1975 2115Determination of the Substitution Pattern of an lsoxazole by 13C NuclearMagnetic ResonanceBy Gavin M. Buchan and Alan B. Turner,rsquo; Chemistry Department, University of Aberdeen, Aberdeen AB9The isoxazole obtained by condensation of nitroethane and 6-bromopiperonal is shown to have the 3.5-dimethyl-4-aryl structure (6) by comparison of its lac n.m.r. spectrum with those of several model compounds.2UE, ScotlandTHE standard methods for determination of the substitu-tion pattern of an isoxazole are hydrogenation and ozono-lysis.1 The former, carried out at room temperature andatmospheric pressure over Raney nickel, leads,2 byrupture of the 0-N bond, to a P-imino-ketone, which canbe hydrolysed to a readily identified P-diketone. Ozoneattacks the carbon-carbon double bond to give an acyloxime, which can be hydrolysed to an a-diketone and acarboxylic acid.3During attempts to prepare the P-nitrostyrene (1) bycondensation of nitroethane with 6-bromopiperonal (2),we obtained instead in low yield a crystalline compound,C,,H,,BrNO,.Its i.r., n.m.r., and U.V. spectra wereconsistent with the isoxazole structure (3), but the substi-tution pattern in the isoxazole nucleus could not beestablished from these spectral data.One preparation of isoxazoles by base-catalysed con-densation of aromatic aldehydes with nitroalkanes hasbeen known since 1911, when Heim * obtained triphenyl-isoxazole (4) from benzaldehyde and a-nitrotoluene.Similar experiments with para-substituted benzaldehydesgave isoxazoles with the substituted aromatic ring in the4-position ; e.g.9-bromobenzaldehyde formed theisoxazole (5) with a-nitrotoluene. This led to Scheme 1being proposed for the mechanism of the condensation,and in the light of this mechanism structure (6) wouldbe predicted for the isoxazole (3). However, Ruggli6obtained 5-(o-nitrophenyl)-3,4-diphenylisoxazole (7) bycondensat ion of o-nitrobenzaldehyde with a-nitrot oluene.This shows that a second mechanism (Scheme 2) mightoperate to give the alternative substitution patternstructure (S) for the isoxazole (3), although the opera-A. Quilico, lsquo; The Chemistry of Heterocyclic Compounds,rsquo;ed. R. H. Wiley, Interscience, 1962, vol. 17, pp. 24-27.G. S. drsquo;Alcontres, Gazzetta, 1950, 80, 441.E.P. Kohler and N. K. Richtmeyer, J . Amer. Chenz. Soc.,1928, 50, 3092.F. Heim, Bey., 1911, 44, 2016.N. Campbell, W. Anderson, and J. Gilmore, J . C h m . Soc.,P. Ruggli and B. Hegedus, Helv. Chim. Acta, 1939, 22, 405.1940, 446.tion of this mechanism may depend upon the ability of thesubstituent (in this case the nitro-group) in the aromaticBr( 1 ) ( 2 ) R = CHO ( 3 )( 9 ) R = CO,H( 1 0)RZ Rrsquo;QMecii 1 Rrsquo;= H , R ~ = M ~(12) Rrsquo;= Ph,R*= Me(13 1 R1= H, R2= Ph( 1 4 ) R 1 = R Z = Mering to promote Michael addition at the appropriate(3-carbon atom of the intermediate styrene. Sinc2116 J.C.S. Perkin Iroutine spectral data could not be used to distinguishbetween the two isomers, the degradative methodsreferred to above were investigated.0PhPh- H20f-Phrsquo; ()OHArfPhSCHEME 1All attempts to carry out hydrogenation failed, both a t1 atm and a t 4 atm.Ozonolysis of the isoxazole, fol-lowed by acidic hydrolysis, gave only a poor yield of acomplex mixture of products, and although the failure totwo possible products, or would be subject to sterichindrance by the ortho-bromo-substituent .A much simpler solution to the problem was offered by13C n.m.r. ~pectroscopy,~ as it seemed likely that thechemical shifts of the carbon atoms of the methyl groupsand of the isoxazole ring would be markedly influencedby the substitution pattern. Although a number offive- and six-membered nitrogen heterocycles have beenstudied * by this technique, no reference could be foundto its application to isoxazoles.It was thereforenecessary to prepare some simple model compounds,whose spectra could be interpreted unambiguously.The isoxazoles (1 1)-( 14) were readily prepared byliterature methods ; their 13C n.m.r. spectra are collectedin the Table. Assignments follow directly from multi-plicities in the off-resonance decoupled spectra and/orchemical shift values,rsquo; although the assignments for C-3and -5 are tentative, as are those for the methyl groupsattached to these carbon atoms. The signal at 6.6 p.p.m.in the spectrum of (14) could be unambiguously ascribedto the 4-methyl group, since it appeared upfield by ca.4 p.p.m. from all other 3- and 5-methyl signals in themodel compounds, and these showed little variation withAr Ar -CH2IPh-C-NOzIPh -CH-NOz-HZ0 ~ bsol; c / PhCHZNOZ ~ II ArCHO .t PhCH2N02I NO2 /cz PhII CPhrsquo; lsquo;CH-NO,IPhSCHEME 2detect any 6-bromopiperonylic acid (9) was evidenceagainst structure (8), the test was rendered inconclusiveby the failure to detect or isolate any a-diketone (10)which should have arisen from (6).the presence or absence of a 4-substituent.Also thechemical shifts of C-3 and -5 remained virtually unchangedregardless of the substitution pattern, whereas C-4 showeda smooth progression from 100.1-102.3 (no substituent),13C N.m.r. data for isoxazolesCompound C-3 (s) C-4 (d) C-6 (s) 3-CH3 (9) 4-CH3 (9) 6-CH, (4) Aromatic169.0 102.3 169.9 12.1 11.3166.1(12) 169.6(rsquo; 3, 164.2116.7 168.6 11.4 10.7 127.6, 128.4, 128.7, 129.1, 130.2, and 130.6100.1 160.3 11.6 126.8, 127.6, 128.9, and 130.0109.0 159.9 10.7 6.6 10.010.6 166.1 116.9 or 168.5116.411.6 111.3 and 113.0 (2rsquo; and 6rsquo;), 116.9 or 116.4(Srsquo;), 124.0 (1rsquo;), and 147.6 and 148.0 (3rsquo;and 4rsquo;) 102.l(t), OCH,O(14)(6)Unambiguous synthesis of (8) appeared difficult, asthe conventional routes involving 1,3-~ycloaddition ofacetonitrile oxide to an alkyne or diketone synthesis,followed by cyclisation of the mono-oxime, could give7 (a) J.B. Stothers. lsquo; Carbon-13 N.M.R. Spectroscopy,rsquo;Academic Press, New York, 1972; (b) F. A. L. Afet and G. C.Levy, Science, 1973, 180, 141; (c) J. A. Elvidge, Introductionto Spectroscopic Methods for the Identification of Organic Com-pounds,rsquo; vol. 2, ed.F. Scheinmann, Pergamon, Oxford, 1974,pp. 222-230.through 109.0 (methyl substituent), to 116.7 (phenylsubstituent) .The I3C n.m.r. spectrum of the isoxazole (3), recordedunder the same conditions (Table), allowed assignment ofthe signals of the methyl groups, the methylenedioxygroup, and C-2rsquo; and -5rsquo; directly from their multiplicities in8 F. J. Weigert and J. D. Roberts, J . Amer. Chem. SOC., 1968,90, 3543; F. J. Weigert, J. Husar, and J. D. Roberts, J . Ovg.Chem., 1973, 38, 13131975 2117the off-resonance decoupled spectrum, and the C-3 and-5 signals were identified by comparison with the datafrom the model compounds. The presence of varioussubstituents in the aromatic ring made the assignmentsof C-1rsquo;, -3rsquo;, -4rsquo;, and -6rsquo; more difficult, although tables ofsubstituent effects in the benzene ring are a~ailable,~indicating the effects on the chemical shifts of the carbonatoms to which the substituents are attached and of theother carbon atoms in the ring.Although these changesin chemical shift are strictly additive only in those casesin which none of the substituents are ortho to one another(in which case steric effects cause deviations from pre-dicted behaviour), the general trends allow certain assign-ments to be made. Thus a methoxy-group induces ashift of +30.2 p.p.m. in the 8 value of the carbon atomto which it is attached (relative to the chemical shift ofbenzene itself, 128.7 p.p.m.), and a shift of -15.5 p.p.m.in the 6 value of the ortho-carbon atom. This explainsthe low values (111-113 p.p.m.) observed for C-2rsquo; and-5rsquo;, and allows assignment of the two signals at ca.148p.p.m. to C-3rsquo; and -4rsquo;, because the shifts induced by amethoxy-group far outweigh those induced by a bromo-substituent, and similar properties would be expectedfor the methylenedioxy-group.The C-4, -lrsquo;, and -6rsquo; signals could not be identified withthe same certainty, owing to lack of information on theeffects of isoxazoles or comparable ring systems as sub-stituents. However, C-1rsquo; and -6rsquo; would be equallyaffected by the methylenedioxy-group, and since bromineis one of the few recorded substituents (I and CN are theonly others rsquo;) to induce a negative shift on the attachedcarbon atom, it seemed likely that of the remaining threesignals, that 124 p.p.m.corresponded to C-1rsquo; and thosenear 116 p.p.m. arose from C-4 and C-6rsquo;. Despite theuncertainty in the assignments of the last three carbonatoms, there was sufficient information to allow identi-fication of the isoxazole as (6). The methyl signals at10.5 and 11.6 p.p.m. clearly fitted the 3,5-dimethylpattern shown by (ll), (12), and (la), and particularlystriking was the similarity to (12) (10.7 and 11.4 p.p.m.),the closest analogue of (6). The 6 value for C-4 (116 or,possibly, 124 p.p.m.) was far enough removed from thatof C-4 in (14) (109 p.p.m.) to rule out structure (8),and once again a value of 116 p.p.m. is in very goodagreement with the data obtained for the 4-phenyl-Ref. 7a, p. 196.lo Cf. e.g. G.Bianchi, C. D. Micheli, R. Gandolf, P. Griinanger,P. V. Finzi, and 0. V. de Pava, J.C.S. Perkin I , 1973, 1148, andrefs. therein.l1 G. T. Morgan and H. Burgess, J . Chem .SOL, 1921, 697.isoxazole (12). This establishes that the isoxazole (6)is formed by a mechanism analogous to that in Scheme 1(for Ph read Me).Thus 13C n.m.r. proved to be a convenient means ofdistinguishing structures (6) and (8), and the techniquecould find general use for the solution of this type ofproblem. In particular, the orientation of the 1,3-cyclo-addition of nitrile oxides to unsaturated systems is thesubject of a great deal of effort,1deg; and l3C n.m.r. shouldbecome of considerable value in elucidation of the struc-tures of the product isoxazoles and isoxazolines.EXPERIMENTAL13C n.m.r.spectra were recorded for solutions in deuterio-chloroform solution with tetramethylsilane as internalstandard by the Physico-Chemical Measurements Unit,Aldermaston, on a Bruker HX 90E spectrometer operatingat 22.63 MHz.Model IsoxuzoZes.--S, 5-Dimethylisoxazole ( 1 1) was pre-pared by reaction of acetylacetone with hydroxylamine,ll3,5-dimethyl-4-phenylisoxazole (12) by reaction of 3-phenyl-pentane-2,5-dione 12 with hydroxylamine,l3 5-methyl-3-phenylisoxazole ( 13) by reaction of benzoylacetone withhydroxylamine,14 and trirnethylisoxazole (14) by treatmentof nitroethane with aqueous sodium hydroxide.ls4- (6-Bromo-3,4-m.ethyZenedioxyphenyZ) -3,5-dimethyZisox-mole (6) .-A mixture of 6-bromopiperonal (26.5 g), nitro-ethane (2 1.0 ml) , butylamine (2.0 ml) , anhydrous sodiumcarbdnate (1.12 g), and ethanol (130 ml) was heated underreflux for 3 h, and allowed to cool overnight. Concentrationof the mixture in UUGUO, followed by cooling in ice failed t oelicit any precipitate of the expected nitrostyrene, and afteralmost all the solvent had been removed the dark oilyresidue was left at ambient temperature for 1 week.Theresulting prisms were recrystallised from aqueous methanolto give the isoxazole (6) as needles (1.05 g, 3), m.p. 109-110rsquo; (Found: C, 48.6; H, 3.6; Br, 27.1; N, 4.5; M+,294.985 4. C12Hl,BrN03 requires C, 48.6; H, 3.4; Br, 27.0;N, 4.7; M+ for 7OBr, 294.984 5), A,, (MeOH) 219, 250sh,and 298 nm (E 13 900, 6 000, and 4 200), v,, (KBr) 1 640and 1 620 cm-l, 6 (CDC1,) 2.15 (s, 5-Me) 2.30 (s, 3-Me),6.05 (s, OCH,O), 6.65 (s, 2rsquo;-H), and 7.14 (s, 5rsquo;-H), m/e 297/296 (M+, loo), 254(20), 262(20), 228(28), 226(28), 215(13),and 147(67).We thank the S.R.C. for a C.A.P.S. studentship (toG. 34. B.).6/787 Received, 28th April, 19761l2 C. R. Hauser and R. M. Maryik, J . Org. Chem., 1953,18, 688.l3 B. Bobranski and R. Woztowski, Pol. P. 60,520/1966 (Chem.l4 L. Claisen, Bcr., 1907, 40, 3909.l5 W. R. Dunstan and T. S. Dymond, J . Chem. Sec., 1891,Abs., 1967, 66, 65,4802).410
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