Isomerism of semicarbazones of 6-hydroxy-4,7-dimethoxy- and 6-hydroxy-4-methoxy-benzofuran-5-yl methyl ketone and derivatives

摘要

616 J.C.S. Perkin IIsomerism of Semicarbazones of 6- Hydroxy-4,7-dimethoxy- and 6-Hydr-oxy-4-methoxy-benzof uran-5-yl Methyl Ketone and DerivativesBy M. Anteunis * and F. Borremans, Chemistry Department, Laboratory for N.M.R. Spectroscopy, StateW. Tadros, A. H. A. Zaher, and S. S. Gliobrial, Chemistry Department, Faculty of Science, CairoUniversity of Gent, Krijgslaan 271, 6-9000 Gent, BelgiumUniversity, Cairo, U.A.R6-Hydroxy-4.7-dimethoxy- and 6-hydroxy-4-methoxy-benzofuran-5-yl methyl ketone (khellinone and visnagin-one) semicarbazones can be obtained in either of two isomeric forms, depending of their mode of preparation.No syn-anti-isomerism coutd be detected, but the isomers obtained under acidic conditions were shown to becyclic tautomers of the normal semicarbazones.This followed from n.m.r. experiments and from the results ofvan Slyke nitrogen determinations.6-HYDROXY-4,7-DIMETHOXY- and 6-HYDROXY-4-METH-OXYBENZOFURAN-5-YL METHYL KETONE (khellinone andvisnaginone) derivatives can form two isomeric semi-carbazones, depending whether these are prepared inbuffered (sodium acetate) or acid ethanolic solution.Me Me Me MeI H-C-N,I-C=N,NH I NHH,N-CO / HN-co'1 H-C-N,I N H I NI H-?-N,N=C ' ' HN-C, ' / /'OH OHSome possible tautomeric forms of semicarbazonesIsomerism amongst semicarbaz s has been discussedprevio~sly,l-~ and it has been cbduded from electronicspectral behaviourg that it is due to the presence ofhas now been shown not to be due to the presence ofsyn- and anti-forms, but rather to the presence ofcyclic taut omers.U(la) ( l b 1The n.m.r.spectra of the isomeric semicarbazonesformed from 6-O-isopropyl khellinone are shown inFigures 1 and 2. Data for other isomeric pairs arecollected in the Table. Apart from small differencesin the chemical shifts of similarly disposed protons, thespectra differ in that some resonances for those com-M.p. and n.m.r. data for semicarbazones of khellinone and visnaginone derivativesChemical shifts b (J in Hz)Compounda M.p. ("C) Solvent MeA MeB R2 Ha HD R1 NH and/or NH2( l a ; R1 = Et, 168-171 (CD3)2C0 2-21 3.94 and 4-04 7-04 7-80 1-29 4.08 6.16 (2H) andR2 = OMe) C (d, J 2.2) (d, J 2.2) (t, J 6.5) (9, J 6.5) 9.16 (1H)(lb; R2 = Et, 187-190 CDCl, 2.23 3.96 and 4.06 6-83 7.32 1-32 4-04 5.60 (2H) andR2 = OMe) d (d, J 2.5) (d, J 2 4 7.30 (1H)(la; R1 = Pri, 190-192 CDCl, 2-16 3.91 and 4-06 6.83 7.55 1.23 4.47 5.78 (2H) andR2 = OMe) c ~ f (d, J 2.3) (d, J 2.3) (d, J 6.0) (sept, J 6.0) 8.62 (1H)( l b ; R1 = Pri, 190-192 CDCl, 2-26 3.99 and 4.08 6.85 7.56 1.26 4.47 5.60 (2H) andR2 = OMe) d,g (d, J 2.5) (two d) A (sept, J 6.0) 7.38 (1H)(la; R1 = Pri, 193-194 CDCl, 2.12 3.97 6-76 6.79 7.43 1.32 4.48 5.60 (2H) andR2 = H) (d, J 2.5) (a, J 2.5) (d, J 6.0) (sept, J 6.0) 8.21 (1H)R2 = H) (d, JI (dd, J 2-5 (dd) i (two d)b At 100 MHz, in p.p.m.from internal Me,Si.d Prepared with hydrogen chloride in ethanol and semicarbazide hydrochloride.for (la): C, 57.1; H, 6.0; N, 12.3.1 Figure 2. 9 Figure 1.clearly present (double resonance).( l b ; R1 = Pri, 206-208 CDC1, 2-17 4.03 6.72 6.82 7.44 1-31 4.49 5-35 (2H)1.0) and 1.0) iCompound (la; R1 = Me, R2 = OMe) had m.p.174-177'; compound (lb; R1 = Me, R2 = OMe) d had m.p. 188-189'.Prepared with sodium acetate in ethanol and semicarbazide hydrochloride.c Mixed m.p. for (la) and (lb) 170-175deg;; FoundCalc. for C1,H2,N3O,: C, 57.3; H, 6.25; N, 12.5.4 Mutual long-range coupling between R2 and HoFound for (lb): C, 57.6; H, 6.1; N, 12.3.Extra splitting due to diastereotopism; see text.syn- and anti-forms. Interconversion of isomers is pounds prepared in acidic media are duplicated; thisrelatively easy, and can be achieved smoothly by heat is associated with the anisochronism6 for potentiallyor by acids.However, in the case of several khellinone diastereotopic centres. In the ethyl derivative (1 ;and visnaginone semicarbazone derivatives isomerism R1 = Et, R2 = OMe) only a substantial broadeningwas observed, the doubling of the methylene quartet* G. J. Karabatsos, J. D. Graham, and F. M. Vane, J . Amer.V. I. Stenberg, P. A. Barks, D. Bays, D. D. Hammargren,K. Mislow and W. Raban, Topics Stereochem., 1967, 1, 1.1 I. M. Heilbron and F. J. Wilson, J . Chem. Soc., 1912, 101,2 F. J. Wilson and R. 31. Macaulay, J . Chem. SOL, 1924, 125,8 M. Ramart-Lucas and M. Bruzau, Bull. SOC. chim. France,1482.841.1934, 1, 119.Chem. Soc., 1962, 84, 753.and D. V. Rao, J . Org. Chem., 1968, 33, 44021972 617I I I I I I I I L8 7 6 5 4 3 2 1 0FIGURE 1 N.m.r.spectrum (100 MHz) of 6-0-isopropylkhellinone semicarbazone (lb; R1 = Pr', R2 = OMe) in CDCI,Lh+JdI I I ' I I I 1 I I I I9 8 7 6 5 4 3 2 1 06 (p.p.m.1FIGURE 2 N.m.r. spectrum of 6-0-isopropylkhellinone semicarbazone ( l a ; R1 = Pri, RZ = OMe) in CDCI618 J.C.S. Perkin Ibeing unresolved even at 100 MHz. The fact thattwo doublets are found in the spectrum one of theisomers of the isopropylkhellinone derivative (1 ; R1 =Pri, R2 = OMe) (Figure 1) could perhaps be explained interms of slow inversion of one of the nitrogen atoms inonly one of the two syn-anfi-isomers. Slow nitrogeninversion (with AGZ ca. 20 kcal mol-l) has, however,only been observed in nitrogen derivatives whicheither are angle-strained or have N-substituents bearinglone-pairs (e.g.C1, Br, etc.). Normally the barrierfor N-inversion is only 7-8 kcal mol-l in trivalentnitrogen derivatives. Moreover, in our case, theobserved diastereotopism is retained even at temper-atures as high as 150".Further arguments against possible syn-anti-isomer-ism are (a) the close relationship between the electronicspectra of both isomers, and ( b ) the slow interconversionbetween both isomers in trifluoroacetic acid (n.m.r.).An equilibrium mixture containing ca. 35 of theisomer (lb) is only reached after 150 h at 25".The observed isomerism can best be explained in termsof tautomeric ring closure structures (la and b), assuggested * to us by Dr. R. S. Egan, the closed structureresulting in diastereotopism in the -OR1 systems.The existence of ring-closed isomers has been suggestedrecently for several hydrazones of simple aliphaticaldehydes and for thiocarbazone derivatives of simple loaromatic and aliphatic aldehydes and ketones, mainlyt /min.Relative rates of nitrogen liberation as followed byg.1.c.for khellinone semicarbazone isomers and some relatedcompounds: (A) (lb; R1 = Pr', R2 = OMe), normal pro-cedure a t 25"; (B) ( l a ; R1 = Pri, R2 = OMe), normal pro-cedure at 25"; (C) isomer (lb), modified procedure a t 0";(D) isomer (la), modified procedure a t 0"; (E) acetophenonesemicarbazone, modified procedure a t 0" ; C,F) L-glutamic acid(calibration curve), normal procedure a t 25FIGURE 3on the basislo of n.m.r. spectral shift and couplingdata, and further work l1 has substantiated theseclaims. In order to obtain further information onCf.S. J. Brois, J . Amer. Chem. SOC., 1968, 90, 508; Tetra-hedron Letters, 1968, 5997; D. Felix and A. Eschenmoser, Angew.Chem., 1968, 80, 197; F. Montanari, I. Moretti, and G. Torre,Chem. Comm., 1968, 1694; for benzophenone imines see J. B.Lambert, W. L. Oliver, and J. D. Roberts, J. Amer. Chem. SOC.,1965, 87, 5085; D. Y . Curtin and J. W. Hauser, ibid., 1961, 83,3474.the nature of the isomerism in the khellinone semi-carbazones, heteronuclear decoupling experiments wereconducted, but the results were inconclusive.4.5 -4.0 -w -3.5 -3.0 -..... ... ,... ..I I : . I250 300 350X/nmFIGURE 4 U.V. spectra of 6-U-isopropylkhellinone semi-carbazones and related compounds: (A) ( l a ; R1 = Pri,R2 = OMe) in lOOyo methanol; (B) ( l b ; R1 = Pri, R2 = OMe)in 100 methanol ; (C) khellinol (4-hydroxy-9-methoxy-7-rnethyl-SH-furo3,2-g l benzopyran-5-one) in 99.3 ethanol(ref.13); (D) benzofuran in 95 ethanol (G. M. Badger andB. J. Christie, J. Chem. SOC., 1956, 3438; R. A. Friedel, Appl.Spectroscopy, 1957, 11; 13) ; (E) mean absorption curve of the' forme transparente of an aromatic semicarbazone; (F)mean absorption curve of the 'forme absorbante' of anaromatic semicarbazone (E) and (F) from ref. 31We have also examined the rates of liberation ofnitrogen from the two isomers on treatment withnitrous acid,12 in order to obtain further informationon their structure.As might be expected for a ring-closed structure, isomer (lb; R1 = Pri, R2 = OMe)liberated nitrogen more slowly than the correspondingopen-chain isomer (1 a) (Figure 3).One further aspect of the n.m.r. spectra requirescomment. In the ring-closed isomer (lb) the methylgroup is attached to a carbon centre which itself isattached to two nitrogen atoms. This would be ex-pected to result in an upfield shift in comparison withisomer (la). However this is not the case (Table).Conformational evidence obtained from electronicspectra reveals a possible explanation.Figure 4 shows the relevant spectra together withthose of some other closely related structures. syn-and anti-Fonns of semicarbazones are characterised8 R. S. Egan, Chemical Physics Section, N.m.r.Laboratory,Abott Laboratories, North Chicago, Illinois 60064, U.S.A. ,personal communication.9 W. Skorianetz and E. Sz. KovAts, Tetrahedron Letters,1966, 5067.R. W. Lamon, J . Org. Chem., 1969, 34, 756.11 W. R. Roderick and A. M. Von Esch, unpublished work.l2 E. R. Hoffman and I. Lysyj, Macrochem. J., 1962, 451972 619by typical differences in their possibilities for con-jugation, resulting in a ' forme absorbante' and a' forme transparente '.3 In our case both isomers(la and b) show nearly identical chromophoric be-haviour, with no appreciable absorption above 300 nm.The spectrum l3 of khellinol (4-hydroxy-9-methoxy-'i-methyl-SH-furo3,2-g 11 benzopyran-5-one) indicatesthat such absorption would have been expected if thesemicarbazone system had been in conjugation withthe benzofuran nucleus in one of the isomers.In factthe electronic spectra of our semicarbazones are similarto that of benzofuran itself. Thus even the non-cyclised isomer (la) is not appreciably conjugated,indicating that an out-of-plane rotation of the semi-carbazone system, as the result of di-ortho-substitution,is likely. In the light of this, prediction of the shiftfor the methyl group requires one to take into accountpossible diamagnetic contributions by the aromaticnucleus, which are not necessarily identical in bothisomers.EXPERIMEXTALDetails of preparation together with further spectralfeatures will be published elsewhere. The Table gives them.p.s observed for the several acyclic and cyclic semi-carbazone tautomers.U.V. spectra were obtained with aCary model 15 automatic spectrophotometer. N.m.r.spectra were taken with Varian HR-100 and A-60 instru-ments.Nitrogen liberated by the van Slyke nitrous acid methodwas estimated as described 12 by Hoffman and Lysyj.Calibration was performed with L-glutamic acid. Atroom temperature, the normal procedure l2 applied tothe open-chain isomer (la) yielded slightly more than2 equiv. of nitrogen in 20 min. However, the ring-closedisomer was much less soluble in the reaction mixture,so the procedure was changed in subsequent evaluations.Clear solutions were obtained in glacial acetic acid, inwhich interconversion between the khellinone derivativesis negligible (n.m.r.) under the conditions used. In thefinal procedure a saturated aqueous solution of nitrousacid was injected into a solution of the product in aceticacid, and the reaction was slowed down by working a t0 "C.We thank Dr. R. S. Egan (Abott Laboratories, Illinois60064, U.S.A.) for his interest and suggestions, and theNationaal Fonds voor Fundamenteel Wetenschappelij kOnderzoek, Belgium, for financial support.1/802 Received, 19th May, 19711l3 W. Bencze, J. Eisenbeiss, andH. Schmid, J . Chem. Soc., 1956.The results were essentially the same.923