indole--acetic acids and hetero analogues by one pot synthesis including heck cyclisation

1、Indole-3-Acetic Acids and Hetero Analogues by One Pot Synthesis including Heck CyclisationPergamon 0040.4020(95)0060 1 -X Tetrahedron Vol. 51, No. 37, Copyright Printed in Gear 10323-10342, 1995 pp. 0 1995 Elsevier Britain. All rights reserved 0040.4020/95 Science Ltd $9.50+0.00 Indole-3-Acetic Acid

2、s and Hetero Analogues by One Pot Synthesis including Heck Cyclisation David Wensbo, Ulf Annby2, Sale Gronowitz 1* (1) lkpartment of Organic Chemistq 1, Clcncal Center, Box 124, 221 00 Lund, Sweden (2) Synthelec AB, IdCon, 223 70 Lund, Sweden, Abstract: tienopymles aryl amines. one pat reaction, (13

3、d). The BOC (lla-c) were similarly Bz-substlrured (14a, e) and selenolopymle Allylaticm with ethyl 4.bromocroonate, yielded K-BOC group was readdy prepared indole-3-acelic acld ethyl were prepared followed (Ue-g), thernmlly esters (14e-g) stamng by palladium-caralysed thienopymoles after adsorption

4、and heteroanalogues. protected rmg closure (13a-c), and selenolopymole on silica. Oxothienopyrroles i.e. (14d), from h-BOC mode in a prowted mdoles removed INTRODUCTlON Indole-3-acetic thts type have been shown to possess for example plant growth, antiinflammatory, antn-heumatic, muscle relaxant, an

5、d serotonin-like modified indole-3-acetic acids are thcrcfore of importance. halo anilines3, has previously been utilized for the synthcsls of mdole-3-acetic acid and derivatives thereof are of great biological and medicinal interest. Compounds of analgesic, antipyretic, activities. General syntheti

6、c methods of substituted and The Heck cyclisation* acid derivatives of N-ally substituted o- (eq. 1). Ac kC >=I. Br In connectlon with our previous work5 on flndmg synthetic methods tobvard 3-substituted condensed pyrroles we decided to investigate suitably substituted ally1 or acryloyl group on

7、the nitrogen atom of a ringsubstituted hetarylamine, and thereafter achieve palladium-catalysed indoles and hetero this pathway. The synthetic strategy was thus to introduce a o-halo aniline or o-halo ring closure to form the pyrrole moiety. IO323 10324 D. Wsso et 1. Other methods, concermng develop

8、ed in rcccnt years.8 The Heck cyclisatton attention. Thts paper deals with improvement acetrc actd dertvattvcs, and is applted to the preparatton of isosteric heterocondensed of N-BOC-o-iodo-arylamines as precursors. Existing procedures seem quite ctrcumstantial.” ” the syntheses of Bz-substttuted i

9、ndole-3-acetic has however acid dertvatives not, until now, attracted any have been approach of this procedure towards synthesis of Bz-substituted indole-3- pyrroles, by employment of thienopyrroles for construction usually RESULTS AND DISCUSSION N-MOCoioilonrv/lrnirrrs. substitucnt due to the insta

10、brltty of electron rtch hctarylamincs”. selected as N-protcctrve group In the starting hctarylamines, followng reasons: (a) These compounds startmg from the corrcspondtng NHBOC-substttucnt might serve as dtrectrng group, for Introduction Sclcctvc removal 01 the BOC-group condrtrons Is, thus ptvrng a

11、ccess to scnsrti,c clcctr-on rrch systems such as the thienopyrrole The o-halo-hctarylamlne precursor has to bear an electron-withdrawing The tert-butosycarbonyl and as N-substituent acccssiblc by the modtfrcd LICIT. or directly from the anilincs of the u-iodine, in the frnal product could bc achtev

12、ed (BOC) group was in the anilines, Curtius rearrangement”, by substrtution. via o-lithiation.” under mild nucleus. for the arc readily carboylrc (b) The (c) thermolyttc NHBOC NHBOC NHBOC I 2 3 NHBOC 4 5 a: R=NO, b: R=Br - c: R=OMe Aminothrophcnes diphenylphosphoryl 71 % yrcld, butoxycarbonylamtno)t

13、htophenc rodoselenophene the carbosylic butanol at rctlu gav.c N-BOC protected 2-ammo-3-rodoselenophenc 1 and 2 vcrc prepared trcrm the corresponding arrde rn rrr/-butanol. It1 The N-BOC protected 3-amtno-Ztodothiophcne In a fashion stmtlar to corresponding wtth N-iodosucctntmtde 6 wrth LDA rn dtcth

14、yl ether, followed actd 7. Treatment of this wtth dtphenylphosphoryl carboxyltc acids by treatment with 3 was prepared in by iodtnation tetrachlortde. Ltthiatton bromtnattonr, in carbon by quenching with carbon dioxide, gave 29 % yield of azide and trtethyl amine (TEA) 4 in 42 % yield (eq. 2). of 3-

15、(N-terf- of 3- in tert- I 1 l.LDA (39%) 2.cOq (PhO),PON, ) 4 CO,H (42%ro) (2) 6 I Indole-3-acetic acids and hetero analogues 10325 The N-BOC substituted ambnes Sa-b free anilmes 8a-b, catalysts, followed chlorides, in 94 and 65 % yteld respechvcly (eq. 3). WCK prepared by the mtroduction tn THF unde

16、r 4-(N,N-dimethylamino)pyridine by selcctre removal of one N-BOC group wtth trifluoro of two N-BOC substituents on the with excess BOC-anhydride (DMAP) acetic acid (TFA) in methylene cccss (BOC)?O cat. DMAP TFA, CHICI, (65-9476) ) 5a b - (3) 8 a: R=NO, b: R=Br - It was found that trcatmcnt 01 these

17、anrlrncs vvrth cqurmolar temperature, rth or I rthout DMAP substttuted pn>ducts. Amllne SC was prepared by o-lithrntron methoxy amlincx quantrtres of BOC-anhydride rn formation of both N-mono- i todinatron starting from N-BOC substituted 4- in THF at room and N,N-diBOC catalysis, resulted Allylrr

18、liott irrrrl ilcrlovlt/iotr of !v-IIOC prolrcrrtl I and 3, usmg excess ethyl 4-bromocrotonatc or potassrum Only trace amounts of. the desired N-allylated trttiitro/kiophrtrs 1 ittrd 3 (eq. 4). Imtial attempts to as allylatrng fert-butoxide, ally late N-BOC protected amrnothiophcnes under inllucncc o

19、f strong bases, such as sodrum hydrrdc decompositton of the ethyl 4-bromocrotonatc. 12 could be isolated )I- dctcctcd. along vrth most of the unmatted agent, resulted in raptd products 12a and stamng material. Table 1. Alllatron Condrttons 01 S-BOC PI-otcctcd Amtnothtophcncs with Ethyl 4-Bromo-Croto

20、nate Under Drffercnt 10326 D. WENSBO er ul. When the relatively rapidly and in quantitative proper conditions aminothiophenes as solvent (Table 1). It was found that allylation such as potassium or cesium carbonate. or tluoride, to give N-allylated from 37 to 91 %. Corresponding acryloylation also i

21、nvestigated, and found to give the expected N-acryloylated (Table 2). The overall lower yield of 9c and 12. compared nucleophilicity of the mtrogen atom m the 3-, compared to Z-position of the thiophene ring. msensitive ally1 bromide yields, showmg that allylation chosen. In order 1 and 3 were allyl

22、ated with ethyl 4-bromocrotonate, was used under the same conditions, with ethyl 4-bromocrotonate to evaluate better N-allylation might be possible if the two N-BOC using different bases in DMF or DME by use of weaker bases products chloride under different conditions products 9a and 9c in yields fr

23、om 51 to 83 % to 9a and 12a respectively, proceeded were methods, protected could be achieved more effectively 12a and 12c in yields ranging with ethoxyfumaroyl were indicates lower Table 2. Acryloylation Conditions. of N-BOC Protected Aminothiophcnes with Ethovyfumaroyl chloride Under Different WlC

24、lll etboxyfumrul chlonde(rqw )” I 1 9a I. ll:A (S) TIIF cat I)hUP d I.5 5 2 r.1. 83C 2 K;,(C 1 (S) m11: cat. I)hi.I d 5 r.t. 6sb 3 39c ., .I b.l (3 lI11, I. cat DhlAPd 1 .%O.S+O 5 . . 72 r.t. Sib ab. 1 72 f SO “C c Pal/nirtrn117r17/srtl c,li.scr/iorl (eq. 4). Cyclisation solvent, gave thienopyrrolc

25、palladium acetate (0.05 cqm.), and tnphcnylphosphine vvas found necessary for complete triphenylphosphmc wax omitted (47 h, 69 %). Incomplete reaction, and pronounced resulted surprisingly 11 tctrabutlammonlum conditions. This result is contmrv to the normally of TEA as base, nslcaci of sodium carbo

26、nam, gave essentially the same yield and reaction lime. Cychsation of the N-acryloyl aminothiophencs 9a and 9c, in THF as solvent, gave the oxothienopyrroles and 18 % yield when treated w 1t11 TEA (IO cqmv.). palladium (0.1 equiv) for 5 h at rctlux and 96 h at i-oom tcmpcraturc respectively. Attempt

27、ed cyclisation rcflu, DMF OI- McCN at room temperature, with or without added triphenylphosphine, rapid formation ot. a deep blue color. with only TV-xc amounts (TLC) of 9c and 10 present in the reaction mixture. Cyclisation to the dcsixd condcnscd PSI-nilcs from pyridinesz3 16, also failed. Only co

28、rnpIe mittncs or uni-catted materials were obtained. The presence ot 16 was found to inhibit the cycliation ot its N-BOC cubstitutcd analog Ya. Without any 16 present, 9a cyclised at room tem- perature lo gc 43 2 ycld ot. 10a afux 10 h. reaction. Lrndcr the same conditions carbonate, 0.05 cquiv,. pa

29、lladium acetate, 0. I cqui, rripheny Iphosphine) to 14 and 0 % , In pi-esence of 15 and I00 mol,Z of 16 respecti,ely. of the N-allylaminothiophene 12a m DMF as 13a in 85 7( ymld M hen trcatcd with a mixture of sodium carbonate (3 equivl.), (0.1 cqmv) for 4 h at GO-65 “C. Longer reaction time i-eacti

30、on, and lower yield of thicnopyrrole was obtained formation when of by-products, chloride (I cquiv.) c elfects of this rcagcnt in Heck reactions.” was present under otherwise similar The use pcwt 1Oa and 1Oc in 60 acetate (0.05 equiv.), and triphcnylphosphine of 9c in THF at resulted in all cases in

31、 15a-b, or N-acryloyl aminothiophene (DMF, 3 cquiv. potassium and reaction times, yields decreased Indole-J-acetic acids and hetern analogues 10327 Pd, THF 1-4 5a-c 9a-c 10a-c: R=BOC lla-c: R=H SihC 1 tntnHg 50C gCl (4) CO,Et CO,Et Pd DhlF BOC 17a-g R Sillcil 1mmHg _SO”C gel a: Z-N, 3-l thqhcnc b: 3

32、-N, 4-I thlophcnc i thIcno3,4bpqrrnlc c: 3-K, ?-I thlophcnc i thicno3,7-blpgrrolc d: Z-N, 3-l sclcnophcnc i sclcnolo?-,3-bp!,rrcslc e: a-NO?, 2-I aniline 15NO, f: 40Me, 2-l aniline I S-O& g: l-Dr. 2-l anihne / 5-k ! thieno7,3-bprrc,le mdole indolc indale 15a: R=H b: R=BOC 17a: R=H b: R=BOC 10328

33、 I). WENSBO ef 11. Since the same base and solbent could be used In both steps, cyclisatlon arylamlnes (12a-g, 9a-b) could advantageously lntroduccd the ally1 or acryloyl umt, hetcrocondensed catalytic amounts of palladium acetate and trlphenylphosphinc approach toward selenolo- and thlenopyrrolcs.

34、in this “one pot procedure”, no slgnil.lcant dccrcasc in yxld was found, compared to the two step process with Isolation of mtcrmcdlate product. In one case onl> the two step process was found preferable. Thus 18 % yield of oxothicnopyrrolc IOc was obtained by cycIIsatlon of N-acryloyl procedure”

35、, starting 11.om amlnothwphenc 3, cjnl> I-esultcd In tract amounts of the dcsn-ed product (table 3, entry 11). of N-ally1 and N-acryloyl isolation. were formed by addition be achie ed directly pyrroles without After having and indoles (table 3). To our know,lcdge, this is a novel the cyclisation

36、step demanded longer reaction times of Although amlnothiophene 9c, while the “one pot Table 3. One Pot Synthesis l)crl atles from N-BOC Protcctcd o-Iodo-Ar! of Indolc-, Thlcnop>rl-c)lc-, lamnes”. and Sclcnolopyrrole Acctlc Acid Ethylester It !ias obscrcd, resulting donatmg groups (Table 3, entry

37、6). or 3-amlnothlophcncs cth!,l 4-bromocrotonatc (II- cthoxl fumaroql Unreactcd ql odldcs could, In some ol those casts, bc Isolated after cyclisatlon one case, I hen the qcltsatlon bias stopped al.tcl-4 h. could Grcd lndolc (Table 3, cntrq 7). Tautomcnsutlon ton NMR In lcutcr-chlorc)l(li. under Inl

38、lucncc 01 a catal> tic amount of TEA. No trace of this tautomer could be detected I hen the same <!cllsatlon VYIS conrlnucd for 24 h (Table 3, entry 8). In agrccmcnt vith others:, from O-cndo-c),clIsatlon that 5-cxo- f as 11 owed wcr h-cndo-cychsatlon. could In no case bc dctccted. Substrates

39、such as anilincs (Table 3, entry 3, 3, IO), needed extra addmon 01 chloride lor allqlation / acryloylatlon Products vlth electron- to proceed satisfactorily. (Table 3, entry 6, 10). In the tautomcr 13g be Isolated together with the dc- ot this compound to indole could easdy be monltorcd by pro- Indo

40、le-j-acetic acids and hetero analogues 10329 X-ray crystallographic structure of this compound, and its N-BOC protected precursor 1Oa. Assignment the exocyclic double bond in 1Oa and lla stereochemistry of the two differently fused isomers lob and lOc, as well as the unprotected and llc, was thereby

41、 also confirmed since all three isomers, with and without very similar spectroscopical properties. Without unprotected (1 la-c), oxothienopyrroles proved otherwise impossible the thienopyridinones 17a and 17b , which would result from imaginable unprotected isomers lla-c showed similarities 6.71 res

42、pectively), and H-13C coupling constants (3J (H-vinyl-CON, respectively). The corresponding N-BOC protected compounds shifts (a (H-vinyl, deuterochloroform)=6.57,6.76, vinyl-CON, deuterochloroform)=7. 2, 6.8, 6.0 Hz respectively). stereoisomer is formed during cyclisation of N-acryloyl detected by T

43、LC-analysis of the crude products, or by H NMR of the purified compounds. analysis ” of N-unprotected oxothienopyrrole lla was performed of the (E)-stereochemistry to ensure the at could, by this analysis, be made with certainty. The regio- and analogues llb protection, protected (lOa-c), (H shifts

44、and JcmH) from 6-endo-cyclisation. deuterochloroform)=6.52,6.70, deuterochloroform)=7.1, lOa-c also showed similarities 6.53 respectively), and H-13C coupling It might be concluded aminothiophenes 9a-c, since no other isomer could be N-BOC showed or N- reference material these N-BOC to distinguish T

45、he three N- in their tH shifts (a (H-vinyl, 6.5, 5.8 Hz in their H constants (3J &I- that only one Thermal remavnl of N-BOC suhsrituents. In order to remove the N-BOC substituent from the indoles and pyrroles obtamed, we used a modified thermal procedure of Rawal and Cava. l5 Although procedure

46、- to heat the substrate to about 180 “C - has been used for deprotection other nitrogen protected compounds”, we experienced it less suitable. Along with the desired products, the N- BOC protected thienopyrroles 13a and 13c also gave large amounts of dark resinous material at this tempera- ture. The

47、 substrate was instead adsorbed onto silica gel and kept at only 50 “C under reduced pressure to remove the BOC group (table 4, eq. 4). When the reaction was performed otherwise identical conditions, it was slow and only trace amounts of product could be detected after 24 h. Only in the case of the

48、highly instable 3.4-b fused thienopyrrole (Table 4, entry 2). The silica gel became black and neither starting material nor product could be detected. hcterocondenscd original the of indolesz6 and at atmospheric pressure, under 13b. the product 14b could not be obtained Table 4. Thermal Removal of t

49、he N-BOC Substituent from Various Substrates.a entry substrate product isolated yield (%) 1 13s 14a 2 13b 14b 3 13.2 MC 4 13d 14d 5 13e 14e 14f 6 13f 7 1% 10a 14i3 lla 8 9 lob llb 10 1OC 1lC 11 9a 16 92 - 86 58 89 89 19 87 77 76 81 al see expaimenlal saxion for a gcned procedure. 10330 D. WENSBO et

50、al. Cotnparison with radical cyclisatian (rq. 5). Comparison of the palladium substituted aminothiophene catalysed, and the radical 10a was made. Induced pathways for rmgclosure of N-acr)iloyl 9a Bu3SnH AIBN toluene, reflux (5) v 18 19 (67%) Hz / Rh(PPh),CI ethanol ! (57%) 10a lla Saturated oxothicn

51、opyrroles 10a and lla respectively. The N-BOC protected oxothienopyrrolc N-unprotected analogue lla, best total yield starting from 9a, usmg palladium-catalysis cychsatlonz8 was performed, with 12.2 mM AIBN as Initiator, a mixture of 18 (9 %) and 19 (4 %) was obtained. The crude product after this r

52、eactlon was more complex compared to that from the Heck cychsation. Despite two successive puritica- tlons by chromatography on slhca gel, the products were not pure according cyclisation of the isomenc N-acryloylated ammothlophenc 18 and 19 could be obtamed by hydrogenation 01. Wilkinsons catalyst

53、m 67 and 57 % (67 % based on consumed 10a proved to be more smoothly hydrogenated which demanded longer reaction time and still was not totally consumed. The as the key step, was thus 36 % of 18. When radical by reaction of 9a with I .2 equiv. tributyltin of unsaturated oxothienopyrroles by employme

54、nt lla) yield than the hydride in refluxing toluene for 5 h to H-NMR. Attempted radical 9c under the same conditions failed. Saponijiccctiot gave, m quantltativc neat or m water solution the correspondmg products. Similar results have been found by Snyder and coworkers I1 in attempts to obtain the c

55、orresponding acid of 21. Dcgradatmn of this itr si/u generated acid, in 0.8 M DOAc / deuteriumoxide, by H-NMR o.ermght. ofthirnoprrole esters 14n crnd 14. Saponification ylclds, potasstum salts 20 and 21 respectively fol- sevenal weeks at room temperature acids, by mlld acidic treatment of the salts

56、 and extractive of esters 14a and 14c with potassium (eq. 6). These salts were stable if protected from light. workup, hydroxide All efforts to obtain resulted m resinous could be monitored Indole-3-acetic acids and hetero analogues 10331 14a, c KOH (want.1 (f-5) COzK ACKNOWLEDGEMENT Grants from the

57、 Swedish Natural Research Council (S.G.), and the foundation are gratefully acknowledged. “Lam Hiertas Minne” (U.A.), EXPERIMENTAL All reactions amino)thiophenet6, procedures. Ethyl 4-bromo-crotonate Merck, N-iodo succinimtde solvents used as eluents for chromatography, ether was distilled over sodi

58、um pnor to use. THF were distilled over sodium under nitrogen atmosphere. Flash column chromatography was performed on TLC-siltca “chromatography”. TLC analyses were performed visualized in UV light, and by amsaldehydeisulfunc acid/ethanol-spray were recorded on a Vat-tan XL 3C0, or XL 300 NMR-spect

59、rometer, respectively. 13C NMR spectra were recorded on the same Varian shifts (a) are reported in parts per milhon downfield from TMS. Mass spectra were obtained on a Jeol SX 102 spectrometer using electron Impact tonizatton at 70 eV. Elemental Mikroanalytisches Laboratorium (Mulhetm, Germany). Wetzlar mtcroscope. were performed 8a29, 8b “) 630, and ethoxyfumaroyl , under mtrogen. Starttng materials, 1 16