Article信州大学工学部紀要 58: 1-8 (1985)departmental bulletin pape

FURUTA,  Hideyuki

ITO,  Suketaka

KAKEHI,  Akikazu

TODOROKI,  Kazuteru

English

Shinshu University Institutional Repository

Journal of the Faculty of Engineering, Shinshu University, No. 58, 1985                   rwllki{l}fiX*es*/Ees gg58E1 Preparation of New Nitrogen - bridged Heterocycles. 12.       Reaction of 2 - (Acylmethoxy) - 3 - vinylindolizines                     in the Presence of a Base Akikazu KAKEI, * Suketaka ITO, ** Hideyuki FURUTA, ***                     and Kazuteru TODOROKI****Z)(Received May 29, 1985)   Reactions of 2-(aroylmethoxy)-3-vinylindolizines (11-18) with diazabicyclo[5,4.O]-7-undecene (DBU) or diazabicyclo[4.3.0]-5-nonene (DBN) and of 2-(ethoxy-carbonylmethoxy)-3-viny!indolizines (l9 and 20) with DBN were investigatedmechanistically from the standpoint of preparatlon. Il-18 react with DBU or DBNin chloroform, with elimination of a methylene compound, to give 2-aroylfuro-[2,3-b]indolizine derivatives in good to excellent yields. In contrast, 19 and 20react with DBN in ethanol to form devinylated compounds, 2-(ethoxycarbony!-methoxy)indolizines, in low yields, with simultaneous formatlon of considerableamounts of polymeric substances. A discussion is made with respect to the effectof substituents on the 3-vinyl group upon the transformations observed andpossible reaction mechanisms.   In our previous papers3-5) we reported a convenient method for syn-thesizing functionalized 2-alkoxy-3-vinylindolizines and allowing tkem totransform to fused heterocycles such as furo[2,3-b]indolizines and pyrano-[2,3-b]indolizines. In order to obtain further information on the reactivity,we have examined the behavior of these 2-(acylmethoxy)-3-vinylindo!izinederivatives under carbanion-generating conditions. In this paper we reporton a new preparative method for 2-aroylfuro[2,3-b]indolizine derivativesand a devinylation of 3-vinylindolizine derivatives.  * Assistant professor ** Professor *** Student of master course**** Graduate student'2 A. KAKEm, S. ITo, H. FuRuTA and K. ToDoRoKieeessults and Discussiest   A treatment of 2-(benzoylmethoxy)-3-[2-cyano-2-(ethoxycarbonyl)vi-nyl]-l-methylindolizine (10, readily obtainable through a reaction of 1-(ethoxycarbonylmethyl)-2-ethylpyrldinium bromide (l) with a base, ethyl(ethoxymethylene)cyanoacetate (5), and phenacyl bromide (8) (see Scheme1>, with DBU in chloroform attherefluxingtemperature,,affordedsmooth-ly a reddlsh crystalline compound 21, mp 12e-1210C, in 92% yield. Thesame compound 21 could also be obtained through reactions of 2-(benzo-ylmethoxy>-3-(2,2-dicyanovinyl)-1-methylindolizine (12) or 2-(benzoylme-thoxy)-3-(2,2-diacetylvinyl)-1-methylindolizlne G3) with DBU ln 50 or 41%,respectively. The 2-cyano-2-(ethoxycarboRyl)vinyl group in the indoli-zine 11 is more effective for this transformation than the 2,2-dicyanovinylgroup in 12 and the 2,2-diacety!vinyl group in l3. A reaction of indolizinell with DBN afforded also a furoindolizine derivative 21 in 91% yield, butthose with organic amines such as triethylamine and pyridine gave noproduct. A simi!ar treatment of 2-(aroylmethoxy)-3-[2-cyano-2-(ethoxy-carbonyl)vinyl]indolizlnes 14-{8 with DBU gave the correspending prod-ucts 22-26 in 58-93% yields. In the case of 3-vinylindolines 11 and 14-18with DBU, a formation of ethyl cyanoacetate 29 (Ri==CN, R2=COOEt)was detected by GLC analysis of reaction mixtures. Interestingly, com-pound 27 or 28 could be obtained directly through reactions of 2-benzyl-1-(ethoxycarbonylmethyl)pyridinlum bromide (4) wkh a base, 5, and phe-Br"(N Rk  COOEt1-4   R1 Me-2. H3 Etk Ph 1)2NaOEtlEtOH 2)EtocH=c(R s--7- 3)BrcH2coR' e-!o..RlR25 CN COOEt.6 CN CN-7 Ac Ac-Rt8 Ph-9 p-･CIC6H410 OEt---.Scheme 1.11!223-!4-±516-IZle1920  RN OCH2COR,      1   --XR21!-ZO-R RI R2 RtMe cN cooEt phMe CN CN PhMe Ac Ac PhMe cN cooEt p-clC6y!t,          PhH CN COOEt,H, 2kl 20,O,E,t, p,-,CiC6H,Et cN COOEt p-CIC6H4Me cN cooEt oEtPh CN COOEt OEt             Preparation of New Nitrogen-bridged Heteroeycles. 12. 3             RR                    DBU or DBN              "-,ORgH2COAr ESti;l]I-ii"`UlfruxincHc N OcoAr + CN2iRgi)R2          y-ls R2 21--ze ---                     1)2NaOEtlEtOH                     2) S                     3) 8 or9          a.N Ph --           k         Br- cooE!           s                        Scheme 2.               RR             INg,2o---O,ccCgNgCEOtOEtth.f.,iB.NEtoH eqt,3-H!ocH2cooEt                                               R                                            30 Me                                            --                                            31 Ph                                            -- -                              Scheme 3.nacyl bromide (8) or P-chlorophenacyl bromide (9) in 40 or 49% yields,respectively.   Reactions of 2-(ethoxycarbonylmethoxy)-3-[2-cyano-2-(ethoxycarbonyl) -vinyl]indo!izine derivatives 19 or 20 with DBN !n ethanol gave a strong-!y fiuorescent, pale yellow substance 30 or 31 in !ow yield, respectively,but that in chloroform afforded only a trace amount of the same product30 or 31. In these reactions considerable amounts of polymerlc substanceswere always formed.   From these experlmental results and related physlcal and speceral in-spections, it is derived that crysta!line compounds 21-28 are 2--aroy!furo-[2,3-b]indolizine derivatives and not any conceivable alternatives such asoxepino[2,3-b]indolizines 33 (see Scheme 4>. Of course, these compounds21-28 were completely in accord with the authentic samples preparedearlier by us.4) The structures of preducts 30 and 31 were determinedmainly on the basis of the presence of the 3-proton (o" near 7.e) and theabsence of the 2-cyaRo-2-(ethoxycarbonyl)vinyl group in their protonNMR spectra.R Ar21 Me Phi-z- Me p-ctC6H4ZRZ4-.25Ht-lEtPhp-CIC6H4Ph"2'-6---Et p-clC6H42-7-28--.PhPhPhp-･CIC6H44         A. KAKEHI,    R               -H+  N OcCHN2COR' RaAr    -AR211,12,14--2O･-- -.- -- --H20 MydroEysisRH,31s.caOCH2COOEt.3.0-ITo, H. FvRuTA     R       OvCOAr   N g- t"        CiN      ---NR   32      2y   NR       v-L'coAr   NcS<      R2   -34..and K. TODORoKI             R  +H'itatha N           3k3- R2  -i-H･ Path bNCCH2R2 +  Z9coArNH  R'N O      H H ecOANC R235l-  RCoAr                                                    21-26                        Scherne 4. -'" --   Mechanistically, the formation of 2-aroylfuro[2,3-b]indolizine deriva-tives 21-26 can be interpreted in terms of the intramolecular Michaeladdition of anionic species 34 generated by the proton abstraction fromthe active methylene group of 2-(aroylmethoxy)-3-vinylindolizines ll-l8,followed by the aromatization of the resulting tricyclic adducts 35 alongwith the elimination of a methylene compound 29 <Path b); the otherroute (Path a) leading to oxepino[2,3-b]indolizines 33 seems not to pro-ceed because of the more hindered comformation of intermediate carban-ion 32. Furthermore, the route4) vi-a the hydrolysis of the 3-vinyl groupof ll-18 followed by the condensation between the･ 3-formyl group andthe active methylene group, may also be neglected because no conversionof such vinyl groups to a formyl group occurs under the reaction con-ditions emp!oyed here.6) The direct formation of 2-aroyl-9-phenylfuro-[2,3-b]indolizines 27 and 28 must have resulted from the high reactivityof intermediate 2-(aroylmethoxy)-l-phenyl-3-[2-(ethoxycarbonyl)vinyl]in-dolizines once formed.   The formation of 2-(ethoxycarbonylmethoxy)indolizine derivatives 30and 31 may be a result of retro-vinylation since the vinylation of 3-un-substituted indolizines with some active ethoxymethylene compounds in thepresence of a base is well lcnown.3,7)   This method in which 2--(aroylmethoxy)-3-[2-cyano-2--<ethoxycarbonyl)-vinyl]indolizines are used for the preparatlon of 2-aroylfuro[2,3-bl-indolizines, has a high utility because of its manageability including the            Preparation of New Nitrogen-brldged xxeterocycles. 12.easy handling of indolizines 11 and 14-18.5ExperirneR{al'   Melting points were measured with a Yanagimoto mlcrome!ting pointapparatus and are uncoyrected. Microanalyses were carried out on aPerkin-Elmer 240 elemental aRalyzer. The NMR spectra were obtainedwith a Varian EM36eA spectrometer in deuterlochloroform with tetrame-thylsllane as an internal standard. Chemicai shiftd are expressed in 6values. IR spectra were taken with a Hitachi 260-le infrared spectropho-tometer.   PreParations of 2-(Acylmethoxy)-3-vinylindolizines 11-20 and 2-Aroyl-9-Phenylfuro[2,3-b]indolizines 27 and 28. These 2-(acylmethoxy)-3-vinyl-indolizine derivatives ll-20 were synthesized through reactions of l-(eth-oxycarbonylmethyl)pyridinium saks 1-4 according to the procedure re-ported earlier by us3,4) and recrystallized from ethanol. Similar reactionsof 2-benzyl-1--(ethoxycarbony!methyl)pyridinium bromide (4), with a base,ethyl (ethoxymethylene)cyanoacetate (6), and phenacyl bromide (8) orp-chlorophenacyl bromide (9) did not give expected 2-(aroylmethoxy)-1-phenyl-3-vlnylindolizines, but afforded 2-benzoyl- (27> (mp l86-1880C fromethanol) and 2-(p-chlorobenzoyl)-9-phenylfuro[2,3-b]indolizine (28) (mp227-2290C from ethanol) in 40 and 49% yields, respectively. Compounds l2, 19,and 20 were completely in accord with the authentic samples. 3,4) Some physicaland spectral data of the new compounds are as fo!lows. 31: 97%, orangeneedles, mp l91-1920C, p(KBr) 22e2 (CN) and 1681 cm-i (CO). AnaL Calcdfor C23H2oN204: C, 71.12; H, 5.19; N, 7.21%. Found: C, 7e.89; H, 5.22;N, Zl2% 13: 29%, orange prisms, mp 200-20!OC, v (KBr) 1687cmnti (CO).Anal. Calcd for C23H2iNO`: C. 73.58; ff, 5.64; N, 3.73%. Found: C, 73.42;H, 5.62; N 3.90% 14: 63%, orange needles, mp 203-2050C, v (KBr) 2210(CN), l693 <CO), and 1686 cm"' (CO). AnaL Calcd for C23HigN204Cl: C, 65.33;H, 4.53; N, 6.62% Found: C, 65.33; H, 4.38; N, 6.77% 15: 24%, orangeneedles, mp 165-1670C, v (KBr) 2208 (CN), l680 (CO>, and 1670 cm" (CO).AnaL Calcd for C22HisN204: C, 70.58; H, 4.85; N, 7.48%. Found: C, 70.66;H, 4.94; N, 7.30%. 16: 22%. orange need!es, mp 169-l710C, v <KBr) 22e9(CN), l689 (CO), and 1682 cm-i (CO). Anal. Calcd for C22Hi7N204Cl: C, 64.63:H, 4.19; N, 6.85% Found: C, 64.90, H, 4.20; N, 6.57% l7: 87%,orange needles, nip 166-1680C, v (KBr) 2201 (CN) and i690 cm-' (CO). Anal.Calcd for C24H22N204: C, 71.63; H, 5.51; N. 6.96% Found: C, 71.51;H, 5.30;N, 6.89%. 18: 58%, orange needles, mp 198-2000C, v <KBr) 2201 (CN> and6 A. KAKEm S.        'ITo, g. FuRuTA and K. ToDoRoKi1687 cm-"i (CO). Anal. Calcd for C24ff2iN204Cl: C, 65.98; H, 4.85;N, 6.41.%.Found: C, 66. 17; H, 4. 72; N, 6. 15%.   PreParations of 2-Aroylfblro[2,3-b]indolizines 2Z-26. General Method:A mixture of 2-(aroylrnethoxy)-3-vinylindolizine (1 mmol>, DBU or DBN(e.5g), and chloroform (50ml) was heated under refiux in a water bath untilthe disappearance of the starting indolizine was completely confirmed byTLC. The resulting reddish solution was concentrated under reduced pressure,and the residue was separated by column chromatography on alumina usinghexane, ether, and chloroform as eluents. The ether and chloroform layerswere concentrated under reduced pressure and the crude product was col-lected. A recrystallization from ethanol gave red needles of 2-aroylfuro-[2, 3-b]indolizine.   In the reactions of 2-(aroylmethoxy)-3-[2-cyano-2-(ethoxycarbonyl)vinyl]-indolizines 11 and l4--18 with DBU, ethyl cyanoacetate could be detectedby GLC analyses of reaction mixtures. No use of triethylamine or pyridineas a base caused such reactions. These furo[2,3-b]indolizines 21-26 thusobtained were complete!y in accord with the samples synthesized earlier byus.4) Some data of these reactions are shown in Table 1.   PreParations of 3-Uitsubstituted 2-(EthoxycarbonNlmethoxy)indolizines 30and 31. General ]N([ethod: An ethanolic so!ution (50 ml> of 2-(ethoxycarbonyl-methoxy)-3-vinylindo!izine (1 fnmol) and DBN (O.5g) was heated at the refiuxtemperature until the starting indolizine was disappeared (as confirmed byTable 1. Some Daea of 2-Aroylfuror2,3-b]indolizinesCompd Reactant Reaction time Base Yieldl% mplOc212223242526131111li1213l415l6l7i83021010304220353e3025minhhhminhminminminminminDBUDBNTEAa)Pyb)II)BUDBUDBUDBUDBUDBUDBU9291oo5041c)7458879372120-121197-199124-127185-187117-119188-190a)b)c)Triethylamine.Pyrldine.The 2-(benzoylmethoxy)-3-<2,2-diacetylvinyl)-1-methylindolizine (13)recovered in 54%.was             Preparation of New Nitrogen-bridged Heterocycles. 12. 7TLC). The solution was then concentrated under reduced pressure. and theresldual oil was separated by column chromatography on alumina usinghexane and ether. The evaporation of the solvent from the ether layerafforded 2-(ethoxycarbonylmethoxy)indolizine derivative.    The reactions of 3-vinylindolizines 39 and 20 under the same conditionsw!th the preparations of furoindolizines 21-26 always gave considerable a-mounts of po!ymeric tars, and only a trace amount of devinylated compounds30 and 3i could be isolated. Furthermore, slmilar treatment of 19 and 20wlth DBU in ethanol afforded the same products 30 and 31 in very !owyields (1-3%).    Some data of products 30 and 3i are as fo!lows. 30: 4e% (reaction time8h),pale yel!ow oil (its picrate, mp l37-1380C (dec)), v (KBr) l751 cm""i (CO),8)6 (CDC13) 1.31 (3H, t, 1 =7.0 Hz, OCH2CH3), 2. 27 (3H, s, 1-Me), 4.30 (2H, q,J==7.0Hz, OCH2CH3), 4.61 (2H, s, OCH2), 6.39 (IH, br t, J=7.0 and 7.0Hz, 6-il[), 6.65 (IH, br t, J=9.0 and 7.0 Hz, 7-H), 6.93 (IH, s, 3--H),7.25 (IH, br d, J=:9.e Hz, 8-H>, and Z81 (IH, br d, J== 7.0Hz, 5-H). AnaLCalcd for CigHisN40io: C, 49.36; H, 3.92; N, 12.12% Found: C, 49.19; H,3.87; N, 11.89%.8) 31:28% (reaction tim.e 9h), pale yellow oil, v (neat) 1751cm-'i (CO), 6(CDC!3) 1.30 (3H, t, J=:7.0Hz, OCH2CH3), 4.31 <2H, q, J :ZOHz, OCU2CH3), 4.63 (2H, s, OCH2), 6.68 (1ff, br t, 1==Ze and 7.0Hz, 6-H),6,80 (IH, br t, J=9.eand 7.e Hz, 7-H>, Z04 (IH, s, 3-H). and 7.I-8.3 (7H.m, 5-H, 8-H, and phenyl protons).9)                         RefereRces and Notes 1) For Part ll of this series, see A. Kakehi, S. Ite, M. Ito, T. Yotsuya, and K.  Nagata, Bull. Chem Soc IPn., 58, 1432 (1985). 2) Present address: Shinkou Denki Co., Ltd., Kurita, Nagano 380. 3) A. Kakehi, S. Ito, B. Wada, K. Watanabe, K. Nishimura, and A. Kumagai, Bt{ll.  Chem. Soc. Jpn 55, 3590 (1982). 4) A. Kakehi, S. Ito, T. Ohizumi, and M. Ito, Bull. Chem. Soc. IPn., 56, 1219  (1983). 5) A. Kakehi, S. Ito, S. Mural<ami, and H, Sano, Bull. Chem. Soc, .Ipn., 57,  548 (1984). 6) J.B. Paine III, R.B. Woodward, and I). Dolphin, f. Org. Chem,, 41, 2826 (1976). 7) Y. Yamashlta, D. Suzuki, and M. Masumura, Lleteroaycles, 16, l499 (1981). 8) Picrate. 9) The preparation of the analytical sample of 2-(ethoxycarbonylmethoxy)-1-phenyl-  indolizlne (31) was unsuccessful because of its instabiHty and non-availability of  lts plcrate.

Preparation of New Nitrogen-bridged Heterocycles. 12. Reaction of 2-(Acylmethoxy)-3-vinylindolizines in the Presence of a Base

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Preparation of New Nitrogen-bridged Heterocycles. 12. Reaction of 2-(Acylmethoxy)-3-vinylindolizines in the Presence of a Base

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