40561677 novel analgesics and molecular rearrangements in the morphine thebaine group iv acid...

8/4/2019 40561677 Novel Analgesics and Molecular Rearrangements in the Morphine Thebaine Group IV Acid Catalyzed Rear

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3293Novel Analgesics and Molecular Rearrangements in theMorphine-Thebaine Group. IV.' Acid-CatalyzedRearrangements of Alcohols of the6,14-endo-EthenotetrahydrothebaineeriesK . W . Bentley, D. G. H a r dy , a nd B. MeekContribution from the Research Laboratories, Reckitt and Sons Ltd.,Kingston-upon-Hull, England. Receioed September 26,1966

Abstract: Alcohols of general structure I have been dehydrated to olefins I1 which have been furthe r converted into14-alkenylcodeinones V, themselves transformed by further acid-catalyzed reactions into recyclized products VI1and IX and derivatives of 5,14-thebainone (XV). 14-(3-Methylbut-2-enyl)codeine (XXVII) has been convertedinto a derivative XXIX of (-)-sinornenilan, the struc ture of which has been demo nstrated by spectral studies and byconversion via the bases XXX and XXXIII into th e olefin XXXIV.

he alcohols of the 6,14-etheno- and -ethanotetra-T ydrothebaine and -0r ipavine groups descr ibed inthe preceding tw o p apers in this ser ies2 are al l unstablein acid media, in which they suffer dehydration andrearrangem ent, the speed, extent, and course of whichdepends on the nature of the alcoholic group and the6,14 br idge and on the condit ions of the reaction. Inall cases the first prod uct ap pears to be an olefin. Th eolefins are generally preparab le in goo d yield by heatingthe alcohols in 98-100% formic acid, though in somecases further reaction takes place before completedehydration occurs. In no case was evidence obtainedof the production of more than one olef in, and in thecases examined the olefin is the product of dehydrationin the side chain rather tha n toward C-7.The olefin 11 (R1 R 2 = H ) on ozonolysis affordsformaldehyde and the ketone 111, and the olefin I1( R ' = H , R 2 = Et) yields propionaldehyde, thusconfirming the structures assigned to these bases.The structure I1 (R 1 = R 2 = H) for the olefin der ivedf rom the a lcohol I (R = Me) is further confirmed by itsproduction from the ketone I11 by the Wittig reaction,and by i ts nmr spectrum, which shows a two-protonsignal at 6 4.80 (H2C=C


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3294

$3R \CH3

IV

IMeoH

IX

H +MeOH-HC(OMeI3

MeO

0 P N M e

R CH jV

M e0

iVMeHO !i:H,C/ '

VI11lacks the signals at 7.23 and 2.02 and shows insteadsignals at 1.68 (3 H) and 1.47 (3 H) at t ribu ted to themethyl groups in the system C=CM e2.Catalytic reduction of the 14-alkenylcodeinones pro-ceeds very sluggishly an d affords poo r yields of 14-alkyldihydrocodeinones (X), but isolation of pure mate-rials is difficult since mixtures of isomers appear to beform ed in most cases. Red uction only of the a$-unsaturated ketone system of the base V (R = M e)could n ot be accomplished w ith zinc and acetic acid o rwith sodium amalgam, both of which reagents yieldedmixtures containing phenols resulting from opening ofthe 4,5-oxygen bridge. The dihydro compound XI(R = Ph) was, however, obtained, together with thealcohol XI1 (R = Ph), by the reduction of the unsat-urated ketone with sodium borohydride in pyridine.T h e alkenyldihydrocodeinones XI are not accessible bythe rearrangement of the 6,14-ethano alcohols analogousto those of structure I, since they appear to suffer fur-ther rearrangement in acid media very much morereadily tha n their & ,@-unsaturated counterparts , andth e rearrangem ents only furnish either olefins or phe-nolic bases. Th e C-6 carbo nyl group in the 14-alkenyl-codeinones and their reduction products can be reducedvery readily with sodium bo rohydride t o give the relatedderivatives of codeine, for exam ple, the 14-alkenyl-codeines (XII) . In this reduction there is no evidence

(4 ) We are indebted to Dr. J. W . Lewis and Mr. M. J. Readhead ofthis laboratory for details of this reaction, the further implications ofwhich will be discussed in a subsequent publication.

H*

,'//-H+/1,/,P

MeO

HO ,PR 'CH,

VI

VI1of the production of more than one alcohol, and thereis no reason t o suppose that the reduction occurs lessstereospecifically than does that of codeinone, whichgives only codeine,5 since only one side of the carbonylgroup is readily accessible to hydride ion. Th e corre-

KR MeXI/"\"R MeX

KR Mex I1sponding morphinones and morphines are accessibleby the rearrangement of alcohols of the tetrahydro-oripa vine series.

( 5 ) M. Gates, J . Am. Chem. SOC., 5, 4340(1953).Journal of the American Chemical Society / 89:13 / June 21 , 1967


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3295intensity of absorption at this wavelength is somewhatless than in these three bases. This absorptio n band inflavothebaone has been attributed by Meinwald andWiley'O t o charg e transf er between the quinol nucleusand the enone system as shown in formula XXI, butsuch charge transfer is not possible in bases of generals tructure XV, in which n o oxygen atom is available t osupply electrons. Bentley, Dom inguez, and Ringe,*however, have suggested that this long wavelength ab-sorption band is s imply the absorption band of thea,@-unsaturated ketone system, which normally ap-pears in this region but which in normal circumstancesis very weak (emax -50) intensified (emax -2000) as aresult of the perturbation of the enone system by thespatially proximate 7r orbitals of the unsaturated system,the precise nature of which (quinol, naphthaquinol,styrene, or isolated double bond) appears to be of littleimportance.Bases of general structure XV can arise from the 14-alkenylcodeinones by protonation of the oxide bridge,bridge fission, and Ma rkovn ikov addition of the result-ing carbonium ion t o the s ide-chain double bond, as inXI11 + XV. Non-M arkovnikov addition, clearlyunlikely, would lead to a base of structure XVI, whichis demo nstrably no t that of the produ ct. Alternatively,since the alkenylcodeinone is in equilibrium with therecyclized carbo nium ion VI in acid solution, rearrange-ment may take place by way of such an ion and theolefin XVII, in which conce rted bridge fission and m igra-tion in a pinacolone type rearrangement can occur.The geometry of the molecule of the olefin XVII isparticularly favorable for such a 1,2 shift. In view ofthe formation of the olefin I1 from the carbonium ionIV, the ion XIV might be expected to give the olefinXVIII instead of the actual product XV.Other bases analogous to the base XV (R = R 1 =Me), bearing substituents other than a methyl groupon the nitrogen atom, are preparable in abo ut 40-50%yield by the rearrangement of the correspondinganalogs of the alcohol I (R = Me), and the related3-hydroxy compounds may be obtained either by thedemeth ylation of the 3-methoxy bases with 48 '% hydro-bromic acid or by the combined rearrangem ent anddemethylation of the appropriate alcohol with thisreagent.Zinc and acetic acid reduction of the unsaturatedketone XV (R = R 1 = Me) affords the saturated ke-tone," which is the sole end produ ct of the rearrange-ment of the 6,lbethano analog of the alcohol I (R =Me). In this reaction, the 14-alkenyldihydrocodeinone(X, R = Me) has not been detected an an intermediatein the reaction and it may be concluded that this baseis rearranged more rapidly than the correspondingcodeinone.During the rearrangement of the alcohol I (R = M e)and the codeinone V (R = Me), a second process com-petes with the formation of the phenol XV ( R = R' =Me) giving rise to an isomer of the latter. This process,

(IO) J. MeinwaldandG.A. Wiley,J. Am. Chem. Soc., 79, 2569 (1957).(1 1) 14-Hydroxycodeinone undergoes bimolecular cou pling duringreduction with zinc and acetic acid [L. . Sargent and U. Weiss, J .Org . Chem. , 25 , 987 (1960)], but the enone system present in the basesof general structure XV is so shielded by the other parts of the moleculethat bimo lecular coupling is very seriously hinder ed. In the 14-alkenyl-codeinones of structure V the enone system is much less hindered, andbimolecular coupling may be assumed to be involved in part in the form a-tion of the very complex product of reduction of these bases with zincand acetic acid.

The 14-alkenylcodeinones and morphinone s are, how-ever, only intermediates in the complex rearrangementsthat the alcohols of s tructure I and their phenolicanalogs undergo in acid media. When the alcohol 1( R = Me) is warmed a t 45" with 6 N hydrochloric acidfor 6-7 hr or kept in the same medium a t 25 O for 3 days,it is converted in good yield into th e 6-hydroxy analogVI1 (R = Me), the infrared spectrum of which is verysimilar to that of the parent alcohol I (R = Me) andshows no carbonyl absorption. The nmr spectrumshows no band attr ibutable to the C -6 methoxyl group,but does show two bands at 6 4.71 and 4.48 that dis-appe ar after shaking the base with deuterium oxide andthat must, therefore, be due to two hydroxyl groups,the rest of the spectrum being virtually identical withtha t of the parent alco hol. Since the ketones I11 (alsoC H 3 = Ph) are unaffected under the conditions underwhich the alcohol I (R = Me) is demethylated, thisdemethylation may be assumed to proceed throu gh thealkenylcodeinone V ( R = Me), by recyclization to thecarbonium ion VI (R = Me), which can then eitherlose a pro ton to give the 6-hydroxyolefin VIII , or reactwith a water molecule to give the alcohol VI1 (R = Me).This process has, indeed, been accomplished separatelystarting with the codeinone V (R = Me), which onstanding in cold 6 N hydrochloric acid afl'ords the al-cohol VI1 (R = Me) in good yield. The olefin VI11has not yet been isolated. Fur ther support for thismechanism is forthcoming from the action of methylorthoformate, methanol, and perchloric acid on thecodeinone V (R = Me) which leads, presumably uiathe carbonium ion, to the carbinol methyl ether IX(R = Me) (40%) and the olefin I1 (R1 = R 2 = H)(4%).6 The alcohol VI1 (R = Me) can be convertedback in to the alkenylcodeinone V (R = Me) by heatingwith 100% formic acid.If the alkenylcodeinone V (R = Me), the alcoholsI (R = Me) and VI1 (R = Me), or the olefin I1 (R1 =R 2 = H) is heated with 6 N hydrochloric acid at 100"for a short period, further rearrangement occurs, andthe major prod uct is a phenolic base isomeric with thecodeinone V (R = Me) and, l ike the latter , an a,P-un-saturated ketone. Th e phenolic hydroxyl must appearas the result of fission of the 4,5-oxide bridge, in whichcase a new bond must be formed to C-5, and the baseis clearly an analog of flavonepenthone (XV, R = H,R ' = Ph)317 an d ma y be assigned the structu re XV(R = R 1 = Me). This is supported by the nm r spec-trum of the base which shows signals (in 6 units) at6.58 ( two aromatic H), doub lets centered at 6.77 (C-8 H)and 5.67 (C-7 H ) = 10 cps), single ts at 4.42 (C -5 H),3.77 (arom atic OCH,), 2.36 (N C H J and 1.86 and 1.70(=CMe2), and by the ozonolysis of the base, which af-fords acetone.The ultraviolet spectrum of the base XV (R = R 1 =M e) further supports the assigned s tructure, showing asit does the long wavelength absorption band A 3350A , which is a characteristic feature of the spectra offlavothebaone (XIX),s benzflavothebaone (X X),B andflavonepenthone (XV, R = H , R ' = Ph),a though the

(6) We are indebted to Dr. J. J. Brown of Lederle Laboratories, PearlRiver, N. Y . , or details of this reaction.(7 ) K . W . Bentley and J. C. Ball, J . O r g . C h e m . ,23 , 1725 (1958).(8 ) K . W. Bentley, J. Dominguez, and J. P. Ringe, ibid., 22 , 418(1957).(9 ) K . W. Bentley, J. C. Ball, and H. M. E. Cardwell, ibid. , 23 , 941(1958).Bentley, et al. Acid -Cata lyzed Rearrangements of Alcohols


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3296

XIII .,H+n

X VI

RkR-H+

x V xvxXIX xx XX I

which is discussed in the following pape r,I2 becomes th edominant one in the rearrangement of alcohols I inwhich R is not a methyl group, with the result that basesof structure XV then become m inor produc ts of thereaction. Fo r example, the rearrangem ent of the al-cohol 1 ( R = Ph) affords only 1 . 6 x of the phenol XV( R = M e, R1 = Ph). This competing reaction, how-ever, involves the 14-alkenylcodeinone (V) as an es-sential intermediate and is not operative in the rear-rangem ent of the 6,14-ethano alcohols. Rear range -ment of the alcohols XXII ( R = n-Pr) , XXII (R =n-Bu), XXII ( R = n-Am), however, affords mixturesin each case of two isomeric phenols. Th e produ ctsf rom the a lcohol XXII ( R = n-Bu) have identical infra-red spectra, and these are presumably cis-trans isomersXXIII and XXIV, which could obviously arise fromthe intermediate carbonium ion, whether this be of thetype XIV or VI.The presence of the carbonyl group in the alkenyl-codeinone V ( R = Me) is essential for the rearrange-ment of this base to the phenol XV (R = R1 = M e)by recyclization to the carbonium ion VI a nd concertedoxide bridge opening and rearrangement as in XVII,and may be necessary for activation of the 4,5-oxidebridge if the rearrangement proceeds as shown informulas XI11 + XV. The reaction of the 14-alkenyl-

(12) Part V : I


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3291all of these requirements are met by the mechanismshown in formulas XXVII + XX IX. The resultingstructures for base A XXIX and base B XXX are inagreeme nt with all of the know n facts abo ut these bases.A model of the structure XXIX, which can be con-structed with very little strain, shows that steric hin-drance is least with the CHO group disposed on th esame side of the molecule as the oxide bridge, andit may be noted that the infrared spec trum of the alcoholXXXI derived from base A shows a band attr ibutableto a hydrogen-bonded hydroxyl group and that hy-drogen bonding is easily accommodated in the structureXXXI but is impossible in the epimeric structureXXXII .

of sodium etho xide to give a deep yellow solution, whichcouples readily with diazotized sulfanilic acid to give ablood red solution. Base A is recovered from theyellow ethoxide solution on the addition of water , butthe addition of an excess of ammonium chloride solu-tion results in the precipitation of a new base B,which is isomeric with base A and shows phenolichydroxyl absorption and carbonyl absorption at 1690cm- i n the infrared. Base B is readily soluble inethanol, and the solution rapidly deposits base Aon the addition of a small amount of aqueous sodiumhydroxide. Th e reduction of base A with sodiumborohydride in neutral solution affords a nonphenolicalcohol, whereas reduction in the presence of sodiumethoxide yields a phenolic alcohol, and both of theseproducts are s table to alkalis.Base A reacts relatively slowly with bromine and,hence, cannot contain an olefinic center, and this isconfirmed by the failure of ozonolysis to yield eitheracetone or formaldehyde. The nmr spectra of basesA and B show that both of these bases are alde-hydes. Both spectra show signals attribu table to theC-1 C-2 aromatic protons and protons of the OCH3,NC N3, and two C C H 3 g roups. The two C C H 3 peaksappear at 6 1.0 and 0.77 in the spectrum of base A and at 6 1.16 and 1.03 in the spectrum of base B,indicating that neither base contains the system =CM e2,and that some change in the distant environment of thetwo methyl groups occurs in the conversion of baseA into base B. The aldehyde proton s ignal in thespectrum of base A is a doublet at 6 9.35, J = 2 cps,suggesting that the system >C H CH O is present in thisbase, whereas the corresponding signal in the spectrumof base B is a singlet at 6 9.76, which is consistentwith the presence in this base of the system C=CCHO.This interpretation is consistent with the shift of car-bonyl absorption frequency from 1730 to 1690 cm-in the conversion of base A into base B. Thereversible conversion of the system CCHCHO intoC= CC HO with the s imultaneous appearance of aphenolic hydroxyl group suggests that base A and baseB are related as shown in part s tructures XXV andXXVI, and in agreement with this the C-5 proton ofXXV is revealed in the nmr spectrum of base A by adoublet centered a t 6 5.15, J5,6 9 cps, which is absentfrom the spectrum of base B. The spectrum of base B,however, shows a one-proton signal at 6 7.68, which isabsent from the spectrum of base A and is attributableto the C-5 proton in XXVI.

Me0

H0.pH CHO ckoXXV XXVI

The spectrum of base A shows no s ignal attr ibutableto an olefinic proton and, hence, both of the doublebonds in the base XI1 (R = Me) must be involved in acyclization process, in which case the side-chain methylgroups would appear as a gem-dimethyl group in th eproduct. Th e appearance of an aldehyde group inbase A indicates the contraction of ring C of XI1 and

XXVII

P&YMe0 ,H-0 M eMe

XXVIII

xx X

XXXII XXXIM e0

@NMeHOkeMe

XXXTh e primary alcohol XXXIII, obtained by the reduc-tion of base A in sodium ethoxide solution, might beexpected to suffer dehydration in acids by the mecha-nism show n, with 4,5-oxide ring closure, to give the ole-fin XXXIV, by analogy with the way in which bothisomers of the dienol XXX V are cyclized to thebaine. 3 - I 6

(13) D. H. R. Barton, G. W. Kirby, W. Steglich, G. M. Thomas,A.R. Battersby, T. . Dobson, and H. Ramuz, J . Chenr. SOC. , 423 (1965).(14) A . Matthiessen and C. R . A. Wright, Proc. Roy. SOC., London),18, 83 (1869); A. Matthiessen and C. R . A. Wright, Ann. Suppl . , 7, 36 4(1870); L. Knorr and H. Horlein, E e r . , 40 , 4883 (1907).(15) L. Know and H . Horlein, ibid., 41 , 969 (1908).(1 6 ) The numbering of the ring system is given in structure X V. The5,14-ethano bridge is on the same side of the molecule as are the hydro-gen atoms at C-5 and C-14 in the bainone, as is implied by the nomen-clature used.Bentley, et a[ . Acid-Catalyzed Rearrangements of Alcohols


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3298The alcohol is recovered unchanged from hot dilutehydrochloric acid but on heating with concentratedhydrochloric acid is converted into a crystalline basethat shows n o hydroxyl absorption in the infraredbut does show nmr signals ( in 6 units) at 6.67 (twoaromatic H), 3.92 (C-3 OCH,) , 2.46 (NCH,) , 1.07(6 H , 2C H3), a complex one-proton signal at 5.60(C-5 H, split by the methylene protons) , and a two -pro-ton doublet at 4.95 showing fur ther spli tt ing, du e to thesystem CHC(=C H2)CH . There is l i tt le do ubt thatthis base has the structure XXXIV .

HtXXXIII XXXIV

xxxvThe alkenylcodeine XXX VI, which is an an alog of thebase XXVII, on heating with concentrated hydrochlor icacid gave a mixture f rom which abo ut 10 % of a crystal-line solid was easily isolated. This base was isom ericwith the codeine XXXVI, but the infrared spectrumshowed n o carbonyl group absorption. I t did notreact readily with bromine, and the nmr spectrumshowed no signal at tr ibutable to an olef inic proton.

This spectrum showed signals (in 6 units) at about 7.2(phenyl group protons) , 6.72 (C-1 and C-2 H), 4.70(doublet , C-5 H, J5,6 9 cps) , 3.92 (C-3 O CH,) , 3.05(2 H), 2.40 (NC H3 ), and 1.39 (PhCC H,) . I t is c learfrom this spectrum that both of the double bonds pres-en t in the codeine XXXVI have disappeared with theconversion of the system CH =C M eP h into C-(C-)-CMePh during the production of this new base, and arational interpretat ion of this is that the reaction pro-ceeds through the cyclized carbonium ion XXXVII,which is an analog of the ion XX VIII .This carbonium ion could be converted into a neutralproduc t in several ways, e .g . , by the loss of a protonfrom C-6 or C-8, by reaction with a water molecule togive a glycol, by ring contraction to give an aldehydesimilar to the aldehyde XXIX , or by the loss of a proto nfrom the hydroxyl group with the formation of anepoxide r ing XXXVIII . Since the infrared spectrumof the base shows neither carbonyl nor hydroxyl groupabsorption, and the nmr spectrum shows no signalattributable to olefinic or hydroxyl protons, only thestructure XXXVIII seems tenable for this compound.The complex two-proton s igna l a t abou t 6 3.05 in thenmr spectrum of the base may be at tr ibuted to the pro -tons at C -6 and C -7.The base is recovered unchanged after treatment withli thium aluminum hydride or acetic anhydride, and is

XXXVI XXXVII

XXXVIIIattacked only very slowly by potassium periodate in2 N sulfuric acid. The exam ination of models of thestructure XXXVIII and i ts C-5 diastereoisomer showsthat in both structures at tack from above the moleculeat C-7 by a hydride ion (which gives an axial C-6 hy-droxyl group in the product) is very severely hinderedby the methyl or phenyl group at C-5 . Also, al thoughthe oxygen atom of the epoxide r ing may be at tackedby a solvated proton , completion of the reaction with theformation of a trans-diaxial 6,7-glycol is very severelyhindered by the C-5 substituent. Th e stability of thebase to the reagents ci ted above is thus explicable onthe basis of the structure XXXV III .It may be assumed that the acid-catalyzed rearrange-ments of the codeines XXV II and X XXVI are complexprocesses leading to a variety of products, the aldehydeXXIX and the epoxide XXXVIII simply being themost easily crystallized reaction products in the twocases.Th e dehydration of the alcohols I to th e olefins I1 an drearrangement to the 14-alkenylcodeinones (V) resultsin a substantial decrease in analgesic potency, butfur ther transformation into the analogs of flavone-penthone results in the production of bases of highpotency. Fo r example, the base XV ( R = R = M e)is about twice as potent and i ts methyl ether is abo ut 15t imes as potent as morphine.Experimental Section

6,14-endo-Etheno-7cr-isopropenyltetrahydrothebaine11, R = R 2 = H) (Anhydro-19-methylthevinol). a. 6,14-endo-Etheno-7~~-(l-hydroxy-l-methylethyl)tetrahydrothebaineI, R = M e, 19-methylthevinol) (10 g) was boiled un der reflux with 98-100z formicacid (2 5 ml) for 45 min. Th e mixture was diluted with ice-water(100 ml) and basif ied with amm onia, and the product was isolatedby ether extraction. Th e dried extract was evaporated, and theresidue was dissolved in benzene (250 ml) and passed dow n a colum nof grade 1 neutral alumin a (75 9). A yellow band rapidly developedon the c olumn, which was eluted with benzene until this band justreached the foot of the column. Th e eluate was concentrated andrechromatographed on alumina with elution again only of materialrunning in f ron t of the (narrow ) yellow band. Evaporation of theeluate in uacuo gave a crystalline residue (3.8 g) w hich was recrystal-l ized from methanol when the olefin was obtained as white i f-regular plates, mp 151 .Anal . Calcd for CIAHeQNOs:. 76.0: H. 7.7. F o u n d : C,. .. . , .75.7; H, 7.5.The hydrochloride, prepared in ethanol-ether had m p 198-200.Elution of the yellow band on the alumina column with benzenecontaining 5% of chloroform gave 3.8 g of 14-(3-methylbut-2-eny1)codeinone (V , R = Me ) (see below).

Journal of the American Chemical Society 1 89:I3 1 June 21, I967


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3299lizable viscous gum characterized as the picrate, which was obtainedas yellow needles, mp 194", fro m 2-ethoxyethanol.Anal . Calcd for CZ4H 33NO3.CBH3N307: , 58 .9 ; H , 5 .9 ;N,9 .2 . Foun d: C, 58 .9 ; H, 5 .9 ; N,9 .4 .6,14-endo-Etheno-7cu-(l-methylprop-l-enyl)-te~~ydrothebaine(Anhydro-19-ethylthevino1,11, R1 = H , R 2 = Me). a. 6,14-endo-Etheno-7a-(l-(R)-hydroxy-l-methylpropyl)tetrahydrothebaine 19 -ethylthevinol, I, R = Et) (1 g) was heated a t 100" with 98-100%formi c acid (10 ml) for 2 hr. Th e solutio n was diluted with ice-water and basified with ammo nia. The product was isolated byether extraction and crystallized and recrystallized from aqueousmethanol when the olefin (11, R1 = H , R 2 Me) (0.6 g) was ob-tained a s white irregular plates, mp 12C-12I0.Anal . Calcd for C25H31N03:C, 76.4; H, 7.9. Found: C,76.7; H, 8.0.b. 6,14-endo-Etheno-7a-(l-(S)-hydroxy-l-methylpropyl)tetrah~drothebaine (I , R = M e ; M e = Et) (1 g) was dehydrated in thesame way and gave the same olefin, melting point and mixturemelting point with material prepared as in part a, 12G121" .6,14-endo-Etheno-7a-(l-methylbut-l-enyl)tetrahydrothebaineAn -hydro-9-propylthevinol,II, R1 H, 2 = Et). 6,14-endo-Etheno-7a-(l-hydroxy-l-methylbutyl)tetrahydrothebaine (19-propylthe-vinol, I, R = n-Pr) (10 g) was boiled under reflux with 98 -1 0 Zform ic acid (50 ml) for 3 hr. The mix ture was diluted with ice-water and basified with ammonia, and the product was isolated byether extraction. On crystallization an d recrystallization fro maqueous methanol, the olefin I1 (R1 = H , R 2 Et) (6.8 g) was

b. Methyltriphenylphosphonium bromide (3.6 g, 0.01 mole)was added to a solution of butyllithium (0.01 mole) in hexane-etherunder a n atmosphere of nitrogen, and the mixture was st irred atroom tempera ture for 4 hr . 7cu-Acetyl-6,14-endo-ethenotetra-hydrothebaine (111, 3.8 g) in dry ether (100 ml) was added to theresult ing orange solution, and the mixture was then st irred atroom temperature overnight. Solid matter was removed from themixtu re by filtration and washed well with ethe r; the filtrate andwashings were then washed with water, dried, and evaporated.Th e oily residue was crystallized from petroleum ether (bp 40-60"),and the product was shown by thin layer chromatography to con-sist of approximately a 3 : 1 mixture of the olefin I1 (R1 R 2 H )and the ke tone 111. Chromatographic separation of the two wasachieved in ether on a silica column, from which the olefin waseluted first and was obtained on recrystall ization from methanolas white prisms, mp 151 O, alone or mixed with material preparedfrom the alcohol I (R = Me) as in a above. Use of a 5 0 z e x ce ssof the ylide resulted in no improvement in the yield of olefin, andwhen the ylide was generated with sod ium h ydride in dimethylsulfoxide the yield of olefin was reduced, since base-catalyzed re-arrangement of the ketone also took place.

Ozonolysis of Anhydro-19-methylthevinol (11, R1 = R 2 = H).Ozonized oxygen, with an ozone delivery rate of 0.5 mmole ofozone/min, was passed into a solution of anhydro-19-methylthevinol(0.38 g, 1 mmole) in 4 N acetic acid (50 ml) cooled in ice water.After 1 2 min, when 2.1 mmoles of ozone had been absorbed, zincdust was added t o the solution, which was shaken for 5 min, filtered,and neutralized with sodium bicarbonate, and then warmed. Allof the evolved gas was drawn through a solution of 2,4-dinitro-phenylhydrazine in dilute sulfuric acid, in which a precipitate offormaldehyde-2,4-dinitrophenylhydrazone, p and mmp (with anauthentic specimen) 166", was formed.In a second ozonolysis ozone uptake was l imited to 1 mmoleand after the n eutralization with sodium bicarbonate the mixt t irewas extracted with ether. Th e ether extract on evaporation affordeda solid from which on chromatographic separation on si l ica theolefin, mp 151O , and 7a-acetyl-6,14-endo-ethenotetrahydrothebaine,mp 121", were recovered. Th e aqueous phase after the etherextraction on treatment with dimedone gave the formaldehydederivative, mp 186", undepressed on mixing with an authenticspecimen.

6,14-endo-Etheno-7a-(l-phenylvinyl)tetrahydrothebaine (An-hydro-19-phenylthevinol, 11, R 1 = R2 = H, C H I = Ph).6,14-endo-Etheno-7a - (1- (R)-ydroxy -1- phenylethy1)tetrahydrothe-baine (I , R = Ph) (10 g) was dissolved in boil ing 98-10%form ic acid (25 ml), and t he so lution was boiled for 1.5 min andpoured in to ice-water. The solution was basif ied with ammon ia;the product was isolated by ether extraction and was chromato-graphed on grade 1 neutral alumina in benzene solution. Th ecolumn was eluted with benzene, and the eluate was collected untila yellow band reached the foot of the column. Evaporation of th ee lua te in uacuo and recrystall ization of the product f rom m ethanolafforded the olefin (1.8 g) as pale fawn plates, m p 145-146".Anal . C a l c d f o r C 2 D H 3 1 N 0 3 :C, 79.0; H, 7.1. Found: C,79.1; H,7.1.Elution of the yellow band from the alum ina column with ben-zene containin g 5% of ch lorofor m afforded 5.3 g of 14-(3-phenyl-but-2-enyl)codeinone, m p 168-169 a (see below).

6,14-endo-Ethano-7cu-isopropenyltetrahydrothebaine Anh ydr o-dihydro-19-methylthevino1, 11,R 1 RZ = H, ,144hano). 6,14-endo-Etheno-7a-(l-hydroxy-1-methylethyl)tetrahydrothebaine di -hydro-19-methylthevinol, 2.0 g) was boiled under reflux with 98-100% formic acid for 10 min. The mixture was diluted with water,basif ied with ammonia, and extracted with ether. Th e dried etherextract on evaporation gave a viscous residue which was chroma-tographed on alumina in benzene solution with elution with benzenecontaining 5% of ethyl acetate until the presence of a second basein the eluate was just detectable by thin layer chromatography.The eluate was then evaporated, and the residue was crystall izedand recrystallized fro m petro leum eth er (bp 40-60"), when the olefin(0.8 g) was obtained as prisms, m p 127".Anal . Calcd for C Z ~ H ~ , N O ~ . O . ~ H ~ O :, 73.9; H, 8.2. Found:C, 73.7; H, 8.2.

6,14-endo-Ethan0-7a-isopropyltetrahydrothebaine Dihydro-19-methylthevinan). 6,14-endo-Etheno-7~u-isopropylpenyltetrahydro-theba ine (anhydro-19-methylthevinol, 1.0 g) was shaken underhydrogen a t 22" (760 mm) in the presence of 5 % palladiumon charcoal (250 mg) unti l absorption of hydrogen (130 ml, 2moles) ceased (3 hr). Th e solution was filtered from catalyst andevaporated, when the saturated b ase was obtained as an uncrystal-

obtained as white plates, mp 110".Anal . Calcd for CMH IANOI: C. 76 .7 : H , 8 .2 . Foun d: C,... - . . ,76.7 ; H, 8.3.The same olefin was obtained by the de hydration in the same wayof 6,14-e~do-etheno-7a-(l-(S)-hydroxy-l-methylbutyl)tetrahydro-thebaine, which is the G 1 9 epimer of the alcohol I (R = rz-Pr).Ozonolysis of Anhydro-19-propylthevinol (11, R 1 = H , R 2 =Et). Ozonized oxygen, delivering 0.6 mmole of ozoneimin, waspassed into a solution of anhydro-19-propylthevinol 0.41 g, 1mmole) in 4 N acetic acid (50 ml). The reaction was stopped when2 mmoles of ozone h ad been absorbed (8 min), and the reactionmixture was reduced with zinc dust, filtered, and neutralized withsodium bicarbonate. The neutralized solution was divided intotwo pa rts, on e of which was warmed, and th e evolved gas was passedthrough a solution of 2,4-dinitrophenylhydrazine n dilute sulfuricacid, when a 2,4-dinitrophenylhydrazone, mp 146", was obtained.This depressed the melting point of pentan-2-one dinitrophenyl-hydrazone (mp 142") but did not depress the melting point ofpropionaldehyde dinitrophenylhydrazone (mp 146"). The secondportion of the neutralized reaction mixture was treated with dime-done, when the propionaldeh yde derivative was obtained, mp 154"undepressed on mixing with a n authentic specimen (m p 155").

6,14-endo-Etheno-7a-(l-methylbut-l-enyl)tetrahydrothebaineAn-hydro-19-propyldihydrothevino1, 11, R 1 = H , R 2 = Et, 6,14-etheno). a. 6,14-endo-Ethano-7a-(l-(R)-hydroxy-l-methylbutyl)-tetrahydrothebaine (5 g) and 98-100Z formic acid (100 ml) wereboiled together under reflux for 20 min. Th e solutio n was dilutedwith ice-water an d basified with amm onia, and the produ ct was iso-lated by ether extraction and chromatog raphed on neutral aluminain benzene solution. Elution of the column with benzene:ethylacetate, 95: 5, gave the olefin (3 g) as white plates, m p 65-67", frompetroleum eth er (bp 40-60") characterized a s the hydrochloride,mp 218-219".Anal . Calcd for C2sHaaNOa.HCI: C, 70.0; H , 8.1; Cl, 7.95.F o u n d : C , 6 9 . 6 ; H , 8 . 1 ; C l , 8 .3 .b. 6,14-endo-Etheno-7a-(I-methylbut-l-enyl)tetrahydrothebaine(1 g) was hydrogenated a t 20" (760 mm) over 5% pal-

ladium on charcoal (0.25 g) in ethanol. Hydrogen (50 ml, l mole)was absorbed over 90 min. Evaporation of the solution affordedan oil giving a hydrochloride, mp 218-219", identical in meltingpoint , mixture m elting point , and infrared absorption with thatobtained as in part a above.Other Olefins. Th e following olefins were prepa red by the sameprocess as the one described above for the preparation of6,14-endo-etheno-7cu-(l-methylbut-l-enyl)tetrahydrothebaine: ,14-endo-etheno-7a-(l-methylpent-l-enyl)tetrahydrothebaine (anhy-dro-19-butylthevinol, 11, R1 H , R 2 n-Pr, white plates, mp 75",f rom methanol , Anal. Calcd for CZ 7Ha5 NO 3: , 77.0; H,8.4. Foun d: C , 76.9; H,8.4) ; 6,14-endo-etheno-7a-(l-methyl-hex-1-eny1)tetrahydrothebaine (anhydro-19-amylthevinol, 11, R 1

= H , R 2 n-Bu, white plates, mp 180", f rom methanol . Anal .Calcd for ClsH a7N 03.0 .5Ht 0: C, 75 .7; H, 8.6. Found: C,75 6; H, 8.3); 6,14-endo-etheno-7 a-( 1 -dime thylpen t- 1 enyl)-Bentley, et al. Acid-Catalyzed Rearrangements of Alcohols


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3300tetrahydrothebaine (anhydro-19-isoamylthevinol, 11, R1 = H,R 2 = i -Bu, noncrystalline, hydrochloride, white prisms, mp 170",from water. Anal . C a lc d f o r C Z 8 H a 7 N O 3 . H C I . H 2 0 : , 7 1 .5 ;H , 8 .5 . Foun d: C, 71 .4 ; H, 8.4); N-(2-methylallyl)-6,14-endo-etheno-7ar-(l-methylprop-l-enyl)tetrahydronorthebaine N-methyl-allylanhydro-19-ethylnorthevinol,1, R 1 H, R 2 = M e , N M e =NCH ?CM e=CH ,, white plates, mp 110", from me thanol. Anal.Calcd for C, ,H3;NO3: C, 77.6; H , 8.2. Fou nd: C, 77.5; H,8.2) ; N-propargyl-6,14-endo-etheno-7a-(l-methylpent-l-enyl)tetra-hydronorthebaine (N-propargylanhydro-19-butylnorthevinol, 1,R 1 H , R 2 = tz-Pr, N M e = NCH ,C=CH, white plates, mp 108",f rom methanol. Anal . C a l c d f o r C 2 1 H 3 8 N 0 3 . 0 . 5 H 2 0 :C, 76.7;H , 7.9. Found : C, 76.7; H , 7.9); and , 6,14-endo-ethano-7a-(I-methylprop-1-eny1)tetrahydrothebaine (anhydro-19-ethyldihy-drothevinol, 11, R' = H , R 2 = Me, 6,14-CH?CH 2, oncrystall ine,hydrochloride white prisms, mp 222-223", from ethanol. Anal.C a l c d f o r C 2 b H 3 3 N 0 3 . H C I . 0 . 5 H 2 0 :C, 69.5; H , 7.9; C1, 8.2.F o u l i d : C , 6 8 . 2 ; H , 8 . 1 ; Q 8 . 4 ) .N-Cyano-6,14-endo-etheno-7a-(l-methylbut-l-enyl)tetrahydro-northebaine (N-Cyanoanhydro-19-propylnorthevino1, 11, R1 =H , R 2 = Et,NMe = NCN). T h e olefin 11 (R1 H, R 2 = E t)(5 g) , cyanogen bromide (2 g) , and m ethylene chl oride (100 ml) wereboiled togeth er under reflux fo r 24 hr. Evap oration of the solventand crystall ization of the residue from methanol afforded the N-cyanonor compound (4 g) as prisms, mp 138".A / ? u / . Calcd for G,H30N203: C, 74.7; H, 7.2 . Found: C,75.0; H , 7.2.6,14-etido-Etheno-7a-(l-methylbut-l-enyl)tetrahydrooripavine.6,14-etido-Etheno-7a - (1- (R)-ydroxy -1- methy1butyl)tetrahydroori-pavine (19-propylorvinol, I, R = m P r , 3 0 M e = 3 0 H ) (2 g)was heated at 100" with 98-100 x formic acid (20 ml) for2 hr. The m ixture was diluted with ice-water a nd basifiedwith amm onia and the product collected. I t was n ot immediatelysoluble in dilute aqueous sodium hydroxide, and the infrared spec-trum showed a carbonyl absorption band at 1730 cm-'. I t wasevidently the 3-0-form yl ester of the phenol and was hydrolyzedby heating to boiling for 2 min with potassium hydroxide (0.25 g)in ethanol (10 mi). The solution was diluted with water, and thephenol was precipitated with aqueous ammonium chloride andisolated by ether extraction. Th e resulting viscous gum was dis-solved in ethanol ( 5 mi ) made acid with ethanolic hydrogen chlorideand diluted with ether when the hydrochlo ride crystallized. Thiswas collected and recrystallized from ethanol-ether and was ob-tained as prisms: mp 122".A M I / . C a lc d f o r C 2 3 H 3 1 N 0 3 . H C 1 , 0 . 5 H 2 0 : , 6 8 .5 ; H , 7 .6 .F o u n d : C , 6 8 . 2 ; H , 7 .7 .

14-(3-MethyIbut-2-enyl)codeinone (V , R = Me). a. 6,14-e~ido-Etheno-7~~-(1-hydroxy-l-methylethyl)tetrahydrothebaine19 -methylthevinol, I, R = M e) (10 g) was boiled under reflux for 3 hrwith 98-100% form ic acid (30 ml). Th e solutio n was diluted withice-water a nd basified with am mo nia. Th e prod uct was collected,washed well with water, air dried. and recrystallized fro m me thano l,when the codeinone (6.5 g) was obtained as pale cream prisms,mp 139-140", vmn l 1690cm-l.A / i a / . Calcd for Cc3H2:N03: C, 75.6; H, 7.5. F oun d: C ,75.4; H , 7.4.Th e hydrochloride formed prisms, mp 286-288". The base wasinsoluble in aqueous sodium hydroxide, and in methanolic sodiumhydroxide solut ion gave no color with diazotized sulfanilic acid.b. 6,14-~~ido-Etlieno-7ar-isopropenyltetrahydrothebaine11, R1= R 2 = H ) ( 1 g) was boiled with 98-1COx form ic acid (15 ml) for3 hr. Isolation of the p roduc t as in part a gave 0.75 g of the samecodeinone, mp 139-140".N-Propargyl-14-(3-rnethylbut-2-enyl)norcodeinoneV, R = M e,N M e = NCH2C=CH). Prepared as above f rom N-propar-gpl-6,14-rndo-etheno 7a - 1- hydroxy- 1- methylethy1)tetrahydronor-thebaine (N-propargyl-l9-methylnorthevinol,, R = M e , N M e =NC H2C =CH ) this base was obtained as prisms, mp 126", frommethanol.Ajial. Calcd for C,;Hz;NOa: C, 77.2; H , 7.2. Fou nd: C,77.2; H, 7.0.N-(3,3-Dimethylallyl)-14-(3-methylbut-2~nyl)norcodeinone V ,R = M e, N M e = NCH2CH=CM e2) . Prepared as above f romN-(3,3-dimethylallyl)-19-methylnorthevinolI, R = M e , N M e =NCHpCH=CMe2) this base was obtained as prisms, mp 123",f rom m ethanol.A m / . Calcd for C2i H33 N03 : C, 77 .4 ; H, 7 .9 . Fou nd: C,77.5: H, 7.8.Ozonolysis of 14-(3-Methylbut-2-enyl)codeinone (V , R = Me).Ozonized oxygen, delivering 0.5 mmole of ozon e/min was passed

into a solution of 14-(3-methylbut-2-enyl)codeinone 0.365, 1mmole) in 4 Na ceti c acid (50 ml). The reaction was stopped when2 mmoles of ozone had been absorbed, and the mixture was reducedwith zinc dust , f i l tered, neutralized with sodium bicarbonate, an dwarmed. The evolved gas was passed through a solution of 2,4-dinitrophenylhydrazine in dilute sulfuric acid, when acetone 2,4-dinitrophenylhydrazone (0.182 g, 0.765 mmole) was obtained, m p125" undepressed on mixing with an authentic specimen.14-(3-Methylbut-2-enyl)codeine (XII, R = Me). Sodium boro-hydride (0.5 g), 14-(3-methylbut-2-enyl)codeinone V, R = M e)(10 g) , and 2-ethoxyethanol (30 ml ) were boiled together underreflux for 15 min. Water was added to th e ho t solution until sep-aration of crystalline material began. A small amoun t of a st ickysolid separated initially but dissolved as more water was added.The mixture was cooled in ice-water; the solid was collected andrecrystallized fro m aqueo us 2-ethoxyethanol, when the codeine (8.9g) was obtained a s white plates, mp 168-169".Anal . Calcd for CZ3H29NO3:C, 75.3; H, 8.0 . Found: C,75.5; H, 8.0.7,8-Dihydro-14-(3-methylbutyl)codeinone X , R = Me). 1443-Methylbut-2-eny1)codeinone(V , R = Me) (1.9 g) was shaken underhydrogen at 22" (750 mm) in ethanol (100 ml) over 5% palladiumon charcoal (250 mg). Hydrogen (250 ml, 2 moles) was absorbedover 75 min. Filtrat ion and evap oration of the solution affordedthe d ihydrocodeinone as a viscous gum th at crystall ized on keepingfor several weeks. Tritu ratio n of the partly crystallized mass withice-cold metha nol afforded prisms, m p 125-126", vmal 1715 cm-l.A m l . C a l c d f o r C 2 3 H 3 1 N 0 3 :C, 74.8; H: 8.4 . Found: C,74.6; H , 8.2.

14-(3-Phenylbut-2-enyl)codeinone (V, R = Ph). 6,14-endo-Etheno-7a-(l-(R)-hydroxy-l-phenylethyl)tetrahydrothebaine I, R= Ph) (10 g) was heated under reflux with 98-100Z form icacid (50 ml) for 30 min. Th e solution was diluted andbasified with amm onia. Th e precipitated base was crystallizedfrom a queous 2-ethoxyethanol, when the codeinone was ob tainedas white prisms, mp 156-157", vmar 1690 cm-', A 240 and 295m p , e m n x 20,000 and 4000.Anal. Calcd for C28 H2D N03 : , 78 .6 ; H, 6.8. Found: C,78.6; H , 6.7.The picrate formed yellow prisms, mp 160-161 ', from 2-ethoxy-ethanol.Anal. C a l c d f o r C 2 8 H 2 D N 0 3 . C b H 3 N 3 0 , :, 62 .4 ; H , 4 .8 ; N,8 .5 . Fou nd: C, 63 .0 ; H, 5.0; N , 8 .2.The oxime formed white prisms, mp 182", from 2-ethoxyethanol.A m / . Calcd for C29H30N203:C, 76.1; H, 6.8. Found : C,76.4; H , 7.0.The same base was obtained by heating the alcohol I (R = P h )

at 100" with 2 N hydrochloric acid for 5 rnin and also by heating theolefin I1 (R = R 2 = H , C H I = Ph) with formic acid for 30 min.14-(3-Phenylbut-2-enyl)codeine (XII, R = Ph). Sodium boro-hydride (0.5 g), 14-(3-phenylbut-2-enyl)codeinone V , R = P h)(10 g), and 2-ethoxyethanol (50 mi) were boiled together underreflux for 30 min. Wa ter was added to the hot solutio n until theinitially sticky precipitate dissolved and until separation of crystal-line mater ial began. Th e mixt ure was then cooled in ice-water,and the product was collected and recrystall ized from aqueous2-ethoxyethanol, when the codeine (8.5 g) was obtained as off-white plates, m p 172'.Anal . Calcd for C28H31N03: C, 78 .3 ; H, 7 .2 . Foun d: C,78.2; H , 7.3.7,8-Dihydro-14-(3-phenylbut-2-enyl)codeinone XI, R = Ph).14-(3-Phenylbut-2-enyl)codeinone 9.5 g) was added to a solutionof sodium borohydride (4 g) in anhydrous pyridine (150 ml), andthe mixture was kept at the room temperature for 4 hr . It wa sthen pou red slowly with vigorous st irr ing into water (1200 ml)and the precipitated base was collected, washed well with water,and dried. The dried solid (8.5 g) in benzene was chromatograp hedon alumina, and elution of the column with benzene gave start ingmaterial (0.2 g) whereas elution with 2z ethyl acetate in benzenegave the dihydro ketone XI (R = Ph) (1.1 g) which was obtainedf rom methanol as white elongated plates, mp 160-162", vmax 1720cm-l.Anal. Calcd for C28H31N03:C, 78 .3 ; H , 7 .2 . Foun d: C,78.4; H , 7.1.Elution of the column with 50% ethyl acetate in benzene afforded14-(3-phenylbut-2-enyl)codeine XII, R = Ph) (1.2 g), mp 168-170' undepressed on mixing with an authentic specimen.14-(3-Phenylpent-2-enyl)codeinone (V , = C ( - M e F P h = =c(-Et)-Ph). 6,14-endo-Etheno-7a-(l-(S)-hydroxy-l-phenylpropyl)-tetrahydrothebaine (1 g) was heated at 100" with 98-100% formicJournul of the American Chemical Society 89:13 1 June 21 , 1967


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3301(27 g) was collected. This was dissolved in aqueous methanol,and the base was precipitated with ammo nia. It was recrystallizedreadily only f rom m ethanol, fro m which it separated as off-whitesolvated prisms, mp 138", vmax 1690 cm-I.Anal. Calcd for C23H2iN0 3.0.5CH30H: C, 73.0; H, 7 .6 .Fou nd: C, 72.8; H, 7 .8 .The hydrochloride was obtained as white prisms, m p 320", fromwater.Anal. C alcd fo r C Z 3 H 2 , N 0 3 . H C I :C, 68.7; H , 7 .0 . Found :C, 68.4; H , 7 .2 .The picrate was obtained as yellow needles, mp 224", fromaqueous 2-ethoxyethanol.

Anal. Calcd for C23H2,N03~C6H3N30i.1.5Hy0:, 56.0; H,5.2. Fou nd: C, 55.8; H, 5 .2 .b. The same base was obtained from 6,14-endo-etheno-7a-(1-hydroxy-1methylethyl)dihydrocodeine (VII, R = Me), f rom6,14-endo-etheno-7a-isopropenyltetrahydrothebaine11, R = R 2= H), and f rom 14-(3-methylbut-2-enyl)codeinoneV, R = M e)by the sam e process as in a above, the yields being com parable withthat in a in all cases.The base was almost insoluble in aqueous alkalis but dissolvedreadily in aqueous methanolic potassium hydroxide to give anorange solution that readily coupled with diazotized sulfanilic acidto give a blood red solution. The alkaline solution was readilymethylated a nd ethylated with methyl and e thyl sulfate, respec-tively.The 4-0-methyl ether was prepared most conveniently from thehydrochloride obtained directly from the acid-catalyzed rearrange-ment of the alcoho l (I, R = Me). Th e hydrochloride (20 g) wassuspended in methyl sulfate (50 ml), and the mixture was cooled inice. A solution of potassium hydroxide (40 g) in water (80 ml )was slowly added to the vigorously stirred suspension at a ratesufficient to keep the temperature of the mixture between 15 and20". When all of the alkali had been added, the mixture was stirredat 20" for 2 hr. Water (150 ml) was added, and the solid base wascollected, washed, and recrystallized from methanol, when it wasobtain ed as off-white prisms, mp 176-177",vmaX 1690 cm-'.Anal. Calcd for C24H2gN03: C, 76.0; H, 7 .7 . Found : C ,76.0; H , 7.8 .The 4-0-ethyl ether was obtained from aqueous methanol aswhite prisms, mp 126-127", vmax 1690 cm-'.Anal. Calcd fo r C2 jH 31N0 3: C , 76 .4 ; H, 8.0. F o u n d : C ,76.4; H , 7.9.Ozonolysis of 5,14-Ethano-18-isopropylidenethebainone (XV,R = Rl = Me). Ozonized oxygen, delivering 0.5 mmole of oz one/min was passed into a solution of 5,14-ethano-18-isopropylidene-thebainone (0.365 g, 1 mmole) in 4 N cetic acid (50 ml). After26 min, when 2 mmoles of ozone had been absorbed, the mixturewas reduced with zinc dust, filtered, neutralized with sodium bi-carbonate, and warmed, The evolved gas was passed through asolution of 2,4-dinitrophenylhydrazine n dilu te sulfuric acid, whenacetone 2,4-dinitrophenylhydrazone (0.192 g, 0.807 mmole) wasobtained, my 125" alone or mixed with a n authe ntic specimen.7,8-Dihydro-5,14-ethano-l8-isopropylidenethebainone(XXIII,R = Me). a. 6,14-endo-Ethano-7a-(l-hydroxy-l-methylethyl)-tetrahydrothebaine (dihydro-19-methylthevinol, XII , R = M e)(2 g) was heated with 10N hydrochloric acid (20 ml) for 2 hr at 100".The mixture was diluted with water, and the base was precipitatedwith ammonia, collected, and recrystallized from methanol, whenit was obtained as white prisms, m p 142", v m n l 1715 cm-l.Anal . Calcd fo r CZ3 Hz8N O3: , 75 .2 ; H , 7 .9 . Fou nd :C, 75.2; H, 7 .8 .The hy drochloride formed prisms, m p 245", fro m water.Anal . Calcd fo r C Z H ~ ~ N O ~ . H C I . ~ . ~ H ~ O :, 64.1; H , 7 .7 .F o u n d :b. Zinc dust (2 g) was added to a vigorously stirred boilingsolution of 5,14-ethano-18-isopropylidenethebainone V, R = R 1= Me) in glacial acetic acid (25 ml) and w ater (2 ml). The mixturewas stirred and heated under reflux for 2 hr, filtered, diluted withaqueous ammonium chloride, and basified with ammonia. T h eprecipitated base was collected an d recrystallized from meth anol,when it was obtained as prisms identical in melting point, mixturemelting point, a nd infrared absorption with m aterial prepared as inpart a above.The 4-0-m ethyl ether, prepared by methylationof the phenol andby reduction of th e correspondin g thebainone methyl ether withzinc dust and acetic acid, was obtained as off-white prisms, mp168-169", v m a x 1715 cm-l.Anal . Calcd fo r C24H31N03:C , 75 .6 ; H , 8 .1 . Foun d : C ,75.8; H, 8.0.

C, 64.1 ; H, 7.5.

acid ( 8 ml) for 30 min. The base isolated in the usual way wasrecrystallized fro m aqu eous 2-ethoxyethanol, when it was obtainedas white prisms, mp 176-177', vmax 1690 cm-1.A d . Calcd fo r C20H31N03:C, 78.9; H, 7.0. F o u n d : C ,78 .3 ; H , 7 .2.6,14-e,?do-Etheno-7a-(1-hydroxy -l-methylethyl)dihydrocodeine(VII, R = Me). a. 6,14-endo-Etheno-7a-(l-hydroxy-l-rnethyl-ethy1)tetrahydrothebaine (I, R = Me) (20 g) was heated a t 45" with6 N ydrochloric acid (160 ml) for 6 hr. The mixture was diluted,and the base was precipitated with ammonia, collected, and re-crystallized from ethanol, when the dihydrocodeine derivative(13.3 g) was obtained as white prisms, mp 265".Anal. Calcd fo r C2 ,H 29N 04: C , 72 .0 ; H , 7 .6; N , 3 .7 ; OM e( l ) , 8 .1 . F o u n d : C , 7 2 . 0 ; H, 7.6; N , 3.7; OMe, 8.0.The hydrochloride was obtained as white prisms, mp 262",f rom ethano l .Anal . C alcd fo r C 2 3 H 2 9 N 0 4 . H C I . H 2 0 : , 6 3. 1; H , 7 . 4.F o u n d : C , 62.6; H , 7 .5 .b. 14-(3-Methylbut-2-enyl)codeinoneV, R = M e) (1 g) washeated at 45" with 6 N hydrochloric acid (10 ml) for 6 hr. Thebase recovered as above was obtained as white prisms, mp 262"alone or mixed with m aterial prepared as in a. The bases preparedby both m ethods had identical infrared spectra.6,14-e~zdo-Etheno-7~-(l-methoxy-l-methylethyl)tetrahydrothe-baine (IX, = Me). a. Perchloric acid (1.5 ml, 72%) was addeddropwise to a stirred solution of 14-(3-methylbut-2-enyl)codeinone(V, R = Me) (500 mg) in methylene chlor ide (10 ml), metha nol (10ml), and trimethyl orthoformate (10 ml), and the mixture was keptat roo m temperatu re fo r 20 hr. Methylene chloride was added,and the mixture was washed with aqueou s sodium bicarbonate andwater and dried. Thin layer chromatograph y showed the productto consist of one ma jor and on e minor, less po lar , componen t . Thegum obtained by the removal of solvent was dissolved in n-hexane,and the solution was chromatographed on alumina (20 g, Woelm,activity 11). Fractio ns of 10 ml were collected and examined bythin layer chrom atogr aphy . The colum n was eluted first with 5and then with 10 % chloroform in n-hexane, when the less polarcompone nt was eluted. The material (12 mg, c 2.5 %) was identicalin melting point (143-145") and infrared absorption with 6,14-endo-etheno-7a-isopropenyltetrahydrothebaine11, R1 R 2 = H )obtained by the dehydration of the alcohol (I , R = Me). Con-tinued elution of the column gave a mixture of the two compone ntsfollowed by the more polar component. The column was theneluted with 25 and 50% methylene chloride in n-hexane. Evapora-tion of appropriate fractions gave a gum which was crystallizedfrom aqueous methano l to g ive 6,14-endo-etheno-7a-(l-methoxy-l-methylethy1)tetrahydrothebaine (130 mg), mp 97-99". A further90 mg was obtained from the mother liquors making a total yieldof 39%. The compound showed no carbonyl absorption in th einfrared and had nmr signals (in 6 units) at 6.57 and 6.51 (C-1 Hand C-2 H ; doublets , .I1,'9 cps), 5.72 and 5.37 (C-18 H andC-17 H; doublets = 10 cps), 4.56 (C-5 H ), 3.82 (C-3 OMe),3.58 (C-6 OMe), 3 .18 (C-19 OMe), 2 .36 (NMe), 1 .30 and 0.95(C-19 methyls).Anal . C a lc d f or C 2 i H 3 3 N 0 4 :C, 73 .0 ; H , 8 .1 ; N, 3.4. Fou nd:C, 72 .5 ; H , 7 .9 ; N, 3.5.b. 6,14-endo-Etheno-7a-(l-hydroxy-l-methylethyl)tetrahydro-thebaine (19-methylthevinol, I, R = Me) (1 g) was added toa solution of potassamide (from 0.2 g of potassium) in liquidamm onia (-100 ml), and the mixture was stirred for 15 min.Methyl iodide (1 ml) was then added and the mixture stirred for10 min more and pou red cautiously into water (200 ml). The pre-cipitated product was isolated by ether extraction and shown bythin layer chromatography to consist of approx imately 30% of

starting material (I , R = M e) an d 7 0 z of a less po lar compound .The mixture was dissolved in a 1 : l m i xt ur e of benzene and n-hexane and ch romatographed on a co lumn of alumina (Woelm,activity If). The column was eluted with benzene, and 25-ml sampleswere collected, the composition of these being followed by thinlayer chromatograph y. The first material to be eluted from thecolumn (500 mg) was obtained as a gum, which crystallized onkeeping for several hours. On recrystallization from aqueousmeth anol it was obtained a s white prisms, mp 96-98", identical ininfrared absorption with material prepared as in part a above.5,14-Ethano-18-isopropylidenethebainone (XV, R = R 1

= Me). a. 6,14-endo-Etheno-7a-(l-hydroxy-l-methylethyl)tetra-hydrothebaine (19-methylthevinol, I , R = M e) (50 g ) was heateda t 100" with 10 N hydrochloric acid (150 ml) for 45 min, duringwhich time crystalline material separated. The mixture was di-luted with water (150 ml) and cooled in ice, and the hydrochlorideBentley, et ai. 1 Acid-Catalyzed Rearrangements of Alcohols


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3302N-Allyl-5,14-ethano-18-isopropylidenenorthebainoneXV , R = R1

= M e , N M e = NCH*CH=CH2). N-Allyl-7,14-etzdo-etheno-7a-(1-hydroxy-1-methylethy1)tetrahydronorthebaine (1 g) was heated100" with 10 N hydrochloric acid (10 ml) for 2 hr. Th e mixtur ewasdiluted with w ater; the hydrochloride (0.38 g) was collected andrecrystallized from aqueous methanol, when it was obtained aswhite prisms, mp 186-188", vmax 1690 cm-l.Anal . C alcd fo r C ?5 H 2 D N 0 3 . H C 1 :C, 70 .1 ; H , 7 .0 . Fou nd :C, 70.2; H, 7.2.The base co uld not be crystallized.The following hydroch lorides were preparedfrom the appropr ia teN-substituted 6,14-endo-etheno-7~-(l-hydroxy-l-meth~lethyl)tetra-hydronorthebaines, and hot concentrated hydrochloric acid withisolation of the sparingly solub le salt : N-propargyl-5,14-ethano-18-isopropylidenenorthebainone XV , R = M e, N M e = NCH2C-CH, prisms, mp 155". Anal . C alcd fo r C Z 5 H Z iN O 3 . H C 1 . H 2 0 :C, 67 .6 ; H, 6 .8 . Fou nd : C , 68 .0 ; H, 6.7); N-(3,3-dimethyl-allyl)-5,14-ethano-l8-isopropylidenenorthebainoneXV, R = Me,N M e = NCH2CH=CMez, p r isms, mp 196". Anal . Calcd fo rC 2 iH 3 3 N 0 3 . H C 1 . H 2 0 : C , 6 8 . 3 ; H, 7 .6 . Foun d : C , 68 .3 ; H ,8.0); an d N-cyclopropylmethyl-5,14-ethano-18-isopropylidenenor-thebainone (XV, R = M e , N M e = N-cyclopropylmethyl, whiteprisms, mp 206". Anal . C alcd fo r C g 6 H 3 , N 0 3H C l . H 2 0 : C,67.9; H , 7 .4 . Fou nd: C, 67.8; H, 7.4).3-0-Desmethyl-5,14-ethano-18-isopropylidenethebainoneXV ,R = R 1 = M e , O M e = OH). a. 5,14-Ethano-l8-isopropylidene-thebainone ( 5 g) was boiled under reflux with 48% hydrobromicacid (50 ml) for 1 hr. Solid material that separated was dissolvedby the addition of water (10 ml ) and methano l (50 ml), an d th esolution was then basified with ammonia and the solid collectedand recrystallized from methanol, when it was obtained as prisms(3 g), nip 268".Anal . C alcd fo r C 2 2 H 2 5 N 0 3 :C, 75.2; H, 7 .1 . Found : C ,75 .6 ; H , 7 .0 .The hydrochloride was obtained as prisms, mp 342", fromaqueous methanol.Anal . C alcd fo r C 2 2 H 2 S N 0 3 . H C 1 : , 6 8 .1 ; H , 6 .7 . F o u n d :C, 68 .0 ; H , 6 .8 .

b. The same base (2 g, identical in melting point and infraredabsorption with the above) was obtained by the direct rearrange-ment and demethylation of 6,14-endo-ethano-7cr-(l-hydroxy-l-methy1ethyl)tetrahydrothebaine(5 g) with 48 % hydrobromic acid(45 mi). The hydro bromide was separated and dissolved inaqueous ethano l, and the base was precipitated with am monia .N-Allyl-3-O-desmethyI-5,14-ethano-lS-isopropylideneno~hebai-none (XV, R = R 1 = M e , O M e = O H , N M e = N C H ~ C H = C H Z ) .N-Allyl-6,14-endo-etheno7 - (1- hydroxy -1- methylethyllt etr ahyd ro-nororipavine (N-allyl-19-methylnororvinol) ( 6 g) was heatedunder reflux with 4 N hydrochloric acid (40 ml) for 3 hr. Th esolid hydrochloride was collected, dissolved in aqueous methanol,an d converted t o the base with ammo nia, the base being obtainedfrom metha nol as white prisms, mp 260" dec.Anal . Calcd for CZ4H 2,NO3: C, 76.4; H , 7 .3 . Fou nd : C,76.2; H , 7 .2 .5,14-Ethano-lS-(rnethylbenzylidene)thebainone (XV, R = M e , R 1= Ph, Methylflavonepenthone). 6,14-endo-Etheno-7a-(l-(R)-hy-droxy-1-phenylethy1)tetrahydrothebaine (I, R = Ph) (20 g) washeated with concentrated hydrochloric acid (75 ml) and ethanol(10 ml) at 10 0" for 30 min, during which time a crystalline hydro-chloride separated. The mixture was diluted with water (100 ml )and thoro ughly cooled in ice. The crystalline solid was collected.This consisted of the hydroch lo rides o f 7,8-dihydro-5'-phenylcyclo-hex-4 '-eno[l ' ,2 ' : 8 ,14]codeinone and the cyclohex-5 '-eno isomer(see following pa per), and a solution in aqueous methanolic sodiumhydroxide gave only a pale pink color with diazotized sulfanilicacid.The filtrate from the collection of this hydrochloride, whichgave an intense diazo coupling reaction in alkaline solution, wasbasified with ammonia and the relatively small amount of gummybase produced was extracted rapidly with ether. The extract wasshaken for 15 sec with magnesium su lfate and filtered. Rosettesof needles quickly separated f rom the ether solution and these werecollected, washed well with ether, and recrystallized from aqueous2-ethoxyethan ol, when the thebainone derivative (320 mg) wasobta ined as off-white needles, mp 290", vmax 1690 cm-l.

Anal . C alcd fo r C 2 5 H 2 8 N 0 3 :C, 78 .8 ; H, 6.8. F o u n d : C ,78.7; H , 6.7.The 0 -m ethy l e ther was ob tained as a crystalline precipitate onthe addition of methyl sulfate (0.25ml) t o a solution of the phenol(100 mg) in methano l (3 ml), water (1 ml), and potassium hydroxide

(200 mg), and on recrystallization from aqueous 2-ethoxyethanolwas recovered, as almo st white needles, mp 168-169".Anal . C alcd fo r C 2 0 H 3 1 N 0 3 :C, 79.0; H, 7.1. Found: C ,79 .3 ; H , 7 .0 .The 0-ethyl ether, prepared in an analogous manner using ethylsulfate, was obtained from aqueous ethanol as white needles, mp144".Anal . C alcd fo r C 3 0 H 3 3 N 0 3 :C, 79 .2 ; H , 7 .3 . Found : C ,79.3; H , 7 .4 .6a-Formyl-5'5 '-dimethylcyclopentano[l',2' 8,1414 -))-sinome-nilan (Base A ; XXIX). 14-(3-Methylbut-2-enyl)codeine (XII,R = Me) (5 g) was heated at 100" with concentrated hy drochloricacid (10 ml) for 45 min. The solution turned first pale yellow, thenpink, and finally dark red brown. Th e solution was diluted withwater (40 ml) and basified with amm onia. The sticky precipitatewas washed three times with water by decantation and trituratedwith hot methanol (35 ml), when a white crystalline solid sep arate d.The suspension was cooled, and the solid was collected, washedwith cold methanol, and recrystallized from aqueous 2-ethoxy-ethanol when "base A" (1 .5 g) was obtained as large irregularprisms, mp 200", vmnx 1730 crn-'.Anal . Calcd for C23HZ1NO3: C, 75.3; H, 8.0. Found : C ,75.8; H, 7.9.The base was very sparingly soluble in cold ethanol, but dis-solved readily in the presence of sodium ethoxide to give a deepyellow so lution.The perch lorate formed prisms, mp 241-242", from aqueousethanol.Anal. Calcd fo r C23H20N03.HC1O4: C, 59.15; H , 6.5.Foun d : C , 59 .15 ; H, 6 .4 .6-Formyl-5 '3 -dimethylcyclopentano[l',2 ' ,1414- -dihydro-sinomenil-Sene (Base B ; XXX). Base A (XXIX ) (1 g) was dissolvedin ethanol (10 ml) containing sodium ethoxide (from 0.25 g ofsodium), and the yellow solution was boiled for 1 min and coo led.The so lu t ion was poured in to an excessof 1 N hydrochloric acid,and the base was precipitated with ammonia, collected, washedwith water, and recrystallized from aqueou s methanol, when i t wasobta ined as white felted needles, mp 157-158", vmax 1690 cm-l.A n d . C alcd fo r C 2 3 H 2 8 N 0 3 :C, 75.3; H , 8.0. Found : C ,75.6; H , 7.9.The same base was obtained, less conveniently, when the sodiumethoxide solution of base A was poured in to aqueous ammoniumchloride. The base was readily soluble in aqueous sodium hydride,and the solution gave a deep red color with diazotized sulfanilicacid. Base B (5 0 mg)was dissolved in methanol (1 ml ) a n d on e drop o f 2 N aqueoussodium hydroxide was added. The solution became yellow andon warming rapidly depo sited base A (40 mg), mp 200" alone ormixed with an au thentic specimen.Reduction of Base A with Sodium Borohydride. BaseA (XXIX,500 mg) and sod ium borohydride (5 0 mg) were stirred together incold ethanol (10 ml) until all the base had dissolved and then fora further 15 min. The product was precipitated with water andisolated by ether extraction, when 6-hydroxymethyl-5',5'-dimethyl-cyclopentano[l ' ,2 ' : 8 ,14]-(-)-sinomenilan (XXXI) (500 mg) wasobtained as a viscous oil, characterized as the 3,5-dinitrobenzoate,which was obtained as yellow needles, mp 190".Anal . Calcd for C30H33 N308: C, 64.0; H, 5 .9; N, 7 .5 . Fou nd:C, 64.3; H, 6.0; N, 7.8.Reduction of Base A with Sodium Borohydride and Sodium Eth -oxide. Sodium borohydride (150 mg) was added to a solution ofbase A XXIX ) (1 g) in ethanolic sodium ethoxide solution (20 m l),and the mixture was warmed until the yellow color disappeared.The almost colorless solution was poured into aqueou s ammon iumchloride and the product isolated by ether extraction, when 6-hydroxymethyl-5',5'- dimethylcyclopentano[1',2': 8,141- (-)-dih y-d rosinomenil -Sene (XXXIII) (1 g) was obtained as a viscousoil which could not be crystallized. On distillation a portion wasobtained a s a colorless glass, bp 190-200" (b ath temp) (0.2 mm).Anal. Calcd fo r CZ3H3,N03: C , 74 .8 ; H, 8.1. Found:C, 74 .7 ; H , 8.0.6-Methylene-5 ,5 '-dimethylcyclopentano[l ,Z' 8,14]-(-)-sino-menilan (XXXIV). 6-Hydroxymethyl-5',5'-dimethylcyclopentano-[1',2': 8,14]-(-))-dihydrosinomenil-5-ene XXXIII) (250 mg) wasboiled with concentrated hydrochloric acid ( 5 ml) for 2 min, an dthe mixture was diluted with water and basified with ammonia.The product, isolated by ether extraction, was a viscous oil thatcrystallized in part on trituration with 80% methanol. The crys-tals so obtained dissolved readily in petroleum ether (bp 40-60"),

Conversionof Base B (XXX) into Base A (XXIX).

Journal of the American Chemical Society J 89:13 June 21 , 1967


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3303in ether solution on alumina plates. From th e plates a nonphenolic@unsaturated ketone XI11 (R = Me, R ' = Ph), a nonphenolicsaturated ketone, and a nonphenolic aldehyde were obtained aswell as a phenolic saturated ketone. Chromatographic separationof a further part of th e same viscous gum on silica plates resulted inth e separation of th e material into a nonphenolic fraction an d sixnonphenolic bases which on recovery from th e plate showed almostidentical infrared absorption lacking any band attributable to acarbonyl group. The amounts of material recovered in this waywere too small to permit further study.

The authors wish to thank Dr .D. E. Webster of the University of Hull, England, forthe determination of nmr spectra, Mr. A . C. Youngfor chrom atographic separations, a nd th e following forexperimental assis tance: M r. J. Fulstow, Mr. T. J.Johnson, Mr . G. Mellows, Mr. T. M . Su t ton , and thela t e Mr . S . R . Duff.

Acknowledgments.

in which th e noncrystalline matter was virtually insoluble. Con-centration of th e petroleum solution afforded th e olefin XXXIV(75 m g) as white elongated prisms, mp 107-108".Anal. Calcd for CZ3Hz9NO2: , 78.6; H, 8.3. Found: C,78.2; H, 8.2.Rearrangement of 14-(3-Phenylbut-2-enyl)codeine XXXVI). 14-(3-Phenylbut-2-eny1)codeine XXXVI) (2 g) wa s heated at 100"in th e water bath with concentrated hydrochloric acid (20 ml) for45 min. Th e pink solution was then diluted with 50% aqueousethano l , cooled in ice, and basified under ether with ammonia.The ether extract wa s set aside overnight, and th e crystalline matterthat separated during that t ime was collected, washed with methanol,and recrystallized from 2-ethoxyethanol, when 8,14-dihydro-6,7a-epoxy-5'-methyl-5'- phenylcyclopentano[lf,2'8,141deoxycodeine D(XXXVIII) was obtained as white prisms, mp 234" (0.3 9).Aiial . Calcd fo r C28H31N03:C, 78.3; H, 7.2. Fo u n d : C,78.2; H, 7.2.The ether solution after removal of this base was evaporated toleave a brown viscous g u m , part of which was chromatographed

Novel Analgesics and Molecular Rearrangements in theMorphine-Thebaine Group. V.' Derivatives of7,8-Dihydrocyclohexeno 1',2': 8,141codeinoneK. W. Bentley,2aD. G. Hardy,'" C. F. Howell,2bW. Fulmor,2bJ. E. Lancaster,2cJ. J. Brown,2bG. 0. orton,2ban d R. A. Hardy , JrSzbContribution ro m the Research Laboratories, Reck itt and Sons Ltd.,Kingston-upon-Hull, England, and The Organic Chemical Research Section,Lederle Laboratories, Division of American Cyanamid Co. , Pearl River, New Yor k .Received September 26,1966

Abstract: The acid-catalyzed rearrangem ent of alcohols of the 6,14-endo-ethenotetrahydrothebaine eries ofgeneral structure I has been shown to proceed in most cases via the 14-alkenylcodeinones (11) to 7,s-dihydro-cyclohex-4'-eno- and -cyclohex-5'-eno[l f ,2 f 8,14]codeinones of general structures X and XI. The structures oftypical bases have been elucidated by nmr spectral studies and by chemical means. Analogous derivatives of di-hydromorphinone and a series of nor bases and N-substituted nor bases have also been prepared. The mecha-nisms of the rearrangem ents are discussed.

n the preceding paper i t is shown that the alcoholsI of general s tructure I can be rearranged to 14-alkenylcodeinones (11), which may be further trans-formed by concentrated hydrochloric acid into 5,14-bridged thebainone derivatives 111. The last of thesetransformations, however, competes with an alternativeprocess, which in general represents the major reaction,the thebainone derivative I11 being the m ajor productonly in special cases. Th e alternative rearran gem entof the codeinone I1 affords a nonphenolic nonconju-gated ketone as the s table end product, which is , ofcourse, obtained also by the complete rearrangement ofthe alcohol I under the same conditions, and from theolefin which is an intermediate in the conversion of thealcohol into the codeinone I1 (see preceding paper).As would be expected, s ince carbonium ion inter-mediates are clearly involved in the dehydration andrearrangement of the alcohol I to th e codeinone 11, di -Chem. Soc., 89 , 3293 (1967).Lederle Laboratories, Pearl River, N . Y .tories, American Cyanamid Co., Stamford, Conn.

(1) Part I V : I

40561677 novel analgesics and molecular rearrangements in the morphine thebaine group iv acid...

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