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1442 J . O r g. C h e m . 1989, 4, 1442-1445of C a n a d a f o r f i n a n c i a l s u p p o r t .

Supplementary Material Available: Syntheses of diethyl[ [l-(methoxymethyl)-2-phenyl-5-imidazoly1]methyl]malonate24),14, and 15 (3pages). Ordering information is given on a n y currentmasthead page.

A n E f f i c i en t S y n t h e s i s of t h e4a-Aryl-6-oxodecahydroisoquinolinesB. E. Cantrell, J. W. Paschal, and D. M. Zimmerman*

Li l ly Research Laborator ies , E l i L i l ly and Com pany, L i l lyCorporate Center , Indianapol i s , Indiana 46285Received August 26, 1988

T h e s y n t h e s i s of p a r t s t r u c t u r e s of t h e m o r p h i n e m o l -ecu le and s t ruc tu ra l m odi f i ca tion o f t hese f ragm ent s hasl ed to t he d i scovery of man y im por t an t medic ina l agen t sand re sea rch too l s. Conseq uen t ly , t h e e f f ic i en t syn thes i sof mor ph ine base s t ruc tu re s has been a goa l of o rgan icchemis t s fo r many yea r s .R e c e n t l y t h e m e t a l a t e d e n a m i n e s 1 (F igure 1) haveproven to be use fu l i n t he syn thes i s o f morph ine pa r tstructure^,'-^ a n d w e h a v e r e p o r t e d t h a t t h e trans-4a-aryldecahydroisoquinoline 2 can be readi ly synthesized inj u s t t w o s t e p s f r o m 11v4b y u s i n g t h e m e t a l a t e d e n a m i n eapproach . Pharmacological evaluat ion of compound 2 a n di t s m - h y d r o x y a n d N - s u b s t i t u t e d a n a l o g u e s i d e n t if i e dp o t e n t o p io i d a na lg e si c ac t iv i ti e s w i th i n t h i s ~ e r i e s , ~n dfur the r modi f i ca t ion o f t he aryldecahydroisoquinolinem o l e c ul e w a s d e e m e d a p p r o p r i a t e .Because severa l imp or t a n t op io id recep tor l i gands havebeen d i scove red th roug h fu r the r func t iona l i za t ion o f t he6-ke to g roup in oxycodone (F igure 1) a n d r e l a te d m o l e -c u l e ~ , ~ - ~h e trans-4a-aryl-6-oxodecahydroisoquinolineappea red to be a l og i ca l i n t e rmedia t e fo r new ana loguesynthesis . Th ou gh the synthes is of the i soquinoline 3 hasbeen previously reported: we soug ht a more di rect route ,which would mak e the syn thes i s o f la rge quan t i t i e s o f 3prac t i ca l . In t h i s pap e r we desc r ibe an e f f ic i en t rou te t oth e trans-4a-aryl-6-oxodecahydroisoquinolines,mployingas a key s t ep the use of a me ta l a t ed enamine . In add i t i on ,p rac t i ca l syn thes i s o f t he cis-4a-aryl-6-oxodecahydroiso-quino l ine 4 a n d t h e cis- a n d trans-4a-aryl-6-decahydro-i soqu ino l s 5-8 ( S c h e m e s I a n d 11) was d i scove red .

R e s u l t s a n d D i s c u s s io nT h e s y n t h e t i c r o u t e e m p l o y e d f o r t h e s y n t h e s i s of t h eoxodecahydroisoquinoline 3 i s dep ic t ed in Schem es I a n d11. A l k y l at i on o f t h e m e t a l a t e d e n a m i n e 10'O w i t h t h e(1) Evans, D. .; Mitch, C. H.; Thomas, R. C. ; Zimmerman, D. M.;(2) Shenvi, A. B.; Ciganek, E. J. Org. Chem. 1984, 49, 2942-2947.(3) Evans, D. A.; Mitch, C. H. Tetrahed ron Lett . 1982, 285-288.(4) Zimmerman, D. M.; Cantrell, B. E.; Swartzendruber, J. K.; Jones,N. D.; Mendelsohn, L. G.; Leander, J. D.; Nickander, R. C. J.Med. Chem.

Robey, R. L. J. Am. Chem. SOC.980, 102, 5955-5956.

1988,31, 555-560.(5 ) Portoghese, P. S.;Takemori, A. E. In T he Chemical Regulation ofBiological Mechanism s; Creighton, A. M., Turner , S.,Eds. ; WhitstableLitho-Ltd: Whitstable, Engk nd, 1982;p 181.(6) Portoghese, P. S.; Takemori, A. E. Life Sci. 1985, 36, 801-805.(7 ) Lipkowski, A. W.; Tam, S. W.; Portoghese, P. S. J. Med. Chem.1986, 29,-1222-1225.(8) Portoghese, P. S.;Ronsisualle, G.; Larson, D. L.; Takem ori, A. E.(9) Weller, D. D.; Gless, R. D.: Rapoport, H. J. Org. Chem. 1977, 42 ,J. Med. Chem. 1986, 29, 1650-1653 a nd references cited ther ein._ _1485-1496.(10) We have since shown tha t 9, which is the 3-methoxy analogue ofthe Parkinsonian-causing agent M PT P, is, like MPT P, highly neurotoxic.We now recommend using the N-ethyl derivative as described in Zim-merman, D. M.; Cantrell, B. E.; Reel, J. K.; Hemrick-Luecke, S. K.; Fuller,R. W. J . Med. Chem. 1986, 29, 1517-1520.

0022-3263/89/1954-1442$01.50/0

1 2 3HO

HMorphine Oxycodone

F i g u r e 1.Scheme IcH30pBull

H 3 c - 0 4 HHH N-CH3 + H3c0&$ N-CHIPh3PBr2

Br\

13 14( C H ~ C O I Z OC F ~ C O Z H

1

18 21 20oxi rane de r iva t ive 22, o l lo w e d b y s p o n t a n e o u s a d d i t i o nof the a lcohol generated to th e imm oniu m moiety, gave ingood yield a mixtu re of th e oxa-8-azabicyclono nanes 11 an d12. Sepa ra t ion was ach ieved by us ing p repa ra t ive HP LC ,

0 1989 American Ch emical Socie ty

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Notes J . Org. Chem. , Vol. 54 , No. 6 , 1989 1443Similar hydrogenation of 20 gave the i someric isoquinol inol6, a l so t r ans- fused .I n c o n t r a s t , h y d r o g e n a ti o n of 19 a n d 21 or 20 wi thp la t i num ox ide in ace ti c ac id a f fo rded th e c i s - fused i so-qu ino l ino l s 7 a n d 8 , re spec t ive ly , i n h igh y i e ld . T h e ra -t i ona l e fo r t hese s t e reose l ec t ive red uc t ions h as been p re -v i o u s l y d e s c r i b e d i n t h e s y n t h e s i s of t h e t r a n s - l a -phenyldecahydroisoquinoline 2).l T he re l a t i ve conf igu-ra t ions of compounds 5-8 were establ ished by com parisonof t h e i r ' H N M R s p e c t r a a n d p h y s i c al p r o p e r t i e s w i t ht h os e pr ev io us ly d e ~ c r i b e d . ~ x ida t ion o f 5 or 6 u n d e rSwern cond i ti ons12 p rov ided the des i red t runs-4a -a ry l-6 -oxoperhydroisoquinol ine 3 in near quant i ta t ive yie ld, whi lesimi lar oxidat ion of 7 or 8 afforded th e c is-fused analogue4 , a l so in h igh y i e ld .T h u s b y t h i s m e t h o d w e h a v e d e s c r ib e d t h e s y n t h e s i sof truns-4a-(3-methoxyphenyl)-6-oxodecahydroisoquinoline(3 ) i n s e v e n s t e p s f r o m t h e r e a d i ly a v a il a b le t e t r a h y d r o -pyridine 91 in a n approx im a te 21% overall yield. Becausewe wante d to fu l ly cha rac t e r i ze a l l o f t he i n t e rm edia t e s ,w e h a v e d e s c r i b e d t h e s y n t h e s i s of 3 u s in g t h e s e p a r a t e disomeric oxoazabicyclononanes 11 a n d 12; however , t h i swould no t be necessa ry in a p repa ra t ive syn thes i s of 3.

Scheme I1

5

20 H z l h O zTOH ~ cH30Q -MSOxalyl cH30Dchloride6 3

Isand21 Hz1402CH3C02HIETOH cH30D

p r o v i d i n g 11 a n d 12 i n 40% an d 34% y ie ld , r e spec t ive ly .R e a c t i o n of e a c h w i t h t r i p h e n y l p h o s p h i n e d i b r o m i d e a f -fo rded th e 342 -bromo e thy l ) de r ivat ives 13 a n d 14 in goodyie ld.T h e re la t i ve conf igura tions o f 13 a n d 14, a n d c o n s e -q u e n t l y t h o s e o f 11 a n d 12 , were deduced wi th 'H NMR.F o r b o t h c o m p o u n d s , t h e s h a p e o f t h e r e s o n a n c e fo r H-1i s t h e s a m e , a n d p r o t o n d e c o u p l i n g s h o w s t h a t c o u p li n gst o H-1 are 11.74 and 3.69 Hz. T h i s r e q u i re s t h a t H-1 havea n a n g l e o f e i t h e r a p p r o x i m a t e l y 1 80 ' o r 0' wi th re spec tt o H -3 . W i t h s t r u c tu r e 13, w h i c h h a s b o t h r i n g s i n t h ec h a i r c o n f o r m a t i o n , t h e H-1 H - 3 a n g l e is a p p r o x i m a t e l y180'. In this mod el H-1 is very c lose to H-2 , and one woulde x p e c t a n NOE be tween the se two pro tons ; t h i s was con-f i rmed expe r imenta l ly . T h e o the r i somer , comp ound 14 ,m u s t s u r e l y h a v e a c h a i r / b o a t c o n f o r m a ti o n , a n d H - 1w o u ld h a v e t h e s a m e a n g le s t o H - 3 a n d H - 4 a s f o u n d w i t hc o m p o u n d 13. F o r c o m p o u n d 14, H-1 i s pos i t i oned fa rfrom H-2. Therefore , no NO E between H-1and H -2 wouldb e p r e d i c t e d , a n d n o n e w a s f o u n d .T r e a t m e n t o f t h e b i c y c lo e t h y l b r o m i d e s (1 3 a n d 14)w i t h t r i fl u o ro a c e ti c a c i d a n d a c e t ic a n h y d r i d e a t r o o mt e m p e r a t u r e g a v e t h e b r o m o e n a m i n e s 15 a n d 16," whichin ace ton i t r i l e (KzCO3, r e f lux) were conve r t ed wi tho u ti so l a t ion to t h e b i cyc l ic enam ines 17 a n d 18 i n a n ove ra lly i e ld f ro m 13 a n d 14 of 80 a n d 8 2 % , r e sp e c ti v el y . C o m -p o u n d s 17 and 18 were readi ly deacetyla ted to th e cis- a n dt r a n s -6 - h y d r o x y b i c y c li c e n a m i n e s 19 a n d 20 . A n e x a m i -n a t i o n o f t h e lH NMR s p e c t r u m o f t h e m a t e r i a l d e r i v e df rom 17 showed th a t i n benzene -d , i t ex i st ed a s a mix tu reo f c o m p o u n d s 19 a n d 21 . T h e r a t io o f 19 t o 21 ini t ia l lya f t e r d i sso lu t ion w as approx im a te ly 2 .4 1 .0 ; however, a f t e rthe mix ture s tood fo r 3 days a t room t empera tu re , t he ra t i ochanged to 1 .0 :1 .3 . Th e s t ruc tu ra l a ss ignment fo r 21 w ass u p p o r t e d b y its 13C N M R s p e c t r u m w h i ch s h o w ed t h epresence of a dou ble t a t a posi t ion consistent for a methine ,w h i c h h a s a n o x yg e n a n d a n it r o g e n a t t a c h e d . A t t e m p t st o i s o la t e 21 f r o m 19 were unsuccess fu l ; however , i t wasf o u n d t h a t t h i s m i x t u r e c o u ld b e re d u c e d i n n e a r q u a n -t i ta t ive yield in e thanol wi th hydrogen a nd p la t inu m oxidet o t h e t r a n s - f u s e d p e r h y d r o i s o q u i n o l in o l 5 ( S c h e m e 11).

E x p e r i m e n t a l S e c t i o nMelting points were determined for all solids on a Thomas-Hoover melting point appa ratus and are uncorrected. Massspec tra were recorded on a CEC 21-110 mass spe ctrom eter. 'HNMR (300 MHz) and 13CNMR (67.9 MHz) spectra were recordedon a GE Q E-300 and a Bruker WM-270 spectrometer, respectively.Infrared spectra were recorded on a Nicolet lODX FT IR spec-trometer. All spectra were consistent with assigned structure s.All compounds were elementally analyzed within 0.3% of theo-retical value unless otherwise indicate d. Where m elting pointsare not indicated, the substance is a liquid at room tem perature.Thin -layer chrom atograph y (TLC ) was performed on Kieselgel60 F,, plates (0.25 km) w ith visualation by UV light and iodinestain. Column chrom atograph y was performed by gravitationalflow with use of Allied Fisher silica (70-150 mesh). Pre par ativ eliquid chromatography was performed with the Waters Pre pLC/500 apparatus and dual sil ica prep pack cartridges. Al l

temp eratu res are internal temp eratu res unless otherwise stated.P r e p a r a t i o n of t h e 5-(3-Methoxyphenyl)-8-methyl-3-[ (tetrahydro-2H-pyran-2-yl)oxy]methyl]-2-oxa-8-azabicy-clo[3.3. l ]nonanes (11 an d 12). A solution of l-methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine9)l0(40.0g, 0.20 mol)in lo00 mL of TH F was cooled to 0 "C under nitrogen and trea teddropwise with 1.6 M n-BuLi (130 mL, 0.21 mol) at a rate tomaintain a tem perature of 0 -5 "C . After the addition was com-plete, the resulting dark red solution was allowed t o stir at 0 "Cfor 10 min. This solution was then cann ulated , using nitrogenpressure,intoa solution of tetrahydro-2-(oxiranylethoxy)-W-pyran(33.7 g, 0.20 mol) in 50mL eth er at -10 "C. The resulting solutionwas stirred for 10 min at -5 "C . A solution of 16.0 g of NaOHpellets and 52.0 g of N aCl in 400 mL of HzO was then add ed ,maintaining the temp erature at 0 "C, and this mix ture was im-mediately poured into lo00 mL of cold H 20 . The de sired productwas extra cted into two 500-mL portions of ether. The e therportions were washed with HzO,dried over KzCO3, and concen-trated under reduced pressure to yield 70.0 g of th e crude mixtureof isomers as a viscous oil. TLC showed the pr esen ce of twoseparable fractions,Rf values of 0.18 and 0.14 (eth yl ace tate) . T heisomers were separated by preparative liquid chromatography witha gradient solvent system, (toluen e-toluene/ethyl acetate, 1:l).For 11: yield 29.7 g ( 4 0 % ) ;R, 0.18 (ethyl acetate); 'H NMR(CDC13) 7.27 (t, 1 H) , 6.94 (br d, 1 H), 6.86 (t , 1 H) , 6.76 (d d,1 H ), 4.67 (br t , 1 H), 4.62 (br t, 1 H) , 4.33 (m, 1 H) , 3.88 (m , 2H ), 3.82 (s, 3 H) , 3.52 (m, 2 H) , 3.25 (m , 1 H) , 3.05 (b r t , 1 H ),2.57 (d , 3 H), 2.24-1.45 (m , 16 H) ; mass sp ectrum, m / e (relative

(11)T he use of trifluoroacetic anh ydride to liberate an enamine of thistype was first described by Shenvi and Ciganek in ref 2. (12) Mancuso, A. J.; Huang, S.-L.;Swern, D. J.Org. C h e m . 1978,43,2480.

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1444 J . Org. Chem., Vol. 5 4 , N o. 6, 1989intensity ) 375 (M', 8), 346 (2),318 (21, 290 (13), 246 (301, 202 (loo),189 (25), 96 (15), 70 (25). Anal. Calcd for CZ2H3,NO4:C, 70.37;H , 8.86; N , 3.73. Foun d: C, 70.10; H , 8.63; N, 3.55.Th e hydrochloride sa lt of 11 was mad e by using HC1 in ethera t 0 "C. Th e salt could be recrystallized from ethyl acetate: mp109-110 "C. Anal. Calcd for C22H34N04C 1:C, 64.14; H, 8.32;N, 3.40. Foun d: C, 64.07; H, 8.18; N, 3.55.Fo r 12: yield 25.4 g (34%);R, 0.14 (ethyl acetate); H NM R(CDCl,) 6 7.25 (t, 1 H), 6.87 (br d, 1 H) , 6.81 (t , 1 H) , 6.74 (d d,1 H) , 4.82 (b r d, 1 H) , 4.58 ( t, 1 H) , 3.85 (m, 3 H) , 3.82 (s, 3 H) ,3.52 (m, 2 H) , 2.83 (d t, 1 H) , 2.61 (m, 1 H) , 2.46 (m, 1 H), 2.41(9, 3 H ), 2.05 (dd, 1H ), 1.94-1.42 (m , 1 2 H); mass spectrum, m/e(relative intensity ) 375 (M', 4), 318 (l), 290 (8),246 (20), 202 (loo),189 (231, 96 (32), 70 (78). Ana l. Calcd fo r CZ2H33NO 4: , 70.37;H , 8.86; N , 3.73. Fou nd: C, 70.59; H, 8.88; N, 3.54.Th e hydrochloride salt of 12was made with HC1 in ether at0 "C . Th e salt could be recrystallized from ethyl acetate: mp123-125 "C. Anal. Calcd for C22H34N 04C1:C, 64.14; H, 8.32;N, 3.40. Fou nd: C, 64.27; H, 8.29; N, 3.19.(1s ,3S ,5S )-3-(2-Bromoethyl)-5-(3-methoxyphenyl)-8-methyl-2-oxa-8-azabicyclo[3.3.1]nonane13). A solution of30.0 g (0.073 mol) of th e hydr ochlo ride salt of 11 an d 33.4 g (0.13mol) of triphenylphosp hine in 350 mL of dry tetrahydro furan wastreated dropwise with 20.5 g (0.13 mol) of b romine un der a ni-trogen atm osphe re while a temperature of 10 "C was maintained.The reaction was allowed to warm to room temp erature (15 min)and treated dropwise with 44.0 mL of methanol. After the ad-dition, the reaction m ixture was concentrated under reducedpressure, and th e resulting c rude bromide salt was liberated tothe free amine a t cold tempera ture with 1 N NaOH and etherextraction. Th e ether layer was washed twice with H2 0 ,driedover K2C0,, and concentrated un der reduced pressure to yield53.0 g of semicrystalline material. Th e crude amine was slurriedin 100 mL of cold hexane, and t he triphe nylpho sphine oxide wasremoved by filtration. Th e filtrate was concen trated, yield 23.0g, and further purified by preparative liquid chromatography withuse of a gradien t solvent system (hexane-hexane/ethyl acetate,1 :l ) affording 18.5 g (7 2% ) of a clear viscous oil: R, 0.28 (ethy lacetate/hexane, 1:l); H NM R (CDClJ 6 7.27 (t, 1 H), 6.90 (dd ,1 H) , 6.85 (t , 1 H), 6.76 (dd , 1H) , 4.66 (br t, 1H ), 4.39 (m , 1H ),3.80 (s, 3 H ), 3.62 (m, 1H) , 3.50 (m, 1H ), 3.27 (m, 1H ), 3.06 (m,1H) , 2.61 (s, 3 H ), 2.19 (br dd, 1 H ), 2.12-1.99 (m , 4 H ), 1.84 (m,2 H ), 1.55 (ddd, 1H); mass spectrum, m/ e (relative intensity) 353(M', 4) , 274 (a) ,246 (33),202 (loo ), 189(44), 6 (31 ), 70 (63). Anal.Calcd for CI7Hz4NO 2Br:C, 57.63; H , 6.83; N , 3.95. Found: C,57.44; H, 6.88; N, 3.80.(15*,3R*,55 )-3-(2-Bromoethyl)-5-(-methoxyphenyl)-8-methyl-2-oxa-8-azabicyclo[3.3.l]nonane14). This compoundwas prepared as above from 22.5 g (0.055 mol) of th e hydro chloridesalt of 12. Purification was performed by preparative liquidchrom atograph y with use of a gradient solvent system (hexane-hexane/ethyl acetate, l:l ), affording 12.4 g (63%) of crystallinematerial: mp 84-86 "C ; R, 0.22 (hexane/ethy l acetate , 1:l); 'HNMR (CDC1,) 6 7.27 (t, 1 H ), 6.87 (d d, 1 H ), 6.82 ( t , 1 H ), 6.75(dd , 1 H), 4.84 (b r d, 1 H ), 3.90 (m , 1H ), 3.81 (s, 3 H) , 3.53 ( m,2 H), 2.79 (dd d, 1 H), 2.63 (m , 1 H), 2.47 (m , 1H ), 2.40 (5, 3 H),2.10-1.72 (m, 7 H ); mass spec trum , m/e (relative intensity) 353(M', 4) , 274 ( lo ) , 246 (32 ), 202 (1001, 189 (26 ), 96 (2 3), 70 ( 50) .Anal. Calcd for C17H,,N0,Br: C, 57.63; H, 6.83; N, 3.95. Foun d:C, 57.49; H, 6.73; N , 3.71.2-Methyl-laa-(-methoxyphenyl)-2,3,4,4a,5,6,7,8-octa-hydro-6~-isoquinolinolcetate (17). A solu tion of 10.0 g of13 was treated with 35.0 mL each of trifluoroacetic acid and aceticanhydride and stirred for 1h at room temperature. The solutionwas then made strongly basic with 50% NaOH and ice, and theprodu ct was extracted into 300 mL of ether. Th e ether layer waswashed once with H 2 0 , ried over KZCO,, an d concentrated underreduced pressure a t 0 "C to yield 10.8 g of 15 as a yellow oil. Thi sunstable material was used without further purification anddissolved into 250 mL of acetonitrile containing 11.4 g K &0 3 an dheated a t reflux under a nitrogen atmosph ere for 2 h. Th e mixturewas cooled to room temperature and filtered. Th e resulting solidwas washed two times with 5 0-mL portions of methylene chloride.These ex tracts were combined with th e filtrate and concentratedunder reduced vacuum t o yield 8.42 g of crude product. Pu ri-fication w as performed by prepar ative liquid chromatography with

Notesuse of a gradient solvent system (hexane-hexane/ethyl acetate,4:1), yielding 5.92 g (75%) crystalline prod uct: m p 83.5-85 "C;R, 0.31 (hexane/ethyl aceta te, 4:l); 'H NM R (CDCI,) 6 7.25 (t,1H), 7.02 (d, 1H) , 7.00 (br d , 1 H) , 6.74 (dd , 1 H), 5.91 (5, 1 H ),4.53 (m, 1 H) , 3.82 (s, 3 H), 2.83 (d dd, 1 H) , 2.63 (m , 1 H) , 2.60(s, 3 H ), 2.50 (ddd , 1H ), 2.21-2.00 (m, 2 H) , 2.00 (s, 3 H), 1.96-1.80(m, 3 H), 1.48 (ddd, 1 H), 1.34 (m, 1 H); mass spectrum, m/e(rela tive intensi ty) 315 (M', 53), 272 (4), 256 (67), 214 (15), 148( loo) , 12 2 (9 ). Anal. Calcd for C19HZ6NO3: C, 72.35; H, 7.99; N,4.44. Foun d: C, 72.08; H , 7.88; N, 4.50.2-Methyl-4aa-(-methoxyphenyl)-2,3,4,4a,5,6,7,8-octa-hydro-6a-isoquinolinol Acetate (18). This compound wasprepared a s above by starting with 11.0 g of 14. The only dif-ference was that a 2-h stirring a t room temperature was neededfor complete conversion to the intermediate 16. Purification ofth e 8.25 g of cru de 18was accomplished by preparative liquidchrom atograph y with use of a gradient solvent system (hexane-hexane/ethyl acetate, l : l ), affording 5.90 g (61%) as a viscousoil: R, 0.22 (hexane/ethyl acetate, 4:l); 'H NMR (CDCI,) 6 7.20(t ,1 H) , 6.93 ( br d, 1H) , 6.92 (br s, 1H) , 6.67 (dd, 1H) , 5.94 (s,1 H) , 4.97 (m, 1H) , 3.80 (s, 3 H) , 3.02 (ddd , 1 H) , 2.64-2.47 (m,2 H ), 2.57 (s, 3 H ), 2.34 (ddd, 1 H ), 2.03-1.47 (m, 6 H) , 1.30 (s,3 H ); mass spectrum, m/ e (relative inten sity) 315 (m', 96), 272(8), 256 (go), 214 (19), 148 (lo o) , 122 (9). Anal. Calcd forC19HE N03: C, 72.35; H , 7.99; N, 4.44. Fou nd: C, 72.06; H , 8.05;N, 4.47.2-Methyl-4aa-(3-methoxyphenyl)-2,3,4,4a,5,6,7,8-octa-hydro-6@-isoquinolinol (19) and 3-(3-Methoxyphenyl)-6-methyl-11-oxa-6-azatricyclo[5.3.1.03~8]undecane21). A so-lut ion of 7.20 g (0.023 mol) of 17 and 13.0 g of KZCO, in 200 mLof methanol was stirred at room temperature under nitrogen for2 h. Th e mixture was then filtered, and th e filtrate was con-centrated un der reduced vacuum. Th e resulting residue was takeninto 200 mL of methylene chloride, washed twice with brine, d riedover KZCO,, an d concentrated und er v acuum to yield 6.80 g ofa viscous oil. Purification was perform ed by column chrom a-tography (hexan e/ethyl acetate, 1:l) o give 6.0 g ( 96 %) of 19 an d21: R , 0.15 (hexane/ethyl ace tate, 1:l);H NMR (C6D6) takenimmediately after dissolution) 6 7.18 (m, 1 H) , 7.09 (d, 0.7 H ),7.04 (t ,0.7 H) , 6.93 ( d, 0.3 H ), 6.79 (t, 0.3 H) , 6.69 (m , 1 H) , 5.74(d, 0.7 H ), 4.58 ( d, 0.3 H), 3.85 (m, 0.3 H), 3.40 (s, 0.3 H) , 3.39(s, 0.7 H) , 3.39 ( m, 0.7 H ), 2.89 (t d, 0.3 H ), 2.70 ( dt, 0.7 H ), 2.50(s, 0.7 H ), 2.29 (s, 0.3 H ), 2.48-2.25 (m , 3 H) , 2.25-2.08 (m , 2 H ),2.03-1.60 (m , 4 H ), 1.46-0.91 (m, 4 H ), 0.87-0.65 (br m, 1 H); HNMR (C6D6) after standing for three days a t room temperature)6 7.18 (m , 1 H), 7.09 (d , 0.4 H) , 7.04 ( t, 0.4 H ), 6.93 (d , 0.6 H ),6.79 (t, 0.6 H ), 6.69 (m , 1H), 5.74 (d, 0.4 H), 4.58 (d, 0.6 H), 3.85(m, 0.6 H ), 3.40 (s, 0.6 H) , 3.39 (9, 0.4 H), 3.39 (m , 0.4 H ), 2.89(td,.6 H ), 2.70 (dt, 0.4 H ), 2.50 (s,0.4 H ), 2.29 (s,0.6 H ), 2.48-2.25(m , 3 H) , 2.25-2.08 (m , 2 H) , 2.03-1.60 (m, 4 H), 1.46-0.91 (m ,4 H ), 0.87-0.65 (b r m, 1H); mass spectrum,m/e (relative intensity )273 (M', loo) , 244 (2 4), 228 (511, 189 (4 1), 166 ( loo ) , 122 (73),77 (38). Anal. Calcd for C17HZ3N02:C, 74.67; H , 8.48; N , 5.12.Foun d: C, 74.40; H , 8.41; N, 5.03.%-Methyl-laa-(-methoxyphenyl)-2,3,4,4a,5,6,7,8-octa-hydro-60-isoquinolinol 20). This compound was prepared asabove from 3.70 g (0.012 mol) of 18. A 24-h stirring at roomtemperature was needed to complete the reaction. Purificationwas performed by column chromatography (hexane/ethyl acetate,L l) , giving 2.95 g (90% ) of 20: R, 0.11 (hexane/ethyl acetate,1:l ); H NMR (CDCl,) 6 7.25 (t , 1H), 7.08 (d , 1 H) , 7.04 (t, 1 H ),6.74 (dd, 1H) , 5.94 (9, 1H) , 4.09 (m, 1 H), 3.81 (9, 3 H), 2.82 (m ,1 H ), 2.65-2.29 (m, 3 H ), 2.57 (s,3 H ), 2.OC-1.87 (m , 2 H ), 1.8C-1.70(m , 2 H), 1.51 (m, 1H), 1.03 (d, 1H); mass spectrum, m/ e (relativeinte nsi ty) 273 (M', 66), 244 (15), 22 8 (27), 202 (1 8), 166 (1001,1 2 2 (46), 44 (20). A nal. Calcd for CI7Hz3NO2:C, 74.67; H, 8.48;N , 5.12. Foun d: C, 74.42; H, 8.60; N, 5.09.2-Methyl-4aa- 3-methoxypheny1)-,2,3,4,4a,5,6,7,8,8a@-decahydro-6~-isoquinolinol5). A solution of 2.73 g (0.010mol)of 19 and 21 in 150 mL of anhydrou s ethanol was hydrogenatedover PtO, a t a hydrogen p ressure of 60 psi for 16 h. A t the endof this period the cataly st was filtered off, an d the solv ent wasremoved und er reduced pressure to afford 2.70 g of cru de product.Purification was performed by chromatog raphy on a silica columnwith m ethanol as eluen t, giving 2.28 g (84 % ) of a crystallinemateria l. This was recrystallized from hexane/benzene (1:l): mp

8/4/2019 An efficient synthesis of the 4a-aryl-6-oxodecahydroisoquinolines - J. Org. Chem., 1989, 54 (6), pp 14421445

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J.Org. Chem. 1989, 4 , 1445-1447 144588.5-90 C; R, 0.22 methanol); H NM R (CDCl,) 6 7.21 (t, 1H ),7.03 d , 1 H ), 7.02 d, 1H ), 6.70 dd, 1H ), 3.81 s,3H ), 3.31 m,1 H ), 2.71 m , 2H ), 2.52 dd, 1H ), 2.40 ddd, 1H ), 2.25 s, 3H ),2.20-1.30m, 10H); mass spectrum, m / e (relative intensity ) 275(M', 78), 258 (38), 187 (12),167 31) ,121 (16), 71 (loo),57 (37).Anal. Calcd for Cl7HZ5NO 2:C, 74.14; , 9.15; , 5.09.Found:C, 73.97; , 9.15; , 4.81.$-Methyl-laa-(-methoxyphenyl)-1,2,3,4,4a,5,6,7,8,8aj3-decahydro-6a-isoquinolinol6). This compound was preparedas above from 1.0 (3.7 mol) of 20. Purification wa s performedby column chromatography (methanol) to yield 0.82 (82%) ofcrystalline product that recrystallized from hexane: mp 116-117"C (lit? mp 117-117.5 C); Rf0.23methanol); H N MR (CDCl,)6 7.26 t,1H ), 7.13 d , 1 H ),7.11 br t, 1H ), 6.72 dd, 1H ), 4.02(b r s, 1H ), 3.80 s, 3H ), 2.78 ddd, 1H ), 2.72 dd, 1H ), 2.54 m,2 H ) , 2.32 m , 1 H ), 2.27 s, 3H ), 2.09-1.42 m, 8 H ), 0.80 (br s,1 H) ; mass spectrum, m / e (relative intensity) 275 (M', 34), 260(7), 04 (33), 167 (16), 121 (19), 1 20) ,71 ( loo),57 (79).Anal.Calcd for C1,HwN 02: C,74.14; , 9.15; , 5.09.Found C, 73.92;H , 9.06; , 5.09.%-Met yl-4aa-(-methoxyphenyl)-1,2,3,4,4a,5,6,7,8,8aa-decahydro-6j3-isoquinolinol7). A solution of 1.0g (3.7mmol)of 19 an d 21 in 50 mL anhydrous ethanol/acetic acid (1:l)washydrogenated over PtO z at a hydrogen pressure of 60 si for 16h. A t the end of this period, the catalyst was filtered off, andthe solvent was removed under reduced pressure to afford 0.96g of crude product. Purification was performed by columnchromatography with methanol eluent, yield 0.73g (73%): R,0.30 methanol); 'H NM R (CDC13)6 7.25 t, 1H ), 7.04 d, 1H ),7.00 t, 1H ), 6.73 dd, 1 H ),3.80 s, 3H ), 3.67 m, 1H ), 2.62 m,3H ), 2.50 ddd, 1H ), 2.32 (s,3 ) , 2.25 ddd, 1H ), 2.08 d, 2H ),1.86-1.32m , 7H) ; mass spectrum, m / e (relative intensity) 275(M', 20), 258 (16), 87 lo ) , 167(14), 21 (12), 1 (92), 1 ( loo),57 (28).Anal. Calcd for Cl7HZ5NO 2: , 74.14; , 9.15; , 5.09.Found: C, 74.36; , 8.93; , 4.87.2-Methyl-4aa-(3-methoxyphenyl)-,2,3,4,4a,5,6,7,8,8aa-decahydro-6a-isoquinolinol(8). This compound was preparedas above from 1.0g (3.7 mol) of 20. Purification was performedby column chrom atography with methanol so lvent, affording 0.68g (68%) of 16, hich could be recrystallized from benzene, mp95-96 C (lit.Bmp 95-97 "C), or from hexane/ethyl acetate (4:1),mp 104-106 "C: R, 0.25 metha nol); 'H N MR (CDC13)6 7.27 t,1H ), 6.99 d , 1H ), 6.95 br t, 1H ), 6.75 dd, 1H ), 3.92 m, 1H ),3.82 s, 3 H ), 2.64 br d , 1 H ), 2.46 d, 1 H ), 2.26 m , 3 H ), 2.11(s, 3 H ), 2.09-1.66 m , 6 H ), 1.35 m , 3 H); mass spectra, m / e(relative intensity) 275 (M', 37), 258 (8), 04 (581, 87 (141, 21(19), 1 (13), 1 (97), 8 (47), 4 (100).Anal. Calcd for C17Hw N02:C, 74.14; , 9.15; , 5.09. Found: C, 74.29; , 9.30; , 5.18.General Procedure or the Synthesisof the 6-Oxodeca-hydroisoquinolines and 4. A solution of 8.7mL of DMSOin 25 mL of methylene chloride was added dropwise to 5.1mLof oxalyl chlor ide in 130mL of methylene chloride under nitrogen,and a temp erature of -55 C was maintained. After the additionwas complete, the reaction was stirred for 2 min at this tem-perature. A solution of isoqu inolino l(l5.0 g, 0.055 mol) in 52mLof methylene chloride was added dropw ise to this mixture, anda temperature of -55 C was maintained. Th e resulting mixturewas then stirred an additional 15min at -55 "C. Triethylamine(36mL) was added, and th e reaction mixture wa s allowed to warmto room temperature. Water (250mL) was added dropwise tothe mixture, and the layers were separated. The organic layerwas washed two times with brine, dried over KzCO3, and con-centrated unde r reduced vacuum . Purifica tion was achieved byeither column chrom atography or recrystallization.2-Met yl-4aa-(3-methoxyphenyl)-,2,3,4,4a,5,6,7,8,8aB-decahydroisoquinoline (3). This compound was prepared asdescribed above from 15.0 (0.055mol) of 5 or 15.5 (0.056mol)of 6. The resulting solids were recrystallized from hexane/ethylacetate (1:l) o yield 13.7 (91%) rom 5 an d 14.2 (92%) rom6:m p 90-92 C; mp 93.5-94.5C (hexane/benzene, 1:l; it.g mp94-95 C); R, 0.23 methanol); 'H NMR (CDCl,) 6 7.22 t, 1 H ),6.98 m, 2H ), 6.71 dd, 1 H ), 3.79 s, 3H ), 2.93 d, 1H ), 2.84 dd,1H ), 2.68 t, 1H ), 2.59 d , 1H),.53-2.20m,5H ), 2.33 s, 3H ) ,2.13-1.84m, 4H) ; mass spectrum, m l e (relative intensity) 273(M+, oo) , 258 ( l l ) ,02 (13), 65 (28), 150 (32), 71 (72), 57 (65),44 (40); R (CDCl,) 1709.05 C=O ) cm-'. Anal. Calcd for

0022-3263/89/1954-1445$01.50/0

Cl7H,NO2: C, 74.69; , 8.48; , 5.12.Found: C, 74.97; , 8.68;N, 5.39.2-Methyl-4aa-(3-methoxyphenyl)-1,2,3,4,4a,5,6,7,8,8aa-decahydro-6-oxadecahydroisoquinoline 4). This compoundwas prepared as above from 1.90g (0.0069mol) of 7 nd 1.40(0.005 ol) of 8. Th e resulting viscous oils were purified by columnchromatography w ith methanol solvent to yield 4, .60 (84%)from 7 nd 1.20 (86%) rom 8. Material crystallized on standing :m p 66-67.5 C (hexane); R, 0.46 methanol); 'H NMR (CDC1,)6 7.24 t,1H ), 7.00 m,2H ), 6.75 dd , 1H ), 3.79 s,3H ), 2.90-2.46(m , 6 H ) , 2.36(s,3 H ), 2.36-2.10 m , 4 H ), 1.86-1.64 m , , 2H ),1.58 m , 1H); mass spectrum, m / e (relative intensity) 273 (M+,21), 258 5) , 202 (6), 65 (6), 15 (9), 6 (8),9 ( loo),57 (36), 4(67);R (CDCl,) 1706.16 m-' (C =O ). Anal. Calcd for C17HBN 02:C, 74.69; , 8.48; , 5.12. Found: C, 74.39; , 8.77; , 4.94.Registry No. 3, 61528-04-9;, 1528-05-0;, 61528-21-0;,61528-20-9; , 61528-23-2;, 61528-24-3;, 73224-22-3;1,118864-98-5;1.HC1, 118724-76-8;2, 118864-99-6;2.HC1,118916-31-7;3, 18724-77-9;4, 18724-78-0;5, 18724-79-1;16, 18724-80-4;7, 18724-81-5;8,118724-82-6;9,118724-83-7;20, 18724-84-8;1, 18724-85-9;2, 8055-58-7.

Electron-Transfer nduced Rearrangement ofSpirofluorenebicyclo[6.l.O]nonatriene toSpirofluorenebarbaralane

Tsutomu Miyashi,*p' Yasutake Takahashi,' Akinori Konno,'Toshio Mukai,t*tHeinz D. Roth,*,$JMarcia L. Schilling,$ andChristopher J. Abelt$JDep a r t men t of Chemistry , F acul ty of Science, TohokuUniversi ty , Sendai 980 , Japan, and AT& T Bel lLaboratories, Murray Hill , New Jerse y 07974

Received January 25 , 1988Bicyclo[6.l.O]nonatriene (1) a n d i t s d e r i v a t i v e s a r ea m o n g t h e m o s t t h o r o u g h l y i n v e s t i g a t e d h y d r o c a r b o nsys t ems. A mul t ip l ic i t y o f t he r ma l and pho tochem ica lr e a r ra n g e m e n t s a r e o b s e r v e d , a n d s u b s t i t u e n t s a t C-9 af -fec t t he course of t he rea r rangem ent i n r emarkab le f a sh -ion . ' We a re in t e re s t ed in t he s t ruc tu r e and the po ten t i a lrearrangements of radical ca t ions.2 Accordingly, we in-ves t iga t ed the pho to induced e l ec t ron t r ansfe r r eac t ions o fspirofluorenebicyclo[6.l.O]nonatriene lap and 9 ,9 -d i -phenylbicyclo[6.1.O]nonatriene l b ) . 4 In pola r so lven t s ,la unde rgoes a nove l r ea r rangement , ch i e f ly t o sp i ro -f luoreneba rba ra l ane(2a), type of rearrangement wi thoutpreceden t i n r ad i ca l ca t ion chemis t ry ...=.."(,"

1

T he f luorescence of 9, lO-dicyanoa nthracene (DCA) wase f f ic i en tly quen ched by e i t he r la (kq = 1.4X 1O'O mol-'dm 3 s - l, E1,20X 1.52 V v s S C E ) 5 o r lb (kq = 1.8 X 1O1OTohoku U niversity.* Current address: College of I ndu stry, Nihon U niversity, Koh-riyama 963, apan.AT&T Bell Laboratories.

11 Current address: Department of Chemistry, Rutgers U niversity,Current address: Department of Chemistry, The College ofNew Brunswick, NJ 08903.William and Mary, Williamsburg,VA 23185.

0 1989American C hemical Socie ty