trapping of the radical intermediates

Syntheses sf azapolycyclic compounds by aminium radical routes: trapping of the radical intermediates1 RICHARD A. PERRY, ROBERT W. LOCKHART,' MASAYUKIKITADANT.' A N D YUANL. CHOW

Can. J. Chem. Downloaded from www.nrcresearchpress.com by 202.110.74.245 on 05/28/13 For personal use only.

Deyiirtrncr~tc;f'Cher~~i.stl:v, Sirr~or~ Fr.iiser. Uni~.ei..sit~, Btrrricrhy, B.C., Cor~citltiVS.4 IS6 K e c e i ~ e dMa]-ch27. 1978 RICHRD A. PLRRY,ROBERTW. LOCKHART, MASAYUKI KITADAN.and YLAUL. CHOW.Can. J. Cheni. 56, 2906 (1978). Photolysis o f three alkenyl nitrosaniines in the presence of oxygen o r bromotrichloromethane resulted in the interception of the intern~ediateC-radicals by these radical trapping agents and the reaction pathmays \?ere cleanly diverted leading to the formation of the nitrate esters or halides \$ith pyrrolidine ririgs as the priniarq products. The exo-nitrates in the oxidatibe 1.3hotolqses decon~posetibq secondary ionic p a t h ~ a j s these : reactions \\ere hydrolysis, nitrous acid elimination ant1 a clca\-age reaction ipronioted by a p-amino group), anlong others. The efficiency of the cleavage reaction is controlleci b j a stereoelectronic factor that requires the participating bonds and the lone-pair nitrogen orbital he orieiiteci in an antiperiplanar conformation. When such a conformation exists in a rigid o r se~niflevibleframework, cleavage occurs e-itensi~elj-.Ho\\e\er, in freely rotating acyclic systems, cleavage does not occur even when the required conforniation can he attained. O n l j halides resistant to int~~arnolecular nucleophilic displaceiiieiit t o form the aziridinium intermediates were isolated in the bromotrichioromethane trapping e ~ p e r i m e n t s Other . c'xo-halides under\vent solvolysis via aziridinium ion intermediates. MASAYUKI KITADANI et YUAUL . CHOW.Can. J. RICHARDA. PERRY,ROBERTMI. LOCKHART, Cheni. 56. 2906 (1978). L a photol3-se de trois alheiiylnitrosailiii1es en prescnce d'oxygene ou de hromotrichloromethane a donne lieu ii l'interception des C-radicauv interiiiidiaires par ccs piegcs 3 radicaus et les cheiiiins rCactioniiels ont CtC nettenient dehiei vers la formation ci'esters nitrates ou d'halogenures axec des noyaux pyrr-olidines coninie pr-oduits priniaires. Les nitrates exo en photolyse o x ~ d a n t esc dkconiposaient par voies ioniques secondaires; ccs reactions Ctaient, entre autres, I'h>drolyse, l'eliniination ci'acitle ~iitreuxou une rCaction de clivage (favoriske par u11 groupe (i-amino). L'eficacite de la reaction de clihage est sous le contrBle d'un facteur stCr6oelectronique exigeant que lei liaisons participaiites et I'orhitale de l'arote renfermant la paire libre sc trou\ent dans des conforniations antiperiplanaircr. Quand une telle conformation existe dans une structure rigide ou semitlexible, le clivage se produit bien. Cependant, dans les syst6nles ac\-cliques en rotation libre, leclivage ne se produit pas, m6rne quand les conformatiolis esigees peu\,eiit exister. Les seuls halogCnures isoles ont Cte ceu-i qui possedent une barrikre d'knergic ele\Ce pour le deplacement nucleophilique intrarnoleculaire menant aux intermediaires aziridinium. Les autres halogenures exo ont suhi iine sol\oIqse passant par l'intermidiaire cle I'ion aziridinium. [Traduit par le journal]

As shown 111 the preceding report (2), applications of the lntra~uolecularphotoaddlt~onof the alkenyl nitrosamines in the synthesis of azatricyclic compounds may be complicated by the ring-opening reaction proiiloted by a /3-amnnonium group partly due to cumulative ring strain. Since photoreactio~l occurs by a step\\ise radical addition (3, 4), it is envisaged that the C-radical intermediate B might be intercepted by a suitable radical trapping reagent so that a stable and isolable azapolycyclic derivative coulcl be obtained. 'Some of these results have been published in a preliminary communication ; see ref. I . 'NRCC Scholarship holder 1973-1 976. 3011 study leahe from College of General Education, K o b e University, Kobe, Japan.

(CH2),-YH-

c Efficient iilterception of a C-rad~cal~ ~ i t e r ~ i l e d i a t e by oxygen 111 intermolecular photoadditiolis of nitrosamines (4-7), nitroamines," and tet~.azenes(8) 4Y. L. C h o ~ El. , Richard, and R . \V. Snyder. Unpublished results.


PERRY E T AL.

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the primary products. the nitrates (or the pernitrite). M~ssingIn the crude product was euo-n~trate5 \\111ch \\a, prepaled fiom cxo-alcohol 4 and nab found to deco~upoie 1ead11y on stolage to glle ketone 7 ; deco~upositionmas eken raster in basic solution. In contrast, enrib-nitrate decomposed to ketone 7 only In a sotl~umh>drouide solut~onbut \ \ a > stable on storage. Reduction of the crude product ~ v i t hlithiunl alurniniu~n hydride folloived by Jones' oxidation gave ketone 7 in 55"; overall lielct: the loll; yield was attributed to the volatility of alcohols 2 and 4 (ride i ~ ~ f iand a ) poor yields froin the Jones' oxidation. I n a photolysis reaction carried out in the presence o r perchloric acid, we failed to obtain salts of tlie arnine nltrates by cr>stall~zat~on. T h ~ sattempt also $ho\\ed that the n1t1ate estel s decomposed e x t e n s ~ ~ edl yu lng ~ ac~d-base treatments of the crude products A small A good radical trapping agent in the present case amount of ctirlo-alcohol 2 \\a\ also isolated In t h ~ s should react sluggishly uith electrophilic arniniu~n leaction. radicals but \igorously with nucleophilic alkyl Both euo-alcohol4 and rndo-alcohol2, p a ~ t ~ c u l a r i y i bromo- the latter, codist~lled u ~ t h the sol\ents d u r ~ n g radicals. As well as oxygen, s h o ~ i above, trichloro~nethaneis expected to fill the requireme~lts e\ a p o r a t ~ o nand \sis sho\ved that the major peak could be phosgen oximc: 115 (3"3-C1, 65): 1 I3 (35C'12,87), 98 (1 I), 96 ( i s ) , 80 (46), 79 ( 3 9 , 78 (100); 77 (74), 63 ( l l ) , 61 (30), 47 (13), 43 (22). The distilled blue sol\ent showcci a peak rrhich corresponded to a minor peak of the neutral fraction and \\as assu~nedto be that due to trichloronitroso~ncthane.

C'niiei. Ox~geiz A solution of .?--nitrostmine 8 (2 g. 0.011 mol) and concentrated HCI (1.0 ml, 0.06 .Y) in niethanol (200 1111) \vas photolysed under oxygen for 3 11. The usual \\orb-up gave a 11eutral fraction (130 n ~ g ) :is: 3350 (m, br), 3055 (\v), 1715 (~v),1640 (m), 1550 (ni) c m - I ; nmr r : 0.20 (ti, J = 2.5 Hz), 3.90 (111). The mother liquor \\as basified and extracted nith CH2CI2(3 x 50 mi) \\hicli \\as dried and evaporated to a crude basic residue (1.8 g): il-: 3300 (r\, br), 3060 (\v), 1720 (ni), 1670 (ill), 1620 is), 1275 (mj, and 865 (m) e m - ' . After 24 h the ir band at 1720 c m - ' became stronger relatike to the others. In n similar experiment the basifed mother liquor was extrucieil \\it11 ethel- (4 x 50 1111):thc extracts \verc drictl and imnlediatcl) treated n i t h L A H (2 g), and on work u p gare a yellom oil ( A ; 1.2 g). The aqueous l a ~ e mas r further extracted with CH2C12 (3 x 50 nil) t o give oil B (130 mg). Finally, the aqueous layer !%as continuouil~ extracted ~ i t hCHzClz for 3 d a j s to afford crude hydroxy lactam 11 (180 n?g): ir: 3380 (s: Or), 1655 (s), 1065, 1040, and 1020 (m) c m - ' : a m r r : 6.45 (111; 3H) and 6.92 (dd, J = 10 and 1 Hz, IH) 12). Oil A (1.0 g) mas chromatographcd on neutral alumina (50 g). Elution \\..it11 0 . 4 2 methanol-CH2C12 gave a crude olcfinic alcohol (1 10 111%):ir: 3380 (m), 3055 (n?), 1660 (w),1030 (m), 778, anif 705 (s) em-' ; ms fir,'ello\\r needles, mp and mp 011 admixture n i t h an authentic sample (2) 138-139 C. Continued elution \\ith 3-5z niethanolCH2C12 gare tric~clica n ~ i n oalcohol 1.3 (216 mg, 12.5z): ir: 3350 (s, bi-), 1650 (w),1130. 1040 (m), and 1015 (s) c m - ' ; nmr r : 6.3 I (m, W1,, = 3.5 Hz, Hd), 7.05 (m. D,O exchangeable), 7.27 (m, 3H), 7.50(s, N-CH,), 7.68 (111,1tI),7.90(m,3H),8.29.1 (m, 4H); 1115 it7,'e: 154 (4), 153 (M', 37), 152 i7), 136 (121, 124 (22), 96 (91), 95 (36), 94 (loo), 82 (621, 57 (45); nmr (HCI salt) r : 5.28 (111, D,O exchangeable), 5.90 (m,it/, = 3 Hz, H,,), 6.69 (d. J = 5 Hz, Ha), 6.72 (d, J = 10.5 Hz, H,), 7.02 (dd, J = 10.5 and 5 Hz, H,); 7.20 (s, N-CH). T h e picrate of 13 \\as recrystallized three times from ethanol, 1i1p 185-187'C. Ai~ril.calcd. for Cl,Hl,N,O,: C 47.12, H 4.76, N 14.65; f o u ~ ~C d :46.84, El 4.66, N 14.55. Basic extract B (95 mg) was reduced \\ ith LAH (2 g) in T H E (200 1111) and was ~vorkedup and purified in the usual manner t o gire a crude amino alcohol 12 (46 nig, 55%). I11 tire Prrseilce of Bron1oti.icI1loi.on7etha12e A mixture of nitrosamine 8 (1 g, 0.006 mol), coliceatrated RCI (0.55 ml), and CBrCI, (100 1111) \vas photolpsed under N, for 2 11. The fluorescent blue mixture was removed under vacuum ant1 the residue was separated into neutral (350 mg)

a n d basic (666 mg) fractions. The neutral fraction exhibited n o .\--methll signal in the iimr spectrun~. The basic fraction exhibited o i ~ l yone major spot at R, 0.37 and a faint spot a t R, 0.19 on a silica gel ilc plate (10"; methanol-CH,C12); the nmr spectrum was essentiall~that of 18 (ca. 90";) \\ith veak signals of 19. Silicic acid chromatograph) (1": methanol-CH2C12) of this fraction (500 111g) afforded an oily bromo aminc 18 (148 mg); is: 1185, 1165 (b), 935 (s), and 6.90 (s) cm-' : nmr T: 6.15(1n; W1,2 = 4 H z , H , , ) , 6 . 5 6 ( c i , J = 4 . 5 H z , H , j , 7 . 1 0 ( d d , J = 9 . 5 a n d 5 H z , H l , ) , 7 . 5 0 ( d , J = 9.5Hz,HC),7.50(s,su13erin~posedon doublet, N-CH,), 7.80 (111, 2H), and 8.4-9.0 (rn, 3H); ms nr, (. 217 (16), 215.03 10 (M+,calcd. for C,H,,P*j;ogr: 235.0295, 161, I36 (loo), 96 (38), 95 (27), 94 (100); and 82

(z):

(30). The bronlo anline 18 gale a dark tar o n atteniptcci \acuLiin distillation and the picrate deri\ati\-e (mp 180-190C, tlec.) decomposed o n repeated recrystallization. The minor co~nponent(ca. 57; of the major coniponent) of the basic fraction was isolated by preparative scale \ p c (6 ft x $ in., 20:'; SE30, l5OP&',retenlion tiine 10.8 min) as an oily chloro atnine 19: ir 1630 (x~v),940 (m), and 740 (111) till-' ; 11n1r c : 6.25 (111, It', = 3.5 Hz, H,), 6.80 (d, J = 5 Hz, H,), 7 , 1 0 ( d d , J = 9 . 5 a n d 5 H z , H , , ) ; 7 . 5 0 ( d , J = 9.5 Hz,H,),7.50 (s, superimposed on the do~iblet,N-Ck-I,), 7.80 (in, 3H); and 8.0-9.0 ( m , 3H); ms iii, e ('5):173 (lo), 171.0825 (calcd. for C,H,,UCI: 171.0814, 30), 136 (85), 96 (461, 95 (29), 94 (loo), ancl 82 (19). P i i o t o l ~ ~ ~f is-,l'irro.rnt~lirle .~ 14 Lr7ik.i O . u ~ e i l 4 solution of nitrosamiiie 14 ( 2 g, 0.011 n1olj and colicentratcd HCl (I .O n-11,0.06 .Y) ill methanol (200 ml) mas photol ~ s e i u~iciev l oxqgen for 1.5 11. The \\ark-up ga\e an oily neutral fraction (80 mg). The aqueous solution was basified and extracted with ether (3 Y 50 n ~ l )The . ether solution was dried and itirred overnight \\it11 LAH (2 g). \Vork-lip in the usual \\a) ga\e the retluced product (980 mg). The aqueous layer \\'as fiirlher extracted \\ith CH,CI, (3 x 50 mlj to give an additional babic extract (420 mg): ir: -1380 (rn, br), 3040 (1111, 1700 (s), 1625 is), 1270 (in), allti 1050 (111)c m - ' ; i1111rc : 6.2 (m), 6.67 (s), 7.15 (m), 7.48 (s), 7.6 (~il),aiid 8.2 (in). The recluced ektract (980 mg) \\as chromatographed on neutral alun~itla(50 g). Elutio~iuith 0.5U; methanol-CN2CI2 ga\e a n olcfinic fraction (340 mg); ir: 3040 (m) and 692 (s) c i t i l ; nmr T : -3.70 (in). Exa~nir-iationof this fraction by gc-ins (20";; SE30, 170 C') d 1 o ~ e dit to contain the parent amine, 16, and 17, and an unknor~ri olefiiic compound as the major coniponent. Elution a i t h 1'5 methanol-CHzCI2 ga\e bicyclic aniino alcohol 17 (254 mg, 13:x) \chic11 tlistillccl at 30'C 0.05 Torr: ir: 3350 (s, br) and 1040 (5) c m l ; nmr 7 : 6.58 (m, 2H), 7.0-7.75 (nl, I H ) , 7.62 (s, N-LCH,), 7.8-8.2 (m, 2H), ancl 8.4 (m, 6H): 111s /17 e (%I: 169.1446 (M-, calcd. for C,,H19KO: 169.1467,33), 168 (38), 152 (lo), 138 (45), atid 57 (100). Trradiation at c 8.4 resultcd in collapse of the pattern at r 6.58 to a broadened singlet ( W , = 4 I-lz). Attempts to prepare the p-nitrobenzoate and picrate derivati~esof17 \\ere unsuccessful. Flution ~ i t h 2''; methanol-CH2CI2 gave exo-amino alcohol 16 (269 mg, 13;';) as an oil mhich on sublimation at 30'C 0.05 Torr ga\e white crlstals: 111p 73-74'C; ir: 3350 (s, br), 1052 (s), 1025 (s), and 980 cm-' ; 111nr r : 6.01 (111, D 2 0 exchangea hle), 6.20 (. W. L,. C H A Z GCan. . J. Chem. 49, 3069 (1971). 4. Y . L. C H O M Acc. . Chem. Res. 6.354 (1973). 5. Y . L. CHOW.J . N . S . T.w. C. J . COI.ON.and K. S . P I L L A Y . Can. J . Chem. 56,2469 (1973). 6. K . S. PILL.\Y. K . HANAY.\.and Y . L . CHOW.Cii11. J . Chem. 53. 3022 (1975). 7. K . S . P I I - I . ~ and > Y . L. CHOW.J . Chem. Sue. Perkin 11.93 ( 1977). 8. L.M A C ~ D Z I ' Vand S K IY. L . CHOW.J . Am. Chem. Soc. 100. In Broi~iotricl~IoioiiietIi~ine 2444 (1978). A mixture of nitrosamine 14 (0.5 g, 0.0028 niol), concen, L. C . 9. D. H. R. BARTON.R. H. HFSSE.M . M . P E C H E Iand trated HCl (0.3 nil), a n d CBrCI, (100 ml) \\as photolysed S L I I T HJ.. Chern. Soc. Chern. C o m n ~ i ~754 n . (1977). under N, for. 2.75 11. The mixture \vas ciistillcd iciidel-\acuum a t 10. D. D. . ~ . % S N ~R.RJ.. ARHART.E . V . Bl 4 C K B U R 1 . . E.C . 20'C and the b l ~ i etiis~illateMas trapped in a coolecl recei\er. D4s. zind N. WAD-\.5 . Am. Chern. Soc. 99. 2190 11975); The neutral extract (204 mgj \\as a mixture of a1 least iix D. D. T s h ~ ~and r t N . WADA.J . Am. Chern. Soc. 97. 829 cornponeiits as deterinined by ~ p and c exhibited n o .\--metl?\l (1974). signal in the nmr. The basic fraction (205 mg) had the Eollo\\ing 1 I . J . H . H.\KGIS.J . Org. Chem. 38, 346(1973). physical constants: ir: 3300 (\\, br), 3030 (m),1720 ( \ \ I , 1660 12. 6. J . G L E I C I I E Tetlxhedl-on, R. 30,935 (1974). (iv), 1162, 950, and 700 ( m ) e m - ' ; 111i1r7 : 3.75 (m), 5.60 (rnj, 13. B. GIESE.Angew. Chem. Intern. Ed. (Engl.). 15, t73(1976): 5.80 (111, D,O exchanaeahle), anci 7.0-9.0 ( ~ ~ i i r e \ o l ~ e c ! ) . 15. 174 (1976): 15.688 (1976). Analqsis of this fraction by gc-ms (207; SE30, 150 C ) sho\veii 14. F. K. V E L I C H K O and L. V. VI%OGK,\UO\I.\. I L L . . Akad. three peaks in the ratio of l . 2 : 3 . 1 : 1.0; peak 1 (3.2 min) Mas Nauk SSSR Ser. Khim. 1192 (1972). 1101 identified; peak 2 (3.5 nlin) cxhibiletl ari in\ pattern 15. D. I . D.\VIESand L . 7'. P A R F I II . J . Chem. Soc. (C), 1401 identical to that of the pa~.cntan1ine: and peak 3 (9.3 min) (1969): 2691 (1967). which exhibited nis fragineiits at 111 c : 23 1 (7); 229 (7), 150 (4h), 16. G . I . F ~ t - \ rG . . R . GEES, D. I. D A V I ~ L..S . T . P,IRFIII . and 94 (loo), and 82 (40). A n atteml,t to isolate the third con^iLI. J . PARROTT. J . Chem. Soc. Perltin 1. 729 (1074). ponent by silicic acid chroni;rtograph> \\as u~isiiccessii~l. 17. R . E . PERRY.S. C. C H E N ,5 . C. M ~ N O NK. H A ~ A Y ant1 A. I11 a separatee*l?erime~?t, asolutioiico~isisti~ly o r iiitrosaniine Y . L. CHO\\..Can. J . Chem. 54.2385 (1976). 14 (3.9 gj; methanol (120 ~ n l ) concenti.ated , h>cirochloric acid 18. J . W. B ~ s T - A B LJE. . D. HOBSON.ilnd Mi. 1). R I D D ~ L JL. . (3.5 mi), and CBrCI, (2301111) \\as irl-adicited at - 2 0 C until the Chem. Soc. Pel-kin 1.2205 (1972). absorption rnaxi~iiumat 350 11111 disappeared. The photo1)sate 19. W . P R ~ \ D T Land E K . S E N N ~ W A LChem. D. Bel-. 6%. 1754 \\as rapidly e\apo~,atedto d~.jnesi.The nnir spectruiil of this i 1929). resid~icin trifluoroacetic acid \ h o n e d a narrom siglial (LV, = 20. >I AKHTAR. . D. H. R. BARTO\.and P. G. SALI%IES. J . Am. 4 Hz) at r 5.6. T o t h e ~ e s i d u e(3.7 g) taken u p iii ~?iethaiiol Chem. Soc. 87.4601 (1965i. (10 mi) was added \rith sodi~iinmethoxide (10";) in mcthanol 21. R. FURSTOSS.R. TAL)AYONI. and B. WAEGELL.J . 01.g. until strongly alkaline t o Iitni~istests. Thc hasic solution mas Chem. 42. 2844 (1977): R. FUKSIOSS.R. T A D A Y O Vand I, ~vorkedLIP in the iisual manner to afFord brown crude baiic B.WAEGELL.Nouv. J . Chim. 1. 167(1977). fmction (2.7 g). The vpc spectrurii o r this crude oil sho\zed one 22. J . M. SCRZUR.L . STELLA,and P. N A U G LEIK . Tetrahedron major peak corresponding to 21 Oield, ca. 20";) and at least Lett. 903 (1971). 40 nlinor pealis. Chromatography of this oil in beilreneether 23. K . H r u s r ~ n Tell-ahedl-on . Lett. 97 (1970). gave a [orerun (230 ~ n g follo\\ed ) by n mixture; thc forerun 24. 0. E . EDWARDS. 6 . BERNATH, J . DIXON.J . M . P A ~ O N iind , \\as distilled l o g i ~ e~nethoxy aniinc 21: picrate m p and D. VOCELLI,.Can. J . Chem. 52.2123 (1974). mixture nip 171.5-172.5-C (2). 2 5 . Y , L. CHOW,S . C. C H ~ NK,. S. PILLAI.and K . A. P ~ R I I Y . Can. J . C h e n ~SO. . 1057(1972). 26. G . F. H ~ N N I Oand X A. C . HAZY.J . Or-g. Chem. 30. 2650 (196.5): C . F. H A M M E RM , . CACARTHYALI. and J . D. U'EBER.Tetrahedr-on, 29, 1767 (1972). The author., are g r a t c f ~ ~tol the Natlonal Research . O X U M U R and ~ . K . K A W A I AJ . C o u n c ~ lof Canada. Otta\\a for c n c r o r l i operating 27. W . NAGATA.S . H I R A IT. Am. Chem. Soc. 91, 1650 (1969): 89,5046 (1967). grants for the projects. 28. H. TEUFEL.E. F. J E N N Yand , K. HEUSL.ER. 'retrahedr-on Lett. 3413 (1973): H. J . T R ~ DE~. .F. J E N N Y .and K . 1. I(.S. P I I ~ L ~RY . W. , L O C I I H ~ R 1'. T . T F Z U K . ~and . Y . L. H E L S L ~ KTetrahedron . Lett. 3425 (1973); W. MOLICK, CHOW..I. Chem. Soc. Chem. Commun. 80 (!974). E. F. J E N N Y ,and K . HEUSLER.Tetrahedron Lett. 3421 2. K. W . LOCKHART. M. K I T ~ U AF.~ W I .. 5 . E I I L S T E Iand ~. 11973). Y . L. CHOW.Can. J . Chern. This issue. 29. P. DESLOXC;(.HA~IPS. Tetrahedron. 31,2463 (1975).

io~~ acid gave a picl-atc (ycllo\z ~iecdles,SIOU d c c o ~ ~ i p o s i t 160200'C) 15hich deconiposecl on repeated attempts at recrystalliration. An acetone solution (3 1111) of amino alcohol 16 (65 mg) izas treated mith Cr0,-H2S0, in acetone at 0-C. The green solutioii \\as stil-~eclfor 1.5 t ~ The . acetone \\.as exapol-ated and the residue \\;as basitied \vith aqueous N a 2 C 0 , and extracted i\ith CH2CI, (4 x 15 iiil) to gi\e a clear oil (25 mg). The nmr and ir spectra of this oil \rere identical \\it11 those of the corresponding keto~ieisolated previous!) (2).


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