Synthesis of compounds related toendo-6,14-ethenotetrahydrothebaines

摘要

644 J.C.S. Perkin ISynthesis of Compounds related to endo-6,14-EthenotetrahydrothebainesBy Trevor A. Crabb and John R. Wilkinson, Department of Chemistry, Portsmouth Polytechnic, PortsmouthDiels-Alder adducts obtained from 6-methoxy-N-methyl-l,2,3,4,7,8-hexahydroisoquinoline and from 7-methoxy-N-methyl-l,2,3,4,5,6- hexahydroisoquinoline with ethyl acrylate, methyl vinyl ketone, and acrylonitrile are described.PO1 3QL, HampshireDIELS-ALDER addition of suitable dienophiles to the-baine (1) m occurs readily only on the exposed face of thediene system and gives rise to derivatives of endo-6,14-ethenotetrahydrothebaine, in which the etheno bridge isdisposed ' inside the tetrahydrothebaine skeleton.Addition of unsymmetrical dienophiles to thebaine givesexclusively C-7 substituted derivatives which may possesseither the 7cr- (2; R' = H) or '7p-configuration (2; R =The introduction of the new two-carbon bridge acrossring c of thebaine confers rigidity on the adduct mole-cules and it was hoped that the reduced flexibility anddifferences in peripheral shape would make such com-pounds unacceptable at some of the receptor surfaces andthus give rise to a separation of the various physiologicalH).M e O f i M e O f iM e O ' d M e O qR R'11) 12)effects of morphine.In fact both epimers of (2; R,R' =COMe,H) are potent analgetics whereas the relatedesters (2; R,R = C0,Me or CO,Et,H) are inactive.It The terms exo and endo are used to designate epimeric Diels-Alder adducts and have the same stereochemical connotationas for substituted exo- and endo-bicyclo[2.2.2]oct-2-enes in whichthe substituent is respectively C ~ S and trans to the ethano-bridge.For convenience, the alternative symbols, a and @, are alsoemployed to indicate ando- and exo-dispositions relative to theC=C double bond by analogy with the terminology used forthebaine adducts.1 K.W. Bentley and D. G. Hardy, J . Amer. Chem. Soc., 1967,89, 3267.W. Sandermann, Ber., 1938, 71, 648.Adducts with 7P-substituents tend to be marginallymore active than the more accessible 7a-epimers.'With this in mind the Diels-Alder reaction betweensuitable dienophiles and the dienes (3) and (4) was under-taken, with the aim of producing adducts bearing struc-tural resemblances to those (2) from thebaine.Sincethese would lack in particular the aromatic ring of the-baine, the number of receptor sites at which these mole-cules would be acceptable would be expected to be limitedthus allowing a possible separation of analgetic actionfrom unwanted side effects.Formation of Adducts.-The dienes (3) and (4) reactedwith ethyl acrylate, methyl vinyl ketone, and acrylo-nitrile to give in each case two adducts; data relatingto these are given in Tables 1 and 2. The mixtures wereseparated by fractional crystallisation of the picrates(for ethyl acrylate and acrylonitrile adducts) and bycolumn chromatography over alumina (for methylvinyl ketone and acrylonitrile adducts). Table 3 pro-vides details regarding the two adducts obtained from6-ethoxy-l,2 ,3,4,7,8-hexahydro-2-methylisoquinoline andmethyl vinyl ketone.Assignment of Stereockmistry to Adducts.-To facilitatethe argument the structure and stereochemistry assignedto the individual isomers will be presented before the dis-cussion of the results on the basis of which the individualassignments were actually made.The adducts derivedfrom (3) were assigned the structures (5)-(10) and from(4) the structures (11)-(16). For each pair of isomericadducts (Tables 1-3) isomers A were exo-adducts andisomers B endo-adducts.?(a) Esters [ ( 5 ) , (6), (ll), and (12)]. The n.m.r. spectraof the esters (5) and (6) obtained from compound (3) andethyl acrylate display features analogous to those re-C. Schopf, K. von Gottberg, and W.Petri, Annalen, 1938,536, 216.4 S. I. Kanewskaya and S. F. Mitryagina, J . Gen. Chem.(U.S.S.R.), 1947, 17, 1203.5 K. W. Bentleyand A. F. Thomas, J . Chem. SOL, 1956, 1863.6 J. W. Lewis, M. J. Readhead, I. A. Selby, A. C. B. Smith,and C. A. Young, J. Chem. SOG. (C), 1971, 1158.7 K. W. Bentley and J. W. Lewis, reported to the Committeeon Problems of Drug Dependence, 1968.8 T. A. Crabb and J. R. Wilkinson, J . C . S . Perkin I , 1975, 581976 645portedg for the exo- and endo-adducts (17) and (18). Thusshielding of the olefinic proton (6 5.83) in the endo-ester(5), relative to the corresponding proton (6 6.02) in theexo-ester (6), is observed. Also, the signals due t o theethyl protons occur at slightly higher field for the endo-ester [IS 4.07 (9) and 1.22 (t)] than for the exo-ester [S4.15 (m) and 1.26 (t)].Shielding of the olefinic and ethylIn the 220 MHz n.m.r. spectrum of the endo-ester (6),the signals representing the ethoxycarbonyl group pro-tons are, as expected, a quartet (6 4.07) and a triplet(6 1.22) with J 7 Hz. However, in the exo-ester (5), themethylene protons of the ethoxycarbonyl group give riseto a symmetrical 16-line multiplet (6 4.15), which mustlargely be a consequence of restricted rotation of theTABLE 1Diels-Alder reactions of 1,2,3,4,7,8-hexahydro-6-methoxy-2-methylisoquinoline (3)3f.p. of deriv. Order of("C) Dienophile Adduct 0. 01 /o M.p. ("C) B.p. ("C) [mmHg] elutionc Derivative45 120 [0.02] Picrate 14055 120-122 [0.005] Picrate 17640 112-114 [0.02] 1 Methiodide 20650 58 128-130 [0.005] 1 Picrate 18650 85 2 Picrate 143CH,:CH*CO,Et {CH,:CHCOMeCH,XH.CN { 2(decomp.)60 35 116-118 [0.02] 2 Picrate 190 { :TABLE 2Diels-Alder reactions of 1,2,3,4,5,6-hexahydro-7-methoxy-2-methylisoquinoline (4)Order ofDienophile Rdduct a yo M.p.("C) B.p. ("C) [mmHg] elutione Derivative45 121 [0.01] Picrate55 123-125 [O.Ol] Picr ate CH,:CHCO,Et {A 40 50 118 [0.02] 1 MethiodideCH,:CHCOhIe -( B 60 120 [0.02] 2 Methiodide-4 50 107CH&CH.CN i B 50 941 Picrate2 Methiodide3f.p. of deriv("C)140178188200(decomp.)162248(decomp .)TABLE 3Diels-Alder reaction of 6-ethoxy- 1,2,3,4,7,8-hexahydro-2-methylisoquinolineOrder of M.p. of deriv.Dienophile Adduct yo M.p.("C) B.p. ("C) [mmHg'j elution* Derivative ("C)40 35 1 0 6 1 0 6 [0.05] 1 Methiodide 21660 34 106-108 [0.05] 2 Methiodide 178CH,:CH-COhle { 2a h and B are respectively the exo- and eitdo-epimers.chromatography on Woelm neutral alumina (activity 111).b Percentagelof adduct in the initially obtained misture. e Columnprotons in the endo-isomer, compared with the exo-isomer, is similarly encountered in the esters (11) and(12). Reference to Dreiding models of the endo-estersI 5 * L151 R ' CO,Et, R 2 = H ( e x o l(61 R' -H, R2:C02Et Iendol17) R' ZCOMe, R 2 - H ( e x o )(81 R'-H, R2:COMe l e n d a lI91 R ' : C N , R 2 - H ( e x 0 1I l O I R ' zH, Rz=CN [ e n d o ) (16)R1--H, R 2 = CN ( e n d o )(6) and (12) indicates that, in certain conformations, theethyl protons of the ethoxycarbonyl group will beshielded by the C=C bond.The anisotropic effect of thecarbonyl of the ethoxycarbonyl group depends upon itsorientation, but its net influence is apparently to shieldthe olefinic proton.A . A. Othman, M. A. Qasseem, and N. A. J . Rogers, Tetva-hedvon, 1067, 23, 87.( 1 1 ) R ' : C 0 2 E t , R2:H ( e x o i(12) R'=H, R Z - C O ~ E ~ ( e n d o )t131 RUOM~, R ~ - H i e x o )( 1 4 ) R ' - H , R 2 =COMe ( e n d o )( ' 5 , ~ ' - CN, RLH I e x o )methylene group. A Dreiding model of the exo-ester (5)shows the methylene group of the ethoxycarbonyl func-tion to be hindered by one of the C-H bonds of theethano-bridge in certain conformations, whereas restric-tion of free rotation is less apparent in a model of theendo-ester (6). Another example of a complex n.m.r.splitting pattern due to a sterically hindered ethyl grouphas been reported recently.1°In the n.m.r.spectra of the adducts (5)-(16) the ABsignals due to H-Sa and H-8P [in (5)--(lo)] and to H-5zand H-5p [in (11)-(16)] are obscured, but the lowerfield X signal due to H-7x or H-7P [in (+-(lo) and toH-6cc or H-6p in (11)-(16)] is clearly distinguishable.Consequently the true values of the vicinal couplingconstants cannot be determined and because the ob-served splittings may not approximate t o the true valueof J , the symbol ' J ' will be used to designate the appro-priate splittings of the H-7a and H-7p signals for (5)-(lo), and of the H-6cc and H-6P signals for (11)-(16).In the n.m.r.spectrum of the exo-ester (5) the H-7cc sig-nals are centred a t 6 2.74 as a quartet (' J',a,8cr 11,10 D. E. Caddy and J. H. P. Utley, J.C.S. Peykin 11, 1973,1258M 6 J.C.S. Perkin I' J '7a,88 5 Hz) which is further split into doublets (' J '2 Hz). In the n.m.r. spectrum of the endo-ester (6),H-7P gives rise to a triplet at 6 2.91 (' J '78,88= '.J '7@,8a =8 Hz) with no evidence of further splitting. Theshielding of an endo-proton relative to an exo-proton ofotherwise similar environment has been encounteredfrequently in the spectra of bicycl0[2.2.2]octenes.~~--~~The additional splitting of the H-'la quartet for theexo-ester (5) is attributed to long-range coupling of H-7awith the corresponding proton at C-10 for which thearrangement of the four intervening bonds is a ' planarW '.Such an arrangement does not exist for H-7P in theendo-ester (6) and long-range coupling is not observed.Thus convincing n.m.r. evidence for the exo- and endo-stereochemistry of (5) and (6), respectively, is providedby comparison of the olefinic and ethoxycarbonyl protonchemical shifts with those of the analogous adducts (17)and (18),9 complex splitting for the methylene protons Meom R'R2(17) R':CO=R, R2- H(181 R':H, R2:C02Rof the ethoxycarbonyl group in (5) but not in (6), shield-ing of H-7a in (5) relative to H-7P in (6) , and long-rangecoupling of H-7a with H-10 in (5), but not of H-7p withH-10 in (6).The apparent vicinal coupling constants (' J ') alsoafford a useful indication of stereochemistry, althoughthe assignment of an exo- or endo-configuration on thisbasis must be undertaken with caution.14 In the ad-ducts of thebaine with methyl vinyl ketone and withacrylonitrile coupling between endo-protons is reported 11to be larger than between exo-protons.This apparentlyapplies to the Diels-Alder adducts (5)-(16) and confirmsthe stereochemical assignments.The 220 MHz n.m.r. spectra of the exo- and endo-esters (11) and (12) [derived from (4)J display featuressimilar to those of the corresponding esters (5) and (6).In the 8x0-ester (11), the H-6a signal at 6 2.76 againappears as a quartet (' J '&,sa! 11, ' J '6a,68 5 Hz) showingevidence of further splitting (' J ' 2 Hz) arising from long-range coupling with H-10.The H-6P signal at 6 2.93for the endo-ester (12) is a triplet (' J '68,58 = ' J '6&5a =7.5 Hz) showing no evidence of further long-rangecoupling.In neither ester, (11) or (12), is a simple quartet ob-served for the O*CH,*CH, protons. Both restrictedrotation and asymmetry of the molecule may renderthese protons non-equivalent, but the more complexsplitting observed in the spectrum of the exo-isomer (11)may be taken as indication of a more restrictive environ-ment, as in the corresponding exo-ester (5). The posi-11 W. Fulmar, J . E. Lancaster, G. 0. Morton, J . J. Brown,C. H. Howell, C. T. Nora, and R. A. Hardy, J. Amer. Chew.SOL, 1967, 89, 3322.lg W. A. Ayer, C. E. McDonald, and J. B.Stothers, Canad.J. Chem., 1963, 41, 1113.tion of the C=C bond relative to the ring nitrogen in iso-mers (11) and (12) is readily apparent from examin-ation of the AB quartet due to the C-1 methylene pro-tons. For both isomers, the value of Jscm (-15 Hz)is characteristic of N-CH,-C=C.15(b) Ketones [(7), (€4, (13), and (14)]. The 220 MHzn.m.r. spectra of the ketones (7) and (8) show significantdifferences in the chemical shifts of the olefinic and acetylmethyl signals. The observed shielding of the acetylmethyl group (6 2.07) in the endo-isomer (8), relative tothe corresponding signal (6 2.23) in the exo-isomer (7),is again attributable to the anisotropy of the C=C bond.12As in the analogous esters, the H-5 olefinic signal is athigher field (6 5.83) for the endo-ketone (8) than for theexo-ketone (7) ( 6 6.02).Evidence for the exo- and endo-configurations of theketones (7) and (8) is furnished by the chemical shiftsand splittings of the H-'la or H-7P signals.In the n.m.r.spectrum of the exo-ketone (7), H-7a absorbs as a broad-ened quartet (centred at 6 2.91) for which the value ofJ7a& + J7a,88 is 15 Hz. If we assume that the splittingfor each of the two doublets is a measure of the smallercoupling constant, J7a.88, the estimated values of thevicinal coupling constants are ' J '7a& 11.5 and ' J 'va,88 3.5Hz. In the n.m.r. spectrum of the endo-ketone (8), theH-713 signal appears as a sharper quartet at 6 2.99(' J J78,8B 9, ' J '7B,8a 6 Hz). In addition further splittingof the H-6a quartet in the spectrum of (13) into an octetowing to long-range coupling (J 1.5 Hz) with H-10(' planar W') is observed, whereas the signal of H-6P in(14) is a sharp quartet.From a knowledge of the n.m.r.spectra of the ketones(7) and (€9, the stereochemistry of the closely relatedadducts from methyl vinyl ketone and 6-ethoxy-1,2,3,4,-7,8-hexahydro-2-methylisoquinoline were established (seeExperimental section).(c) Nitriles [(9), (lo), (15), and (16)]. In the 220MHz n.m.r. spectrum of the exo-nitrile (9), the H-7a sig-nals appear at 6 2.67 as an octet, first-order analysis ofwhich gave values of ' J ' 7 a . 8 ~ ~ ' J '7a.88, and ]70r,10 of 12,5 , and 2.5 Hz, respectively, characteristic of an exo-isomer.The H-7P signals at 6 2.92 in the 220 MHz n.m.r.spectrum of the endo-nitrile (10) appear as a well definedquartet arising from vicinal coupling with H-8P (' J '78,889.5 Hz) and H-8a (' J ' 7 8 , ~ ~ 5 Hz).Unlike the endo-ester(6) and the endo-ketone (€9, the endo-nitrile (10) gives anolefinic singlet at slightly lower field than that in theexo-isomer (9) (6 6.00 cf. 5.93).The stereochemistry of the isomeric nitriles (16) and(16) [derived from (4)], can also be deduced from thechemical shift and splitting of the H-6 signal in the220 MHz spectra. In the exo-nitrile (15), H-6a couplesvicinally with H-5a ( ' J '6a,5a 11.6 Hz) and H-4318 K. Tori, Y. Takano, and I. Kitahonoki, Chem. B e y . , 1964,14 F. A. L. Anet, H. H. Lee, and J. L. Sudmeier, J.Amev.16 R. Cahill, R. C. Cookson. and T. A. Crabb, Tetrahedron,97, 2798.Chem. Soc., 1967, 89, 4431.1969, 25, 46811976 647(' J '6cr,5p 5.5 Hz). Further splitting of the H-6a signalcentred at 6 2.71 is attributable t o long-range couplingwith H-10 ( J 2.5 Hz).The H-6P signal a t 6 3.00, for the endo-nitrile (16),appears as a quartet ( ' J '6B,sB 9.5, and ' J '6p,5a 4 Hz)showing little evidence of further splitting due to long-range coupling. The olefinic H-8 signal is again at lowerfield for the endo-nitrile (16) than for the exo-nitrile (15)(6 6.03 cf. 5.92).Thus again the exo-isomers (9) and (15) differ from thecorresponding endo-isomers (10) and (16) in exhibiting ahigher field chemical shift of the H-7 signal in (9) than in(10) and of the H-6 signal in (15) than in (16), furthersplitting of the H-7 signals in (9) and of the H-6 signals in(15) due to long-range coupling with H-10, and thegreater magnitude of ' J ',a,ga compared with ' J '713,8p in(9) and (10) and of ' J ' 6 a , 5 ~ compared with ' J '6B,58 in(15) and (16).Confirmation of Stereochemical A ssigizments by ChemicalMethods.-Although the expected products of Diels-Alder reaction between the diene (3) and methyl vinylketone are the 7-acetyl adducts, (7) and (8), the alterna-tive mode of addition would give the corresponding 8-substituted derivatives.Acid-catalysed rearrangementof the exo-ketone (7) and the endo-ketone (8) demon-strated that the acetyl group was attached at C-7 sincethe observed ring opening is possible only for a carbonylsubstituent vicinal to the bridgehead methoxy-group.16When the picrate (m.p.190.) of the endo-isomer (8)was broken down on acidic alumina, a liquid was ob-tained which gave a n.m.r. spectrum with singlets repre-senting an acetyl group (6 2.13), an N-methyl group (62.23), and one olefinic proton (6 5.68), but no O-methylsinglet. The i.r. spectrum showed strong bands at1 710 (non-conjugated C=O) and 1670 cm-l (conjugatedGO). U.V. absorption at Amax. 234 nm (E: 14400) alsoindicated that the rearrangement product was an ap-unsaturated ketone. The spectroscopic information andanalytical data for the methiodide (m.p. 154") supportthe assignment of structure (19) which can arise by ring-opening, as shown.Acid-catalysed rearrangements of;2H' ( 8 )M e-C 4II0 (191the same type have been observed with some thebaineadducts l7 and with adducts of 1,3-dihydroanisoles andmethyl vinyl ketone.16Treatment of either ethoxy-ketone (20) or (21) with2N-hydrochloric acid at 100 "C, followed by work-upwith aqueous 30% sodium hydroxide, yielded a mixture(m.p. 90-looo) of two components (ratio ca. 7 : 3). Twodiastereoisomeric hydroxy-compounds, A and B, wereisolated from this mixture by fractional crystallisationand were assigned structures (22) and (23), formed byaldol ring closure of the rearrangement product (19).If I I0 120) 0 1211The presence of an ctp-unsaturated oxo-group in bothisomers was indicated by U.V. absorption at A,, 235nm and a strong i.r.band at 1660 cm-l. The majorconstituent of the initial mixture, isomer A (m.p. loti"),showed a sharp i.r. band at 3 590 cm-l, the frequency ofwhich was independent of concentration (CCl, solution),whereas a corresponding much weaker band a t 3650cm-l was observed in the spectrum of the minor isomer B(m.p. 148"). These frequencies are within the range forfree OH stretching in alcohols and indicate that isomer Apossesses structure (22), since intramolecular hydrogenbonding with the carbonyl group in structure (23) wouldresult in a lowered intensity of the free OH stretchingband, relative to that in (22). A higher free OH stretch-ing frequency for equatorial hydroxy-groups than forO H( 2 2 )Me( 2 3 1axial hydroxy-groups in related compounds has beenreportedls and apparently also occurs in the alcohol(23) as compared with the alcohol (22), assuming that thehydroxy-substituted rings adopt chair conformations.Both isomeric alcohols also gave broad OH stretchingbands (3 410 for isomer A and 3 450 cm-l for isomer B)within the range for intermolecularly hydrogen bondedhydroxy-groups, and in dilute solution isomer B showeda band at 3510 cm-l attributed to the OH stretchingvibration of the intramolecularly hydrogen-bondedhydroxy-group in the alcohol (23).The n.m.r.spectrum of the more abundant isomer Ashowed singlets at 8 5.88 (1 olefinic proton), 2.33 (N-Me),and 1.25 [C(OH)CHJ. In the n.m.r. spectrum of isomerB, corresponding signals respectively occurred at 6 6.02,2.33, and 1.43.Thus the singlet due to the methylgroup attached to the hydroxy-substituted carbon atomis at higher field for isomer A ( 6 1.25) than for isomer B(1.43). In a Dreiding model of (22), this methyl groupis situated above the plane of the C=O bond and asmall shielding influence is anticipated, whereas in (23)the methyl group is unaffected. In addition, axialmethyl protons normally absorb to lower field of equa-torial methyl protons.19Confirmation of these assignments is afforded by therelative susceptibilities of the isomers to dehydration.I. L. Allsop, A. R. H. Cole, D. E. White, and R. L. S. Willix,7. Chem. SOC.. 1956. 4868. lo A. J. Birch and J. S. Hill, J . Chem. SOC. ( C ) , 1966, 419.l7 K. W. Bentlev and T.C . Ball. T . Ow. Chem.. 1958. 23. 1720. - u " , ---. " l9 S . Brownstein and R. Miller, J. Oyg. Chenz., 1959, 24, 1886648 J.C.S. Perkin IDuring an attempted separation of the isomeric al-cohols by column chromatography over Woelm neutralalumina (activity 111), a new product, C,,H,,NO (m.p.74"), was obtained. In the n.m.r. spectrum, a broadsinglet at 6 5.43 and a sharper singlet at 6 5.70 representedtwo olefinic protons and 3-proton singlets a t 6 2.33 and1.77 were attributed to methyl protons; no OH stretch-ing band was present in the i.r. spectrum. This com-pound is therefore considered to be the dehydrationproduct (24) which also arose as a side-product from acid-catalysed rearrangement of (20) and (21).In the hydroxy-compound (22), the axial hydroxy-group is trans to the axial hydrogen atom of the adjacentmethylene group.It was therefore anticipated thatelimination of water should occur more readily from thisisomer than from the equatorial alcohol (23). Applica-tion of isomer A to an alumina column, followed by elu-tion with ether, yielded the dehydration product (24),whereas similar treatment of isomer B did not result indehydration. The assignment of structure (22) to isomerA was thus confirmed.Biological Activity .-The biological results are sum-marised in Table 4. Codeine has been included as areference drug.Of the compounds tested only the ketones (7) and (13)showed reasonable levels of antinociceptive activity. Inboth cases, however, this was associated with toxic sideeffects which precluded any further biological investig-ations.In neither compound was the activity of theTABLE 4Biological activity [hot-plate test (HP) and antagonism ofphenylquinone-induced writhing (PQ)] of Diels-AlderadductsPQ HPCompound (100 mg per kg) (50 nig per kg) + (7) + (13)f (14)(16) 1- (16) i( 20) i(21) f(22) + (23) f +--- -- -Codeine ++ ++(20 mg per kg (60 mg per kgbody weight) body weight)same order of magnitude as that of thebaine. This sug-gests that the aromatic ring in the thebaine skeleton isessential for the intense biological action of this type ofmolecule.(a) Antagonism of phenylquinone-induced writhing.2o L. C. Hendershot and J. Forsaith, Proc. SOC. Exp. Biol.Med., 1959, 125, 237.The method was based on that of Hendershot and For-saith.20 Test compounds were either dissolved in distil-led water or suspended in 5% gum acacia solution andadministered orally to groups of 3 male mice using a doseof 100 mg drug per kg body weight and a dose volumeof 0.4 ml per 20 g body weight.Control mice received anequivalent volume of vehicle. After 1 h, phenylquinone(2 mg per kg) in normal saline solution was injectedintraperitoneally. Immediately foIlowing phenyl-quinone injection the mice were observed for 20 min andthe total number of writhes per group recorded. Anti-nociceptive activity in terms of yo inhibition of writhingwas expressed as follows: 25-49y0 = & ; 50-75% =A modification of the method de-scribed by Woolfe and MacDonald2l was used.Testcompounds were dissolved in normal saline solution orsuspended in 5% gum acacia solution and administeredsubcutaneously to groups of 3 male mice. The dose was50 mg drugper kg body weight and the dose volume0.2 ml per 20 g body weight. Control mice received anequivalent volume of vehicle. Thirty min after injectioneach mouse was placed on a hot-plate maintained at55 "C and the reaction time noted. -4 maximum cut-off' time of 60 s was imposed. Increases in meanreaction time (R) were calculated as a percentage of thismaximum from equation (i).+; 75%=++.(b) Hot-$Zate test.x lOO(i test group R - control group R60 - control group R increase = % 'Antinociceptive activity was expressed as follows10--24y0 increase = -J-; %-5Oy0 increase = +50% increase = + + .EXPERIMENTALElemental analyses were carried out by PortsmouthPolytechnic analytical section.U.V. spectra were ob-tained (Unicam SP 800 spectrophotometer) for solutionsin absolute ethanol. 1.r. spectra were determined for liquidfilms or solutions in carbon tetrachloride with a Perkin-Elmer237 spectrometer. N.m.r. spectra were recorded on a VarianT6O spectrometer or an HR 220 spectrometer (PCMU,Harwell) for solutions in CDCI,.Ethyl 1,2,3,4,6,7,8,8a-Octalzydro-6-nzethoxy-2-methyl-6,8a-etJtanoisoquinoline-7~- (5) and -7u-carboxylate (6) .-A mixtureof 70% pure 1,2,3,4,7,8-hexahydro-6-methoxy-2-methyliso-quinoline (3) (3.0 g ) and ethyl acrylate (15 ml) was heatedunder reflux in the presence of hydroquinone (0.1 g) for8 h.Residual ethyl acrylate was removed in vacuo andunchanged diene (1.3 g) was recovered by vacuum distilla-tion. The mixture of epimeric adducts (2.1 g) was distilled(b.y. 110-115° a t 0.001 mmHg) to give a viscous oil.A picmte, m.p. 176" (1.6 g) (Found: C, 52.2; HI 5.8; N,11.1. C22H,,N40i, requires C, 52.0; H, 5.55; N, 11.0%)was obtained by mixing hot ethanolic solutions of thefreshly distilled oil (2.0 g) and picric acid (1.7 g), followedby recrystallisation from ethanol. This picrate (1.5 g) was21 G. Woolfe and A. D. MacDonald, J . Pharmacol. ExP. They.,1944, 80, 3001976dissolved in acetone and applied to an alumina column (50 gWoelm neutral; activity 111). Elution with ether affordedthe pure endo-ester (6), b.p.120-122" at 0.005 mmHg (0.6g), 6 5.83 (5-H), 2.29 (NMe), 3.34 (OMe), 4.07 (OCH,*CH,),Hz.The picrate mother liquors gave a second picrate (0.7 g),m.p, 140" (from ethanol) (Found: C, 52.0; H, 5.9; N,IO.GY&), which afforded the exo-ester (5), b.p. 120" at 0.02mmHg (0.3 g), when broken down on alumina; 6 6.02(5-H), 3.40 (OMe), 2.28 (NMe), 4.15 (OCH,*CH,), 1.26Ethyl 1 , 2,3,4,4a, 5,6 , 7-Octahydro-7-methoxy-2-nzethyZ-4aJ 7-ethanoisoquinoti.~ze-6P- (1 1) and -6a-carboxylate (12) .-Bythe procedure described above, a mixture of epimericesters (1.5 g), b.p. 120-125" at 0.01 mmHg, was obtainedfrom the isomerisation mixture (3.0 g) containing 70% of1,2,3,4,5,6-hexahydro-7-methoxy-2-metliylisoquinoline and257; of 1,2,3,4,5,8-hexahydro-7-methoxy-2-methyliso-quinoline after heating under reflux with ethyl acrylate( 15 ml) for 4 h.The isomeric adducts were again separatedTtia the picrates. The picrate, m.p. 178" (1.2 g) (Found:C, 51.8; 13, 5.8; N, 10.9. C22H28N4010 requires C, 52.0;H, 5.55; N, 11.0%) of the endo-ester (12) afforded thepure isomer, b.p. 123-125"at 0.01 mmHg (0.5g), when brokendown on alumina, v,,, (film) 1730 cm-l (ester C=O), 65.82 (8-H), 3.34 (OMe), 2.28 (NMe), 4.08 (OCH,*CH,), 1.23Hz. A second fiicrate, m.p. 140" (0.5 g) (Found: C, 52.0;H, 5.3; N, ll.Oyo) isolated by fractional crystallisation fromethanol gave the exo-ester (ll), b.p. 121" at 0.01 mmHg(0.2 g), when broken down on alumina; vm, (film) 1725cm-1 (ester GO), 8 6.01 (8-H), 3.40 (OMe), 2.29 (NMe),4.14 (OCH,*CH,), 1.26 (OCH,*CH,), and 2.76 (H-64, J 6 a .47p- (7) and 7u-Acetyl- lJ2,3,4,6,7,8,8a-octahydro-6-methoxy-2-methyt-6,8a-ethanoisoquinoline (8) .-The isomerisationmixture (8.0 g) containing 70% of (3) was heated underreflus on a water-bath with methyl vinyl ketone (40 ml)in the presence of hydroquinone (0.1 g) for 4 h. The excessof methyl vinyl ketone was removed in vacuo and unchangeddiene was recovered by vacuum distillation. The mixtureof ketone adducts distilled over at 110-120" and 0.03mmHg (6.4 g).A column was prepared, in light petroleum, from Woelmneutral alumina (activity 111) (250 g). The mixture ofketone adducts (6.0 g) was dissolved in light petroleum (10ml) and the solution was carefully applied to the surface ofthe alumina.Elution with light petroleum (200 ml frac-tions) removed aromatic impurities and starting material.Further elution with 95 : 5 light petroleum-ether affordedthe exo-ketone (7). When the proportion of ether was in-creased to loyo, a mixture of ketones (7) and (8) was even-tually obtained, but continued elution gave the pure endo-ketone ( 8 ) . On further increase of eluant polarity (up tolOOyo ether), the remaining endo-ketone (8) was eluted fromthe column. The chromatographic fractions were readilymonitored by means of t.1.c. on alumina with ether as sol-vent (Table 5).The exo-ketone (7) (2.0 g), b.p. 112-114" at 0.02 mmHg,formed a methiodide, m.p. 206" (decomp.) (from ethanol)(Found: C, 49.5; H, 6.9; N, 3.2.C16H,,N0, requires C,49.1; H, 6.65; N, 3.6%). After distillation of the endo-ketone (8) (3.1 g), b.p. 116-118" at 0.02 mmHg, prolongedcooling a t - 40 "C induced crystallisation, and recrystallis-1.22 (OCH,*CH,), and 2-91 (H-~P)J J7P.88 8, J7j3.8a 8, J7B.6 1(OCH,*CH,), and 2-74 (H-7a)J . / ~ ~ . 8 c r 111 J7a,Sj3 51 J7a.10 2 Hz.(OCH,*CH,), and 2-93 (6P-H)) J6B,6fl 7.5J J6j3.6a 7.51 J @ , 8 5, J6C4.10 Hz.ation from a small quantity of light petroleum afforded thepure endo-ketone ( S ) , m.p. 35". When ethanolic solutions,containing equivalent amounts of the endo-ketone (8) andpicric acid, were mixed, picrate was formed; m.p. 190'(from ethanol) (Found: C, 52.4; H, 5.4; N, 11.95. CZl-H,,N,O, requires C, 52.7; H, 5.4; N, 11.95%).The exo-ketone (7) showed vmx 1 710 cm-' (GO) ; 6 6.02 (5-H), 3.37(OMe), 2.27 (NMe), 2.23 (COMe), and 2.91 (H-7a), J7a,8a 11.5,TABLE 5Chromatographic separation of (7) and (8)Eluant - 01 / OPetroleumWP-40-60")100100959090900O /Ei!ier005101010100Fractionnumber(41-345-1011-1617-181920-22Combinedmass( €90.4 0.010.61.40.30.13.0Compositionof eluateand impuritiesexo-Adduct (7)exo-Adduct (7)Mixture of adductsendo-Adduct (8)endo-Adduct (8)f 3)J7a,86 3.5, J7a.10 1 Hz. The endo-ketone (8) showed vmax1710 cm-l (GO); 6 5.83 (5-H), 3.31 (OMe), 2.29 (NMe),6p- ( 13) and 6a-Acetyl- 1,2 , 3,4,4a, 5,6 , 7-octaJzydro-7-metlz-oxy-2-nzethyl-4aJ 7-ethanoisoquinoline ( 14) .-The isomeris-ation mixture (3.0 g) containing 70% of (4) was heated underreflux with methyl vinyl ketone (15 ml) and hydroquinone(0.1 g) on a water-bath for 4 h.After removal of startingmaterial, the mixture of isomeric adducts was distilled ;b.p. 130-140" at 0.01 mmHg (yield 2.1 g). The exo- (13)and endo-ketone (14) were separated by chromatography onWoelm neutral alumina (grade 111), as described for theketones (7) and (8).The exo-ketone (13) (0.7 g) was distilled (b.p. 118" a t0.02 mmHg) and crystallised on cooling. The pure isomerwas isolated as a white crystalline solid, m.p. 50" (from lightpetroleum) (Found: C, 72.55; €3, 9.6; N, 5.4. C1,H,,NO,requires C, 72.25; H, 9.3; N, 5.6%). It formed a nzethio-dide, m.p.188" (from ethanol) (Found: C, 48.8; H, 6.7;N, 3.4. C16H2,N0, requires C, 49.1; H, 6.65; N, 3.6%).The endo-ketone (14) (1.1 g), b.p. 120' at 0.02 mmHg, alsoformed a mthiodide, m.p. 200" (from ethanol) (Found:C, 49.4; H, 6.9; N, 3.5%). The exo-ketone (13) showedv,, 1710 cm-l ( G O ) ; 6 6.00 (8-H), 3.36 (OMe), 2.271.5 Hz. The endo-ketone (14) showed vms. 1710 cm-l(GO); 6 5.79 (8-H), 3.32 (OMe), 2.28 (NMe), 2.09 (COMe), and1 , 2,3,4,6,7,8,8a-Octahydro-6-methoxy-2-methyl-6,8a-ethano-isoquinotim-7a- (9) and -7a-carbonitrite ( 10) .-The isomeris-ation mixture (5.0 g) containing 70% of (3) was heated underreflux on the water-bath with acrylonitrile (15 ml) in thepresence of hydroquinone (0.1 g) for 4 h. -4fter removal ofstarting material, the mixture of epimeric nitriles was dis-tilled (b.p.120-130" at 0.002 mmHg) to give a viscous,pale yellow liquid (3.0 g). Treatment with picric acid(3.0 g) in hot, ethanolic solution yielded a picrate which wasrecrystallised t o constant 1n.p. (186') and broken down (2.6g) on alumina to give the exo-isomer (9), b.p. 128-130' at0.005 mmHg (1.0 g). The viscous oil solidified on coolingand recrystallisation from ether-light petroleum afforded2.07 (COMe), and 2.99 (H-7@), J7fi,8j3 9, J78,SCr 6, J7j3.8 1 Hz.(NMe), 2-23 (COMe), and 2.93 (H-64, J6Q.50 11, Jsa.@ 4, J6a.103.02 (H-6@), J6,3.6,9 92 J6/3,6a 6~ J6j3.8 HzJ.C.S. Perkin Ithe pure exo-nitrile (9) as a white, crystalline solid, m.p.58" (Found: C, 72.5; HI 8.8; N, 12.2.C14H2,N20 re-quires C, 72.4; HI 8.7; N, 12.1%), 6 5.93 (5-H), 3.40 (OMe),2.29 (NMe), and 2.67 (H-74, J 7 a . 8 ~ 12.0, J7c(,8fi 5.0, J7Q.102.5 Hz.A second picrate (1.0 g), m.p. 143", was isolated from themother liquors and, when applied t o an alumina column,produced the endo-nitrile (10) as colourless crystals (0.4 g).A sample of m.p. 85" was obtained by recrystallisation fromether-light petroleum (Found: C, 72.2; H, 8.7; N, 12.0y0),6 6.00 (5-H), 3.40 (OMe), 2.29 (NMe), and 2.92 (H-7p),J 7 f i . s ~ 9.5, J7)3,8a 5.0, J 7 , 9 5 . 1 Hz. The isomeric nitriles(9) and (10) (1.0 g) were also separated by column chroma-tography on Woelm neutral alumina (activity 111) [elutionwith light petroleum-ether (4: l)] to give first the exo-adduct (9) (0.3 g) and then the endo-adduct (10) (0.4 8).1,2, 3,4,4a,5, 6,7-Octahydro-7-~lzethoxy-2-methyl-4a, 7-ethanoisoquinoline-6P- (1 5) and -6u-carbonitrile ( 16) .T h eisomerisation mixture (3.0 g) containing 70% of (4) washeated under reflux on a water-bath with acrylonitrile (10ml) and hydroquinone (0.1 g) for 4 11. After removal ofstarting material, the mixture of nitrile adducts was distilled(b.p. 130-140" a t 0.01 mmHg) to give a viscous liquid(1.6 8). The exo-isomer (15) was isolated by treatment ofthis liquid (0.5 g) with picric acid (0.5 g) in ethanolic solu-tion, recrystallisation of the picrate to constant m.p.(162") (0.3 g), and breakdown on alumina. The exo-nitrile (15) solidified on cooling and was obtained as a white,crystalline solid (0.1 g), m.p.107" (from ether-light petrol-eum) (Found: C, 72.6; HI 8.8; N, 11.8. Cl,H2,N,0requires C, 72.4; HI 8.7; N, 12.1%), 6 5.92 (8-H), 3.40(OMe), 2.27 (NMe), and 2.71 (H-64, J8a,5a 11.5, JgcL,5~ 5.5,The initial mixture of adducts crystallised on cooling togive a solid (m.p. 75-80') containing approximately equalamounts of the nitriles (15) and (16). When this solid (1.0g) was chromatographed yoelm neutral alumina (grade111) ; light petroleum-ether) the exo-isomer (15) (0.4 g)and the endo-isomer (16) (0.3 g) were obtained. Recrystal-lisation from ether-light petroleum afforded the pure endo-nitrile (16), m.p. 94" (Found: C, 72.7; H , 8.95; N, 12.3%),6 6.03 (8-H), 3.43 (OMe), 2.32 (NMe), and 3.00 (H-6P),6-Ethoxy-1,2,3,4,5,8-hexahydro-2-methyl~soqu~~l~ne.- Asolution of 6-ethoxy-1,2,3,4-tetrahydro-2-methylisoqu~no-line (41.5 g) in dry methanol (300 ml) was carefully addedto liquid ammonia (2 1) with dry ether (200 ml) as co-solvent.Sodium (40 g) was then carefully introduced insmall portions (the blue colour was allowed to fade betweenadditions) with stirring continuously throughout. Afterevaporation of ammonia, water (ca. 200 ml) was cautiouslyadded and the product was extracted with ether. Thedried extract was evaporated and methanol was removedin vacuo. The product, b.p. 102-104" a t 0.7 mmHg, wasan oil (38.3 g) which solidified on cooling at -40 "C t o givecrystals, m.p. 28", 6 4.43 (olefinic proton), 2.27 ( W e ) , and1.27 and 3.65 (OEt).It formed a methiodide, m.p. 178"(from ethanol) (Found: C, 46.5; H, 6.7; N, 4.25. C13H22-IN0 requires C, 46.6; H , 6.6; N, 4.2%).6-Ethoxy- 1 , 2,3,4,7,8-hexahydro-2-rnethylisoquinoline.-6-Ethoxy-1,2,3,4,5,8-hexahydro-2-niethylisoquinoline (38.0g) was thoroughly mixed with a solution of potassium t-pentyl oxide (from 15 g of potassium) in t-pentyl alcohol(350 ml) and heated on a water-bath for 4 h. t-Pentylalcohol was removed iut vacuo, water (50 ml) was added, andJ43a.10 2.5 Hz.16S.Sj3 lo.o, J@.Sa 4.0, J8fi.S Hz*the isomerisation product was extracted with ether. Thedried extract was evaporated and the residual liquid dis-tilled (b.p. 106-110" a t 1 mmHg) (36.8 g). This isomeris-ation mixture contained the conjugated diene (65y0), 64.62 (olefinic proton), 2.27 (NMe), 1.32 (OCH,*CH,), and3.37 (OCH,CH,), and the non-conjugated isomer (35%).The methiodide, m.p.162", of 6-ethoxy-l12,3,4,7,8-hexa-hydro-2-methylisoquinoline was isolated by treatment of theisomerisation mixture with methyl iodide in ethanol solu-tion followed by recrystallisation from ethanol (Found :C, 46.6; H, 6.5; N, 4.3. C1,H2,1N0 requires C, 46.4;HI 6.6; N, 4.2%).7p- (20) and 7a-Acetyl-6-ethoxy-1,2,3,4,6,7,8,8a-octahydro-2-methyZ-6,8a-ethanoisoquinoline (2 1) .-The isomerisationmixture (36.0 g) containing 65% of 6-ethoxy-1,2,3,4,7,8-hexahydro-2-methylisoquinoline was heated under refluxwith methyl vinyl ketone (50 ml) and hydroquinone (0.2 g)on a water-bath for 5 h. After removal of starting material,the mixture of epimeric ketone adducts was distilled (b.p.100-110" a t 0.05 mmHg) to give a viscous oil (30.4 g).The oil (10.0 g) was dissolved in light petroleum (10 ml) andapplied to an alumina column [300 g of Woelm neutral(activity 111) in light petroleum].Elution with lightpetroleum removed side-products and further elution with95 : 5 light petroleum-ether afforded the exo-ketone (20)(3.1 g), a mixture of ketones (20) and (21) (0.7 g), and theendo-ketone (21) (5.4 8).The exo-ketone (20), b.p. 104-106" a t 0.05 mmHg, solidi-fied on cooling a t -40 "C and was obtained as crystals,m.p. 38" (from light petroleum a t 0 "C), 6 6.02 (5-H), 2.36and 2.32 ( W e and COMe), 3.58 (OCH,*CH,), 1.23 (OCH,.CH,), and 2.92 (7a-H), J7GL,BtL 11, J7a,8g 4 Hz. The rnethiodidehad m.p.216" (from ethanol) (Found: C, 52.3; H , 7.25;N, 3.7. C,,H,,INO requires C, 52.4; €3, 7.2; N, 3.6%).The endo-ketone (21), b.p. 106-108" a t 0.05 mmHg, simi-larly solidified a t -40 "C and was isolated as a low-meltingcrystalline solid by suction on sintered glass. A puresample, m.p. 34" (from light petroleum) showed 6 5.85 (6-H),2.17 (COMe), 2.35 ( m e ) , 3.58 (OCH,*CH,), 1.23 (OCH,*CH,),and 3.07 (7P-H), J , ~ , ~ f i 9, J7p,8cr 6 Hz. The methiodide hadm.p. 178" (from ethanol) (Found: C, 52.5; H, 7.3; N,3.6%).1,3,4,7,8,8a-Hexahydro-2-rnethyZ-8a-(3-oxobutyl)isoqzaina-lin-6(2H)-one (19).-The picrate, m.p. 190" (0.5 g), of theendo-adduct (8) waq dissolved in acetone and applied toan alumina (type H) column. Elution with ether affordedthe rearrangement product (19) as a viscous liquid (0.1 g),v- (film) 1710 ( G O ) and 1670 cm-1 (conj. GO), Lx234 nm (E 14400), 6 2.13 (COMe), 2.23 (NMe), and 5.68(olefinic proton). The msthiodide had m.p. 154" (fromethanol) (Found: C, 47.6; H, 6.4; N, 3.6. Cl,H,,IN02requires C, 47.8; H, 6.4; N, 3.7%).Acid-catalysed Rearrangement of the Ethoxy-ketones (20)and (21) .-Each ethoxy-ketone (0.5 g) was heated separatelyin 3~-hydrochloric acid (15 ml) on a water-bath for 3 h. Themixture was basified with 30% sodium hydroxide solutionand extracted with ether, and the dried extract was evapor-ated. The rearrangement product derived from each ketone[and from the analogous ketones (7) and (S)] was a solid(ca. 0.35 g), m.p. 90-loo", containing two major compon-ents, as indicated by t.1.c. on alumina (ether as eluant).Fractional crystallisation from ether afforded the twodiastereoisomeric lO-hydroxy-3,lO-dirnetJzyZ-3-azatricycZo-[7.3.1.0196]tridec-6-en-8-ones (22), m.p. 105" (Found: C,71.3; H, 9.1; N, 5.9. C,,H,,NO, requires C, 71.451976 651H, 9.0; N, 5.95%), and (23), m.p. 148" (Found: C, 71.6;H, 8.8; N, 5.7%).The alcohol (22) (0.2 g) was dissolved in ether (1 inl) andquires C, 77.4; H, 8.8; N, 6.45%). The alcohol (23) (0.2g)was not dehydrated to the olefinic enone (24) under theseconditions.applied to an alumina column [lo g of Woelm neutralazatricycZo[7.3. 1.01.6]trideca-6, lO-dien-8-one (24) (ca. 0.1 g),(activity III)]. Elution with ether gave 3,1O-dimejh~/l-3- We thank and Hanburys for"Ie for the 220 MHz spectra.1n.p. 74" (Found: C, 7 7 . 2 ; H, 8.9; N, 6.4. Cl,H,,NO re- [5/1850 Received, 26th September, 1975