl) hept-3-en-2-one ( 18) .-4-(p-Methoxy-pheny1)butan-1-01, was prepared by the method of Bairdand Winstein.13 It was oxidised to the aldehyde which wasconverted into the title ester in 41 yield by the methoddescribed earlier.The analytical sample was distilled togive an oil, b.p. (bulb-tube; bath temp.) 175-180' a t1-5 mmHg (Found: C, 72-9; H, 8.35. Cl5H2,O3 requires C,72.55; H, 8-1), vmX 1720s and 1655m cm-l; T (CDC1,)8.70 (t, J 7 Hz, CH,CH2), 8-50-7.20 (m, CH,,), 6.20and 3-30, 3-10, 2-95, and 2.85 (4 x ArH superimposed onHydrolysis of the foregoing ester with sodium hydroxidesolution ( 2 ~ ) containing ethanol for 1 h gave 6-(p-methoxy-phenyl) hex-2-enoic acid (72) as microcrystals, m.p. 83-85"(from ethyl acetate-light petroleum) (Found: C, 70.95; H,7.15. C,,H,,O, requires C, 70.9; H, 7-3), v,, 2660w,br,1690s, and 1645m cm-l; T (CDC1,) 8.85-7-20 (m, CHJ,),6.25 (s, OCH,), 4.10 (d, J 15 Hz, 2-H), 3.20, 3.05, 2.90, and2.73 (4 x ArH superimposed on 3-H), and -1.3br (s,C0,H).Reaction of the same aldehyde above with acetonyltri-phenylphosphonium chloride using the method of Djerassigave 7-(p-methoxy$henyZ) hept-3-en-2-0~~ (54:4,) after chroma-tography over Kieselgel.Distillation gave an oil, b.p.(bulb-tube; bath temp.) 160-170" a t 0-7 mmHg (Found:C, 77-55; H, 8.1. C14H18O2 requires C, 7'7.05; H, 8.3),vmar 1680s and 1630m cm-l; 7 (CCl,) 8.50-7.10 (my3-H), and 3.56-2-90 including peaks at 3.35, 3.20, 3.05,and 2.90 (4 x ArH superimposed on 4-H).Synthesis of 7,7-Bis-(p-methoxyphenyZ) hept-3-en-2-one ( 19).-Powdered aluminium chloride (15.0 g) was dissolved indry nitrobenzene (200 m1) with stirring a t room temperature.The solution was cooled to O', anisole (14 g) was added, andthen the mixture was treated with 4-(+-methoxyphenyl) -butyrolactone (9.1 g) l4 in small portions keeping thetemperature below 5".After addition, the flask wasstoppered and kept in a refrigerator (3 'C) for 13 days. Theresulting red solution was poured onto a 1 : 1 mixture of iceand concentrated hydrochloric acid and then steam dis-stilled until all nitrobenzene was removed. Extraction ofthe residual solution with ethyl acetate ( x 3), drying of theethyl acetate, and evaporating gave a brown oil (13.6 g).13 R. Baird and S. Winstein, J . Amer. Chem. SOC., 1962, 84, 78.14 M. Julia, S. Julia, and B. BCmont, Bull. SOC.chim. France,7 Hz, 3-H).(s, OCH,), 5.80 (a, J 7 Hz, CHaCH,), 4.20 (d, J 16 Hz, 2-H),3-H).CHJ,), 7.90 (s, CH,CO), 6.25 (s, OCH,), 4-05 (d, J 15 Hz,1960, 3041974 401The n.m.r. spectrum revealed that this was a mixture of theexpected acid and its demethylated product(s), and methyl-ation of the crude material was carried out by dissolving inacetone (200 ml) and heating under reflux with dimethylsulphate (6-6 g) and potassium carbonate (7-3 g). Most ofthe acetone was removed, water added, and the solutionextracted with ether. The ether extract was washed withsodium hydroxide solution ( 2 ~ ) , sodium chloride solution,dried, and evaporated. A dark brown oil (4.6 g) was ob-tained which was purified by chromatography over silica(180 g) using benzene-ethyl acetate (2 : 1) and then distilla-tion to give methyl 4,4-bis-(p-methoxyphenyZ)butyrate (20)(3.2 g, 22) as a glass, b.p. (bulb-tube; bath temp.) 190-200' a t 0-06 mmHg (Found: C, 72.95; H, 6-9. C10HzZO4requires C, 72-6; H, 7-05), vmx 1735s crn-l; 'c (CDCI,)7.70 and 7.65 (2 narrow m, CH2I2), 6.35 (s, 'CO,CH,) and6.20 (s, 2 x OCH, superimposed on 4-H), and 3.25, 3.10,2.90, and 2-75 (8 x ArH),4,4-Bis-($J-methoxyphenyl) butan-1-01 was obtained byreduction of the ester (20) with excess of lithium aluminiumhydride in ether. The product was purified by chroma-tography over silica using ethyl acetate-benzene (2 : 1)giving the alcohol (79), vmx. 3380m,br cm-l; 7 (CDCI,)8-7-7-7 (m, CHd, and OH), 6.45 (t, J 6 Hz, CH,OH), 6.30(2 x OCH,, superimposed on 4-H), and 3-30, 3.15, 2-95,and 2.80 (8 x aromatic H).The foregoing alcohol (0.5 g) was oxidised with chromiumtrioxide (1.43 g) in dichloromethane (40 ml) and pyridine(2.3 ml) as described earlier except that the solution wasstirred for 15 min a t room temperature before the mixturewas decanted and worked up. The crude aldehyde washomologated with acetonyltriphenylphosphonium chloride(0.5 g) and sodium carbonate (0.17 g) in water (1.5 ml) andtetrahydrofuran (5 ml) as described earlier. Chroma-tography over Kieselgel eluting with benzene-ethyl acetate(3 : 1) and distillation gave 7,7-bis-(p-methoxy$JhenyZ) hefit-3-en-2-one (19) (240 mg, 42) as a glass, b.p. (bulb-tube;bath temp.) 240-250' a t 0.5 mmHg (Found: C, 77.75;H, 7.35. C,,H,40, requires C, 77.75; H, 7-35), ymX. 1670sand 1625m crn-l; 't (CDCI,) 7-90 (s on a narrow m, CH,COand CH,,), 6.30 (s, 2 x OCH,, superimposed on 7-H), 4.05(d, J 16 Hz, 3-H), and 3.35, 3.20, 3.00, and 2.85 (8 x ArHsuperimposed on 4-H) .We thank the S.R.C. for a grant (to R. H. G.).3/1976 Received, 20th September, 1973