摘要:

744 J.C.S. Perkin IAddition Reactions of Heterocyclic Compounds. Part LX1.l Reactionsof Electrophilic Acetylenes with Conjugated Cyclic EnaminesR. Morrin Acheson and John Woollard, Department of Biochemistry, South Parks Road, Oxford OX1 3QU[I -Alkylpyridin-4(1 H ) -ylidene] acetates and related compounds react at the exocyclic double bond with efectro-philic acetylenes to give 1 : 1 and 1 : 2 adducts by simple Michael addition followed by proton shift. Withtetracyanoethylene a related product was isolated and also a compound in which the ester group had been lost.Methyl [l -alkylpyridin-2(1 H) -ylidene] acetates give analogous products with methyl propiolate, but-3-yn-2-0ne.and 4-phenylbut-3-yn-2-one.ALICYCLIC enamines react with electrophilic acetylenesto give zwitterions (1) which initially ring-close to affordbicyclic compounds (2); these can then undergo ring-opening to give monocyclic compounds (3) , depending onthe substituents and the size of the ring2" Similarbehaviour is found with indole,g 3-dialkylaminoindolesJ7and lJ2-dihydro- * and 1,4-dihydro-pyridine~.~ We haveE = C02Me in all formulae\ / NI a:( 3 )now examined reactions of some electrophilic acetyleneswith dihydropyridines possessing an exocyclic doublebond.Compounds (4)-(7) were obtained by the action ofbase on the appropriate quaternised pyridine.1° Com-pounds (4)-(6) reacted with dimethyl acetylenedi-carboxylate in chloroform to give the bright red dihydro-pyridines (8)-( 10).With diethyl acetylenedicarboxyl-ate compound (5) gave the dihydropyridine (11) and aclosely similar 1 : 2 adduct which has been assignedstructure (12).The n.m.r. spectra of compounds (8)-(12) showed the ring proton signals at similar positions tothose of (4)-(6) but the vinyl proton resonance had beenreplaced by a signal at the correct position for a fumaratechain.ll Models suggest that the fumarate unit is un-likely to be coplanar with the rest of the molecule, andthis is supported by the spectra of compounds (8) and (9)1 Part LX, R. M. Acheson and J. M. Woollard, precedingpaper.G. A. Berchtold and G. F. Uhlig, J . Org. Chem., 1963, 28,1454.3 C. F. Huebner, L. Dorfman, M. M. Robison, E. Donoghue,W. G. Pierson, and P. Strachan, J . Org. Chem., 1963, 28, 3124.K.C. Brannock, R. D. Burpitt, V. W. Goodlett, and J. G.Thweatt, J . Org. Chem., 1964,29, 818.A. J. Birch and E. G. Hutchinson, J . Chem. SOC. (C), 1971,3671.a R. M. Acheson, J. N. Bridson, and T. S. Cameron, J . Chem.SOC. (C), 1972, 968.M.-S. Lin and V. Snieckhus, J . Org. Ckem., 1971, 36, 646.in trifluoroacetic acid which show that protonationoccurs at the 2'-position.The dihydropyridines (4)-(6) with methyl propiolategave the 1 : 1 adducts (13)-(15). The n.m.r. spectra ofthese contained AB quartets ( J 15 Hz) and low fieldA,B, systems showing that the ester and the trans-acrylate group have essentially the same deshieldingeffect ; resonance contributions by charged forms such as(22) (cf. ref. 12) could make the 4,2'-double bond lessrigid than normal. Minor products from compounds (5)and (6) were (16) and (24).The structure (24) wasdeduced by comparison of spectra with those of otherind0li~ines.l~ A route for this merely requires a protonshift in (6) to form the ylide (23),14 followed by Michaeladdition and cyclisation. The dihydropyridine (4) withbut-3-yn-2-one and its 4-phenyl derivative gave com-pounds (17) and (18) , respectively.Initialelectrophilic attack by the acetylene at the 4-substituentof the dihydropyridine [e.g. (4)] would give a zwitterion,which could either undergo a proton shift, or cyclise to acyclobutene (25) and ring-open a s shown. The evidencefavours the former route.Hydrolysis and decarboxylation of the adduct (17)gave the pyridine (26), the structure of which followsfrom spectral comparisons with (27).13 The dihydro-pyridine (7) with dimethyl acetylenedicarboxylate gaveonly tar; migration of a methyl group to a negativecentre is not expected, and cyclobutene formation wouldnot be affected.Tetracyanoethylene with the dihydropyridine (4) gavemainly compounds (21) and (29), hydrogen cyanide beingeliminated as in many reactions of this olefin, and a traceof the diester (28), identified from its spectra and com-parison (u.v.) with the corresponding diethyl ester.15The N-methyl n.m.r. signals for compounds (21) and (29)are at low field, indicating the presence of considerablepositive charge on the rings, but although the U.V.Scheme 1 shows two routes to these adducts.8 R.M.Acheson and G. Paglietti, J.C.S. Chem. Comm., 1973,666.9 R. M. Acheson, N. D. Wright, and P. A. Tasker, J.C.S.Perkin I , 1972, 2918; R. M. Acheson and N. D. Wright, Chem.Comm., 1971, 1421.10 R. A. Jones and A. R. Katritzky, Austral. J . Chem., 1964,1'7,466.11 N.m.r. Spectra Catalog, Varian Associates, Palo Alto, 1962.12 G. H. Crabtree and D. J. Bertelli, J . Amer. Chem. SOC., 1967,13 R. M. Acheson and D. A. Robinson, J . Chem. SOC. (C), 1969,l4 C. A. Henrick, E. Ritchie, and W. C. Taylor, Austral. J .l5 G. V . Boyd and A. D. Ezekiel, J . Chem. SOC. ( C ) , 1967,1866.8'7, 2908.2311.Chem., 1967, 20, 24671975 745spectrum of (21) resembled those of (13) and analogous Compounds (32)-(35) were synthesised as above,1° andcompounds, the U.V.spectrum of (29) was quite different. with the appropriate acetylene gave the deep red di-The ring protons of (29) gave rise to an A2B2 system in the hydropyridines (36)-(42) ; in these cases the 1 : 2n.m.r. spectrum, indicating that the molecule might be adducts were formed rather readily. These reactionsR2 R'H (81 MeH ( 9 ) CH2PhH (10) CH2EMe (11) CH2%(12) CH2f'h(13) Me(14) CH2Ph(15) CH2E(16) C H f i(17) Me(18) Me(791 Me(26) Me(21) Mesymmetrical. The i.r. spectrum showed one strong CENabsorption, at 2198 cm-l, in contrast to (21) which showedIR(22)EI(23)several, and the long-wavelength position is consistentwith some double bond character in the carbon-nitrogenlinks. Thus the zwitterion structure gives a better repre-sentation of the compound than uncharged structures;moreover the cyano-group is known to stabilise negativecharge.16Compound (S), in which the funiarate side-chain canhardly be coplanar with the ring, did not react withmethyl propiolate.The dihydropyridines (13) and (17),in which coplanarity with the ring and maximum reson-ance interaction with the ring are sterically possible, bothreacted with dimethyl acetylenedicarboxylate. Com-pound (13) gave the dihydropyridine (19), with somepentamethyl benzenepentacarboxylate, via Scheme 2,and compound (17) gave the dihydropyridine (20).l6 C . Leonte and I. Zugravescu, Tetrahedron Letters, 1972, 2029.l i B. R. Baker and F. J. McEvoy, J . Org. Chem., 1955,20,118.R2 R3 R"E E HE E HE E HC02Et QEt HC&Ef C 0 g t trms-C(C02Et):CH COzEtH H EH H EH H EH H AcPh H AcH trQnS-CH:CHE EH ~~u~s-CE:CHE EH trUns-CE:CHE ACCN CN CNparallel the formation17 of (31) from (30) with phenylisocyanate.A second product in the reaction of 4-phenylbut-3-yn-2-one with (32) was the furan (43), inwhich a major contribution by the illustrated chargedstructure accounts for the low-field positions of thela' I 1 N IRSCHEME 1n.m.r. signals due to the 6-proton and N-methyl group.The base peak in the mass spectrum was at M - 99t N I I Me(26) Me Ac(27) ~/RDs-CH:CHE Evariousroutesproduct was the azaheptadienedioate (45). The requireddeamination of the pyridine has precedent in the acid-catalysed deamination of 9-diacetylaminoacridine.lsIn no experiment did we find any evidence for attackSCHEME 2and mass spectra.Representative U.V. and n.m.r. spectraonly are listed in Tables 1 and 2; these types of spectra forR2 dRlR’ R2(30) CHfi H(31) CH2Ph CDNHPh(32) Me E(33) CHRh E(34) Me n E t(35) Me COEtR’(36) Me(37) CHPh(38) Me(39) Me(40) Me(41) MeR2OMeOMeEtEtOMeOMeR3 R4 R5H trm-CH:CHE EH trans-CH:CHE EH rrans-CH:CHE EHa Hb EH rm-CH:CHAc ACHa Hb Ac(42) Me M e ph H AC( 4 3 )6 IMe(44). -Ha H a(45)at a double bond other than the exocyclic one, nor forformation of cyclobutenes, even as intermediates.EXPERIMENTAL pared as described.The instruments and procedures have been described inearlier papers in the series.All analyses for new com-pounds were within accepted limits for C, H, and N and are* For details of Supplementary Publications, see Notice toAuthors No. 7 in J.C.S. Perkin I , 1973, Index issue.all the other new compounds axe available in the Supple-mentary Publication.But-3-yn-2-one 19 and 4-phenylbut-3-yn-2-one 2O were pre-18 A. M. Grigorovsky, Compt. rend. Acad. Sci. U.S.S.R., 1946,and B’ ‘* L’80 D. Nightingale and F. Wadsworth, J . A m r . Chem. Soc.,55, 229.w ~ e ~ ~ , ~ ~ j & . l ~ ~ ; ggs’ E’ R. H’1946, 67, 4161975 747General Procedure for the Preparatiow of 2- and PMethyZ-ene-substituted Dihydropyridines.-The appropriate 2- or 4-methylpyridine was stirred with an equimolar quantity of analkyl halide in ether, with gentle warming if necessary.After 6 h the salt, which sometimes formed as an oil, wasdissolved in water, and an equimolar amount of B~-sodiumhydroxide was added.The product was extracted withchloroform and the extract dried (MgSO,), filtered, andevaporated to give the pyridine, which was then recrystal-lised.General Procedure fov Reactions between 2- and 4-Methylene-substituted Dihydropyridines and A cetybnes.-The acetyleneThe results are summarised in Table 3.TABLE 1N.m.r. spectra a (60 MHz; 7 values; J in Hz) for solutionsin deuteriochloroform with tetramethylsilane as internalstandardCompound Proton resonances Ester Me2,6-H,, 3-3-3.6m; 3-H, 2 . 3 2 ~ ; 5-H, 6.402,6-H,, 3.26br; b 3-H, 1.96br.d; 6-H,4*00br,d; J2,s = Js,# = 7.6; 4'-H, 3.34;NMe, 6.602,6-H,, 1-33d; 3,6-H,, 1.69; J2,3 6.7;1-Me, 6.68; 2'-H, 3.63; 4'-H, 2.702,6-H,, 3.06,a J 8.4; 3-H, 1.97br,d;5-H, 3-98br,d; vinyl H, 3.36; NCH,,5-26; ArH,, 2+32;d (OCH,),, 6.88q,ArH,, 2,6-H,, 2-6b-3-2m; 3-H,1.9br,d; 6-H, 3.96d; J2.3 = J3., = 8 ;vinyl H, 3.32; N-CH,, 6.29; (OCH,),,5.86br,q; (OCH2*CH3),, 8.66-9.0m2,6-H,, 3 ~ 0 4 d ; ~ 3,6-H,, 2~63br.d;~ J2.32,6-H,, 2-91d;e 3,5-H,, 2.49d;s J2,3Ac, 7-782,6-H,, 1.25;@ 3,5-H,, 1-96," J 7; NMe,,5.51, 5-66; Ac, 7.66, 7-68; set (a):3'-H, 2.8Ot; 4'-H,, 6-82d, J 6.8; setring-H,, 2-8-3.2m; 3'-H, 2-16; 6'-H,3-516.08q; (CH,*CH,),, 8.83t, 8.94t, JEt 7.27.8; 3'-H, 2.16d; 4'-H, 3.92, J 158.0; 3'-H, 2.15d; 4'-H, 3*63d, J 16.1 ;(b) : 3'-H, 2.28t; 4'-H,, 6*47d, J 7.46.33, 6.42,6-606.08, 6-10,6.126.646-486.29, 6.32,6.46 36.28, 6-38 f6.04, 6.086-32, 6-38,6.42, 6.43,6-46 f2,6-H2, 1.27d; 3,6-H,, 1.88d; J2.3 6.6;3'-H, 2.55d; 4'-H, S.lld,'J 10.6; 6'-H,2.69; NMe, 5-662,6-H2, 1-36d; 3,6-H,, 2.lld; J&3 6.9; 6-38NMe, 6.822-H, 2.12; 5-H, 0.62q; 6-H, 3.13q; 6.15, 6.347-CH2, 6.34; 8-H, 1-84q; JS,% 7.2; JS,*1.2: r e e 2.0 , " ",V 5-H, 4-05br,d, J 8; 1'-H, 4.76d, J 13.2;7-90; NMe, 6-70NMe, 6-472,6-H,, 1-44d; 3,6-H,, 2.31d; J2,s 6.8;NMe.6-872'-H, 2.35q; 3'-H, 4.26d, J 14.4; Ac,2,6-H,, 3.07d; 3,6-H,, 2.54d; Ja,s 8.1; 6.29, 6.292,6-H2i 1.66d; 3,6-H,, 2 - l l d ; J 2 , 8 6.8;NMe. 6-763-H,'1-62q; 4-H, 3.lm; 6-H, 4 ~ 0 9 ; ~ 6-39Ja,s = 6.6; vinyl H, 6-63; NMe, 6.753-H, 2-44q; 4-H.2.06t;l 6-H, 2.73m; 6-46, 6-466'-H, 4-O6d, J 16; NMe, 6.02; COCH,,3,6-H,, 2.26-2-66m; 4-H, 1.85m; 6.68, 6-583-37d; 6-H, 4-3Od; J 16; NMe, 6.12;COCH,, 7.41q; CH,*CH,, 8*98t, J B t7.26-H, 3.04d; J3.4 10.6; J3.6 1.6; J4.5 =6-H, 1.77d; J3 4 8.4; J3 , 1.8; J4 , 7.8;J5,,, 6.6; 3'-H, 1.82; '6'-H, ca: 3-0;7.26q; CH,.CN,, 8.83t, J E t 7.26-H, 1.18d; Js.8 6; 3'-H, 2.02; 6'-H,TABLE 1 (Continued)(39) 3,4-H2, 2.05m; 5-H, 2-79m; 6-H, 6.378Ester Me Compound Proton resonances1-75br)d; J S , ~ 6; Ha, 1.88d; Hb, 5.25d,Ja, b 14.7 ; NMe, 6.08 ;" COCH,, 7.36q;CH2*CH3, 8*83t, J E ~ 7.21.10d; J S . 6 6; 3'-H, 2.12t; 2'-H,,(39) 3,5-H,, 1-8-2.15m; 4-H, 1.35m; 6-H, 6.126,68d, J 7.2; NMe, 5.78; COCH,,(43)fvm 3-H, 3-15d; 5-H, 2.22t; 6-H, 2.62m;6.6; ArH,, 2.66;d NMe, 6-79; Ac, 8-03(45) NH, -O-OZbr,t, J 11.4; 2 x Ha, 2.38q;a Many of the spectra include A,B, systems, and the J valuesrecorded are those measured from the spectra assuming a first-order interpretation.a Apparent doublet. I n trifluoro-acetic acid. Apparent singlet. e Assignments could bereversed. f Includes an N-methyl. Apparent triplet.Could be at 2'-position. { I n [2H,Jdimethyl sulphoxide.J As a mixture with (17). Six lines. With further splitting.At 100 MHz.6*87q; CHZCH,, 8.73t, Jab 7.26-H. 1.36d; J3.4 = J4.5 = 8.5; J6.66-46, 6-462 X Hb, 4*85d, Ja,b 13.7TABLE 2U.V. spectraCompound Solvent @ L J n m (10-4~ in parentheses)MAMAMAMAMAMAM, A3%AM, AMAMAMAM, methanol;perchloric acid.210 (2.64), 266infl (0.93), 368 (2.62), 420(0.73)211 (2.66), 260infl(0.77)207 (0*52), 224 (0*67), 268 (0*42), 264 (0*37),379 (0-65)206 (0.41), 225 (0.661, 258 (0.48)) 264 (0.41)210 (1.59), 366 (2-25), 430 (0.61)215 (1.92), 265infl (1.47), 261 (0.66), 267infl(0.51)212 (2.30), 260infl (0.92), 293 (1.90).390(1*13), 601 (2.67)212 (2.33), 245infl (1.26), 260infl (l-le), 290236 (1*13), 337 (1*22), 469 (2.16)236 (1.10), 267infl (0.88), 266infl (0.77),286infl (0-43), 375 (0.27)220 (1-19), 269 (1.06), 354 (1*14), 488 (1.89)220 (1.02), 246 (1.14), 370infl (0.66), 433(1.40)226 (1.87), 243infl (3.03), 248 (3.76), 270infl(1.24), 277 (1-69)) 320infl (1.63), 331 (1.70)208 (0*74), 230 (0*66), 260 (0.61)) 371 (3.42)206 (0*45), 226 (0*61), 261 (0.46), 266 (0.42)236infl (0-72), 267infl (0.60), 320infl (0.62),367infl (0-72), 394 (0*90), 414 (0.91).489(1.40). 660 (1.96)210 (0.71), 265infl (0.18), 306 (1-69), 313(1.94). 384 (0.73)209 (0-46), 266 (0.66)268 (0*79), 363 (0*99), 436 (1.60)267 (0*80), 308 (0.78), 381 (1.34)313 (1.22)313 (0.75)A, methanol acidified with 1 drop of 72%(0.88)TABLE 3DihydropyridinesYieldCryst. solventMeOHMeOH-CHCl,Et,O-MeOHE t ,O-MeOHPetroleum-PhMeMeOHMeOHEt,O-MeCNa Lit.M.p . ("C) Appearance11 1-1 12.5 Silveryparallelipipeds169-160 Pale brown rods124-126.6 Silver plates107-110 Plates93-94 Yellow plates126-127 Yellow needles60-52 Yellow67-69.5 Yellow needles,lo m.p.52-54".(%I607440678079264748 J.C.S. Perkin ITABLE 4Products of reactions with acetylenesCom- Crystallisation Yieldpound solvent M.p. ("C) Appearance (%)(8) MeOH-CHCl, 176-180 Vermilion 63(10) MeOH-CHC1, 153-156 Scarlet prisms 29Red gumCrimson gum 3056 (1 3) MeOH-CHCl, 1 8 6 1 85.5 Yellow micro-need 1 e s(14) d MeOH-Et,O 147-149.5 Red(16) MeOH-Et,O 138-140 Red plates(17) MeOH-Et,O 166-168 Red 38(18) a MeOH-Et,O 182-184 Orange-red rods 1760-65 Red 20136-141 Cerise 36241-243 Orange h (21) Me,CO(9) a MeOH-CHCl, 11 7-1 22 Cerise needles 57(11)(12)(15) MeOH-CHCl, 180.5-182.5 Yellow micro- 45needles(19) a f(20) a gMeOH 118-123 Fluffy needles 3 [i:;: MeOH 163-165-5 Pale yellow 1rhombsmicrocrystals(29) MeOH-Me,CO 230-235 Intense violet h(36)" Me0Hi.j 150-154 Crimson crystals165.5-167.5 Cerise powder 29(37) a Et,O-MeOH 130-133 Maroon 26Red gum 16162-168 Crimson powderCarmine gum145-150 Yellow micro- 12crystalsRed gum 39 (38) "1: kk(43)' MeOH Sub.240 Crimson 3(45) MeOH 196-198 Needles 5a Isolated after chromatography. b After three recrystal-lisations. C Includes more material obtained after chromato-graphy of the residue. After double chromatography of apart sample &(methanol) (14) 0-71, (16) 0-72. Isolated byfractional crystallisation. f Decomposed to (8) on attemptedrecrystallisation. Decomposed on attempted recrystal-lisation. h Isolated as a mixture of (21) and (29): partialseparation achieved by hand.f From chromatography of thefiltrate. j Recrystallisation gave two forms, separable byhand. Could not be recrystallised. Reaction solventtoluene.(0.03 mol) was added at room temperature to the pyridine(0-015 mol) in chloroform (20 ml). The mixture rapidlydarkened and became warm. After several days the solventwas evaporated off and the residue triturated with methanol ;if this failed to give any solid, the residue was chromato-graphed. The results are summarised in Table 4.Methyl 2-(4-PyridyZ)~ropionute.-Sodium hydride (50%dispersion in oil; 1-9 g) was first washed with dry petroleumand then added to methyl (4-pyridy1)acetate (4.87 g ) in drybenzene (20 ml). The mixture was refluxed for 90 min, thencooled, and methyl iodide (4.6 g) in benzene (5 ml) was addedbefore refluxing for a further 90 min. The solid was filteredoff, and the filtrate distilled to give the ester (53y0), b.p.107-115" a t 20 mmHg, vmaX.1745, 1604, 1565, 1499, 1460,1438, and 1419 cm-l.In a similar preparation using methyl (2-pyridyl) acetate,the n.m.r. spectrum of the oily product indicated that themethylation proceeded to the extent of only 50%.Attempted Hydrolysis of the Dihydropyridine (17) .-Com-pound (1 7) (120 mg) was dissolved in water ( 5 ml) containingpotassium hydroxide (0.6 g) by boiling. After 2 h the deepred solution was extracted with chloroform (4 x 4 ml).The n.m.r. spectrum of the extracted material, a crimsongum, showed signals due to compound (17) and to 5-[l-methylpyridin-4( lH)-ylidene]pent-truns-3-en-2-one (26), inapproximately equal amounts.l-Methylpyridin-4( lH)-imine (49) .-The imine, preparedas reported 21 by the action of concentrated aqueous potas-sium hydroxide on 4-amino- l-methylpyridinium iodide, andextraction into hot toluene, had m.p. cn. 130' (crude solid),vmx. 3280br, 1673, 1665, 1545, and 1450 cm-l [lit.,22 vmX.(CHC1,) 1656 and 1542 cm-l].We thank Mrs. E. E. Richards for the 100 MHz n.m.r.spectra, Dr. R. F. Flowerday for the mass spectra, and theS.R.C. for a studentship (to J. W.).[4/1885 Received, 16th September. 1974321 L. C. Anderson and N. V. Seegar, J . Amer. Chem. SOC., 1945,22 C. L. Angyal and R. L. Werner, J . Chem. SOC., 1952, 2911.71, 340

ISSN:1472-7781    

DOI:10.1039/P19750000744

出版商:RSC    

年代:1975

数据来源: RSC