1308 J.C.S. Perkin IThermal Elimination Reactions of Nitrones. Part 1. Applications,Limitations, and StereochemistryBy Derek R. Boyd and David C. Neill, Department of Chemistry, Queen's University of Belfast, BelfastBT9 5AGA series of N-(fluoren-9-ylidene)alkylamine N-oxides has been synthesised by direct oxidation of the parentimines with peroxy-acid. Most of these nitrones underwent a thermal elimination reaction (analogous to theCope elimination of tertiary amine oxides) to produce olefin and oxime products. The elimination reaction wasfollowed by g.1.c. and mass and n.m.r. spectroscopic techniques, and the results are rationalised in terms of severalfactors including statistical and steric effects and olefin stability. The applications and limitations of this nitroneelimination reaction and the relationship between the stereochemistry of reactants and that of products has beenexaminedforvariousnitrones R1R2C=N+(O-)R3(R1 = aryl, R2 = H ; Rland R2 both alkyl; R1 = alkyl, = aryl;R1 and R2 both aryl).THE N-oxides of amines differ from those of imines(nitrones) in having tetrahedral and trigonal nitrogenconfigurations, respectively. Further differences arefound in their thermal reactions : tertiary amine oxidesupon heating decompose to form hydroxylamines andolefins (Cope elimination l), whereas nitrones are re-ported to give different types of products includingoxime O-ethers or an i m i ~ ~ e .~ During their extensiveinvestigations of thermal reactions of tertiary amineN-oxides and nitrones Cope et al.did not report anyelimination from nitrones. Thus, prior to the prelimin-ary form of this work 5 no detailed report on the elimin-ation reaction of nitrones was available.Two literature reports, however, were of particularrelevance to the problem of t-hermal elimination innitrones. Emmons found that the gas-phase pyrolysisof 3-phenyl-2-t-butyloxaziridine gave a mixture ofnitrone, oxime, and isobutene gas and proposed that thelatter two products could result from an elimination re-action of the intermediate nitrone. Kim and Wein-traub postulated that unstable nitrones were being1 A. C. Cope, Org. Reactions, 1960, 11, 317.J. Hamer and A. Macaluso, Chern. Rev., 1964,64,473.A. C. Cope and A. C. Haven, J . Amer. Chem. SOC., 1950, 72,J. B.Bapat and D. St. C..Black, Austral. J . Chem.. 1968, 21,4896.2521.5 D. R. Boyd, Tetrahedron Letters, 1973, 3467.formed in situ in the reactions of several aldehydes withN-alkylhydroxylamines and that the putative nitroneswere spontaneously breaking down to oximes and olefinsat ambient temperature.Our interest in the thermal elimination of nitronesarose from the observation that N-(fluoren-9-ylidene)-methylamine, on oxidation with m-chloroperbenzoic acid(MCPBA) (5 min; 60 "C; CHCl,) gave the nitrone (1) inhigh yield (>%yo) with traces of oxaziridine. Thisresult was unexpected since N-alkylimines derived frombenzophenone yield oxaziridines only after acid oxi-dation by peroxy-acid.*In view of the availability of a general syntheticmethod for hindered diarylmethyleneamines 9~10 and therequirement for a route to hindered nitrones, a rangeof N-(fluoren-9-ylidene)alkylamines were obtainedand oxidized with MCPBA in chloroform at 60 "C.N-(Fluoren-9-ylidene)-t-butylamine N-oxide initiallyproved difficult to obtain in pure form.When anysignificant amount of heat was used during oxidation orwork-up some oxime was isolated. Even in [2H]chloro-W. D. Emmons, J . Amer. Chem. SOC., 1957, 79, 5739.H. K. Kim and P. M. Weintraub, J . Org. Chem., 1970, 35,4282.8 J . Bjerrgo and D. R. Boyd, J.C.S. Perkin 11, 1973, 1575.9 J . Weingarten, J. P. Chupp, and W. A. White, J . Org. Chem.,1967, 82, 3246.10 I. Moretti and G. Torre, Synthesis, 1970, 1411977 1309TABLE 1/ON E- 'R+ olefin/OHN heat___)No.ofatomsRelative p-hydrogenratesRelativeratesTemp.("C) Olefin [yo]0H H1 C 3 0.332.4210180 2.4 13 2 1 7.7 1 7.7 1805 81H14 3 4.6 18065 6 10.9 180155801324 3 4411 600 000 9 180 000Me MeMexH12*,Me Me400 000 800 000 2 80TABLE 1 (Continued overleaf1310 J.C.S. Perkin INitroneuEt(8) $ j + \\Me ')f:76 1 80No. ofRelative p-hydrogen Relativeratesc atoms rates3 200 000 6u540 000a Determined by g.1.c. in the presence of other isomeric olefins. Temperature a t which the olefin was first evolved at a sig-form solution a t 35 "C this nitrone showed evidence of correction for the number of p-hydrogen atoms. Thedecomposition. From a sample heated a t 80 "C in a rate difference between, for example, the nitrones (2) andvacuum line, isobutene gas and fluorenone oxime were (7) after correction is still large.isolated in quantitative yield.Where isomeric olefin products are obtained [(3) andThe similarity between the Cope elimination of tertiary (7)] the number of p-hydrogen atoms is more important.amine oxides and this ready nitrone elimination process Thus the corrected relative rates of elimination of (7a andwas evident and prompted a more detailed study of the b) (or 3a-c) are similar.thermal reactions of the nitrones derived from fluorenone. The relatively fast elimination fromCrystalline nitrone samples were heated in a vacuum nitrone conformation (3b) [to give (E)-but-2-ene] assystem connected to a g.1.c.sampling port. The gases compared with (3a) [to give (Z)-but-2-ene] can be mostevolved were identified by comparison (retention times easily rationalized in terms of steric interactions favour-and mass spectra) with authentic samples. ing comformation (3b).The nitrones (2)-(8) all possess p-hydrogen atoms ; Dreiding and space-filling models of the nitrones (6) andthis appears to be a requirement for thermal elimination (7) suggest that interlocking non-bonded interactionsreactions of both tertiary amine oxides and nitrones. between the t-alkyl group and the proximate fluorenylThe temperature at which elimination first occurs (Table hydrogen atoms should be appreciable. These steric1) provides only a crude indication of the relative rates of effects might be reflected in an increase in the C=N bondelimination.Rate constants for thermal elimination length, a decrease in the -0 - - - H interatomic distancewere obtained by n.m.r. studies of the reaction as it and a decreased rate of rotation around the N-C, bond.nificant rate. At 60 "C. Corrected for the number of p-hydrogen atoms. 3.4 i. 0.04 x s-l.(ii) Steric factors.occurred in a thermostatically controlled bath. Nitroneswere dissolved in diphenyl ether and the progress ofthe reaction was followed by observing the disappear-ance of the N-alkyl signal relative to an internal standard(hexamethylbenzene). The relative rate constants at60 "C obtained by extrapolation are shown in Table 1.Further mechanistic information can be obtained fromthe composition of the olefinic products.Whereas thenitrones (2) and (4)-(6) each yield a single olefin onheating, the nitrones (3) and (7) may produce isomericolefins. The relative rates of thermal elimination andolefin compositions shown in Table 1 may be rationalizedin the following way.(i) Statistical factor. The thermal elimination ofnitrones (Table 1) is faster for N-alkyl groups bearing theoptimal number of p-hydrogen atoms. This trend isanalogous to that found in the Cope elimination. Copeet aZ.l found that when a statistical correction for thenumber of p-hydrogen atoms was made the relative ratesof thermal elimination of tertiary amine oxides (devoid(6) R=Me(7) R=EtThe relief of steric strain on elimination of the N-t-alkylnitrones (6) and (7) would be greater than for N-s-alkyl[(3)-(5)] or N-(primary alkyl) nitrones (2) and thesenitrones should show a correspondingly higher rate.The increase in the corrected rate of elimination of(7b) over that of (6) would be consistent with increasedrelief of steric compression in the former.The reversetrend for the nitrones (3c) and (4) may be explained by adiminished preference by the latter nitrones for a ground-state conformation identical with that required forelimination in the transition state. The nitrones (6)and (7), however, probably have similar conformations inof an a-aryl substituent) were similar.statistical factor (entropy effect) is operative, in generalthis is a minor influence.Table 1 shows the relativerates for thermal elimination of the nitrones (2)-(7) afterground and transition states.The present results show that although a similar A low temperature [-lo0 "C; (CD,),CO] n.m.r.analysis of the nitrone (6) did not show non-equivalentmethyl groups, which could have resulted from slowrotation around the N-C, bond1977 1311The nitrone (8), while having six P-hydrogen atoms,does not undergo thermal elimination at the temperaturesstudied (up to 200 "C).that the nitrone (9) did not undergo elimination at 230 "C.The inability of the nitrones (8) and (9) to form theplanar five-membered cyclic transition state necessaryfor N-oxide thermal elimination may again be classifiedas a steric factor since conformational restriction resultsfrom the ring systems present in each case.Similarly it has been reportedt-0(iii) UleJin stabilization.The failure of the nitrone (8)to undergo thermal elimination may also or alternativelybe due to the large energetic requirement for the form-ation of the anti-Bredt olefin adamantene (10). Thishighly strained olefin has previously been detected bytrapping experiments at moderate temperaturesll(iv) Charge development in the transition state. Thethe effect of carbon substitution on several other repre-sentative N-t-butyl nitrones was studied. Thus, N -(4-nitrobenzylidene)-t-butylamine N-oxide (1 1) and itsa-methyl derivative (12) also underwent thermal elimin-ation, at 150 and 120 "C, respectively, to yield the corres-ponding oximes and isobutene.Mono- and di-C-alkyl nitrones are often unstable and4-0,N*C6H4-CR=N+(O-) But (11) R = H(12) R =Meeasily hydrolysed.2 N-t-Butyl di-C-alkyl nitrones havenot, to our knowledge, been reported.However, duringunrelated studies12 on the synthesis and oxidation ofdi-imines the di-C-alkyl nitrone (13) was isolated. Thetrans-bisnitrone (13) melted at 106 "C and eliminatedisobutene at 120 "C, leaving crystals of the dioxime, m.p.280-281" (lit.,13 281). This result confirms that thethermal elimination reaction of nitrones R1R2C:N+(O-)R3can occur in the systems R1 = aryl, R2 = H; R1 andR2 both alkyl; and R1 = alkyl, R2 = aryl.The synthesis, separation, and stereochemistry of E-,kN+ ,OH\ N [ O 1+,O-N0 / + 'B"' HO 2/Me Me Me Me(13)SCHEMEcontribution of olefin resonance stabilization to the rel-atively high rate of elimination of styrene from thenitrone (5) is difficult to estimate in view of the'significantrole which other factors including charge development inthe transition state may play.The rates in Table 1 maybe classified into three groups (primary, secondary, andtertiary N-alkyl nitrones). The unique behaviour of thenitrone (5) and the wide range of rates amongst the threecategories of nitrone may be mainly due to a variation inthe degree of charge separation in the transition state.I t is, however, difficult at this stage to speculate furtheron the importance of the latter factor without havingavailable a suitable range of nitrones containing bothelectron-donating and -withdrawing groups.A newrange of nitrones of this type has been synthesised in theselaboratories and kinetic data from thermal eliminationand conclusions will be reported in Part 2 of the presentseries.We emphasise that although the factors (i)-(iv) maybe among the more important which lead to the widerange of rates shown in Table 1, it is difficult to providean accurate estimate of the relative contributions fromeach at this stage without more accurate kinetic data.Having established the general applicability of thethermal elimination process to a range of N-alkyl nitrones,l1 D. Grant, M. A. McKervey, J . J. Rooney, N. G. Samman,and G. Step, J . C . S . Chem. Comm., 1972, 1186.l2 D.R. Boyd and W. B. Jennings, unpublished data.l3 J . L. E. Erickron and G. C. Kitchens, J . Amer. Chem. SOC.,1946, 68, 492.and Z-nitrones has recently been examined.l43 l5 Whenunsymmetrically substituted nitrones are heated, E-Zisomerization may occur in both the reactants and theproduct oximes. Thus in the sequence shown in the-\ /OH Ar 0 A rheat - \ + /C=NR z 'But R t l;*C=N heat * 'C=NA r A r\4 E +'g R' ' 'OHScheme the barriers to E-Z isomerization of N-t-butylnitrones and oximes will be <29 kcal mol-l l2 and >22-27 kcal mol-l,16 respectively (in the absence of catalysts).Kim and Weintraub examined the stereochemistry ofoxime products and attempted to correlate this with thepredicted stereochemistry of the transient nitrone inter-mediate. Since none of the aldehydes used ' containedl4 T.S. Dobashi, M. H. Goodrow, and E. J . Grubbs, J . Org.l5 J . Bjmgo, D. R. Boyd, D. C. Neill, and W. B. Jennings,R. J. W. Le F h r e and J. Northcott, J . Chem. Soc., 1949,Chem., 1973, 38, 4440.J.C.S. Perkin I, 1977, 254.22351312 J.C.S. Perkin Itwo ortho-substituents (which under identical experimen-tal conditions would give both and E- and Z-nitrone iso-mers 15) the elusive nitrone intermediate would probablyhave had a Z-configuration. Since this elimination re-action of Z-nitrone intermediate occurs a t 0 "C it isappeared,ls and two other groups 1 9 y 2 0 have also reportedthe thermal elimination reaction of nitrones. The latterreports, taken in conjunction with the present data,demonstrate that the thermal elimination of nitronesis a general reaction which parallels the Cope elimin-unlikely thatbrated.ThusmechanismImine RMeEtEtMeCHPriPhMeCHButEtMe2Cl-AdamantylNitrone RMeEtEtMeCHPriPhMeCHButEtMe2Cl-Adamantylisthe product oxime would have equili-Z-nitrone should yield a Z-oxime if theanalogous to that established for theation reaction in type but which may be of greatersynthetic value in view of the more rapid eliminationof suitably substituted nitrones. The large range ofTABLE 2Found (%) Required (%)7 - 7M.p. (b.p.) ("C) C H s Formula C H N 8 R (CDC13)c(125; 0.Oi mkHg) 86.6(152; 0.02 mmHg) 87.2(150; 0.02 mmHg) 86.5(125; 0.01 mmHg) 86.8(165; 0.01 mmHg) 89.2(145; 0.005 mmHg) 86.9(130; 0.03 mmHg) 86.85207 87.9145 (1it.,l6 145-146)85-87 (1it.,l6 87-88)68-70 81.1110 (lit.,15 106-107)142 84.380 81.367-69 81.6155-157 83.7a CH,.Triplet. CH,.5.5 7.2 C1,HllN6.5 6.7 C16H13N7.3 5.9 C17H17N7.0 6.1 C16Hl5N7.45 5.2 C18HlQN6.0 5.0 C21H17N7.5 5.7 C17H17N7.5 4.2 2 3 2 36.9 5.6 C17H17N05.8 4.9 C21H17N06.9 5.6 C17H17N07.1 5.4 Cl8Hl9NO7.0 4.0 2 3 2 3 Nod Quartet. e CH. Doublet.87.086.986.886.889.086.886.788.181.284.381.281.583.9CJ Septet.5.7 7.26.3 6.87.3 5.96.8 6.35.9 4.97.3 5.97.7 5.67.4 4.56.8 5.65.7 4.76.8 5.67.2 5.37.0 4.2h Multiplet.3.901.50,"9b 4.151.38,"~f 4.5,e*h0 . 9 7 , " ~ ~ 1.73 c r d1.41,"J 4.81 e*g1.7OIa*f 5.731.651 .40," 1.O6,"nb1.79 epd1.8-2.34.281.60,"~~ 4.43 c*d1.59,"*f 5.08,e*h0.96,a*b 2.03 e*d1.59,"pf 5.23 e*g1.88,"~f 6.22 e*d1.85 a1 .79," 1 .04,"vb2.34 c*d1.8-2.6'Cope elimination.The observed 7 stereochemistrywas consistent with this proposal.When the Z-nitrone (11) was heated the thermodyn-amically more stable E-oxime was formed exclusively.Similarly the E-nitrone (12) gave E-oxime on heating,showing again that the reaction was thermodynamicallycontrolled. The relatively high temperatures (120-150"C) required for thermal elimination of the nitrones (11)and (12) thus appeared to be sufficient for equilibration ofthe oxime products. The thermal isomerization of E-and Z-ketone oximes in the neat form has been observedpreviously to be fast at 175 OC.I7The trans-bisnitrone (13) gave a dioxime productwhich appeared to be a single isomer and which isassumed to have the trans-stereochemistry from then.m.r.spectrum [a 2.09 (12 H, s) and 5.15 (2 H, s ) ] .Since the preliminary publication of the present workan alternative route to the nitrones (l), (2), and (4) has17 E. G. Vassian and R. K. Murmann, J . Org. Chem., 1962, 27,18 R. N. Pratt, D. P. Stokes, and G. A. Taylor, J . C . S . Perkin I ,l9 M. H. Goodrow, J. A. Villareal, and E. J. Grubbs, J . Org.4309.1975, 498.Chem., 1974, 39, 3447.rates for thermal elimination of the nitrones (2)-(7),however, contrasts with the data from the Cope elimin-ation.EXPERIMENTALThe parent imines of the nitrones (1)-(8) were preparedby condensation of fluorenone with alkylamine in the pres-ence of titanium chloride according t o previously reportedmethods.Q*10 The nitrones (1)-(8) were prepared by theoxidation method previously reported for oxaziridines.21Physical properties and microanalytical and n.m.r.data forthe nitrones (1)-(8) and the parent imines are given inTable 2. Physical data of the nitrones (1 1) and (12) and thecorresponding oximes were identical with those reported.l69 22Nitrones in the crystalline state were heated in a vacuumline tonnected t o a g.1.c. sampling port. Analysis wascarried o u t by using a 25% acetonylacetone column a t ice-bath temperature. The gaseous products were identified bycomparison of retention times and mass spectra with those2O W.M. Leyshon and D. A. Wilson, J.C.S. Perkin I , 1975,21 D. R. Boyd, D. C. Neill, C. G. Watson, and W. B. Jennings,22 I. Perjhoric-Tadic, M. Hranisavljevic- Jakouljevic, S. Nesic,1920.J . C . S . Perkin 11, 1975, 1813.C. Paseual, and W. Simon, Helv. Chim. Ada, 1965, 48, 11571977 1313of authentic samples. Mass spectra were obtained byusing an A.E.I. MS902 instrument or an A.E.I. MSSO-Pye-Unicam 104 g.1.c.-mass spectrometer operating a t 70 eV.N.m.r. spectra were recorded a t 60 MHz with a VarianA-60 instrument. The first-order kinetics for thermalelimination were studied by the n.m.r. technique with thenitrone (0.001~) in purified diphenyl ether (4.5 ml) con-taining hexamethylbenzene (0.05 g) as internal standard.Samples (0.75 ml) were pipetted into each of six n.m.r. tubeswhich were then heated in a thermostatically controlled( f 0 . l "C) oil-bath. Tubes were withdrawn a t suitableintervals and cooled in ice, and spectra were recorded withmultiple integration of the nitrone and standard peaks. Alog plot against time gave the rate constant. Extrapol-ation of the rate data obtained a t several temperaturesallowed the relative rates at 60 "C to be determined.We thank Messrs. W. J . Swindall and B. McKnight formicroanalytical data, Drs. J . I. C. Archibald and J . J .Rooney for the use of the g.1.c. analytical system, Drs.W. B. Jennings, J . J . Rooney, and M. Stubbs for discussion,and the Northern Ireland Ministry of Education for financialsupport (to D. C. N.).[6/2099 Received, 15th November, 1976