Diastereoselective Cathodic Cyclization of 1-(4- and 1-(3-Oxoalkyl)pyridinium Salts to Quinolizidine and Indolizidine Derivatives.код для вставкиСкачать
COMMUNICATIONS Diastereoselective Cathodic Cyclization of 1-(4- and 1-(3-0xoaIkyl)pyridinium Salts to Quinolizidine and Indolizidine Derivatives** Riidiger G o r n y , H a n s J. Schafer,* and Roland Frohlich The umpolung of reactivity by electron transfer has developed into a powerful synthetic principle for cyclizations. In this process. in acyclic molecules with two functional groups of the same reactivity. one of these groups has its reactivity reversed by oxidation or reduction, thereby initiating intramolecular C-C bond formation. The electrode has proven to be a useful reagent for this, as documented by numerous cyclizations at both the anode['] and the cathode."] Acetone and pyridine can be coupled cathodically in acidic electrolytes to form tetrahydropyridyl alkyl alcohols.[3- We report here on an intramolecular version of this C-C bond formation, which opens up a facile route to heterobicyclic systems. We chose oxoalkylpyridinium halides as starting materials. which are readily available by nucleophilic substitution of halogen ketones with pyridine and in which the arene is additionally activated for the reduction by the quaternization of nitrogen. Compound 1 was obtained in 68 Yo yield from pyridine and 5-chIoropentan-2-one.'~]The potential-con trolled electrolysis of 1 in il divided cell at - 1.37 V (relative to the saturated calomel electrode) in 1 0 % aqueous H,SO, gave. after current consumption of 1 h' F r n o l ~I , 12 % 2a,b in a 1.3:1 .O ratio and 28 % 3;[']a t the same time a strong evolution of hydrogen was observed. An electrolysis with a current consumption of 4 F m o l - gave 9 % yield of 2a.b (a:b =1.3:1.0). pronounced passivation takes place when the mercury cathode is replaced with a graphite, glassy carbon, o r Icad cathode. On the lead cathode, if the electrolysis is repeatedly interrupted and the cathode surface is polished a 38 O h yield of' 2 was obtained. The more pronounced passivation on graphite o r glassy carbon cannot be alleviated in this way: 1 was not transformed on these cathodes. The structure of 2a,b was determined by N M R spectroscopy and in the case of 2a confirmed by X-ray analysis (Fig. la). The 'H NMR signals of the olefinic protons at 6 = 5.7 and 5.8 are only consistent with 2a and 2b among the conceivable doublebond isomers. The quinolizidines 2a and 2b were converted by catalytic hydrogenation (H,/Pd/C) to the known (IS*,YaS*)-lmethylquinolizidin-1-01 (4)19]in 9 2 % yield (not shown). u Fig. 1 . a ) Structure of 2a and b) of 29a in the crystal [XI. ' 1 1 2a 2b 3 5a The yield of 2 can be increased by reducing the competing reduction of protons. A decrease of the H + concentration to 5 YO did not improve the yield; at pH 7 2 was not formed at all. However. if the electrolysis was carried out at a constant current the yield of 2 was improved to 3 0 % by reducing the current density (i = 4.2 mAcm-'). A further increase in yield of 2 to 5 8 % was possible by doubling the amount of charge. Under these conditions the best yield was obtained with a 0.2 M solution of 1 ; higher ( 0 . 4 M 1 : 4 4 % 2) or lower concentrations of 1 (0.1 M l:50'Yo 2) led to decreases in the yield. The most favorable sulfuric acid concentration is 10%; in 5 % H,SO, the yield drops slightly, in 20 '9'0 H,SO, more strongly. The temperature only slightly influenced the yield in the range of 3 to 40 "C. In every case the ratio of 2a:2b remained 1.3:l.O. A more or less 5b I. 7 * 1 6 [*I P I o f 11. _I Schiifer. Dr. R. Gorny. Dr. R. Frohlich"' Org'inisch-chemisclies Institut der Universitit ('ori-enstrxsac 40, D-48149 Munster (Germany) Telefax: I n t . code + (251)83 9772 e-mail: sch'ifchin uiii-muenster.de [+I [**I X-rxy ctructure analyses. Elcctroorganic Syntheses, Part 61. This work was supported by the Fonds der Chcrnischen InduTtrie with a doctoral grant t o R. G . a n d from the Graduiertcnkolleg "Hochreaktive Mehrfachbindungssysteme". Part 60, U KlotT-Bei-ciides. H. J. SchHfer. M. Grehl, R. Frohlich. A ~ i p i 'Chetti. . 19Y5. 107, 218 120: A ~ i j i C'lwn. ~ . Int. Ed. En,q/. 1995. 34. 18Y 191. 2b Scheme 1. Postdated course of the reaction I - 2a 2 COMMUNICATIONS Measurements with differential pulse polarography at pH values from 1-4 and extrapolation of the values to 10 % sulfuric acid indicate that the pyridinium group and the carbonyl group are reduced at - 1.43 V and - 1.37 V, respectively. The relative positions of these potentials, the structures of the products, and postulated course[1o1of the cathodic coupling of acetone with pyridine support the mechanism outlined in Scheme 1. The protonated carbonyl group is reduced to the radical, which adds to the pyridinium ring. According to AM1 -calculations the nitrogen in the radical cation 5 has a negative partial charge. thus the cyclization from conformation 5a is favored possibly through a hydrogen bond, whereas cyclization from conformation 5b is sterically hindered because of the interaction between the methyl group and the pyridinium ring. Compound 6 is formed from 5a and has the (lS*,9aS*) configuration; 6 is then protonated to form the immonium ions 7a and 7b, whose 2e reduction leads to 2b and 2a, respectively. In order to demonstrate the utility of this reductive cyclization, substituents were placed on the pyridinium ring and the size of the annulated ring was varied. Thus, the pyridinium salts 8- 12 were prepared from the corresponding pyridines and 5-chloropentan-2-one in 33 -63 % yield and subsequently cyclized under the optimal conditions for 2 to give the quinolizidines 13-17 (Table 1). R3 R3 80 and 88 % yield, respectively, by the alkylation of pyridine and 4-tert-butylpyridine, respectively, with 2-(2-bromoethyl)-2methyl-2.3-dioxolane. Their cathodic reduction under the optimized conditions for 2 gave in each case only one double-bond isomer of the indolizidines 20 and 21, respectively (Table 2). The structures of 20 and 21 were determined by comparison of their spectroscopic data with those of 2a and 16a and in the case of 20 additionally confirmed by an X-ray structure analySiS.'81 While the yield of the cyclization to the five-membered ring is hardly reduced in comparison to that of2, as expected this is not the case for the annulation of the seven-membered ring. Coinpounds 24a,b (14%) and 25a,b (16%) were obtained together with the acyclic alcohols 26 (16%) and 27 (16%) from 22 and 23 (prepared from the reaction of 6-bromohexan-2-one with pyridine and 4-rert-butylpyridine, respectively, in 83 YO and 87 % yield). respectively, using the optimized conditions for 2 (Table 2). R R fa, 19 R3 20,21 R R 1 U U a - 12 - U - 13a 17a 13b 17b Table 1. Reductive cyclization of the 1-(4-oxopentyI)pyridiniumchloride I and 812 to the quinoliddines 2 and 13 -17. respectively [a]. Entry R' 1 1 2 3 4 5 6 8 9 10 I1 12 H CH, H H H CH, Pyridinium salt R1 RA H H CH, H H H H H H CH, iBu H Product R4 H H H H H nBu Yield [ %1 22,23 24a, 25a 24b,25b 26,27 2 58 13 14 40 Table 2. Reductive cyclization of the 1-[2-(2-methyl-1.3-dioxolan-2-yl)ethyl]pyridinium bromides 18 and 19 to the indolizidines 20 and 21, respectively. and 1-(5oxohexy1)pyridinium bromides 22 and 23 to the pyridoarepines 24 and 25, respectively. as well as the alcohols 26 and 27. respectively. For conditions see Table 1 . 45 59 Entry IS 16 17 Pyridinium Salt R 62 41 18 19 22 23 2 3 4 The structures of 13-17 were determined by ' H and 13C N M R spectroscopy and mass spectrometry and in the case of 16a confirmed by X-ray structure analysis.['' Owing to the alkyl substituents. several diastereomers were formed in the reduction of 8, 9, and 12. Six diastereomers were obtained from 9 in the ratio 2.4:1.5:1.2:1.0:3.6:3.6 (according to gas chromatography); however, these could not be separated by liquid chromatography. The unsubstituted carbon C-6 of the pyridinium ring in 8 couples preferentially; products of the coupling at the substituted C-2 were only identified in trace amounts. Doublebond isomers and C-2 epimers from the coupling at C-6 were obtained from 12. The yields for the cyclizations of the 4-substituted pyridinium chlorides 10 and 11 are comparable with those for the unsubstituted 1. The yields of the cyclizations of 8,9, and 12 are slightly lower, possibly because of steric interaction with the substituents on the pyridinium ring. The reductive cyclization of 18 and 19 should lead to the indolizidine skeleton. Compounds 18 and 19 were prepared in Products yield [YO] I%] ~ 1 [a] Conditions: Charge used: 8 F m o l - ' , current density: 4.2 rnAcm-*, 10% sulfuric acid, 0 . 2 pyridinium ~ salt solution. 20°C. yield H tBu H iBu 20 21 24a, b 25a.h 55 58 14 16 26 27 16 16 A tricyclic quinolizidine is also readily available in only three steps from 28. The pyridinium bromide 28 was prepared by alkylation of 7-picoline with 2-(2-bromoethyl)cyclopentanone in 83 % yield. The cathodic cyclization of this compound gave 29a.b in 46 YOyield in the ratio > 20: 1. The structure of 29a was determined spectroscopically and confirmed by an X-ray structure analysis (Fig. 1b) .['I 28 29a 29b COMMUNICATIONS In this case a double-bond isomer was formed regioselectively. and ;it the same time three stereogenic centers were formed diastereoselectively. The preferential formation of the (3aR*,9aS*.9bS*) diastereoisomer in this case can be explained by the smaller steric interaction between the 2-H of the pyridiniu m ring kind the c,.w-orientated angular H atom of the side chain. Quinolizidine and indolizidine derivatives are diastereoselectively accessible in only two or three steps in a simple reaction in which the key step is the new cathodic cyclization described here. scan) by direct methods with the hydrogen atoms in calculated positions. 2a C,,H,.NO. M =167.25. crystdl dimensions 1.0 x 1.1 x I 1 min'. u =7.513(1). h = 8.557(1), c = 8.769(1) 1 = 66.70(1). /I =73.41(2). ;= 66.91(1) , I ' = 470.6(1)~3.p,,,,, = 1 . 1 8 0 g c m ~ 3 . ~5~. 9=c m - ' . % = 2. triclinic.spacegroup Pi (no. 2). 2179 measured reflections ( + / I . + k . * I ) . 1965 independent and 1949 observed [fz2u(f)] reflections. 112 refined parameters. R = 0 043, wR2 = 0.118. max. residual electron density 0.lS i - 0.28) cA-'. 16a C,,H,INO. M = 207.31, crystaldimensions 1.2 x I . U x 1 Omni', (1 =7.871(1). h=9.231(1). c = 9 . 9 9 1 ( 1 ) A . r=76.22(1), /i= X1.79(1), ;.=73.65(1). L ' = 674.3(1) A3. pvrlLd =1.110 gcm-'. 1' = 5.2 c m - ' . , ! = 2. triclinic, space group P i (no. 2). 3027 measured reflections ( f h . * A . f I ) . 2812 independent and 2749 observed [f>2u(f)] reflections. 151 refined paramcters. K = 0.032, wR' = 0.075. ma\ residual electron density 0.25 ( - 0 1 7 ) c k ' . 20 C,H,,NO. M =153.22, crystal dimensions 1.0x0.7xOhmin'. ( I = 7 153(1). Ii=8.375(1). c = 8 . 7 3 3 ( 1 ) A , a = 9 9 . 4 7 ( 1 ) . [ j = l O Y . 6 l K l ) . ;.=lIO.XY(l). I / = 435.80(9) A'. pcd,Ld =1.168 gcm-3. 11 = 6 . 0 c i W ' . / = 2. triclinic. space group P7. 1896 measured reflections ( + / I , + k . * / ) ~ 1773 independent and 1750 obseried [fZZalf)] reflections, 103 refiiied pai:imeters. R = 0.043. u,R' = 0.117. max residual electron density 0.30 ( - - 0 I 7 ) e k ' . 29a C , , H 2 , N 0 . M = 207.31.crystaldimensioiis0.4~0.3xO3 nim'.u =7.134(1). h = 9.402(3), = 9.326(3) A. a = 101.39(3). /j = 98.1)3(?). 7 = 105.46(3)". I = 57~.6(3)A', pr,t,Lci= ~ . ~ ~ g c i n =- 5.7cm.'. ~ , L = 2. triclinic. space group Pi. 2514 meiirured rellections ( + / I . + k . i l l . 3.i63 independent and 211X observed [ I r 2 u ( f ) ] reflections. 139 refined pxameters, K = 0.066. uR' = 0.239. max residual electron density 0.36 ( - 1) 3 7 ) e k 3 Programs used: SHELX-86. SHELX-93. SCHAKAL92. Further details of the crystal btructure inLeatigations may be obtained from the Faciiinformationa~entruiii Karlaruhe. D-76343 Eggenstein-Leopoldshafen (Germ:in\) on quoting the depository numbers CSD-401870 for 2a. CSD-401868 for Iba. CSD-401869 for 20, and CSD-401867 for 29a. A. Silhiinkowi. J. Ldvicka. S. Kafka. M. Ferles. CoI/w I ( X ~ IC'omnnnf. . 1983. 48. 1435- 1439. 7. Nonnka. S. Miyaji. K . Odo. UefikiKugukir 1973. 41. 142 149. [CIwii. Ahstr. 1973. 79. 4677~1. K . Jarowicki. T Jaworski. Monard. CIir~n?.1984. 115. b(l5 612: J. K . Crandall. R . J. Seideuand. J. Org. CImf 1970. 35. 697 -701. A, E.vpcv?nwri ttr l Pro ccclurc 28: I-Mcthylp!~i d i n e (2.79 g. 30 mmol) and 2-(2-hromoethyl)cyclopentanone [I I] (3.Q g. 70 nimoli usere heated to 170 c' for 20 min. After cooling to room temperiiturc the reactioii mixture was treoted with ether (80 mL). slimed for 10 min and tlicn tlir etlier \\.I\ decantcd off. This procedure uas repeated twice nith ether (with 50 mL) The reaiduc was then dissolved in methanol ( 5 mL) with gentle warming. treated uitli ether (XI) inL) and stirred for 5 min before the supernatant was decanted ~ i l f Altei. the final wash with ether (50 mL) and subsequent decanting. the residue , was filtered through ii short column tilled with silica using methanol aseluant. After remowl ol thc mcthanol under vacuum. 4.82g (17 mmol, 83%) 28 remained ' H N M R ((.D,OLI). d =1.61-2.00 (m, ZH. NCH,CH,), 2.03 ~ 2 . 4 5(m. 7H. cyclopciitmone-HI. 1.73 (s. 3H. CH,). 4.65 4.86 ((partially covered by CH,OH) NCfI,l. 7.Y9 ((1. -'.I = 6.5 Hr. 2H. N C H C H ) . 8.91 (d. ' J = 6.5 H r . 2H. N C H ) . " c ' N M R ( C ' D , O L ~ l := ~ 21.9 (t.NCHiC'H,).22.3(q,CH,).30.9(t.0CCH,C'H,). 32.X ( t . O C ' C H ( ' H 2 ) . 38.8 (1. OCCHI), 47.3 (d. OCCH), 60.7 (t. NCH,). 130.3 (d. NCHC'H). I45 3 (d. N C H ) , I617 (s. CCH,). 222.0 (5, CO). 29. 28 (2.84 g. 1ii.O mmol) uas dissolved in 10% sulfuric acid (50 mL) and electrolyzed i i i ii di\idcd beaker type cell with a mercury pool cathode (19 cm') and a platinum ;inode ( 1 cm'). a current density o f 4 . 2 mAcm-' (related to the cathode). ;it ii teinpei-;itui-e o120 C. until the consumption o f 8 2 Fmol- I . Thecatholytc was madc biisic h\ addition of solid sodium carbonate and shaken with dichlorometh~iiir.After drying the organic phase with magnesium sulfate. it was c(1iicciiti:itcd dnd the solution liltered through silica with diethyl ether as eluant to give 0.95 f (4.6 minol. 40%) 29a.b. ' H N M R (CDCI,): 6 =1.44-2.03 (m. 10H). l . 6 X l \ . C ' H 3 ) . 2 ? 3 2.36~in.3H,7-H,,.X-H,,,5-H,,),2.51-2.5X(m.2H,5-H,,and lOn-Ht,2.6l (s. I H. O H ) . 2.71 2.81 (in. 1 H, 7-H,,). 5 3 5 ( s . 1 H. 10-H). " C N M R ~ C ' D C ' I , I : ~ = I ~ ~ I ~ . C - ~ ~ . ~ ~( . t . c~- 3() .~ 3 n.. 4C( tH .c, - i )). . ~ ~ . ~ ( ~ , C - ~ ~ , ~ ~ . ~ 33.5 (1. C-X). 43 X id, C-.Ta), 51.3 (I. C - 5 ) . 52.5 (1. C-7). 63.2 (d. C-l0a). 78.5 (s. r - l l l b ) . 1 l X 5 (rl. C-10). 135.8(s. (-9) Received: April. 18. 1995 [Z7894IE] German version: Anpi!,. CIlwn. 1995. 107. ?188-2191 Keywords: cyclizations . electrochemistry . heterocycles . indolizidines . qiiinolizines [ I ] H . 1. Schafer i n O r ~ u i i i cE i e ~ r u o c h r ~ i i u(Eds.: ~ r ~ H. Lund. M . M . Bairer), Dekker. NCMYork, 1991, p 949. there p. 985: H. J. Schiifer. W. Eilenberg, /f?rcwo[ i'ik, 1989. 28. 979 -985: L. V. Tinao-Wooldridge, K . D. Moeller. c'. M. l l t i d ~ o i i J . Org C'ilcn7 1994. 59. 2381 -2389: S. Maki, K.Tuyodn. S. Ko\emur;i. 5 Yam;imura. C/iCWl. Lcrr 1993. 1059- 1062: S . Yamamura. Y. Shimri. H Shigemori. Y.Okuno, M. Ohkubo. E,rrulicdron 1991. 47. 635-644: F (; C'orley. Y . L. Abramson. J. S. Amato. L. M. Weinstock. ibid 1991. 47. 757 766. [?] M . M. Hiiiicr i n Oi:yunu E / ~ , c r r o ~ I i o ? i i . c(Eds.: lr~ H. Lund. M. M. Baizer). D c k k r r . Ncu York. 1991. p. X7Y: R . D. Little. C. G. Sowell i n €Iwir.oor;nuni< .SinrIw\/.s (Id, : R. D. Little. N.1.. Weinherg). Dekker, Ne% York. 1991, 2 3 . T Stiono. N. Kise. T. Suzumoto. T. Morimoto. J Am. C h m ~Socc . 1986. . 4676 4677; C. G. Sowell. R . L. Wolm. R. D. Little. f i r r o h c d r o n Lrrr. 1990. 3 l . 1 x 5 4XX. N. Kise. T. Su7umoto. T. Shono. J 0r.g. C/W?I.1994, 59. 1407 1113. R D. Little. R. Wolin. G. Sowell. Denki K u p k u oi.ohi K O ~ W 8ursi1r1 h.iirdir 1994. 62. 1105-1 108: [ C h m Ahsrr. 1995. 122, 117416u]: S. r)oiiiicIl>. 1. Grimshau:I Trocha-Grimshnw. .I Cli~vn.Soc. U i w r . ConfiIiuri. 1994. 2171 2171.  T Noi1;ik.i. K Sugino. J. EI<wrrocIicwi.Sot.. 1969. / 1 6 , 615-616.  M . I-erlcb. M Vaiikn. A. Silhinko\.d. CiiIkcr Ciedi.CIirvn. Cinnniwf. 1969. 34. 2108 2113  T Ninirikii. 11 Sekinc. K . Odo. K . Sugino. UwrrocInn~.A<rii 1977. 22. 271 1'7. [h] I). 4 . Iiiegci. M. R . Freq. ,L Orp. C'/i<wi. 1982. 47. 31 1 315.  The hiilts I . 3. X I 2 are present iis chlorides and the salts 18. 19. 22,23. and 28 a\ bromides I.or reasons of clarity the anions are not shown in the diagrams. [XI Data lor tlic lour X-ray structure determinations: The structures were solved on a n Enr:il-Nonius CAD4 diffractometer. ( i = 1.54178 A. T = 223 K. (11-20 ~ ~ Automerizations and Isomerizations in Propynylidene (HCCCH), Propadienylidene (H,CCC), and Cyclopropenylidene (c-C,H,)** Randal A. Seburg and Robert J. McMahon* The structure and rearrangements of triplet propynylidene (1, propargylene) and its derivatives remain topics of current interest.[' -'] Despite considerable experimental and theoretical effort spanning 35 years, a detailed understanding of the structure of 1 emerged only recently. Experimental['] and theoretical121 investigations implicate a C2-symmetric, 1.3-diradical-like structure for 1, rather than the linear structure concluded from early experimentsr3]or the bent C, structure predicted by other theoretical studies14. (Scheme 1). Our '3C-labeling studies not . . H\\\\aH ~-'l H 1 H = ~ 7H H Scheme 1. Currently accepted and previously proposed structurcs for triplet propynylidene (1) [*I Prof. Dr. R. J. McMahon. R. A. Seburg Department of Chemistry University of Wisconsin-Madison Madison. WI 53706-1396 (USA) Telefax: Int. code +(60X) 265-4534 [**I This work was supported by the National Science Foundallon. We acknowledge Eric V. Patterson for providing the QCISD/h-31G* calculations o n triplet propynylidene.