The Application of Metallated Enamines to the Synthesis of Morphine Alkaloids Citation Mitch, Charles Howard (1982) The Application of Metallated Enamines to the Synthesis of Morphine Alkaloids. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/vf0x-tn08. https://resolver.caltech.edu/CaltechTHESIS:05162018-103306929 Abstract Metallated enamines have been used to prepare a number of morphine-based analgesics, including efficient entry to the 4a-phenylisoquinolines and morphinans. Stereocontrolled formation of both cis and trans-fused perhydroisoquinolines has been accomplished by either kinetic or thermodynamic protonation of the corresponding octahydroisoquinoline. Reaction of 4a-phenyloctahydroisoquinolinium perchlorates with diazomethane afforded the expected aziridinium perchlorate with a component of direct cyclization to the morphinan structure also observed. Kornbloom oxidation to the α-amino-aldehyde was accomplished on treatment of the aziridinium salts with dimethyl-sulfoxide. The aldehydes were cyclized to the morphinan structure on reaction with boron trifluoride etherate, providing ready access to intermediates used by Gates in his pioneering total synthesis of morphine. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: (Chemistry) Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Grubbs, Robert H. Thesis Committee: Evans, David A. (chair) Dervan, Peter B. Goddard, William A., III Grubbs, Robert H. Defense Date: 24 May 1982 Record Number: CaltechTHESIS:05162018-103306929 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:05162018-103306929 DOI: 10.7907/vf0x-tn08 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 10897 Collection: CaltechTHESIS Deposited By: Mel Ray Deposited On: 29 Jun 2018 19:58 Last Modified: 28 Apr 2025 23:25 Thesis Files Preview PDF - Final Version See Usage Policy. 73MB Repository Staff Only: item control page

THE APPLICATION OF METALLATED ENAMINES TO THE SYNTHESIS OF MORPHINE ALKALOIDS Thesis by Charles Howard Mitch In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 1982 (Submitted May 24, 1982) ii To My Parents iii ACKNOWLEDGEMENTS I would like to thank Dave Evans for his guidance, support and tolerance throughout the course of this work. His remarkable knowledge of and insight into chemistry provide a unique environment for research. Rich Cherpeck deserves special mention for introducing me to the pl.easures of alkaloid chemistry, as do Scott Biller and John Nelson for being exacting mentors. I would also like to thank everyone else who has contributed in making Caltech a stimulating place to do science~ Finally, special thanks to Gwen Anastasi and Dot Lloyd for invaluable assistance in the preparation of this manuscript. iv ABSTRACT Metallated enamines have been used to prepare a number of morphine-based analgesics, including efficient entry to the 4a-phenylisoquinolines and morphinans. Stereocontrolled formation of both cis and trans-fused perhydroisoquinolines has been accomplished by either kinetic or thermodynamic protonation of the corresponding octahydroisoquinoline& Reaction of 4a-phenyloctahydro- isoquinolinium perchlorates with diazomethane afforded the expected aziridinium perchlorate with a component of direct cyclization to the morphinan structure also observed. Kornbloom oxidation to the a-amino-aldehyde was accomplished on treatment of the aziridinium salts with dimethylsulfoxide. The aldehydes were cyclized to the morphinan structure on reaction with boron trifluoride etherate, e providing ready access to intermediates used by Gates in his pioneering total synthesis of morphine. v TABLE OF CONTENTS PAGE The Application of Metallated Enamines to the Synthesis of Morphine Alkaloids ............ 1 ••••••••o••••••••••••••••••••••••••••• 2 Utility of Metallated Enamines . . . . . . . . . . . . . . . . . . . . 5 Formation and Reactions of Immonium Ions .. ........ 13 Morphinan Synthesis via Aziridinium Salts ......... 18 Synthes is of Morphine Alkaloids . . . . . . . . . . . . . . . . . . . 25 Experimental Section.............................. 34 l-Methyl-4-phenyl-4-(2-propenyl-1,2,3,4tetrahydropyridine C!!~) ..................... 35 l-Methyl-4-phenyl-4-propylpiperidine ..... 36 2-Methyl-5-phenyl-2-azoniabicyclo[3.3.1]non-2-ene perchlorate C!3) ................... 36 2-Methyl-5-phenyl-2-azabicyclo[3.3.l]nonane_ C!~) ................................. 37 2-Methyl-4a-phenyl-2,3,4,4a,5,6hexahydro-2-pyrindine C!~) . . . . . . . . . . . . . . . . . . . 38 cis-2-Methyl-4a-Phenyloctahydroz:pyrindine C!~) ............................ 39 Introduction (~) o trans-2-Methy1-4a-phenyloctahydro2-pyrindine (16) ............................. -v- 39 l-Methyl-4-(4-chlorobutyl)-4-phenyl1 , 2 , 3 , 4 - t e tr ah yd r op yr id in e ( ! ! ~ ) . . . . . . . . . . . . . 41 2-Methyl-4a-phenyl-3,4,S,6,7,8octahydroisoquinoline (~~) . , . . . . . . . . . . . . . . . . . 42 trans-2-Methyl-4a-phenyl~3,4,S,6,7,8,8a­ octahydroisoquinolinium perchlorate(~~) ...•. 43 vi TABLE OF CONTENTS (continued) PAGE cis-2-Methyl-4a-pheny1·3,4,S,6,7,8,8aoctahydroisoquinolinium perchlorate (21) .... ..... 43 trans-2-Methyl-4a-phenyl-decahydro1soquinoline C!~) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 ~ cis-2-Methyl-4a-phenyldecahydro~ TSOquinoline (19) ................... o ••••• 0.. 46 trans-la,2-Dimethyl-4aa-phenylperhydroisoquinoline c3~) 46 0 •••••••••••••••• 0. 0 cis-la,2-bimethyl-4aa-phenylperhydroisoquinoline c3~) · · · · · • • • o • • • • • o • o • • • 47 (4aa,8aa,8bB)-2~Methyl-4a-phenyl~ decahydroaz-irino [1, 2, -a] isoquinolinium perchlorate ( 3~) .. o • • • • • • .. • • • • 48 ... 49 ••. . •••••••••••• 50 • • • • • • • • • • • • • • • (la,4aa,8aa)-1-(chloromethyl)-2~ methyl-4a-phenyldecahydroisoquinoline (14a)-17-Methylmorphinan C~Z) (~~) 4-(2,3-Dimethoxyphenyl)~4-hydroxyc3~) ...................... 51 l-Methyl-4-(2,3-dimethoxyphenyl)l,2,3,6-tetrahydropyridine (30) .............. 52 l-Methyl-4a-(2,3-dimethoxyphenyl)3,4,S,6,7,8-octahydroisoquinoline (~~) ..•.... 52 1-Methyl-4a-(2,3-dimethoxyphenyl)3,4,S,6,7,8,8a-cis-octahydroisoquinolinium perchlorate (~~)............................. 53 (4aa,8aa,8bS)-4a-(2,3-Dimethoxyphenyl)2-methyldecahydroazirino[l,2,-a]isoquinolinium perchlorate (36) .. . .. ... •..... 54 1-methylpiperidine -.... (la,4aa,8aB)-1-Carboxaldehyde- 2-methyl-4a-(2,3~dimethoxyphenyl)- decahydroisoquinoline (37) ,,.,,., ..... ,..... 54 vii TABLE OF CONTENTS (continued) PAGE (108,14a)-3,4-Dimethoxy-10-hydroxy17-methylmorphinan (~~) ....•••••..•..•...... 55 (14a)-3,4-Dimethoxy-17-methylmorphinan (~~) .......•...... e." •• q.......... 56 1,1-bis-hydroxymethylcyclopropane (41) .. .... 57 1,1-bis-bromomethylcyclopropane (42) ...... .. 57 ........... 58 -- ~- ~- 4-Bromo-2-bromomethyl-1-bu~ene -~ (~) trans-4a-(2,3-Dimethoxyphenyl-2-methyl6-methylidene-3,4,4a,5,6, 7 ,8,8aoctahydroisoquinolinium perchlorate (~~~) 59 cis-4a-(2,3-dimethoxyphenyl)-2-methyl6-methylidene-3,4,4a,5,6,7 ,8,8aoctahydroisoquinolinium perchlorate (~~~) 61 (4aa,8aa,8bS)-4a-(Dimethoxyphenyl)-2methyl-6-methylidene-decahydroazirino[1,2,-a]isoquinolinium perchlorate c~z) ..... 61 (la,4aa,8aa)-4a-(Dimethoxyphenyl)-2-methyl6-methylidene-decahydroisoquinoline-lcarboxaldehyde (~~) ......... ................ 62 (10S,14a)-3,4-Dimethoxy-10-hydroxy-6methylidene-17-methylmorphinan (~~) ......... 63 (14a)-3,4-Dimethoxy-17-methyl-6methylidene-morphinan (~~) .................. 64 (14a)-3,4-Dimethoxy-17-methylmorphinan-6-one C~!) ....................... 66 0 (14a)-3,4-Dimethoxy-7-ene-17-methyl-6trimethylsiloxymorphinan (~~) ....... ........ 67 (7a,14a)-3,4-Dimethoxy-17-methyl~7- phenylselenomorphinan-6-one and (7S,14a)3,4-Dimethoxy-17-methyl-7-phenylselenomorphinan-6-one (~~~!~) : . . ••••••••..•••••••• 68 (14a)-3,4-Dimethoxy-7-ene-17-methyl~ morphinan-6-one (54) .............. .. .... .... 69 viii TABLE OF CONTENTS (continued) PAGE 3,4"Dimethoxy-6-hydroxy-morphinan~ S,8"diene"7-one (56a) ....•..•...•••.•...•..• 70 (14S)-3,4-Dimethoxy"7-ene~17-methyl" (~~) ...•........•........... 71 "'< ...... morphinan-6-one (14$)-3,4-Dimethoxy-17-methylmorphinan-6-one c~z) APPENDIX I. IR and 1 H NMR Spectral Catalog . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDIX II. 13 c NMR Spectral Catalog .......... . 121 PROPOSITIONS 152 ........................ 71 81 THE APPLICATION OF METALLATED ENAMINES TO THE SYNTHESIS OF MORPHINE ALKALOIDS -2- INTRODUCTION Efforts aimed at the development of improved analgesics have established that structural subunits of morphine (1) exhibit useful analgesic activity in their own right, exemplified by morphinan (~),phenyl pipiperidi~e recently, phenyldecahydroisoquinoline (3) . 2 (~), 1 as and most Each of these structures contains the l-amino-3-phenylpropane functionality definitive of the qualitative structure-activity relationship known as the morphine rule$ NMe 1 Recent research in our NR 2 3 4 laboratories has demonstrated that metallated enamines provide . d ana 1 gesics. . expedient access to such morphine-base 3 In this -3- report, the application of metallated enamines to alkaloid synthesis will be described in the context of a general route to a number of phenylpiperidine and decahydroisoquinoline analgesics, culminating in an approach to the morphine alkaloids. 4 The key elements of our plan of attack on morphine are illustrated retrosynthetically in Scheme I. Our initial target has been morphinan 5, which comprises the fundamental architectural features of the morphine carbon skeleton and requires only well-documented functional group manipulations for ultimate conversion to the natural producto As originally proposed by Boekelheide in 1947, 5 4a,i-m dissection of the bridging methylene unit then reduces the problem to consideration of aryl-isoquinoline 6. Sequential discon- nection about the ring fusion of 6 reveals an annelation process based on bis-alkylation of metallated enamine 9 by dibromide 8; wherein the double bond in 8 is intended to serve the dual function of providing regiocontrol via allylic activation as well as acting as a latent carbonyl unit. Of the five asymmetric centers found in morphine, control of relative stereochemistry at CS, C6 and Cl4 is well established 4,6 from previous work, so that the main stereochemical problem at hand will be introduction of the bridging methylene unit to the same face of the isoquinoline ring as the aryl substituent. Towards this end, it will also be desirable to achieve control of ring fusion geometry in 6. -4Scheme I. OH OMe NMe 5o, x = o l x Br 6 7 \ OMe Br H2C~ + Br 8 ,_ I ' .... 9 _ NMe .E_, X = CH2 -5- Utility of Metallated Enamines In conjunction with the development of this plan, the utilization of metallated enamines for the preparation of a number of morphine substructural analogues was investigated. The alkylation of metallated enamines (e.g. a-aminoallyl anions·) has been examined previously with the aim of developing . 8 useful homoenolate equivalents. Provided adequate regiochemical control can be obtained, alkylation at the y-position followed by hydrolysis of the resulting enamine affords the desired homoenolate synthon (equation 1) . R2~ -- 0 -- RN ( 1) + y a In general, N-alkyl- orN-arylallyl anions are reported to undergo alkylation exclusively at the y-position in good yield (entries E-H, Table I). 8a-c Alternatively, functionalization of nitrogen as an urethane or N-nitroso derivative provided the opposite sense of regiocontrol, giving rise to exclusive 8 a-alkylation (entries I-K, Table I) . d-e The metallated enamine 10 desired for the present study has in fact been previously reported in the patent literature and found to undergo acylation 8 at they-position exclusively (entry A, Table I) . b 8 I N~ Et02CO J K C6 H6 a 2 4 8 2 d See experimental section~ 70 76 >95:5 >95:5 65 <5:95 n-C H Br 4 9 83 8e 8d Sd 80 <5:95 <5:95 8c 63 8c Sa Sa d d d 8b Ref. >95:5 \ 50 60 70 70 36 Yield >95:5 >95:5 >95:5 >95:5 >95:5 I b,c J_a CH I 3 CH :CHCH I 2 3 CH I 3 (CH ) SiCl 3 3 n-C H Br 4 9 (CH ) Si Cl 3 3 2 CH :CHCH Br Br{CH ) Cl 2 Clco Et Electrophile c A single regioisorner was isolated in each caseo b a an d y re 1 at1ve . . to nitrogen. a Li counterion in all cases. x....._N~ CH 3 /N C 6 Hrt-....~ cN~ / CH3 h Allyl Anion I H G F E D c B A Entry ,.._,.......,,....,.,....,,....,~,.._,.- TABLE I. ' ' O"I -7Tetrahydropyridine ~~, on treatment with n-butyllithium in tetrahydrofuran at -10°C, afforded the metallated enamine 9, as a deep red solution, which underwent alkylation exclusively at the Y-position with a variety of alkyl halides giving endocyclic enamines lla-llc in good overall yield (equation 2) . 7 RBr n-Buli ~ NMe NMe .. NMe ( 2) II 9 10 .2.' R = CHt CH=CH, 77% b, R = (CH,) 1 CI, 70% c' R = (CHt )4CI, 70% The versatility of these endocyclic enamines in the construction of simple morphine-based analgesics is illustrated in Scheme II. Compound lla may be readily transformed to either phenylpiperidines or phenylmorphans in high yield. Similarly, intramolecular alkylation of llb and llc provides ready access to phenylpyrindines and phenylpiperidines, respectively. Allyl substituted lla is obtained in 77% upon alkylation of 9 with allyl bromide. This versatile intermediate may be transformed into phenylpiperidine 4 (R catalytic hydrogenation. 9 1 = c H , R =cH ) by 3 2 3 7 Alternatively, treatment of lla with a 1:1 mixture of formic and phosphoric acids provided -8- Scheme II. NMe 4 13 R ~ NMe 11 !§_, {3-H ~' /j-H ~' 19, a-H a -H -9- phenylmorphan 12in 91% yield (Scheme III). This transformation Scheme I I I. Ila 12 j Ph H H 13 is viewed as proceeding via an irnrnoniurn ion-olefin cyclization followed by a transannular hydride shift. Hydrogenation of 12 then gave the known phenylmorphan 13, previously prepared by a much longer route. 10 Alkylation of metallated enamine 9 with a,w-dihaloalkanes can be readily accomplished provided inverse addition of 9 to -10- a solution of the dihalide is employed. This operation is necessary to prevent competitive coupling of the halogenbearing alkylation products (llb, llc) with unreacted metallated enamine. Such undesired coupling products may comprise as much as 50% of the reaction mixture when direct addition of the alkyl dihalide to the metallated enamine is followede Inverse addition of 9 to a solution of four equivalents of l-bromo-3-chloropropane (-50°C) in ethyl ether afforded the endocyclic enamine !!~' which on treatment with sodium iodide in refluxing acetonitrile for 24 hours afforded phenylpyrindine !~ in 70% yield. Hydrogenation of 15 then gave either cis- or trans-perhydropyrindines depending on the catalyst employed; charcoal gave exclusively !2 (15:16 !? or !§, using 5% palladium on ~ 95:5), while platinum oxide gave a slight predominance of 16 (16:15, 60:40). The assignment of ring-fusion stereochemistry in each case is based on comparison of 13 C-NMR spectra with the analogous cis- and trans-4a-phenylperhydroisoquinolines 18 and 19 of previously established configuration (vide infra). Specif i- cally, the 13 C-resonance of C-7a occurs at lower field in the trans isomer than in the cis, while the resonance of the phenyl ipso-carbon occurs at higher field in the trans than in the cis isomer. Corresponding results are observed for C-8a and the phenyl ipso-carbon for ~~ and 19 as well as for the parent cis- and trans-perhydroisoquinoline and -11- Scheme IV. No I Cl II b j 0 WMe 0 mMe = H 16 decalin ring systems. 14 15 11 12 ' In the absence of further proof of ring-fusion configuration, the assignments for 15 and 16 must be considered tentative. so f orme d The phenylpyrindines !~-!~ . . . . constitute a promising new c 1 ass o f ana 1 gesics. 13 Access to the perhydroisoquinoline ring system is achieved by a homologous annelation sequence (Scheme V). Inverse -12- Scheme V. No I Cl - 11 c j 0 0 17 C()Me CT)Me H 18 19 addition of 9 to a solution of four equivalents of l-bromo-4-chloro-butane in ethyl ether gave endocyclic enamine !!~ which is readily purified as its perchlorate salt, in a yield of 70%. Treatment of llc with sodium -13- iodide in refluxing acetonitrile for 24 hours provided bicyclic enamine 17 in 60% overall yield from tetrahydropyridine 10 without intermediate purification of llc. Either trans- or cis-perhydroisoquinolines ~~ or 19 may be obtained with complete stereocontrol by catalytic hydrogenation over platinum oxide, the stereochemical outcome dependent on solvent choice. In ethanol, the reduction afforded exclusively trans-perhydroisoquinoline 18 (18:19 95:5), while in acetic acid only cis-perhydroisoquinoline 19 was found <!~=!~ ~ 95:5). 14116 This general approach to the 4a-phenylperhydroisoquinolines 18 and 19 is noteworthy for its directness in comparison with other published approaches. 14 16 ' Formation and Reactions of Immonium Ions For the utilization of bicyclic enamines such as 17 in the synthesis of morphinans, it was important that protonation give the corresponding immonium salt with well-defined ringfusion stereochemistry. Treatment of a solution of 17 in ethyl ether with ethereal perchloric acid afforded exclusively the trans-fused isomer, 20 (Scheme VI), as determined by sodium borohydride reduction to 18 (18:19 > 95:5). When 20 (oil) was dissolved in ethanol, after several days the cis-fused isomer, 21, gradually crystallized from solution (95% yield), with the stereochemistry again determined by sodium borohydride reduction <!~=!§ > .95%). Examination of -14- Scheme VI. NaBH 4 HX 17 0 WMe H 20 18 i 0 19 21 more soluble immonium salts (20, 21; x=Cl, OAC) demonstrated that 21 forms as the thermodynamic product and is not being produced as a consequence of lattice energy effects selectively crystallizing a small concentration of 21. solutions of Dichloromethane fQ (x=Cl) were observed by 13 c-NMR to -15- equilibrate to 21 (21:20, 97:3) without accompanying crystallization. Rates of equilibration were conveniently followed by this method and were found to vary with the basicity of the counterion. Solutions of the perchlorate salt of 20 in dichloromethane showed no formation of 21 after 48 hours, while in methanol (2 M, 25°C) an approximate half-life of 16 h was observed for equilibration of 20 to 21. Correspondingly, the approximate half-life for x=Cl (2 M solution in methanol, 25°C) was two hours, while for x=OAc (2 M, methanol, 25°C) equilibration occurred at a rate ~ 13 faster than the C-NMR spectrum could be obtained (T 1 < 5 min). Yi - These results correlate well with the dramatic solvent effects noted above in the hydrogenation of bicyclic enamine 17. It is concluded that 17 is the direct precursor to trans-fused perhydroisoquinoline ~~ when the reaction is carried out in ethanol, while the thermodynamic cis-fused imrnonium salt 21 (x=OAc) is the species reduced in acetic acid. Stereocontrolled formation of either cis- or trans-fused ~Q or fl is thus readily accomplished by either kinetic or 3 16 . protonation . . 18 thermodynamic o f b'icyc l'ic enarnine __ . ' Irmnonium salts ~Q and ~! are appealing intermediates for morphinan synthesis, requiring only incorporation of the bridging methylene carbon. This carbon fragment could be appended onto the isoquinoline unit by nucleophilic addition to the imrnonium salt, provided that the addition can -16- be carried out in a stereoselective manner. ln principle, stereoelectronic factors could provide the necessary stereochemical control element (equation 3)o Given a conformationally Nu @ CD ( 3) boat Nu 22 chair rigid cyclic imrnonium ion (22), maximum orbital overlap between the incoming nucleophile and the irnmonium n* orbital would result in an antiperiplanar alignment of nucleophile with the nitrogen lone pair. 17 Barring other overriding factors, addition to 23 should occur from the beta-face via a lower energy chair transition state, as opposed to the higher energy boat transition state. substituted. The expected product would thus be axially An excellent demonstration of this concept has been reported by Stevens in his elegant synthesis of the . 11.ine an d coccine . 11.ine. 18 1 a d y b ug d e f ense a lk a 1 01. d s, precoccine However, at the outset of this work, the concept of stereoelectronic control in such additions was not yet well documented. If operative with inunonium salts 20 and 21, stereoelectronic control would promote axial attack of the incoming nucleophile via the lower energy chair transition state, resulting in addition cis to the phenyl group, provided -17- such stereoelectronic factors can override the strong steric bias for addition opposite to the bulky phenyl substituent. To test this point, the reactions of 20 and 21 with nucleophiles were investigated (Scheme VII). Treatment of Scheme VII. HX 17 23 l 0 21 24 20 in tetrahydrofuran at -78°C with excess methylmagnesium iodide in ethyl ether resulted in formation of equatorial -18- methyl adduct ~~, as indicated by Jab = 10 Hz in 1 H-NMR, with none of the corresponding axial epimer foundo In contrast to less encumbered examples, 18 this result demonstrates that nucleophilic addition via the higher energy boat-like transition state is feasible given a sufficient steric bias. The similar reaction of cis-fused 21 with methyl- magnesium iodide, however, gave exclusive formation of 24 (Jab= 10 Hz), 19 where a l,3~cis relationship has been established between the phenyl and methyl substituents. If the methyl substituent was appropriately functionalized, this cis relationship would make possible cyclization to the morphinan skeleton. Morphinan Synthesis via Aziridinium Salts --------------~--------------------~----- Towards this end, cis-fused immonium perchlorate 22 in dichloromethane at 0°C was allowed to react with ethereal diazomethane to give aziridinium perchlorate ~~ in 85% yield as a single diastereomer after recrystallization from benzene/ acetone (Scheme VIII). 20 In principle, aziridinium salt 25 could cyclize directly to the desired N-methylmorphinan ~~; however, all attempts to thermally induce such a process have failed in our hands. In the event, regiospecific ring opening with lithium chloride in acetonitrile afforded a 98% yield of a-chloroamine ~~- Ring closure to N-methylmorphinan 27 was then readily accomplished upon treatment of 26 with -19- Scheme VIII. 0 = CD~Me - + H 0 Q:3Me CH 2 N2 CI0 4 - CI0 4- 25 21 I LiCI 0 - AICI! cpMe NMe H CH 2 CI 26 27 aluminum chloride in refluxing benzene, in an overall yield from 22 of 60%. 21 For purposes of verification, ~Z was converted to its picrate and methiodide salts, whose melting points were found to be identical with those previously reported. 22 With a sample of morphinan ?Z in hand, careful scrutiny of the reaction of immonium salt 22 with diazomethane revealed that a 15 % yield of ~2 was formed directly in -20- ~~ competition with aziridinium ion formation. An increase _A)) (\k;J the (4) NMe 27 21 solvent polarity was found to dramatically enhance the amount of ~Z so produced, with yields of 30% in acetone and 40% in methanol being obtained. Having successfully demonstrated the feasibility of this approach for the preparation of simple morphinans, we next sought to apply it to compounds containing the aromatic oxygenation pattern found in morphine. tetrahydropyridine ~Q The dimethoxyphenyl- required for the metallated enamine annelation process was prepared by a two-step sequence. OMe OMe NMe NMe OM• ((OMe DMe 0 28 Li (5) 29 30 1,2-Dimethoxybenzene undergoes exclusive ortho-metallation upon treatment with n-butyllithium at room temperature in -21- ethyl ether. 23 Addition of N-rnethyl-4-piperidone (_28) in ether to a -10°C solution of dimethoxyphenyllithiurn so generated, afforded a 45-50% yield of 4-hydroxy-4-phenylpiperidine 29, with the remainder of the mass balance accounted for by unreacted starting materials (due to competitive enolization) which are easily recovered for reuse in subsequent preparations. Dehydration with three equivalents of p-toluenesulfonic acid in refluxing toluene, with azeotropic removal of water, provided a 95% yield of the desired tetrahydropyridine ~q . The annelation process was then carried out as described for the unsubstituted phenyltetrahydropyridine of ~q ~q. Metallation with n-butyllithium at -10°C in tetrahydrofuran afforded the allyl anion 31, with no competing aryl ring lithiation observed. Inverse addition of ~1 to a -78°C solution of four Scheme IX. n-BuLi 31 30 Nol -22- equivalents of l-bromo-4-chlorobutane in ethyl ether afforded endocyclic enamine ~~' which was directly cyclized by reaction with sodium iodide in refluxing acetonitrile to give a 54% yield of ~~ after distillation. gave a kinetic product ~~' Protonation of 33 again assumed to be trans-fused by analogy to the unsubstituted phenyl case above, which underwent equilibration to crystalline ~~ (~~:~~ ~ 97%). As the thermodynamic isomer, 35 was assumed to be cis-fused. ~OMe """ (X ~ = OMe 33 - OMe ~Me ~~ COM• H OMe H c10 4 - ( 6) CI04- 35 Reaction of 35 with diazomethane afforded aziridinium salt 36 as a single diastereomer. None of the corresponding dimethoxyrnorphinan 39 was found, even in more polar solvents, in direct contrast to the results ·n oted above for the unsubstituted phenyl series. This observation may be a result of the ortho-methoxy substituent forcing a change in the rotomeric conformation of the aryl group. In order to minimize peri-interactions of the ortho substituent, the aryl group may orient itself with the methoxyl pointing away from the isoquinoline unit and the aryl ring bisecting the isoquinoline unit, effectively blocking approach of diazomethane in the conformer most likely to be giving direct -23- Scheme x. CCOMe h : CH1N2 35 h OMe ~ C(Me cpMe OMSO NMe c10 4 H Me CHO 37 36 l BFs·Et20 OMe OMe EtSiH C3 NMe 39 38 morphinan formation in the substituted phenyl case (i.ee the conformer with aryl group axial to the nitrogen bearing ring). At this point, milder cyclization conditions were desired which would be more compatible with the functionality . d f or t h e actua 1 morp h'ine synt h esis. . 24 Towar d s t h'is require end, it was anticipated that cyclization of a-aminoaldehyde 37 -24- would take place under milder conditions than the harsh aluminum chloride process used above. 25 The regiospecific cleavage of aziridinium salts 25 and 36 with nucleophiles such as chloride or hydroxide suggested to us that a Kornbloom oxidation could be effected directly by reaction with dimethyl sulfoxide. Opening of the aziridinium ring with DMSO would liberate the basic nitrogen required for deprotonation and breakdown of the intermediate sulfoxonium salt. 3126 Such was indeed the caseo Simple treatment of 36 with excess dimethyl sulfoxide in anhydrous benzene at room temperature for 24 h afforded a 95% yield of the expected aldehyde ~Z· This exceptionally efficient oxidation of aziridiniurn salts deserves further attention as a potentially generalizable method for the construction of a-arninoaldehydes. Surprisingly, reaction of ~? with boron trifluoride etherate in refluxing benzene produced morphinan ~~ directly (40% yield), instead of the expected 10-hydroxymorphinan 38. Subsequently, it was observed that 38 is indeed produced upon treatment of 37 with BF ·Et o for approximately 1 minute at 2 3 room temperature. In this way, 38 can be isolated in 90% yield as the 108-hydroxy epimer exclusively. It is postulated that the observed reduction to 39 proceeds via BF •Et 2 o 3 promoted ionization of the benzyl alcohol followed by hydride abstraction. It was gratifying to find that inclusion of a good hydride donor greatly improved the reduction. Reaction -25- of with BF 3 ·Et 2 o and triethylsilane in refluxing benzene ~Z afforded an 80% yield of dimethoxymorphinan ~~. 27 With the success of this reaction established, we were now equipped to tackle the synthesis of rnorphinans fully functionalized for elaboration into the natural product. Synthesis of Morphine Alkaloids In order to prepare rnorphinan and intermediate aryl isoquinoline structures functionalized at C-6 via a metallated enamine annelation process, an appropriately substituted dihalide synthonwasrequired. 4-Brorno-2-brornornethyl-l-butene (8) appeared well suited for this purpose. The double bond would serve a dual role in providing regiocontrol in the alkylation process via allylic activation in addition to acting as a latent carbonyl unit. Towards this end, dibromide 8 was prepared in 60% overall yield from cyclopropane dicarboxylic 28 acid (40). [:><C02H C0 2 H [:><CH2X I) BH 1 ·THF 2) PBrs CH 2 X 40 Borane reduction of ~p ~' X =OH 42, X =Br ZnBr 1 C1 H 1 .. H2Ct:::: Br Br 8 and subsequent bromination of diol with phosphorous tribromide 29 ( 7) afforced dibromide 42 in 72% ~~ -26- overall yield. rearrangement of Lewis acid-catalyzed cyclopropylcarbinyl ~~ with zinc bromide in refluxing benzene . then provided the desired 8 in 80% yield. 30 Scrupulously anhydrous conditions and sublimed zinc bromide are mandatory for efficient preparation of ~' a ~ompound which is an appealing synthon for a variety of applications. Inverse addition of metallated enamine 31 to a -78°C solution of two equivalents of endocyclic enamine ~~ ~ in ethyl ether gave as a single regioisomer. necessary to prevent coupling of ~~ ~~' with Excess 43 is though the unreacted second equivalent was easily recovered for reuse later. While 44 in CDC1 3 was observed to undergo spontaneous cyclization to bicyclic enarnine Scheme XI. - -- - -- -- ...... ~Mo OMe ~? over a period of several ltr --Car ~OMe I OMe NMe NMe Br 31 &OMo h 44 / OMe NMe 45 ~ C(OMe h :: OMe C(OMe "= _ OMe W.Me CI04- WM• 46b 460 H • c10 4 - -27- days, the highest yields for this process were obtained by heating ~~ at reflux with sodium iodide and potassium carbonate in acetonitrile. Immediate kinetic protonation of the resulting bicyclic enamine 45 with perchloric acid gave directly the crystalline immonium salt ~§~ (assumed to be trans-fused, vide supra) in 60% overall yield from 30. preferred cis isomer Equilibration to the thermodynamically ~§12 (~§e:~§e = 95:?) then occurred upon dissolution in methanol at 50°C over 24 hours. 31 Treatment of 46b with ethereal diazomethane afforded a 95% yield of aziridinium salt 47 as a single diastereomer. Oxidative cleavage of ~7 was then accomplished upon reaction with dimethyl sulfoxide for 36 hours at room temperature in benzene to give aldehyde ~~ in 95% yield. Cyclization of 48 with BF ·Et o at -10°C in toluene gave an 80% yield of 2 3 10-hydroxymorphinan 12 with almost exclusive formation of the 106-hydroxy isomer shown in Scheme Xll (~9§=~2~ = 95:5). The conf igurational assignment at the hydroxyl center is based on the coupling constant between Eq and Hb in the 1 H-NMR of ~~ and ~~~· For 49, J ab = 6 Hz indicative of a pseudo-axial pseudo-equatorial relationship between the two protons. The Dreiding model of 49a reveals a dihedral angle of approximately 90 9 between Ha and Hb' which is consistant 32 . h Jab - O Hz o b serve d f or t h'is isomer. . wit Attempted deoxygenation of ~~ with triethylsilane and BF ·Et o, as used previously, resulted in competitive exocyclic 2 3 -28- Scheme XII. (l(OMe I : 46b OMe ~ + H CCOMe ~ : DMSO OMe l:PMe Me CI04- CHO 47 48 j BF 5 Et,o OMe OMe I) MsCI, TEA 2) LiEt3 BH 3) Oa0 4 , NaI0 4 NMe 50, X = CHt ~' x = 0 ~ ~, to endocyclic isomerization of the double bond. roa OH Instead, the desired transformation was accomplished in a one-pot operation by sequential methanesulfonation of 49 in tetrahydrofuran followed by reduction of the derived mesylate with lithium triethylborohydride, affording a 90% yield of so. 33134 -29- Morphinan ~~ corresponds to the product expected from direct aryl cyclization upon reaction of immonium salt 46b with diazomethane. With an authentic sample of it was possible to isolate approximately 0.1% of ~Q ~Q in hand, out of the mother liquors remaining from recrystallization of aziridinium ion 47. The small amount of morphinan noted in this instance is in marked constrast to earlier observations (vide supra) that this ring system could be directly constructed from immonium ions related to 11 upon treatment with diazomethane. 3 Again, this observation may be the result of a change in the rotomeric conformation of the aryl group caused by the ortho-methoxy substituent, as discussed above for immonium salt 35. Intersection with the Gates total synthesis of morphine now required cleavage of ?Q to give ketone ?!1 previously employed by Gates in his pioneering work on the preparation of the natural product. 4a After investigating a variety of conditions, it was found that Lemieux-Johnson oxidation of ?! was best prepared by , ~Q using osmium tetroxide (0.05 equiv.) and sodium periodate (3 equiv.) in a solution of 35 · · h gave t h e aqueous tetrahydro f uran an d acetic aci'd , whic 4 Gates ketone 51 in 90% yield. a Having intersected with the Gates approach, it was desired to convert 51 to its C-14 epimer ~~ for purposes of structural validation. -30- Gates has previously demonstrated that C-14 configurRtion may be equilibrated via enones related to 54, thus producing the 14B-epimer 55 as the thermodynamically favored product. 6 Towards this end, ketone ~~ was readily converted to enone ~~ (Scheme XIII) by the usual selenylation, selenoxide elimination Scheme XIII. OMe OMe I) LOA 2) TMSCI NMe 52 51 I PhSeCI OMe OMe t-BuOOH NMe 54 sequence. 36 530, b Enolization of 51 at -78°C in tetrahydrofuran with lithium diisopropylamide followed by trapping with -31- trimethylsilyl chloride provided silylenol ether 52, with no t race o f its regioisomer o b served • 37 o , , Upon 'reaction with phenylselenyl chloride in benzene at room temperature, 52 gave 53 as a 1:1 mixture of selenide epimers in 60% 38 yield from 51. In contrast to the reported failure of enone formation via selenoxide elimination in closely related . 4i 39 morphinan systems, ' treatment of 53 with excess tertbutyl hydroperoxide in dichloromethane with one equivalent of trifluoracetic acid gave a 95% yield of enone 54. 36 The success of this reaction may be attributed to the use of tert-butyl hydroperoxide as the oxidizing agent. 36 a We find that this reagent shows no propensity to oxidize the tertiary nitrogen present (even unprotonated) , 40 an observation which may be of importance for application to other alkaloidal systems. Upon investigating the base-catalyzed epimerization of 54, it was found that upon treatment with potassium tertbutoxide, 54 was converted to diosphenol 56a. Further inquiry revealed that this interesting transformation proceeded best when one equivalent of oxygen was bubbled into the reaction mixture via a gas-tight syringe, though excess oxygen was clearly deleterious to the process (in its absence, it did not proceed at all ) . 41 . . 11 y, Addit~ona . 1 usion . inc o f so d.ium bisulfite in the reaction mixture afforded much cleaner product; however, this reagent was not required to effect the transformation. Optimum conditions were thus found to be -32- two equivalents of potassium tert-butoxide in dimethyl sulfoxide with tert-butyl alcohol along with one equivalent each of oxygen and sodium bisulfite,which gave . ld . 42 yie ~~~in 50% . Th e c 1 ose structura 1 similarity of 56a to salutaridine (~~~) suggests that it could be employed in a biogenetically patterned furan ring closure, as illustrated (Scheme XIV) by the known in vivo or in vitro conversion of 4 43 salutaridinol (~~) into thebaine (~2) , c-f, the direct biosynthetic precursor to codeine and morphine. the potential utility of However, 56a in such a process remains to be established. Returning to the question of Cl4 inversion, treatment of 54 with aqueous potassium hydroxide allowed the anticipated epimerization to take place with a minimum of competing oxidation; providing the desired enone 55 (55:54 = 4:1) along with a small amount of 56a. Inunediate hydrogenation of the reaction mixture followed by chromatographic separation afforded 14B-morphinan-6-one 10% of 14a-epimer ~~- ~~ in 40% yield along The sample of (~) ~~ wi~h so produced was 1 found to be identical in all respects I H-NMR (500 MHz), 13 c-NMR, IR, MS, TLC] with a sample of authentic (+) ~~ prepared by degration from (-) morphine and generously 4 provided by A. Bross1. and H. Sc hm'dh i ammer. -~ -33- Scheme XIV. OMe OMe 51 NMe NMe 54 55 OMe OMe 0 NMe NMe 56a, 57 R, =Me, R2= H ~' R 1 = H, R 2 = Me OMe OMe - RO XO .. NMe 58 59 -34- Experimental Section Melting points were determined with a Buchi SMP-20 melting point apparatus and are uncorrected. Infrared spectra were recorded on a Beckman 4210 spectrophotometer. 1 H magnetic resonance spectra were recorded on either a Varian Associates EM-390 (90 MHz) or a JOEL-FX-90Q (90 MHz) spectrometer and are reported in ppm on the silane. Data are reported as follows: multiplicity (s q o scale from internal tetramethylchemical shift, = singlet, d = doublet, t = triplet, = quartet, m = multiplet, b = broad), integration, coupling constant (Hz), and interpretation. 500 MHz 1 H magnetic resonance spectra were recorded on a Bruker WM-500 spectremeter at the Southern California Regional NMR Facility. 13 c magnetic resonance spectra were recorded on either a JOEL-FX-90Q (22.5 MHz) or a Varian Associates XL-100 (25.5 MHz) and are reported in ppm from tetramethylsilane on the o scale. given above. Multiplicities are reported using the format Mass spectral analyses were performed by either the California Institute of Technology Microanalytical Laboratory on a Dupont 21-492B spectrometer or by the Midwest Center for Mass Spectrometry at the University of Nebraska, Lincoln, on a Kratos MS-50 TA spectrometer. Combustion analyses were performed by Spang Microanalytical Laboratory, Eagle Harbor, Michigan. -35- Flash chromatography was performed according to the general procedure of Still4 ~ employing either EM Reagents 40-63 µm Silica Gel 60 or Whatman 37-53 µm Silica Gel LPS-2. Medium pressure liquid chromatography was performed using EM Reagents LoBar Silica Gel 60 prepacked columns with a Fluid Metering Inc. Model RP lab pump. Thin-layer chromatography was performed using EM Reagents 0.25 mm Silica Gel 60 plates. When necessary, solvents and reagents were dried prior to use. Diethyl ether, tetrahydrofuran and benzene were distilled from sodium metal/benzophenone ketyl. Triethylamine, t-butyl alcohol, dimethyl sulfoxide, diisopropylamine, dichloromethane and trimethylsilyl chloride were distilled from calcium hydride. Methanesulfonyl chloride was distilled from phosphorous pentoxide. Potassium t-butoxide and zinc bromide were purified by sublimation. All other reagents were used as received. l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (10) in 300 mL of anhydrous THF was added, dropwise, 75 mL of 1.6 M n-butyllithium in hexane. After the addition was complete, the mixture was stirred for 10 min. at -10°C, then cooled to -30°C. The resulting deep red solution was transferred via cannula into a -50°C solution of 14.40 g (120 rnrnol) of allyl -36- bromide in 250 mL of ethyl ether. The mixture was rapidly warmed to0°C followed by careful addition of 500 mL of brine. The organic layer was separated, diluted with 2 L of ether, washed with brine, dried (k co ) and evaporated under vacuum. 2 3 Distillation afforded 19.50 g (77%) of the title compound: bp 101-105°C/0.l nun; IR (CHC1 ) 1640 cm 3 87.40 (m, SH, ArH), 6.06 (m, lH, C~=CH 2 ), -1 1 H-NMR (CDC1 ) 3 (d, lH, J = 8 Hz, CH=C!!N), 5.52 5.00 (m, 2H, 2 CH=C~ ), C!:!=CHN), 2.65 (s, 3H, NC!:! ), 2.90-1.97 3 4.60 (d, lH, J = 8 Hz, (m, 6H, aliphatic) ppm. Anal. calcd. for Found: c, c 15 H19 N: C, 84.46; H, 8.98; N, 6.57. 8 4. 15; H, 8. 71; N, 6. 3 4. ~=~:!~¥~:~:P~:~¥~:~:P:~P¥~:P~P::~~~~:-~~~of 1.00 g 7 A solution (4.7 mmol) of ~~~in 50 mL of ethanol was hydrogenated over 0.5 g 5% Pd/C at 60 psi for 4 hat room temperature. Filtration and evaporation under vacuum gave 1.00 g of the title compound: 2. 23 1 H-NMR (CDC1 ) 87.28 3 (100%) (m, SH, ArH), (s, 3H, NC!:! ), 2. 77-0. 70 (m, lSH, aliphatic) ppm. 3 A hydrochloride salt was prepared: 9 204-206). mp 208-209 (lit. 2-Methyl-5-phenyl-2-azoniabicyclo[3.3.l]non-2-ene ----------~-------------------------------------7 perchlorate (12). ----------- ---- A solution of 1.00 g (4.7 mmol) of lla ...... in 2.5 mL of 85% phosphoric acid and 2.5 mL of 90% formic acid was stirred at room temperature for 66 h. The mixture was poured into 180 mL of ice water and basif ied by dropwise -37- addition of SO% aqueous sodium hydroxide. The product was extracted into ethyl ether and the combined extracts were washed with brine, dried (k co ) and evaporated under vacuum: 2 3 1 IR (CHC1 ) 163S cm-l; H-NMR (CDC1 ) 87.32 (m, SH, ArH), 3 3 6.11 (d, lH, J = 8 Hz, NC!!_=CH), 4.30 (d, lH, J = 8 Hz, NCH=C!!_), 3.19 (m, lH, NCH(CH2)2) I 2.74 (s, 3H, NC~3), 2.94-1.14 (m, 8H, aliphatic) ppm. The residue was dissolved in ethyl ether and the perchlorate salt was prepared by dropwise addition of a 1:1 solution of 70% perchloric acid and ethanol, using congo red as the end point indicator. The resulting solid was recrystallized from ethanol to give 1.34 g immonium salt of 12: (91%) of the mp 164-16S; IR (kBr) 1700 cm- 1 ; 1 H-NMR (CDC1 ) 88.97 (s, lH, CH=N + ), 7.43 (m, SH, ArH), 4.37 (m, lH, 3 + + (CH ) C~N ), 3.28 (m, 2H, C!!_ CH=N ), 2.42-1.37 (m, 8H, 2 2 2 aliphatic) ppm. Anal. calcd. for c SH 20 NClo : 4 1 N, 4. 4 6. Found: C, S7.42; H, 6.42; C, S 7. 2 2; H, 6. 3 2; N, 4. 4 6. ~=~~~~¥~:~:P~~~¥~:~:~~~~~:¥:~~!~~~~~!:~~~~~~-~~~~- 7 A solution of 12 (1.00 g, 4.7 rmnol) in 200 mL of ethanol was hydrogenated for 4 h at 60 psi using O.S g of S% pd/c. Filtration and evaporation of the solvent gave 1.00 g of the title compound: ArH), 2.18 ppm. (s, 3H, Nc~ 1 3 ), (100%) H-NMR (CDC1 ) 87.30-6.43 (m, SH, 3 3.00-1.29 (m, 13H, aliphatic) -38- Anal. calcd. for c Found: H N: 15 21 C, 83.67; H, 9.83; N, 6.50. C, 83.43; H, 9.70; N, 6.71. A hydrochloride salt of 14 was prepared and recrystallized from acetone: Anal. calcd. for Found: mp 235-237 (lit. 239-240). 10 c15 H22 NC1: C, 71.55; H, 8.81, N, 5.56~ C, 71.88; H, 8.65; N, 5.64. 2-Methyl-4a-phenyl-2,3,4,4a,5,6-hexahydro-2-pyrindine -----------------------------~-----~~---------------- (14). 7 To a -10°C solution of 25 gm (0.14 mol) of 1-Methyl(~9) 4-phenyl-1,2,3,6-tetrahydropyridine in 450 mL of dry THF was added, dropwise, 90 rnL (0.14 mol) of 1.6 M n-Butyllithium in hexane. The mixture was stirred for 10 min after completion of the addition, then cooled to -30°C. The resulting deep red solution was transferred via cannula into a -50°C solution of 73.30 gm (0.47 mol) of l-Bromo-3chloropropane in 300 m~ ethyl ether. After the addition, the mixture was rapidly warmed to -20°C and 500 mL of ice cold brine was added. The organic layer was separated and washed with cold water. The product was extracted into three, 400 mL portions of cold 1 N HCl. After washing with ether, the extracts were made basic by dropwise addition of 50% NaOH (keeping the temperature at 0°C). into 2.5 L ether, dried over k (at 10°C or below). 2 The product was extracted co 3 and evaporated to dryness The residue was immediately dissolved in 2.5 L acetonitrile; 52.50 gm (0.35 mol) sodium iodide was added and the mixture was refluxed for 24 h. At the end of this period, the solvent was evaporated and the residue -39- partitioned between 800 mL 1 N NaOH and 1 L of ether, with vigorous stirring for 4S min. The ether layer was separated, washed with brine, dried (k co ), and evaporated. 2 3 gave 21.SO gm (70%) of enamine 14: IR (CHC1 3 ) 16S7 cm -1 1 bp 110-112°C (0.07S mm); . ; . H-NMR (CDC1 ) 07.34 3 S.93 (s, lH, N-CH=C), 2 .. S8 Distillation (m, SH, ArH), (s, 3H, N-C!!_ ), 2.91-1.17 (m, lOH, 3 aliphatic) ppm. Anal. calcd. for c Found: H N: 15 19 C, 84 .. 46; H, 8.98; N, 6.57. C, 84.74; H, 8.72; N, 6.28. :~::~:~:!~¥~:~~:P~:~¥~:~:!~~¥~:~:~:P¥:~~~~~=-~~~~· A solution of 7 a.so gm (2.3 nunol) of enamine 14 and 0.5 gm of S% Pd/C in 50 mL ethanol was hydrogenated at 60 psi for 4 h at room temperature. Filtration and evaporation gave · 0.50 gm 1 (quantitative) of the title compound (15): H-NMR (CDC1 ) 3 87.28-7.00 (m, SH, ArH), 2.24 13H, aliphatic) pp; 13 (s, 3H, N-C!!_ ), 2.76-1.37 (m, 3 c-NMR (CDC1 ) 814.82 3 (s), 128.0 (d), 126.S (d), 12S.4 (d), 57.0 (t), 52.5 (t), 46.7 (s), 46.6 (q), 4 2. 6 ( d) , 3 7. 6 ( t) , 3 4. 4 ( t) , 2 8. 0 ( t) , 2 0. 8 ( t) ppm. The HBr salt of 16 was prepared and recrystallized from l.S:l isopropyl ether-isopropanol: Anal. calcd. for c SH NBr: 1 22 Found: mp 209-210°C. C, 60.81; H, 7.49; N, 4.73. C, 60.55; H, 7.49; N, 4.S7. !:~~::~:~:~~¥~:~~:P~~~¥~:~:!~~¥~:~:~:P¥:~~~~~=-~~~~· 5.00 gm (3 mmol) of enamine 14 and 0.50 gm Pto 2 7 in 50 mL ethanol was hydrogenated at 60 psi for 4 h at room temperature. -40- The mixture was filtered and evaporated to dryness. NMR and HPLC (Waters Associates µPorasil 4mm x 30 cm column, 97:3 CHC1 /cH 0H and 0.01% NH CH CH 0H, flow rate 100 mL/h) 3 3 2 2 2 indicated a mixture of approximately 40% cis 15 and 60% 16. The mixture was dissolved in ether and made acidic with excess ethereal HBr. After evaporation, the residue was recrystallized from 30 mL isopropanol and 70 mL isopropyl ether, yielding 2.60 gm (38%) of cis 15 • HBr. The filtrate was evaporated and the residue taken up in water. This was made strongly basic with 1 N NaOH. The product was extracted into ether, washed with water, dried (k co ), and evaporated to give 2.57 gm crude trans 16. The 2 3 product was further purified by conversion to its picrate salt (2e76 gm picric acid) and recrystallized from ethanol to give 2.70 gm (26%) 16 • picrate: Anal. calcd. for c Found: H N o : 21 24 4 7 mp 167-168°C. C, 56.75; H, 5.44; N, 12.61. C, 56.99; H, 5.65; N, 12.46. Stirring over NH 0H and extraction into ether afforded 4 the free base of 16 cis 15): N-C~ 1 H-NMR ( CDC1 ) 87.54-7.04 3 (m, SH, ArH), 2.27 13 3.14-1.30 (m, 13H, aliphatic) ppm; C-NMR 3 ), (CD Cl ) o14 5 . 2 3 3H, (NMR and HPLC confirmed the absence of (s, ( s) , 13 7 . 9 (d) , 12 9 . 0 ( d) , 12 7 • 6 (d) , 12 5 . 1 55.4 (t), 52.0 (t), 49.2 (d), 47 .8 (s), 45.9 (a), 43.1 (t), 41 . 1 ( t ) , 2 5 . 5 ( t) , 21 . 1 ( t) ppm . The maleate salt of 16 was prepared and recrystallized from ethyl acetate: mp 113-114°C. (d) , -41- Anal. calcd. for c Found: H No : C, 68.86; H, 7.60; N, 4.23. 19 25 4 C, 68.66; H, 7.82; N, 3.98. l-Methyl-4-(4-chlorobutyl)-4-phenyl-1,2,3,4-tetrahydro~~----------------------------------------------------- P¥:~~~~~-~~~~2· To a -10°C solution of 5 gm (28.9 mrnol) tetrahydropyridine 11 in 100 mL dry THF was added 20 mL (32 nunol) of 1.6 M n-butyllithium, dropwise. Ten min. after the addition was complete, the solution was cooled to -30°C and added, via cannula, to a -78°C solution of 17 gm (99 mrnol) l-bromo-4-chlorobutane in 60 mL ethyl e·ther. The reaction was warmed to -20°C and 100 mL ice cold brine added. The organic layer was separated and washed with cold water, followed by extraction with three, 90 mL portions of cold 1 N HCl. After washing once with ether, the combined acid extracts were made basic by addition of 50% sodium hydroxide, maintaining the temperature at 0°C. The product was extracted into three, 200 mL portions of ether, dried (k co ) and 2 3 evaporated under vacuum to give 7.10 gm crude tetrahydropyridine ~~9: IR (CHC1 ) 1635 cm-l 3 (m, SH, ArH), 5.93 1 H-NMR (CDC1 3 ) 87.43-6.97 (d, lH, J = 8.4 Hz, N-C!:!_=C), 4.53 (d, lH, = 8.4 Hz, N-C=CH), 2.53 (s, 3H, N-CH ), 3.53-1.00 (m, 12H, -3 13 aliphatic) ppm; C-NMR (CDC1 ) 8149.4 (s), 136.7 (d), 3 J 127.9 (d), 127.2 (d), 125.4 (d), 102.5 (d), 46.3 (t), 44.7 (t), 42. 7 (a), 42.4 (t), 40.0 (s), 37.1 (t), 33.3 (t), 21.6 (t) ppm. The perchlorate salt was prepared by adding a 1:1 solution of 60% perchloric acid and ethanol to the enamine llc in -42- ether. Recrystallization of the resulting precipitate from ethanol gave 7.4 gm (70%) of yellow crystals: mp 170-172°C. Anal. calcd. for c N, 3.97. Found: H Ncl o : C, 52.75; H, 6.36; 16 23 2 4 C, 52.77; H, 6.12; N, 3.73. N-Methyl-4a-phenyl-3,4,5,6,7,8-octahydroisoquinoline -------------------~--------~---------~-----~------- (17). To a -10°C solution of 15 g (86 rnmol) of N-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (10) in 250 mL of anhydrous THF was added 60 mL (90 mmol) of 1.50 ~~-butyl­ lithium in hexane. Ten min after the addition was complete, the solution was cooled to -30°C and added to a -78°C solution of 49 g (286 mmol) of l-bromo-4-chlorobutane in 180 mL of ethyl ether over 30 min. The reaction was rapidly warmed to -20°C and 300 mL of ice cold brine ~dded. The organic layer was separated and washed with cold water, followed by extraction with three, 250-mL portions of cold 1 N aqueous hydrochloric acid. After washing once with ethyl ether, the combined acid extracts were made basic by addition of 50% aqueous sodium hydroxide solution, while maintaining the temperature at 0°C. The product was extracted into three, 600-mL portions of ethyl ether, dried over anhydrous potassium carbonate and the solvent was carefully evaporated under vacuum, keeping the temperature at 10°C or below. The residue was immediately dissolved in 1.5 L of acetonitrile, 32 g (214 mmol) of sodium iodide was added, and the reaction was refluxed for 24 h under an argon atmosphere. After removing the solvent under vacuum, the residue was partitioned -43- between SOO mL 1 ethyl ether. ~ aqueous sodium hydroxide and 600 mL of The ether layer was separated, washed with brine, dried over anhydrous potassium carbonate and the solvent removed under vacuum. (0.02S nun) gave 11.7 g 16SO cm -1 ; 1 Distillation at 100°C (60%) of colorless oil: IR (CHC1 ) 3 H-NMR (CDC1 ) 87.36 (m, SH, ArH), S.88 3 (s, lH, =Cg-), 2o34 (s, 3H, N-NC!:!_ ), 2.82-1.00 (m, 12H, aliphatic) 3 13 ppm; C-NMR (CDC1 ) 8147.6, 132.8, 127ol, 12S.l, 113 .. 3, 3 4 S . 8 , 4 2 . 9 , 41 . S , 3 9 . 9 , 3 .0 ., 3 , 2 8 3 , 2 2 . 9 ppm . o Anal. calcd. for c Found: H N: 16 21 C, 84.S3; H, 9.31; N, 6.16. C, 84026; H, 9.12; N, 6 .. 23. ~=~~~~¥!:~~:P~~~¥!:~!~!~!§LZ!~!~~=~~~~~=~~~~~¥~~~!~~­ g~~~~~~~~~P~:~~~~=~~~-i~~~- To a solution of 100 mg (0.44 nunol) octahydroisoquinoline 18 in 3 -mL anhydrous ethyl ether was carefully added ethereal perchloric acid, until the solution tested blue on congo red paper (pH -3). of the solvent under vacuum gave a colorless oil: (CHC1 ) 1690 cm 3 -1 ; 1 Evaporation IR H-NMR (CDC1 ) 8 8.91 (br, lH, +N=C!:!_-), 3 7.S9-6.9S (m, SH, ArH), 3.83 [s, 3H, =N(cg )-], 3.31-1.0S 3 13 (m, 13H, aliphatic) ppm; c-NMR (CDC1 ) 8 182.3, 139.0, 129.3, 3 127.1, 126.7, Sl.3, 48.7, 47.0, 40.4, 38.8, 37.2, 26e4, 21.6 ppm. ~=~~~~¥~:~~:P~~~¥~:~!~!~!?!~!~~::~~:~:~~~¥~:~~~~~~~~~~­ ~::~~~p~:~~~~:~~~-i3~~. · To a solution of 100 mg (0.44 mmol) octahydroisoquinoline 17 in 3 mL of ethyl ether was carefully -44- added a mixture of 60% aqueous perchloric acid diluted with an equal part of absolute ethanol, until the solution tested blue on conga red paper (pH -3). The solution was evaporated under a stream of nitrogen until most of the ether was removed. Additional ethanol was added and the solution was warmed on a steam bath until the oil layer dissolved. Upon standing for several days, there was obtained 137 mg (95%) of white crystalline perchlorate: 1 H-NMR (CDC1 ) 3 3.71 [s, 3H, 13 mp 162-163°C; IR (CHC1 ) 1690 cm 3 -1 o 8.91 (br, lH, +N=C~-), 7.29 (m, 4H, ArH), =N(C~ c-NMR (CDC1 ) 3 3 )-], 2.69-1.05 (m, 13H, aliphatic) ppm; o 182.2, 143.6, 129.2, 127.1, 125.2, 51.0, 49.1, 42.5, 36.1, 34.1, 31.1, 25.6, 24.4, 2lo2 ppm. Anal. calcd. for c N, 4. 2 7. Found: H N•Cl0 : 4 16 22 C, 58.63; H, 6.76; C, 58. 2 4; H, 6. 6 9; N, 4 .15. trans-2-Methyl-4a-phenyl-decahydroisoquinoline (18). -----------~--------------------------------------~- Method A. 7 Enamine 17 (0.50 g, 2.2 mmol) in 50 mL ethanol was hydrogenated for 4 h at room temperature using 0.5 g Pto and 60 psi hydrogen. 2 evaporated to give 0.50 g (100%) of the title compound, which crystallized on standing: mp 67-69°C; IR (CHC1 3 ) 3000-2800, 1590, 1460, 1442 cm ArH), 2.20 (s, 3H, -1 1 ; 3 The mixture was filtered and H-NMR (CDC1 3 ) Nc~ ), o 7.64-7.07 (m, SH, 2.84-0.88 (m, 15H, aliphatic) ppm; 13 C-NMR ( CDC 1 ) o 14 5 . 0 ( s ) , 13 0 . 0 (d ) , 12 7 . 6 ( d ) , 12 4 . 9 (d ) , 3 58.5 (t), 52.0 (t), 46.4 (d), 46.2 (a), 43.7 (t), 41.4 (s), 2 7 • 2 ( t) I 2 7 • 0 ( t) I 2 2 • 2 ( t) ppm• -45- Anal. calcd. for c Found: H N: C, 83.79; H, 10.11; N, 6.11. 16 23 C, 83.64; H, 9.85; N, 5.85. An HBr salt of 18 was prepared and recrystallized from ethyl acetate-ethanol: Anal. calcd. for c Found: mp 210-212°C. H NBr: 16 24 C, 61.94; H, 7.80; N, 4.51. C, 61.69; H, 7.69; N, 4.47. A picrate salt of 18 was prepared and recrystallized from ethanol: mp 218.5-220 (Lit. 218.5-220°C). 14 H N o : C, 57.76; . H, 5.51; N, 22 26 4 7 C, 57.50; H, 5.69; N, 12.44. Analo calcd. for c 12.25. Found: Method B. To a 0°C solution of 20·0 mg (0. 61 mmol) of trans-immonium salt 20 in 20 mL of methanol was added 116 mg (3.05 mmol) of sodium borohydride. After 30 min, the excess borohydride was quenched by the addition of 10 mL of 1 N aqueous hydrochloric acid. The residue remaining after evaporation of the solvent under vacuum was taken up in 30 mL of 1 N aqueous hydrochloric acid. After washing with ethyl ether, the acid solution was neutralized by careful addition of 50% aqueous sodium hydroxide. This suspension was extracted with three, 20 mL portions of dichloromethane. The combined extracts were washed with brine, dried (k co ) 2 3 and evaporated under vacuum to give 140 mg (100%) of the title compound as a colorless oil. The 1 with material prepared by Method A. H and 13 c-NMR were identical -46- cis-2-Methyl-4a-phenyl-decahydroisoquinoline (19). ~-----~----~-~--~-----------~------------~----~-- Method A. 7 Enamine 17 (2.00 g, 8.8 mrnol) in 100 mL of acetic acid was hydrogenated at 60°C and 60 psi for 15 h over 0.20 g Pto • 2 The mixture was then filtered and evaporatedo The residue was dissolved in water and made strongly basic with 1 N sodium hydroxide. The product was extracted into ether, washed with brine, dried over k co and evaporated 2 3 under vacuum to give 2.00 g (100%) of the title comporind. Gas chromatography (OV-1, 150°-260°C at 10°/min) showed very little of the trans isomer present: 13 C-NMR H-NMR (CDC1 ) 3 NC~ 126.1(d),125.3 (d), 57.5 (t), 52.6 (t), 46.6 3 7 . 3 (d ) ' 2 6 • 9 ( t) ' o 7.17-7.67 3 ), 2.80-1.06 (m, 15H, (CDC1 ) o 148.? (s), 128.3 (d), 3 (m, SH, ArH), 2.28 (s, 3H, aliphatic) ppm; 1 (q), 39.5 (s), 2 2 . 5 ( t) ppm • A HBr salt of 19 was prepared and recrystallized from acetone-isopropanol: mp 219.5-221.5°C (lit. 222-224°C). A picrate salt of ~~ three times from ethanol: Method B. inunonium salt 14 was prepared and recrystallized mp 160-162 (lit. 144-146). 14 The title compound was prepared from cis~~ by the same procedure (Method B) as trans-2-methyl-4a-phenyl-decahydroisoquinoline (18) in 95% yield. The 1 H and 13 c-NMR spectra were identical with material prepared by Method A. trans-la,2-Dimethyl~4aa-phenylperhydroisoquinoline To a -78°C solution of 2.18 g (23). (6.66 nunol) of trans-immonium salt 20 in 25 mL of anhydrous tetrahydrofuran was added 15 mL -4 7 .. (41 mmol) of 2.75 M methylmagnesiurn iodide in ether. After warming to room temperature, the reaction was stirred for 4.5 h. Excess Grignard reagent was quenched by the addition of 50 mL of 1 N aqueous tetrasodium ethylenediaminetretracetate (EDTA). This mixture was extracted with three, 50 rnL portions of dichloromethane. After washing with brine, the combined extracts were dried (k co ) and the solvent evaporated under 2 3 -- vacuum, to give a 3:1:1 mixture of 23:24:17, respectively. .._,,,,.,,._ -- - Chromatography at medium pressure over silica gel (EM Laboratories, size B LoBar column; eluted with hexane and chloroform, 80:20, saturated with ammonia) afforded 920 mg (57%) of the title compound as a colorless oil: IR (CHC1 ) 3 3100-2800, 1490, 1455, 1375, 1260, 1180, 1160, 1028, 1014 cm-l; 1 (d, d, lH, J H-NMR (CDC1 ) 8 7.56-7.01 (m, SH, ArH), 2.61 3 = 10 Hz, J = 6 Hz, NCHCH 3 ), 1.14 (d, 3H, J ppm; 13 = 6 Hz, NCHc~ 3 ), 2.22 (s, 3H, NC~ ), 3 2.51-i.os (m, 13H, aliphatic) c-NMR (CDC1 ) 8 145.3 (s), 130.1 (d), 127 .5 (d), 3 124.9 (d), 59.2 (d), 52.6 (t), 52.2 (a), 44.2 (d), 43.8 (t). 43.5 (t), 42.5 (s), 27.7 (t), 24.5 (t), 21.7 (t), 17.9 (a) ppm. Exact mass calcd. for c H N: 243.199. Found: 243.199. 17 25 cis-la,2-Dirnethyl-4aa-phenylperhydroisoquinoline (24). ------------------------~---------------------------- The title compound was prepared by the same procedure as used above for trans-dimethylperhydroisoquinoline 23. 200 mg (0.610 rnmol) of cis-irnmonium salt 3~, Starting with 140 mg (95%) of -48- the title compound was obtained as a colorless oil: IR (CHC1 3 ) 3100-2800, 1490, 1462, 1442,- 1362, 1262, 1242, 1149, 1104 cm -1 ; 1 o 7.52 (m, SH, ArH), 2~61 H-NMR (CDC1 ) 3 (dd, = 10 Hz, J = 5 Hz, NcgcH3)' 2.31 (s, 3H, Ncg3), 1.18 (d, 3H, J = 5 H, NCHC~3 ), 2.28-1.05 (m, 13H, aliphatic) 13 ppm; c-NMR (CDC1 3 ) o 148. 7 (s), 128.3 (d), 125.8 (d), lH, J 12502 (d), 57.0 (d), 52 .. 8 (s), 43.7 (a), 43.5 (d), 42.5 (t), 40.8 (t), 27.5 (t), 24.1 (t), 22.6 (t), 20.7 (t), 17o2 (a) ppm. Exact mass calcdo for c H N: 17 25 243.199. Found: 2430200. (4a , 8a , 8b )-2-Methyl-4a-phenyldecahydroazirino -~-~---------------------~------------------------- !~!~!:~!~~~9~~~~~~~~~~-~~~:~~~:~~~-~~~2· To a 0°C solution of 460 mg (1.40 mmol) of cis-immonium perchlorate 21 in 20 mL -- ~- of anhydrous dichloromethane was added ethereal diazomethane, dropwise, until the yellow color persisted. evolution was observed. 47 Immediate gas The cooling bath was removed and excess diazomethane evaporated under a stream of nitrogen. When the yellow color had dispersed, the remaining solvent was evaporated under vacuum, to give 457 mg of a white solid. 13 c-NMR showed this to be a mixture of aziridinium salt 25 and morphinan 27 in a ratio of 85:15, as determined by 1 H-NMR integration of the NCH 3 signals. Recrystallization from benzene/acetone gave 407 mg (85%) of the title compound as white needles: 1 H-NMR (CD CN) 3 1 IR (CH cl ) 3060-2870, 1446, 1090 cm- ; 2 2 o 7.46-7.05 (m, SH, ArH), 3.63 (m, 2H, NC~ ), 2 -49- 3.19 (s, 3H, NC~3 ), 3.13-1.53 (m, 14H, aliphatic) ppm; 13 C-NMR (CD CN ) o 14 5 .. 0 ( s ) , 12 9 • 4 (d ) , 12 6 • 9 ( d ) , 12 6 . 5 (d ) , 3 51.5 (a), 51.0 (d), 50.9 (t), 43~6 (t), 36.7 (s), 35.4 (d), 3 3 . 5 ( t) , 31 .. 2 ( t ) , 2 6 • 9 ( t ) , 21 . 8 ( t ) , 21 . 6 ( t ) ppm . Anal. calcd. for c N, 4.10. Found: H No cl: 17 24 4 c, 59.74; H, 7.08; C, 59. 76; H, 6.94; N, 3.99. ~~~!-~~~!-~~~~=~=~~~~9:9~=~~¥~~=~=~~~~¥~:~~=r~:~¥~­ ~=:~~¥~:9~:~~~~9~~~=-~~~~ · A room temperature solution of 1.10 gm of an 85:15 mixture of aziridinium salt 25 (2.86 mmol) and N-methylmorphinan 27 (0.5 mmol), and 685 mg (16.3 nunol) of lithium chloride in 30 mL acetonitrile was stirred for 1 h. The solvent was evaporated under vacuum and the residue taken up in 50 mL dichloromethane. This solution was washed once with 30 mL water, dried (Na so ), 2 4 and evaporated under vacuum, to give 880 mg of a colorless oil. Separation by flash chromatography (3:1, hexane and ethyl acetate, 2.5% triethylamine) gave 770 mg (97%) of the title compound and 73 mg of morphinan ~Z· The 8-chloroamine 26 was indu.ced to crystallize from a solution of hexane placed in a freezer for several weeks: mp 68-70°C; IR (CHC1 ) 3000-2800, 1462, 1152, 1090 cm-l; 3 7.49-6. 98 (m, SH, aromatic), 3. 73 (m, 2H, 1 H-NMR (CD CN) 3 c~ cl), 2 2.28 o (s, 3H, NC~ 3 ), 3.32-1.16 (m, 14H, aliphatic) ppm; 13 c-NMR {CDC1 3 ) o 148.2 (s), 128.4 (d), 125.8 (d), 125.4 (d), 61.8 (d), 52.5 (t), 43.4 (t), 43.1 (d), 40.4 (s), 37.8 (a), 23.7 (t), 22.4 (t), 21.1 (t) ppm. -soAnal. calcd. for c Found: H NC1: 17 24 C, 73.49; H, 8.71; N, 5.04. C, 73.40; H, 8.64; N, 4.95. ~~~~~=~7=~~~~¥~~~:r~~~~~-~~Z~· A solution of 385 mg of an 85:15 mixture of S-chloroarnine 26 and morphinan 27 (1.20 mrnol of 26) and 800 mg (6 rnrnol) of aluminum trichloride in 20 mL of anhydrous benzene was refluxed for 2 h. Upon cooling to room temperature, 20 mL 10% aqueous sodium hydroxide was added and the mixture was stirred for 15 min. The aqueous phase was separated (reserving the organic phase) and extracted with two, 20 rnL portions of dichloromethane. The combined organic extracts were washed once with 30 rnL water, dried so ), and evaporated to give 326 mg of a brown oil. Flash 2 4 chromatography (1:3, ethyl acetate and hexane, 1.5% triethyl(Na amine) afforded 210 mg (60%) of the title compound as a IR (CHC1 ) 3060-2800, 1585, 1446, 1376, 1280, 3 1156 crn- 1 ; 1 H-NMR (CDC1 ) o 7.28-7.03 (m, 4H, ArH), 2.31 (s, 3 13 3H, NC_!! ), 3.26-0.83 (m, 16H, aliphatic) ppm; c-NMR (CDC1 3 ) 3 0 146.3 (s) I 137.5 (s) I 127.5 (d), 125.6 (d) I 125.4 (d) I colorless oil: 123.9 (d), 58.8 (d), 47.5 (t), 43.l (a), 42.1 (d), 36.0 (t), 34.4 (s), 31.7 (t), 27.7 (t), 26.7 (t), 26.2 (t), 22.4 (t) ppm. 2 A picrate salt was prepared: 210-213°C (lit. 210-212.5)} H N o : 23 26 4 7 C, 58.72; H, 5.57; N, 11.91. Anal. calcd. for c Found: C, 58.52; H, 5.46; N, 11.79. A methiodide salt was also prepared: 22 233-236) . mp 233-236 (lit. -51- 4-(2,3-Dimethoxyphenyl)-4-hydroxyl-l-methylpiperidine ~~~~-------~-~---~-~----------~---~--~~~-----~-----~- (29). To 35 g (254 mrnol) of £-dimethoxybenzene in 250 mL of anhydrous ethyl ether at room temperature was added dropwise, 115 mL (203 rrunol) of 1.75 ~ g~butyllithium in hexane. A yellow solution was formed initially, followed by precipitation of ~-dimethoxyphenyllithium. After stirring for 2 h, the reaction was cooled to -10°C and 21 g (186 rrunol) of 1-methyl-4-piperidone in 100 mL of anhydrous ethyl ether was added dropwise and stirred for 6 h. The excess lithium reagent was quenched by addition of 150 mL of H o. The 2 organic layer was separated and extracted with three, 150-mL portions of 1 N aqueous hydrochloric acid. The combined acid extracts were washed with 200 mL of ethyl ether, cooled to 0°C and neutralized by the dropwise addition of 50%. aqueous sodium hydroxide. The resulting suspension was extracted with three, 300-mL portions of dichloromethane. The combined extracts were washed with water followed by brine, dried over anhydrous potassium carbonate and the solvent removed under vacuum yielding 25 g of crude alcohol, as a mixture with 1-methyl-4-piperidone as evidenced by NMR, IR and TLC. Recrystallization from hexane afforded 21.0 g (83.5 rrunol, 45%) of the alcohol as a white crystalline solid: mp 72-73°C; 1 H-NMR (CDC1 ) o 7.07-6.73 (m, 3H, aromatic), 4.19 (s, lH, OH), 3 3. 93 ( s, 3H, OMe) , 3. 8 2 ( s, 3H, OMe) , 2. 3 0 ( s, 3H, N-CH 3 ) , 2.80-1.73 (broad m, 8H) ppm; IR (CHC1 ) 3520, 1590, 1575, 3 1 1490 cm- . -52- Exact mass calcd. for c H No : 14 21 3 251.152. Found: 251.153. N-Methyl-4-(2,3-dimethoxyphenyl)-l,2,3,6-tetrahydro~~~-~----~-~-------~-~~~----------~---------~--~--- P¥:~~~~~-i~~~· A solution of 20 g (80 mrnol) of N-methyl-4- (2,3-dimethoxyphenyl)-l,2,3,6-tetrahydropyridine (29) and 46 g (2 mmol) of E-toluenesulfonic acid in 600 mL toluene was refluxed with azeotropic removal of water for 2 h. The reaction mixture was extracted with four, 250 mL portions of 1 ~ aqueous hydrochloric acid. The combined extracts were washed with 500 mL ethyl ether, neutralized by careful addition of 50% aqueous sodium hydroxide, and extracted with four, 250-mL portions of dichloromethane. After washing once with brine, and drying over k co the dichloromethane ·was 2 3 evaporated under vacuum to give a yellow oil. Molecular distillation at 98°C (0.004 mm) yielded 17.5 g (95%) of a colorless oil: IR (CHC1 ) 1590, 1575, 1460, 1420 cm 3 -1 1 H-NMR (CDC1 ) o 6.81 (m, 3H, aromatic), 5.75 (t, lH, J = 3 0.5 Hz, =C~-), 3.80 (s, 3H, oc~ ), 3. 71 (s, 3H, oc~ ), 3.11 3 3 (m, 2H, aliphatic), 2.62 Cm, 4H, aliphatic), 2.4 (s, 3H, NC~ ) 3 ppm. Exact mass calcd. for c H No : 14 19 2 233.1417. Found: 233.1409. ~=~~!~¥~:~~=~~!~:~~~!~~~¥P~~~¥~~:~!~!~!~~?!~:~~!~~¥~:~­ ~:~~~~~~~~=-~~~~ · The title compound was prepared by the same procedure described for octahydroisoquinoline (17). -53- Following this procedure, 12 g (~~) gave 8 g (54%) of 33 after bulb-to-bulb distillation at 150°C (0.004 mm): cm 5. 75 (s, lH, 2.91-1.05 -1 1 =C!!_~), H-NMR (CDCl ) 3 o 6. 84 IR (rn, 3H, aromatic) , 3.83 (s, 6H, OC!:!_ ), 2o51 3 (s, 3H, NC!!_ ), 3 (m, 12H, aliphatic) ppm. Exact mass calcd. for c H No : 18 25 2 287.189. Found: 287.188. ~:~:!~¥~:~~=~~!~:~~~:!~~~¥P~:~¥~~=~~~!~~~~?!~~~~::~~­ ~:~~~¥~:~~~~~~~~~~~~~~-P:::~~~:~!:_~~~~ · The title compound was prepared by the same procedure as that described for perchlorate · c21), with one modification. After dissolving the initially formed salt in hot ethanol, it was necessary to maintain the solution at 50°C overnight while the cisimmonium salt formed. Upon cooling to room temperature, the product was collected by filtration. Starting with 150 mg (0.52 mmol) of (33), there was obtained 195.5 mg (97%) of white crystalline 1 H-NMR (CDC1 ) 3 (~~): mp 169-170°C; IR (CHC1 3 ) 1690 cm -1 o 8.9 (s, lH, +N=C!!_-), 7.19-6.68 (m, 3H, aromatic), 3.90 (s, 3H, OC!:!, ), 3.88 3 3H, NC!!. ), 3.5-1.05 3 (CD CN) 3 (s, 3H, OC!!. ), 3.71 (s, 3 13 (m, 13H, aliphatic) ppm; c-NMR o 182.2, 154.5, 148.0, 136.6, 124.8, 120.2, 113.2, 61.0, 56.4, 51.8, 49.2, 43.2, 37.7, 33.7, 28.0, 26.7, 25.1, 22.2 ppm. Anal. calcd. for 3.61. Found: c 18 H26 ClN0 6 : C, 55.74; H, 6.76; N, C,55.51; H, 6.84; N, 3.57. -54- (4aa, Saa, 8bB)-4a-(.2,3-Dimethoxyphenyl)-2-methyl~~------~--~------------~-------~~--~--~~~------- decahydroazirinoil,2-a]isoquinolinium perchlorate (36). -----------------------~--------~--~------------------ To a 0°C solution of 1.33 g (3.43 rnrnol) of cis-irnrnoniurn perchlorate ~~ persisted. Immediate gas evolution was observed. in 50 mL of dichloromethane was added . h ane, 47 d ropwise, . unti'l t h e ye 1 low color e th erea 1 d iazomet The cooling bath was removed and excess diazomethane evaporated under a stream of nitrogen, until the yellow color dispersed. Evaporation under vacuum of the remaining solvent gave 1.38 g (100%) of the title compound as a white crystalline solid: 1 mp 184-186°C; OC~ 3 ), ppm; 13 . H-NMR (CD3CN)o 6.94 3.31 (s, 3H, NC~ ), 3 (m, 3H, ArHO, 3.81 (s, 6H, 3.78-1.50. (m, 16H, aliphatic) C-NMR (CD CN) o 154.7, 149.2, 137.7, 124.4, 121.0, 3 112.9, 60.7, 56.4, 52.3, 51.1, 45.0, 37.9, 35.2, 32.8, 31.3, 27.5, 22.8, 22.1 ppm. Anal. calcd. for 3.49. Found: c19 H28 NCl0 6 : C, 56.80; H, 7.03; N, C, 56.92; H, 6.99; N, 3.85. ~!~!-~~~!-~~~l:!:~~:~~~~!~~~¥~~=~=~~!~¥!:~~=i~!~= ~~~!~~~YP~~~Y!l:~=~~~y~:~~~~~~~~!~~~-i~Z~· A room temperature solution of 150 mg (0.373 mmol) of aziridinium perchlorate 36 and 2 mL of anhydrous dimethyl sulfoxide in 10 mL of anhydrous benzene was stirred for 24 h. Saturated aqueous sodium bicarbonate (10 mL) was added and the mixture extracted with three, 15 mL portions of dichloromethane. The combined extracts were washed with five, 15 mL portions of water, dried -55- (Na 2 so 4 ), and evaporated under vacuum to give 125 mg (95%) of the title compound: IR (CHC1 ) 3000-2800, 1722, 1590, 1570, 3 1460, 1418, 1288, 1260, 1058, 1000 cm -1 1 H-NMR (CDC1 ) 8 3 9.36 (m, lH, CHO), 6.99-6.69 (.m, 3H, ArH), 3.82 (s, 6H, 3 OC~ ), 13 2.22 (s, 3H, 3 NC~ ), ; 3.03-1.23 (rn, 14H, aliphatic) ppm; C-NMR (C 6 D6 ) 8 203.1, 154.4, 149.7, 140.0, 123.5, 120.8, 111.4, 71.8, 59.8, 55.4, 50.3, 44.9, 40.9, 40.4, 34.9, 24.7, 23.2, 21.8 ppm. Exact mass calcd. for c 19 H 27 No 3 ~ 317.199. Found: 317.199. (108, 14a)-3,4-Dimethoxy-10-hydroxy-17-rnethyl-----------------------~----------~~--~------~ ~~=p~~~~~-~~~l· To a room temperature solution of 144.8 mg (0.457 mmol) of carboxaldehyde 37 in 10 mL of anhydrous benzene was added 280 µL (2.28 mmol) of boron trifluoride etherate. After stirring for 1 min, the reaction was quenched by addition of 10 mL of 10% aqueous sodium hydroxide. The mixture was.stirred for 15 min, then the aqueous phase was extracted with three, 15 mL portions of dichloromethane. The combined organic extracts were washed with water, dried (Na so ) and evaporated under vacuum. Flash chromatography 2 4 (7:3, hexane and ethyl acetate, 2.5% triethylamine) afforded 130 mg (90%) of the title compound as a colorless oil: IR (CHC1 ) 3300, 3000-2800, 1590, 1570, 1475, 1288, 1270, 1105, 3 1 1078, 1060, 1046, 1040, 1010, 1000 cm-l; H-NMR (CDC1 ) cS 3 7.29 (d, lH, J = 9 Hz, ArH), 6.84 (d, H, J = 9 Hz, ArH), -56- 4 • 5 7 (d , 1 H, J = 6 Hz , ArC!!_OH ) , 3 • 81 ( s , 3 H , OC !!, ) , 3 " 7 6 ( s , 3 3H, OC!!, ), 3.67 3 (br s, lH, OH), 2.73 (s, 3H, NC!!, ), 3.07-1.03 3 (m, 14H, aliphatic) ppm; 13 C-NMR (cnc13> o 152.3 (s), 146.9 (s), 138.0 (s), 135.5 (.s), 123.6 (d), 111.1 (d), 68.3 (d) , 63.3 ( d) , 60.4 (a) , 55.7 (a) , 47.2 (d) , 46.6 ( t) , 42.9 (a) , 38.6 ( t) , 35.7 ( t) , 29 .. 6 ( t) , 26 "7 ( t) , 23.8 ( t) , 22.9 ( t) , ppm. Exact mass calcd. for c H No : 19 27 3 317.199. Found: 317.198. (14a)-3,4,-Dimethoxy-17-Methylmorphinan (39). . To a room . ~~~--------~--~------~---------~---~-------- temperature solution of 100 mg (0.313 mmol) of carboxaldehyde 37 in 10 mL of anhydrous benzene was added 100 µL (0.813 mmol) of boron trifluoride etherate, followed by 60 µL (0.377 mmol) of triethylsilane. After heating at reflux for 2h, the reaction was cooled to room temperature and 10 mL of 10% aqueous sodium hydroxide added. The mixture was stirred for 15 min, then the aqueous phase was extracted with three, 15 mL portions of dichloromethane. The combined organic extracts were washed once with water, dried (Na so ) and evaporated 2 4 under vacuum. Flash chromatography of the residue (7:3, hexane and ethy:1 acetate, 2.5% triethylamine) gave 75 mg (80%) of the title compound as a colorless oil: IR (CHC1 ) 30003 2 8 O0 , 15 7 5 , 14 6 0 , 14 2 0 , 12 8 4 , 12 6 0 , 1218 , 1 0 6 0 , 1 0 0 2 cm 1 H- NMR ( C n ) 6 6 cS 6 . 7 5 (d , 1 H , J J = 9 Hz , Ar H ) , 3 . 71 2.21 = 9 Hz , Ar H) , ( s , 3 H , OC !!_ ) , 3 . 3 7 3 (s, 3H, NCH ), 3.30 3 6 • 56 (d , 1 H , ( s , 3 H , OC!!_ ) , 3 (m, 16H, aliphatic) ppm. -1 ; -57- Exact mass calcd. for c H No : 19 27 2 301.204. Found: 301. 204 e A perchlorate salt was prepared and found to be a monohydrate: mp 121-122.5. H NCl0 : C, 54.35; H, 7.15; N, 19 30 7 C, 54 .. 03; H, 7.08; N, 3.33 .. Anal. calcd for c 3.33. Found: 1,1-bis-hydroxymethylcyclopropane (41). To a -10°c ------------~~----~----~-------------- solution of 100 gm (769 rnmol) of cyclopropane-1,1-dicarboxylic acid in 1 L of anhydrous tetrahydrofuran was added, dropwise, . d 28 2 . 2 L o f 1 M b orane • THF comp 1 ex, over a 2 h perio e Th e cooling bath was removed, allowing the mixture to warm to room temperaturee After 6 h, the mixture was again cooled to 0°C and 1.5 L of methanol was slowly added (caution: gas evolution). vigorous A distillation head was placed on the reaction vessel and 2.8 L of solvent was distilled off, to concentrate the reaction volume to approximately 1.9 L. Five additional times, 1.5 L methanol was added and distilled off (to remove B(OCH ) ). Evaporation of the remaining solvent and 3 3 distillation gave 75.14 gm (96%) of the title compound, whose 48 physical properties are identical to those reported: bp 125°C/10 mm; IR (CCl4) 3400, 3080, 3007 cm -1 ; 1 H-NMR (CDC1 } 5 4.08 (br s, 2H, O~}, 3.53 (br s, 4H, C~ 2 0H}, 0~49 3 13 (s, 4H, -c~2-}, ppm; C-NMR (CDC13) 0 68.0, 24.2, 8.6 ppm. 1,1-bis-bromomethylcyclopropane (42). To a 0°C solution of 68 g (664 mmol) of 1,1-bis-hydroxymethylcyclopropane (41) -58- in 1 L of dichloromethane was slowly added 75 mL (2.6 g, 800 mmol) of phosphorous tribromide dissolved in 200 mL of dichloromethane, followed by 10 mL (15 g, 90 mmol) of 48% aqueous hydrobromic acid. After stirring for 96 h at room temperature, quenching was accomplished by the addition of 1 L of water and sufficient aqueous sodium hydroxide to adjust the pH ~8. This mixture was stirred for 30 min, then the aqueous phase was extracted with two, 500 mL portions of dichloromethanee The combined organic phases were dried - (Mgso ) and evaporated under vacuume The residue was taken 4 up in 1.5 L of ethyl ether, the solution saturated with HBr gas, and stirred for 8 h; 300 mL of water was added and the mixture basified with 50% aqueous sodium hydroxide. Extraction of the aqueous phase with two, 500 mL portions of ether, washing of the combined extracts with brine, drying (Mgso ), 4 evaporation and distillation under vacuum gave 112.9 g (75%) of the title compound whose physical properties are identical 49 with those reported:bp 67°C/5 mm; IR (CH c1 ) 3050-2900, 2 2 1428, 1328, 1254, 1222, 1054, 1021, 966, 958, 879 cm (CDC 1 ) 3 -1 1 H-NMR o 3 . 5 0 ( s , 4 H , C!!2 Br ) , 0 . 9 0 (_ s , 4 H , -C!i_2 - ) ppm . 4-Bromo-2-bromomethyl-l-butene (8). A solution of 28.0 g -----------~--~---------~---~~~--~- (124 rranol} of sublimed zinc bromide and 28.0 g (.122 rranol) of 1,1-bis-bromomethylcyclopropane (42) in 400 mL of anhydrous benzene was refluxed for 24 h. Upon cooling to room temper~ ature, the solution was filtered through a celite pad and -59- washed with three, 250 rnL portions of saturated aqueous bicarbonate. The solution was dried (Mgso ), evaporated under 4 vacuum, and distilled, giving 22.3 g (80%) of the title compound, whose physical properties are identical with the . 30 1 iterature report bp 65°/5 nun; IR (CHC1 ) 3100-2880, 1640, 3 -1 1 1438, 1260, 1140, 924 cm ; H-NMR (CDC1 ) o 5.29 (s, lH, 3 !:!C=C), 5.05 (s, lH, !:!C=C), 3.96 (s, 2H, Brcg C=C), 3.49 (t, 2H, 2 J = 6 Hz, Brcg cH ), 2 . 77 (t, 2H, J = 6 Hz, BrCH cg ) ppm; 2 2 2 2 13 C-NMR (CDC1 3 ) o 142.1, 117.5, 36.5, 35.8, 30.1 ppm. trans-4a-(2,3-Dimethoxyphenyl)-2-~ethyl-6-methylidene- 3,4,4a,5,6,7,8,8a-octahydroisoquinolinium perchlorate (46a). To a -10°C solution of 23 g· (100 rnrnol) of tetrahydropyridine 30 in 300 mL anhydrous THF was added, dropwise, 65 mL (110 rnrnol) of 1.7 M n-butyllithiurn. After stirring for 15 min, the solution was cooled to -30°C and transferred via cannula into a -78°C solution of 49.9 g of anhydrous ether. (220 nunol) of dibromide (8) in 50 mL The reaction was rapidly warmed to -20°C and 300 mL of ice cold brine added. The organic layer was separated and extracted with three, 600 mL portions of cold 1 N aqueous hydrochloric acid. After washing once with ether, the combined acid extracts were made basic by addition of 50% aqueous sodium hydroxide, while maintaining the temperature at 0°C. The product was extracted into three, 600 mL portions of ether, dried (k co ), and the solvent evaporated under 2 3 vacuum keeping the temperature below 10°C. The residue was -60- inunediately dissolved in 2.5 L of acetonitrile with 37o5 g (250 rnmol) of sodium iodide and 28 g (.202 mmol) of potassium carbonate, and then refluxed for 45 min. After filtration and solvent evaporation, the residue was taken up in 200 mL of ether; to this solution was added a 1:1 mixture of 60% aqueous perchloric acid and methanol, until the solution tested blue on conga red paper (pH<3)~ Scratching of the oily precipitate then induced crystallization. Trituration, with 20% methanol in ether, of the collected solid afforded 24 g (60%) of the title compound: IR (CH c1 ) 3050-2840, 1690, 1576, 1460, 1418, 2 2 1 1 1260, 1095 cm- ; H-NMR (CD CN) o 8.67 (br s, lH, CH=N+), 3 6. 97-6. 41 (m, 3H, ArH), 4. 52 (m, 2H, C!! =C), 3. 87 2 (s, 3H, OC!! ), 3.81 (s, 3H, OCH ), 3.46 (br s, 3H, NC!!3 ), 3.73-1.83 3 3 13 (m, llH, aliphatic) ppm; C-NMR (CD CN) o 182.4, 154.6, 148.8, 3 145.1, 131.2, 123.9, 122.3, 113.7, 111.8, 61.3, 56.5, 52.4, 48.8, 47.7, 43.0, 35.2, 34.7, 27.0 ppmo Anal. calcd for c Found: H No Cl: 19 26 6 C, 57.07; H, 6.54; N, 3.50. C, 56.91; H, 6.60; N, 3.41. Partition of immonium salt 46a between dichloromethane and 1 N aqueous sodium hydroxide, followed by solvent evaporation and bulb to bulb distillation (135°C/0.005 mm) afforded 4a-(2,3-dimethyoxyphenyl)-2-methyl-6-methylidene-2,3,4,4a,5, 1 6,7,8-octahydroisoquinoline (45) as a colorless oil: H-NMR (CDC1 ) o 6.91-6.69 (m, 3H, ArH), 5.80 (s, lH, C=C!!N), 4.50 3 (s, 2H, C!! =C), 3.74 (s, 3H, OC!! ), 3.80 (s, 3H, OC!!3 ), 2.52 3 2 -61- (.m, lOH, aliphatic) ppm; 13 C-NMR (s, 3H, NC~ ), (CDC1 ) 3 o 153.2, 147 .. 7, 147.3, 138.9, 133.7, 125.1, 122a0, 3 3. 42-1. 63 112.8, 110.9, 108.4, 60.2, 55.7, 46.7, 46.2, 44.5, 42.7, 37.8, 36.1, 31.8 ppm. Exact mass calcd. for c19 H25 No 2 : 299.189. Found: 299.190. i~~~!.-~~::! . . ~~~~=~~:i~~::~~?~¥P~::~¥~~:~:~:~~¥!:~:1!.1::~~¥~~dene-decahydroazirino- [1, 2-aJ isoquino1inium perchlorate (47). --------------~----~-~-~---~-~--~--~---~-------------~------ Trans-immonium perchlorate 46a (15 g, 37.5 mmol) was equilibrated by dissolution in 1 L of methanol with stirring at 55°C for 24 h. Evaporation of the solvent gave cis-4a- ------ ~~!~=~~1!.1::~~?~¥P~::~¥~~:~:~~~~¥~:~:1!.1~~~¥!~~:~::~!.~!.~~!.~~~!.Z!.~! ~~:?:~~~¥~:?~~?g~~~~~~~~~-P~=~~~~=~~:-~~§~~(cis:trans, 95:5) 1 H-NMR (CD CN) 3 Ar H) , + o 8.63 (br s, lH, CH=N ) , 7 .06-6. 75 50 (m, 3H, 4 . 81 (m , 2 H , C!:! =C ) , 3 • 8 7 ( s , 3 H , OC !:!_ ) , 3 . 8 3 ( s , 3 H , 3 2 OC!:!_ ), 3.49 (br s, 3H, NC!!_ ), 3.73-1.80 (m, llH, aliphatic) 3 3 13 ppm; C-NMR (CD CN) 8 181.4, 154.6, 148.9, 144.6, 136.2, 3 124.8, 120.2, 113.7, 111.9, 61.2, 56.5, 52.2, 49.3, 43.1, 42.6, 39.3, 33.2, 27.6, 27.1 ppm. To a 0°C solution of the cis inunonium salt 46b in 200 mL anhydrous dichloromethane was added ethereal diazomethane, until the yellow color persisted. Inunediate gas evolution was observed, followed shortly afterward by formation of a copious precipitate. Excess diazomethane was evaporated under a stream of nitrogen, then the remaining solvent was removed : -62- under vacuum. Trituration of the residue with cold ethyl ether gave 14.8-g (95%) of the title compound as a tan solid; mp 186-188°C; IR (CH cl ) 3060-2840, 1575, 1465, 1420, 1255, 2 2 1 1090, 1000 cm-l; H-NMR (CD CN) o 7.02-6.87 (m, 3H, ArH), 3 4.81 (m, 2H, C!!_ =C), 3o79 (s, 6H, OC!!, ), 3.07 (s, 3H, NC!!, ), 2 3 3 13 3.72-1.67 (m, 14H, aliphatic) ppm; c-NMR (CD CN) o 154.5, 3 148.8, 145.7, 138.3, 124.1, 121.3, 113.3, 111.4, 60.8, 56.5, 53.5, 50.8, 50.7, 46.2, 43.3, 39.4, 34.8, 30.4, 27.6 ppmv Anal. calcd. for c Found: H NCl0 : 20 28 6 C, 58.04; H, 6.82; N, 3.380 C, 58.08; H, 6.85; N, 3o44. Flash chromatography (1:1, hexane and ethyl acetate, 0.25% triethylamine) of the mother liquors from trituration of aziridinium salt 47 afforded 9.4 mg (0.08%) of morphinan SO. ~~~~-~~~~-~~~~=~~=~~~~=~~~~¥P~:~¥~~:~:~:~~¥~:~: ~~~~¥~~~~~~=~~~~~¥~~~~~~g~~~~~~~~=~=~~~~~~~~~=~¥~=-i~~~: solution of 4.0 g A (9.7 mmol) of aziridinium salt 47 and 20 mL (280 mmol) of anhydrous dimethyl sulfoxide in 100 mL of benzene was stirred at room temperature for 36 h. The mixture was then mixed with 100 mL saturated aqueous sodium bicarbonate for 15 min. After extraction of the aqueous phase with two, 100 mL portions of dichloromethane, the combined organic phases were washed with three, 100 mL portions of water, dried (Na 2 so 4 ) and evaporated, giving 3.04 g 3060-2800, 1729, 1576, 1462, 1422, 1270, 1062, 1005 cm (C D /cD CN) 3 6 6 8 9. 29 IR (CH 2 cl 2 ) (95%) of the title compound: (d, lH, J = 5 Hz, C!!.0), 7. 08-6. 62 -1 ; 1 H~NMR (m, 3H, -63- ArH), 4. 68 (s, 2H, CH =C), 3. 75 (s, 3H, OC!! ), 3 .42 (s, 3H, 2 3 OC!! ), 2.19 (s, 3H, NC!! ), 3.28-1.35 (m, 12H, aliphatic) 3 3 ppm. Exact mass calcd. for c 20 H27 No3 : 329.199. Found: 329.198. ~~~~~-~~~~=~~~=~~~~~~~~¥:~~:~¥~:~~¥:~=~~~~¥~~~~~~=~Z: ~~~~¥~:~~:p~~~~~-~~:~· To a -10°C solution of 403.6 mg (1.22 mmol) of carboxalde 48 in 50 mL toluene and 15 mL dichloromethane was added, dropwise, 380 µL boron trifluoride etherate. (3.09 mmol) of After 2 h, the reaction was quenched by addition of 30 mL of 10% aqueous sodium hydroxide and stirred for 1 hr more. The aqueous phase was extracted with two, 25 mL portions of dichloromethane and the combined organic extracts were washed with brine, dried (Na so ) and 2 4 evaporated to give a brown oil. Filtration through silica gel (6 gm, silica gel 60, 60-200µ; ethyl acetate, 0.5% triethyl amine) gave 318 mg (80%) of a colorless oil composed of the title compound and a trace of the lOa-hydroxy epimer 49a. In a separate experiment, 1.64 g (4.98 mmol) of a mixture of carbinol epimers were separated by flash chromatography (ethyl acetate, 0.5% triethylamine) to give 1330 mg of 10 S-hydroxy-morphinan 49 and 67 mg of lOa-hydroxy-morphinan 49a (49:49a, 95:5). For 49: IR (CH Cl ) 3600, 3080-2800, 1600, 1480, 1260, 2 2 1100, 1060, 1005 cm -1 ; 1 H-NMR (C D ) 6 6 o 7.62 (d, lH, J = 9 Hz, -64- ArH) , 6 . 61 {d , 1 H , J = 9 Hz , Ar H) , 4 • 8 5 (m , 2 H , C!! =C) , 2 4.67 (d, lH, J = 6 Hz, ArCHOH), 3.82-3. 75 {m, lH, H ), 3. 72 52 {s, 3H, OC!!3 ), 3.33 (s, 3H, OC!! ), 2.42 ~s, lH, NC!! ), 2.633 3 13 1.14 (m, 12H, aliphatic) ppm; c-NMR (C o ) o 152.7, 147.4, 6 6 137.0, 123.9, 111.8, 110.0, 69.4, 63.3, 60.0, 55.4, 47.1, 46.6, 45.5, 42.4, 40.3, 35.4, 30.3, 25.2 ppm. Exact mass calcd. for c H No : 20 27 3 329.1992. Found: 329.1991. IR (CH Cl ) 3600, 3020-2800, 1600, 1480, 1260, 2 2 -1 1 1 0 6 0 , 10 0 5 cm ; H- NMR ( C D ) o 7 . 0 7 {d , 1 H , J = 9 Hz , Ar H) , 6 6 For 49a: 6. 56 (d, lH, J = 9 Hz, ArH), 4. 91 (br s, 2H, C!! =C), 4 033 2 (br s, lH, ArC!!OH), 3.88-3.74 (m, lH, H ), 3.70 (s, 3H1 52 OC!!3 ) , 3 . 3 5 ( s , 3 H , OC ~ ) , 2 . 3 0 ( s , 3 H , NC!! ) , 2 . 8 3-1 . 3 7 (m , 3 3 13 12H, aliphatic) ppm; C-NMR (C D ) o 153.4, 147.8, 134.8, 6 6 111.5, 110.2, 72.4, 65.8, 63.9, 60.0, 55.4, 48.0, 44.8, 43 1, 0 39.2, 37.8, 35.1, 29.2, 28.6 ppm. Exact mass calcd. for c H No : 20 27 3 329.1992. Found: 329.1992. i~~~~=~!~=~~~~~~~~¥:!Z:~=!~¥!:~:~=!~¥!~~~~~=~~:P~~~~~ (50). To a -10°C solution of 1.31 g morphinan ~~ (3.98 rrunol) of 10-hydroxy- (containing approximately 5% was added 850 µL ~~~) in 75 mL THF (617 mg, 6 rrunol) of triethylamine followed by 350 µL {518 -mg, 4.5 nunol) of methanesulfonyl chloride. After 1 h, during which time the solution had become heterogeneous, 20 mL of 1 M lithium triethylborohydride in THF was -65- added. Immediate gas evolution was observed along with clearing of the reaction mixture. The cooling bath was removed and 1.5 h later, 50 mL of methanol was carefully added. The mixture was cooled to 0°C and 10 mL of 3 N aqueous sodium hydroxide was added, followed by 10 mL of 30% aqueous hydrogen peroxide (caution: reaction results). a very exothermic Heating at reflux was then carried out after the initial vigorous reaction had subsided. Additional portions of 10 mL 3 N NaOH and 10 mL 30% H o were added at 2 2 2 h intervals over a 10 h period, then the mixture was refluxed for 8 h more. Upon cooling to room temperature, the solution was concentrated under vacuum, diluted with 100 mL of water and extracted with three, 10 mL portions of dichloromethane. Drying (Na 2 so 4 ) of the combined extracts, evaporation, and filtration through silica gel (10 g, 60-230 µm; ethyl acetate, 0.5% triethylamine) afforded 1.12 g (90%) of the title compound: 1280, 1060, 1040 cmArH), 6.54 1 1 IR (CH cl 2 ) 3080-2800, 1480, 2 H-NMR (C6D6) 8 6.73 (d, lH, J = 9 Hz, (d, lH, J = 9 Hz, ArH), 4.93 (br s, 2H, 3.97-3.83 (m, lH, C=CC!!), 3.73 (s, 3H, 3 OC~ ), 2 c~ =C), 3.38 (s, 3H, OC!! ) , 2.19 (s, 3H, NC!!3 ) , 3.12-1.33 (m, 13H, aliphatic) 3 13 c-NMR (C6D6) 0 151.9 ( s) ' 149.1 ( s) , 148.0 ( s) , ppm; 138.4 ( s) ' 132.0 ( s) , 123.2 (d) ' 111.5 (d) , 110.0 ( t) , 60.1 (a) ' 58.7 ( d) ' 55.6 (a) , 48.2 (t) , 45.2 (t) ' 43.1 (a) , 43.0 (d) ' 38.8 ( s) ' 35.1 ( t) ' 30.0 ( t) ' 28.8 ( t) ' 28.7 ( t) ppm. -66- Exact mass calcd. for c H No : 20 27 2 313.2043. Found: 313.2036. A picrate salt was prepared and recrystallized from chloroform-methanol: mp Anal. calcd. for c 10.33. Found: 201.5~203.5. H N o : 26 30 4 9 C, 57.56; H, 5.57; N, C, 57.40, H, 5.57; N, 10.26. ~~~~~=~!~=~~:~~¥~=~~=~=~~¥~=~~:p~~~~~=~=~~:_i~~~To a 0°C solution of 2.44 g (7.78 mrnol) of 6-methylene- morphinan 50 in 60 mL of tetrahydrofuran and 20 mL glacial acetic acid was added 2.9 mL (0.39 mrnol) of 0.135 M aqueous osmium tetrroxide and 47 mL (23.5 mrnol) of 0.5 M aqueous sodium periodate. The solution was allowed to gradually warm to room temperature, accompanied by formation of a copious white precipitate. The precipitate was removed by filtration and washed with glacial acetic acid. After concentration of the filtrate under vacuum, the residue was diluted with 100 mL of water and extracted with three, 75'mL portions of dichloromethane. The combined extracts were washed with 150 mL of water, dried (Na so ) and evaporated under vacuum. 2 4 through silica gel Filtration (10 g, 60-230 µm; ethyl acetate, 0.5% triethylamine) afforded 2.23 g (90%) of the title compound: IR (CH cl ) 3060-2800, 1700, 1480, 1420, 1265, 1150, 1089, 2 2 1058, 1036 cm-l 1 H-NMR (C D ) 8 6.71 (d, lH, J = 9 Hz, ArH), 6 6 6.50 (d, lH, J = 9 Hz, ArH), 3.93 (dd, J = 15 Hz, J = 1.5 Hz, H ) , 3 . 7 7 ( s, 3 H, OC!:.!_ ) , 3 . 3 4 ( s , 3 H, OC!!_ ) , 2 .11 ( s, 3 H , 3 3 52 -67- oc~3 ), 3 . 06-1.38 (m, 13H, aliphatic) ppm; 13 c-NMR cc n ) 6 6 8 209.6 (s), 151.9 (s), 148.7 (s), 136.8 (s), 131.1 (s), 123.2 (d), 111.8 (d), 60.0 (a), 57.8 (d), 55.6 (a), 51.9 (t), 47.9 (t), 42.8 (a), 41.7 (d), 40.8 (t), 40.4 (s), 3.13 (t), 2 8 . 5 ( t ) , 2 6 . 9 ( t ) ppm . Exact mass calcd. for c H No : 19 25 3 315.1836. Found: 315.1831. Anal. calcd. for c 10.15 .. Found: H N o : 25 28 4 10 C, 55.14; H, 5.18; N, C, 54.92; H, 5.12; N, 10.29. (14a)-3,4-Dimethoxy-7-ene-17-methyl-6-trimethylsilyloxy----------------------------~-------------------------~~:p~~~~~-~~~~· A solution of lithium diisopropylamide (LDA) was prepared by adding 590 µL (1.02 mmol) of 1.7 Mn-butyl- lithium in hexane to a -30°C solution of 190 µL (1.36 mmol) of diisopropylamine in 40 mL of anhydrous THF and stirring for 15 min. To the LOA solution (cooled to -78°C) was added 214 mg (0.678 rnmol) of morphinan-6-one (51) dissolved in 4 mL of THF. After 30 min, 1 mL of a solution of 1.75 mL (13.8 rnmol) I of trimethylsilylchloride and 0.9 mL (6.46 rnmol) of triethylamine in 7.3 mL THF, was added all at once. The cooling bath was then removed and when the mixture had warmed to room temperature, 20 mL of saturated aqueous sodium bicarbonate was added, followed by vigorous stirring for 20 min. Dilution of the aqueous phase with 2"0 mL of water, extraction with dichloromethane, drying (Na so ) of the combined organic 2 4 phases, and evaporation under vacuum gave 252 mg (96%) of -68- the title compound: IR (.CH c1 3060-2800, 1685, 1600, 1482, 2 2 -1 1 1275, 1190, 1165, 1150, 1086, 1058 cm ; H-NMR (C D ) 8 6 6 6. 72 (d, lHz, J = 9 Hz, ArH), 6.52 (.d, lH, J = 9 Hz, ArH), (m, lH, OC=C!!), 3 . .77 {s, 3H, OC!!, ), 3.38 {s, 3H, OC!!, ), 3 3 2.43 {s, 3H, NC!!3 ), 3.55-1.18 {m, 12H, aliphatic), 0.28 {s, 5.08 9H, Si{C!!3 ) 3 ) ppm; 13 C-NMR {c o ) 8 151.9, 149.1, 149.0, 6 6 138.0, 131.4, 123.2, 113.2, 111.6, 101.6, 60.0, 57.2, 55.6, 53.4, 48.5, 42.8, 42.3, , 41.8, 38.9, 38.6, 36.7, 30.9, 28.7, 25.9 ppme Exact mass calcd. for c H No si: 22 33 3 387.2231. Found: 387.2223. iZ~!-!~~2:~!~=~~~~!:~~¥:!Z:~~~~¥!:Z:P~~::¥!~~!~::~~~:P~~::~::­ ~:~::~-J~~~~-~::~_jz~!_!~~~=~!~:~~~~~~~~¥:!Z:~~~~¥!:Z:P~~::¥!­ ~~!~::~=~~:P!:~::~:::~:~::~--~~~~2. To a room temperature solution of 338 . 1 mg (0.87 mmol) silyl enol ether 52 in 50 mL of benzene was added 167 mg {0.87 mmol) of phenylselenyl chl_o ride in 3 mL of benzene. After 15 min, 50 mL of saturated aqueous sodium bicarbonate was added and the aqueous phase was extracted with two, 50 mL portions of dichloromethane. The combined extracts were dried (Na so ), evaporated under vacuum, and filtered 2 4 through silica gel {6 g, 60-200 µ; 1:1 hexane and ethyl acetate, 0.5% triethylamine) to give 240 mg (60%) of a 1:1 mixture epimeric selenides. o~ IR (CH c1 ) 3050-2800, 1694, 1595, 1574, 2 2 1 1478, 1450, 1425, 1250, 1055, 1035 cm- . -69- Flash chromatograph (1:1 hexane and ethyl acetate, 0.5% triethylamine) afforded a pure sample of each C-7 epimer of unassigned stereochemistry. 1 H-NMR (c n ) o 7.58 (m, 2H, sePh~), 6 6 6 . 9 0 (m , 3 H , s e P hH) , 6 . 7 0 (d , 1 H, J = 9 Hz , Ar H) , 6 . 5 0 ( d , For epimer A: lH, J = 9 Hz, ArH), 4.09 (m, H, 3.39 (s, 3H, 3 OC~ ), 2.11 (s, 3H, SeC~), 3.75 (s, 3H, 3 NC~ ), OC~ ), 3 3.87-1.53 (m, 12H, aliphatic) ppm. For epimer B: 6.95 (m, 3H, se~h~), H, J Ar~), :::::i 9 Hz, 3.34 (s, 3H, OC~ 6.60 (d, lH, J 4.04 (m, lH, = 9 Hz, ArH), SeC~), 6.49 (d, 3.58 (s, 3H, 3 OC~ ), 3 ), 2.13 (s, 3H, NC~3 ), 3.63-1.53 (m, 12H, aliphatic) ppm. Exact mass calcd. for c H No se: 25 29 3 471.1314. Found: 471.1315. ~~~~~=~!~=~~=~~~~¥:Z::~=:~?:~:~~¥~:~~~P~~~~~=~=~~~ . (54). A solution of 239.8 mg (0.51 nunol) of a 1:1 mixture of selenides 53a and 53b in 30 mL dichloromethane was stirred with 40 µL (0.51 nunol) of trifluoracetic acid and 300 µL (2.55 mmol) of 90% t-butyl hydroperoxide, at room temperature for 3 days. added. Saturated aqueous sodium bicarbonate (30 mL) was After vigorous stirring for 30 min, the organic phase was dried (Na s? ) and evaporated under vacuum to give 143.8 mg 2 4 (90%) of the title -compound: IR (CH c1 ) 3065-2850, 1672, 1482, 2 2 1280, 1150, 1098, 1060, 1040, 1022 cm -1 ; 1 H-NMR (CD CN) 3 o -70- 6. 94 (dd, lH, J = 10 Hz, S = 1 Hz, C_!!C=CC=O), 6. 84 (s, 2H, ArH), 6.02 (dd, lH, J = 10 Hz, J = 3 Hz, C=C!!_C=O), 3.78 (s, 3H, OC_!! ), 3. 75 (s, 3H, OC!!_ ), 2.27 3 3 (s, 3H, NC!!_ ), 3. 723 1.16 (m, lOH, aliphatic) ppm. Exact mass calcd. for c H No : 19 23 3 313.1679. Found: 313.1675. 3,4-Dimethoxy-6-hydroxy-morphinan-5,8-diene-7-one (56a). -------------------~-------~--~------------------------ To a suspension of 64.3 mg (0.21 mmol) enone ~~' 50 mg (0.45 mmol) potassium t-butoxide, and 21.0 mg (0.2mmol) sodium bisulfite in 3 mL dimethyl sulfoxide and 0.5 rnL t-butyl alcohol was added 4.7 mL (0.21 mrnol) oxygen via a gas tight syringe, with immediate formation of a deep red color. After 5 min, 30 mL of water was added and the mixture was extracted with three, 25 mL portions of dichloromethane. The combined extracts were washed with three, 30 mL portions of water, dried (Na so ) and evaporated to give 33.5 mg (50%) of the 2 4 IR (CH cl ) 3425, 3058-2820, 1670, 1650, 1620, 2 2 -1 1 H-NMR (CDC1 ) 8 7.54 ( s' 1482, 1422, 1260, 1218, 1040 cm 3 title compound: 1 H' c =C !!. ) ' 6 • 88 (s ' 2 H ' Ar H ) ' 6 . 4 5 ( s ' 1 H ' c =C !!. ) ' 3 . 94 (s I 3 H' OC!!. ), 3.89 (s, 3H, OC!!. ), 2.48 (s, 3H, NC!!. ), 3.5-1.74 (m, 3 3 3 13 7H, aliphatic) ppm; c-NMR (CDC1 ) 8 181.8, 165.0, 152.1, 3 147.3, 146.9, 131.9, 123.0, 122.6, 120.2, 111.8, 61.3, 60.6, 55.9, 46.4, 43.9, 41.6, 38.4, 32.9 ppm. Exact mass calcd. for c 327.1463. H No : 19 21 4 327.1471. Found: -71- (146)-3,4-Dirnethoxy-17-methyl-morphinan-6-one (57) was -------------~-----~---~-----~--------~----------- prepared by base-catalyzed equilibration of ll4a)-morphinan ~~ to (14B)-morphinan ~~ and subsequent hydrogenation. room temperature solution of 38 mg (0 .12 mmol) morphinan ~~ A (14a) - and 1. 2 mL of 0 .1 M aqueous potassium hydroxide in 3 mL of methanol was stirred for 23 h. Dilution with 10 mL of aqueous sodium bicarbonate, extraction with three, 20 mL portions of dichloromethane, drying (Na 2 so 4 ), and evaporation under vacuum gave 36.8 mg of a mixture of crude enones (14S: 6 14a, approximately 80:20). This mixture was immediately hydrogenated at 1 atrn with 5 mg of 5% Pd/C in 2 mL of methanol, for 24 h. Filtration, evaporation of the filtrate, and flash chromatography (ethyl acetate, 2.5% triethylamine) afforded 15 mg (40%) of (14B)-morphinan 57 along with 4 mg of (14a)-morphinan 51. The 1 H, 13 C-NMR.and IR spectra, as well as the TLC mobility, of 57 were identical with an authentic sample. 45 For (14B)-3,4-dimethoxy-7-ene-17-methylmorphinan-6-one ---~-----------------------------~-------------------- (55): 1 H-NMR (CD3CN) 8 6.81 (dd, lH, J = 10 Hz, J = 3 Hz, C!:!_=C C=O) , 6 . 7 6 ( s , 2 H , Ar H) , 5 . 7 7 (d d , lH , J J = 1 0 Hz , = 3 Hz, C=C!:!_C=O), 3.91 (m, lH, H ), 3.62 (s, 3H, OC!:!.3 ), 52 3.59 (s, 3H, OCH ), 2.34 3 (s, 3H, NC!:!_ ), 3.22-1.28 3 (m, 9H, aliphatic) ppm. Exact mass calcd. for 313.1676. c19 H23 No 3 : 313.1679. Found: -72- For (148)-morphinan 57: 1600, 1480, 1260, 1050 cm Ar H ) , 3 . 9 9 (d d , 1 H , J -1 ; IR (CH cl ) 3060-2800, 1706, 2 2 1 H-NMR (CDC1 ) 6.76 3 (br s, 2H, = 14 Hz , J = 2 • 5 Hz , H5 2 ) , 3 • 9 4 (s , 3H, OC!:!_ ), 3.80 (s, 3H, OC!:!_ ), 2.41 (s, 3H, NC!:!_ ) ppm; 3 3 3 13 c-NMR (CDC1 ) o 210.5, 151.5, 148.9, 130.4, 130.2, 122.9, 3 111.4, 60.3, 57.0, 55.8, 51.3, 46.5, 45.6, 42.6, 41.5, 41.1, 40.0, 27.0, 24.0 ppm. Ex:act mass calcd. for c 315.1830. H No : 14 25 3 315.1836. Found: -73- Refer·e nces and Notes 1) (a) Jacobson, A. E. "Handbook of Psychopharmacology, Drugs of Abuse". Iverson, L. L .. ; Iverson, s. D.; Snyder, S. H., Ed., Volume 12; Plenum Press: 1978, Chapter 2. (b) Eddy, N. B.; May E. L. "Synthetic Analgesics". Part IIB; Pergamon Press: London, 1966. (c) Palmer, D. C.; Strauss, M. J. 72, 1. (d) Lednicer, D.; Mitscher, L. A. ~~zz, "The Organic Chemistry of Drug Synthesis''. and Sons: 2) New York, Chem. Rev. John Wiley New York, 1977; Chapter 15. For recent examples of the numerous patents in this area, see: (a) Marshall, W. S.; Zimmerman, D. M. 1981, 2_!, 3939a. (b) Ripka, W. C. Chem. Abstr. Chem. Abstr. ~~I~' 91 56845a. 3) (a) Evans, D. A.; Mitch, C. H.; Thomas, R. C.; Zimmerman, D. M.; Robey, R. L. J. Am. Chem. Soc. (b) Evans, D. A.; Mitch, C. H. 102, 5955. ~~~~' Tetrahedron Lett. 1982, 285. 4) For previous approaches to the synthesis of morphine and related compounds, see: (a) Gates, M.; Tschud, G. J. Am. Chem. Soc. ~' J. Chem. Soc. 1956, !~~~' 3052. Steglich, W.; Thomas, G. M. 203. 1380. (b) Elad, D.; Ginsburg, D. (c) Barton D, H. R.; Kirby, G. W.; Proc. Chem. Soc., London ~~~~' (d) Barton, D. H. R.; Bhakuni, D. S.; James, R.; Kirby, G. w. J. Chem. Soc., c. ~~~~' 128. (e) Schwartz, M.A.; -74- Zoda, M. F. !~~!' J. Org. Chem. i.§_, 4623. (g) Szantay, c.; Barczai-Beke, M; Pechy, P.; Blask6, G.; Dornyei, G. !~~~' J. Org. Chem. i2_, 594. (h) Beyerman, H. C.; vanBerkel, J.; Lie, T. S.; Maat, L.; Wessels, J.C. M.; Bosman, H. H.; Buurman, E.; Bijsterwald, E. J.M.; Sinnige, H. J. M. (i) Rice, K. C. 12(~, Rec. Trav. Chim. J. Org. Chem. !~~~' !~z~, 43, 1462. ~.; Rice, K. C. J. Org. Chem. (1) Weller, D. D.; Rapoport, H. !~§~, 5) 1979, J. Med. Chem. (m) Gates, M.; Shepard, M. S. Chem. Soc. ( j ) Ii j im a , I , ; (k) Dauben, W. G.; Baskin, C. P.; van Rhiel, H. C. H. A. 44, 1567. 127. 45, 3135. Minamikawa, J.; Jacobson, A. E.; Brossi, J. Ora. Chem. ~' J. Am. §_i, 4125. w. M. Boekelheide, V.; Schilling, !~~z, J. Am. Chem. Soc. .§2_, 790. J. Am. Chem. Soc. ~~~~' 22_, 379. 6) Gates, M.; Helg, R. 7) Compounds 11-19 were prepared in experiments carried out _ ...... -- by Dr. Dennis M. Zinuuerman, Eli Lilly Research Laboratories, Indianapolis, Indiana. 8) (a) Martin, s. F.; Dupriest, M. F. (b) Levine, 3925. 91369p. R~; Rell, v. Tetrahedron Lett. Chem. Abstr. (c) Rauchswabe, G.; Ahlbrecht, H. 663. (d) Renger, B.; Seebach, D. 2334. (e) Macdonald, T. L. (f) Ahlbrecht, H. chimia Chem. ~~zz, 31, 391. Synthesis Ber~ J. Or g . Chem. 1974, 1977, ~' 1974, 1977, 110, 1980, ......, ......, ......, ......, -45,· 193. (g) Ahlbrecht, H.; -75- Bonnet, G.; Enders, D.; Zimmerman, G. Tetrahedron Lett. 1980, 3175. (h) Ahlbrecht, H,; Eichler, J. 1974, 672. (i) Hassel, T.; Seebach, D. Int. Ed. Engl. 1979, 18, 399. Tetrahedron Lett. (1) Ahlbrecht, H.; Rauchswalbe, G. 1974, 279, 609. Synthesis 1973, 417. J. Am. Chem. Soc. McElvain, S. M.; Clemens, D. H. ~' 1974, (k) Savignac, P.; Coutrot, P.; Leroux, Y. c. R. Hebd. Seances Acad. Sci. Ser. C 9) Angew. Chem. ( j ) Ju 1 i a , .M • ; Schouteeten, A.; Baillarge, M. 3433. Synthesis 1958, 3915. 10) May, E. L.; Murphy, J. G. J. Org. Chem. 1954, 19, 618. 11) Booth, H.; Bailey, J. M. J. Chem. Soc. Perkin II 1979, 5100 12) Dalling, D. K.; Grant, D. M,; Paul, E. G. JJ]]' 13) J. Arn. Chern. Soc. 95' 3718. Robey, R. L.; Zimmerman, D. M. Chem. Abstr. 1981, 2_i, 121354t. 14) (a) Boekelheide, V.; Schwilling, W. M. 1950, 7l:_, 712. Werner, L. H. J. Arn. Chem. Soc. (b) Finch, N.; Blanchard, L.; Puckett, R. T.; J. Org. Chem. D. D.; Rapoport, H. !~Zi' 39, 1118. J. Arn. Chem. Soc, (d) Stereochemical Assignments for ~~ ~~z~, (c) Weller, 98, 6650. and 20 were made by comparison of melting points with the literature values: 19·picrate, mp 220-222°C (reported: b,c ~18.5-22 °C); 4 20·HC1, mp 219.5-221.5 (.reported: 14b 222-224PC). The trans -76stereochernistry assigned to 19 was confirmed by X-ray . 15 As d escri'b e d in ' ' ana 1 ysis. the discussion on pyridines 16 and 17, l~ -c-NMR was also found useful for assign.111ent of cis versus trans ring fusion. 11 , 12 15) Chaney, M. O.; Jones, N. D.; Eli Lilly Research Laboratories. 16) Unpublished results. Following our initial report on the stereochernistry of protonation of aryloctahydroisoquinolines, Rapoport has noted similar observations: Rapoport, H. 3 J. Org. Chern. Moos, W. H.; Gless, R. D.; ~~~~' !§_, 5064. For a related system where ring-fusion stereochemistry is determined by protonation of an amide enolate, see ref. 12c and: Weller, D. D.; Gless, R. D.; Rapoport, H. 1977 f 17) ~, 1485. (a) Burgi, H.B.; Lehn, J.M.; Wipff, G. 1974 f 96 I 1956 • Burgi, H.B. Tetrahedron ~~~i' ~' 1563. Angew. Chem., Int. Ed. Engl. (a) Stevens, R. V.; Lee, A. W. M. (b) Hegarty, A. F. Acc. Chern. Res. (c) !_~7_~, 14, 460. J. Am. Chem. Soc. 101, 7032; J. Chem. Soc., Chem. Corrunun. 19) J. Am. Chem. Soc. (b) Burgi, H. B.; Dunitz, J. D.; Lehn, J.M.; Wipf£, G. 18) J. Org. Chern. !.~I~' 1982, 102, 103. 1980, 13, 448. Unfortunately, the relevent stereocontrol elements in this conversion are obscured by the two half-chair conformations accessible to 22. 20) Crist, D. R.; Leonard, N. J. 1969, ~' 962. Angew. Chem., Int. Ed. Engl. -77- 21) For a related cyclization, see: Surzur , J. 1981, 37, 22) Tetrahedron Lett. Gates, M.; Woodward, R. B.; Newhall, ~ (a) Gilman, H.; Swiss, J.; Cheney, L. !~~9, 62, 1963. c. J. Am. Chem. Soc. (b) Bergmann, E. D.; Pappo, R.; J. Chem. Soc. Ginsburg, D. w. F.; Kunzli, M. 1950, 72, 1141. ---~ 24) 1977, 2721; Tetrahedron, 2843~ J. Ame Chem. Soc. 23) Stella, L.; Raynier, B . ; 1950, 1369. While in principle both aziridinium salts 36 and 47 could be cyclized to the morphinan skeleton, neither one could be thermally induced to undergo such a closure reaction. 25) (a) Averbach, J.; Weinreb, S. M. J. Am. Chem. Soc. J. Org. Chem. (b) Gless, R. D.; Rapoport, H. 94, 7172. 1972, 1979, !i_, 1324 . 26) Mancuso, A. J.; Swern, D. Synthesis 1981, 165 and references therein. 27) (a) Doyle, M. P.; West, C. T.; Donelly, S. J.; McOsker, c. c. (b) West, c. T.; Donelly, S. J.; Kooistra, D. A.; Doyle M. P. J. Organomet. Chern. J. Org. Chem. 1973, ~' 1976, 117, 129. 2675. (c) Adlington, M. G.; Orfanopoulis, M.; Fry, J. L. Tetrahedron Lett. Parnes, z. N.; Loim, N. M, (e) Nagai, Y. 28) 1976, 2955. Org. Prep. (d) Kursanov, D, N.; Synthesis Proc~ Singh, R. K.; Danishefsky, S. Int. 1974, 633. 1980, 12, 13. Org. Syn. 1981, 60, 66. -78- 29) J. org. Chem. Sims, H. 30) c. (a) Hutchins, R. O.; Masilamani, D.; Maryanoff, ~~z~, Org. Syn. 41, 1071. ~~§~, (_b) Hwa, J. C. H,; !!_, 49. (a) Applequist, D. E.; Roberts, J. D. ~~~~' ~' 874. J. Arn. Chem. Soc. (b) Applequist, D. E.; Ph.D. Thesis, California Institute of Technology, 1955. 31) The unsubstituted phenyl analogue of 46 equilibrates only to the ~xtent of cis:trans 32) = 90:10. The corresponding benzomorphan analogues show a similar difference in Jab for the 10-0H ~ and (a) Inoue, H.; May, E. L. (b) Inoue, H.; Oh-ishi, T.; May, E. L. B isomers: J. Med. Chem. 1976, 19, 259. ---- -- J. Med. Chern. 1975, 18, 787. 33) Crossland, R. K.; Servis, K. L. J. Org. Chem. 1970, ~, 31955. 34) (a) Holder, R. W.; Matturro, M. G. 42, 2166. J. Org. Chem. (b) Krishnamurthy, S.; Brown, H. C. 1977, J. Org. Chern. 1976, 41, 3064. 35) (a) Djerassi, C.; Vorbruegen, H. ~, 2990. 1957 I 36) (b) Dvornik, D.; Edwards, O. E. (b) Sharpless, K. J. Am. Chem. Soc. Can. J. Chem. 1973, J. Org. Chem. ~~z~, Q, F.; Teranishi, A. Y. B~; Lauer, R~ ~, 6137. (c) Reich, H.J.; Renga, J.M.; Reich, I. L. 5434. l~~~, 35, 860. (a) Hori, T.; Sharpless, K. B. 1689. J. Am. Chern. Soc. J. Am. Chern. Soc. 1975, ~' -79- 37) D~ (a) House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. ~' J. Org. Chem. 1969, Hudrlick, P. J. Am. Chem. Soc. 38) Danishefsky, s.; Yan, c. F. 39) Iijima, I . ; Rice, K. 40) No reaction is observed in the absence of trifluoracetic c. 2324. (b) Stork, G.; ~~?~, ~' Syn. Conrrnun. 4462, 44 64. !~z~, !~Z~, Heterocycles ~' 211. §_, 1157. acid. 41) Gardner, J. N.; Carlon, F. E . .; Gnoj, 0. 1967' 42) ~' J. Org. Chem. 2649., For a related oxidation in which, unlike the present example, bisulfite is reported to be the oxygen source, see: Bjeldanes, L. F.; Rapoport, H. J. Org. Chem. 1972. 37, 1453. 43) Sohar, P.; Schoenewaldt, E. F. Chem. Abstr. 1976, ~' 5226X. 44) Parker, H. I.; Blasche, G.; Rapoport, H. J. Am. Chem. Soc. 1972, 94, 1276. 45) (a) Jacobson, A. E.; Hsu, F. L.; Rozadowska, M. D.; Schmidharruner, H.; Atwell, L.; Brossi, A.; Medzihradsky, F. Helv. Chim. Acta 1981, .§_!, 1248. L.; Beyerman, H. C. (b) Olieman, L.; Maat, Rec. Trav. Chin. 1980, 99, 169. 46) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 47) Arndt, F. 48) House, H. O.; Lord, R. C.; Rao, H. S. 1487. Org. Syn. 1978, ~' Coll. Vol. lI, p. 165. J. Org. Chem. 1956, 2923. -80- Org. Syn .. g, 22. 49) Rifi, M. R. 50) The cis:trans ratio of the imrnonium salts by integration of 13 was determined C-NMR spectra, using gated decoupling to eliminate NOE differences. -81- APPENDIX I IR and 1 H NMR Spectral Catalog -82- Page 41 Cl CHC1 lie 3 '. , .~1 ID - ----- o i.....-._. ... 'T( ____ '! *'> lillGll l . _ .,. I 1 '' -~ I 1100 - CDC1 3 :_. I .", 1, I ~ • If• 1Up11n• ; / ·, tipµm i ~µJ,Jm ltl<J 1~0 -1 I I -1- ppm(..) 10 +r l .'lJ -83- Page 42 17 CHC1 3 CDC1 3 END Of SWHP · ·-;' \' () ' -1 / - 11 -> START OF SWEEP 900H1 I 1 o J I ~n+_· I ' I!i ' r_J . I- I· 7SO 1>00 3 5 300 I I 1 0 I I 4SO I I 4!>0 I 300 I 1!'10 I 90 60 I I 1 I 225 I . I \ . - .. , . . - ·-1· ·- ·· r·-- ·· r- ·- I I i . I . \1 .. . I I : l I I ; , .,~-~-,o--~~--11 , "1--- !.i T- _ ___ -:--_:l--'-----e·--- - 6------. - -~3-~- 0 -84- 0 Page 43 21 CDC1 3 > - 11 STAHT O~ SWHI' !Oppm Sppm I 900Hz no i 450 I 375 1 o . t I 150 --~~- I i I ;. I h- i I . I I i ! '·1 I i i I I Iih _____ J . I bOO I I 120 JOO > JOO 225 150 I I i l Ii I 60 9o ---:--·-··-+--- ··-;·----·-·-· -- : - ·--.· - -!- . ; - - , - - I ' I I\ : I r ENO OF SV I 4 50 I I ! --~-i- i . I I I ! :-. I i+ i ~ i I I I ~t-J.,; .. I ,, I 1, I I ! --+'---r---, - ' j I °'I I -85- 0 ct:) Page 44 CHC1 CDC1 Me H 18 3 3 lI . ! ... --- ~r· ... _. ... '-'-,.- .. ...:_-"-ii': - .,,_ ' ~- .ii .. . . i.· ..· .. ) '• i I . - 1. I I I. · · · r--~ ·7·j . ~i i""1 IA :!--·-·1-'-.,... -:-i . . . . +.......,.I1..-J·.' . ·:' I 1 ' :· ..__,..._,,_ _.,..__-4-....j.-j,._ I !. i I ! i I . . . llf -; ~ 1 · ·" I· ... I ,. . . . 1. .... I t .. Ii .. .. .... 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I 'I ,, 'I 11 I 1Ii I ·I rn , ;1 ; ,:I m , 111 1:, '" ,, : .1i 1 1i, ·i .!i .I . i . ,',i :,, ,'; ·1 , :1 1 :w !;~. .· ·.', "!. ! :I :.. ·Il ' I .I ' :'i : .:1... .~.. :,I i,·,' .':1. 11":.,:,· '. :..' :. !1'.1 1·.;,:,.i.I: ; l 1 .,2".'. 1 i !i ,:i !,:: : : : . ;:1!1 l! i.: '. ' h ! I~ .:1 .:11 I ri l ~ 1 Tll :~.1 , "]' ,l •.:1. ill 1, .!. ·, 1'11' 11! ,/ ., !'1 .lftl •!.: 'I l,i/'1. ro tt,1. :11 : < ! i : ~1 · trti ::r >· 11> 1··· · I 450 .l ;·~ '.·-.·,·. t,: :. ·- - ff..v1fM-icH1'm-'"~' ,.µ+,,.;.;.+ " ;.. ' ..;....,-tT-41~~ 3 STAHT OF SWE EP - '. ; 1lL ,,',· J.,.::·.'. .· . : ' '!! i 1 ~ { 8 ~, :;'1 !'.: ::1, " ,1 i;.I. ~ • :ii'. I:! I' ' 11: 11 . '. !; ,. I I . .' I I 1. I' » 1: I' I 'I I I 1 I ~ ' I I I' '1 I ' I l ,1 Ill , :, I :'1 11! . 1: 1 11 , jl l· . I i:l ;/I , !'· : ... ,"II' : •;, :,: " *1j 111 ! . ii .· 'i 1!llll l!! ;•· t11 :;1 : 'II! Ill. " lil.11 '11 1 r flI ' ' . rt: ·!1 .1.rr. ID 11 1 II . !ii' l •I !I ..nr1 Tij;' JI! :. j 'lll. l'' I T ' r,r:. r,:;!n', I . !J ;~ ' ~ · 11!:; ~::: ·~r J J ~ ·' , . . .. ·1 1 1 .· I ·1 : ~: · I l cq=~'J; ~~l1'~: ,: ~.1·,\,·7...'• : ~~ ~;l,ri ti i ~ .J ~ . 1. ~. i !,l!l!'..· ~h i:: : , . !!i ! , !IJ ~ ~J ~'~ " . . : ,I ill''· :! 1 :11 ,, I , •. ''. ; Ii i ,:, ! , • 1 Iii: ! I I~' I II !• 1 l! " 1n ! i!'. 11 : jfr't, • 1~ " t m +.rft 1 : .;'~~ I . . hi ~ ' !' ::n. ;r, .:, 1 I ·1 I I 'I I 1 1it1 ~ TIT ir 'I : . I J r~ 1 iii .': ,1;q1:t . : ' ti ·H.;... I, ·!· . tJO 111 n ~, :1 ii . ll'Jli, 11: 11! 1 ~ "1'·. 1 . , ~l!j I ~ ; ~ri fl, ~ 1 ID ( rii .,. . 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