1202 J.C.S. Perkin IPhotochemistry of 4,6-Disubstituted Pyrimidine N-OxidesBy Fred Roeterdink and Henk C. van der Plas." Laboratory of Organic Chemistry, Agricultural UniversityWageningen, The NetherlandsPhotolysis of 4.6-di-R-pyrimidine l-oxides (R = Ph or But) in methanol with a high-pressure mercury arc and aRayonet R P R 2537 a lamp, respectively, leads to 3.5-di-R-pyrazoles. In the case R = Ph, in addition to thepyrazole, 2-methoxy-4.6-diphenylpyrimidine is obtained. This compound is considered to be formed via anoxaziridine intermediate, the existence of which was indicated by the liberation of iodine from potassium iodide.DI- AND TRI-SUBSTITUTED pyrimidine N-oxides havebeen shown to rearrange photochemically by a processprobably involving an initial attack of the oxygen atomat C(6) ,la resulting in a laH-oxaziridino2,3-apyrimidineintermediate. No indication of attack of the oxygen atC(2) of the pyrimidine ring was observed.This regio-specificity is in good agreement with the results of PPP-SCF calculations,2 but contradicts those based onLCAO-MO theory, predicting a preferential addition toC(2).3 Although the products obtained on irradiationof monosubstituted pyrimidine N-oxides seem to con-firm the latter theory, a recent report reveals that in thesecompounds also there is a tendency for the oxygen atomto attack at C(6).*Since in the reactions of the pyrimidine 1-oxidesdescribed so far the substituents at positions 2, 4, and6 have been relatively small, we became interested inthe behaviour of 4,6-disubstituted pyrimidine N-oxidesin which the 4- and 6-substituents are bulky, hoping thatsteric interference at these positions would direct thecyclisation to the unsubstituted position 2.We there-fore studied the photochemical behaviour of the 4,6-di-R-pyrimidine l-oxides (I ; R = Ph or But).The photolysis of 4,6-diphenylpyrimidine l-oxide inacetone is reported to yield a complex mixture fromwhich no product was i~olated.~ In our hands photolysisof a methanolic 5 X 10-3M-SOlUtiOn of 4,6-diphenyl-pyrimidine l-oxide (I; R = Ph) with a high-pressuremercury arc (Hanau TQ 150) yielded a mixture fromwhich, by t.l.c., two main products, i.e. 3,5-diphenyl-pyrazole (V; R = Ph) (11) and 2-methoxy-4,6-di-phenylpyrimidine (X) (6) could be isolated.Noindication of the formation of 4,6-amp;phenylpyrimidinewas obtained. Both products were identified by com-parison (lH n.m.r., i.r., and mass spectra) with authen-tic compounds.To our knowledge, this is the first example of a photo-chemically induced ring contraction of a pyrimidine N-t Ground-state addition of an amide ion to a pyrimidine ringusually takes place a t position 4(6) ; in the case of 4,6-diphenyl-pyrimidine the addition of an amide ion has been found to occura t C(2) (J. P. Geerts and H. C. van der Plas, unpublished data).This paper is regarded as Part LII of the serifs ' Pyrimi-dines ' and Part VI of ' Photoreactions of Diazines. For PartLI(V) see (a) F. Roeterdink and H. C. van der Plas, ContributedPaper of the Euchem Research Conference : Useful PreparativeAspects of Photochemistry, Gent, 1975; for Part L see (b)J.P. Geerts, H. C. van der Plas, and A. van Veldhuizen, Org.Magnettc Resonance, 1975, '7, 85.C. Kaneko, S. Yamada, H. Ischikawa, and T. Kubota,Abstracts, Third International Congress of Heterocyclic Chem-istry, Japan, B, 1971, p. 215.oxide to a pyrazole. In this reaction the initia attackof the oxygen must take place at C(2). Apparentlyattack at C(6) is strongly disfavoured owing to sterichindrance by the phenyl group.? Although the mechan-ism of this ring contraction is not completely elucidated,we suggest the following pathway: (a) cyclisation atC(2) ; (b) ring expansion to a 1,2,6-oxadiazepine (111) ;(c) ring contraction to a 3,5-disubstituted N-formyl-pyrazole (IV) , which undergoes deformylation to (V) .PR.,A h3 R.ASCHEME 1An equilibrium between the oxaziridinopyrimidine (11)and the 1,2,6-oxadiazepine (111) has been proposed butnever established; however, it shows a great similarityto the equilibrium between a 1,3-oxazepine and itsoxanorcaradiene isomer, which was recently establishedin the thermal rearrangement of 2-phenyl-l,3-oxazepineto Ibsol;l-formyl-2-phenylpyrrole. In order to investigatethe feasibility of the photodeformylation (IV) ---t (V)(as recently observed during the photolysis of 6-methyl-and 6,9-dimethyl-purine l-oxides ') attempts were madeto prepare (IV) by a procedure analogous to that for thepreparation of N-formylindole.* These attempts failed,however (see Experimental section).The possibilitythat (V) is formed from an intermediate 4,6-diphenyl-J. Streith, C. Leibovici, and P. Martz, Bull. SOC. chim.F. Bellamy, P. Martz, and J. Streith, Tetrahedron Letters,G. G. Spence, E. C. Taylor, and 0. Buchardt, Chem. Rev.,T. Tezuka, 0. Seshimoto, and T. Mukai, Tetrahedron Letters,I;. C. Lam and J. C. Parham, J . Amev. Clzern. SOC., 1975, 9'7,L. Alessandri and amp;I. Passerini, Gaxetta, 1921, 51I, 262.France, 1971, 4152.1974, 3189.1970, 70, 231.1975, 1067.28391976 1203pyrimidin-2-one was ruled out by irradiation of thiscompound under the same conditions; only startingmaterial was recovered.The intermediate formation of an oxaziridine in thephotoreactions of heteroaromatic N-oxides is generallya~cepted,~ but despite many efforts these species havenever been isolated; even recent nanosecond flashphotolysis experiments gave no indication of its inter-mediary existen~e.~J~ The only chemical ' proof 'hitherto available is the ' trapping ' of the oxaziridineby primary or secondary amines during the photolysis of2-cyanoquinoline l-oxides.ll* * We believe that theformation of 2-rnethoxy-4,6-diphenylpyrimidine (X) inthe present reaction can also be considered as a goodindication of the intermediary existence of an oxaziridine.Furthermore, irradiation of 4,6-diphenylpyrimidine 1-oxide in the presence of a seven-fold molar amount ofPh PhM e 0 ' L 3 P h , - Me0 QPhButOH(Dc)SCHEME 2potassium iodide in water produced iodine.Since 4,6-diphenylpyrimidine l-oxide shows no oxidising proper-ties towards iodide ion in the dark, and oxaziridines areknown to be strong oxidising agents which are capable ofliberating iodine from potassium iodide,13 this experi-ment strongly supports the presence of an oxaziridine asintermediate. Since no deoxygenation was observed,the oxaziridine intermediate is the oxidising species andnot atomic oxygen. Identical experiments were per-formed with 2,4,6-trimethylpyrimidine l-oxide and 4-chloro-2,6-dimethylpyrimidine l-oxide. In both experi-ments a twelve-fold molar amount of potassium iodidewas needed to liberate iodine. This can be consideredas an indication that in the case of the 4-R-2,6-dimethyl-pyrimidine I-oxides (R = Me or C1) the oxaziridine hasa shorter lifetime.It has been reported that during theirrahation of 3,6-diphenylpyridazine N-oxide no oxaziri-dine intermediate is formed.10 Photolysis of this N-oxide, in our hands, in the presence of a fifty-fold molar* It was reported recently l2 that 4-alkoxyisoquinolines areformed in the photolysis of isoquinoline 2-oxide derivatives.C. Lohse, J.C.S. Perkin II, 1972, 229.lo K. B. Tonier, N. Harrit, J. Rosenthal, 0. Buchardt, P. L.Kumler, and I. Creed, J . Amev. Chem. SOC., 1973, 95, 7402.amount of potassium iodide in water did not produceiodine. From these results we conclude that the photo-chemical behaviour of heteroaromatic N-oxides is notuniform. In some cases the first step is oxaziridine form-ation; in others the products are formed directly fromthe excited state of the N-oxide.The possibility that the methoxy-derivative (X) isformed from 4,6-diphenylpyrimidine arising by de-oxygenation of the N-oxide was ruled out by irradiationof 4,6-diphenylpyrimidine in methanol : no 2-methoxy-4,6-diphenylpyrimidine l-oxide was formed.Irradi-ation of 4,6-diphenylpyrimidine l-oxide in benzene gaveas main product only 3,5-diphenylpyrazole (V; R = Ph)In agreement with the foregoing results, pyrazoleformation was also observed during the light-inducedconversion of 4,6-di-t-butylpyrimidine l-oxide (I ; R =But) in methanol with light of wavelength 254 nm.Besides the pyrazole (V; R = But) (23) 4,6-di-t-butylpyrimidin-one (XI) (10) was also isolated.Noindication of the formation of 2-methoxy-4,6-di-t-butyl-pyrimidine was obtained. The formation of bothproducts (V; R = But) and (XI) indicates that in thiscase also the attack of the oxygen atom takes place at(9).C(2)-EXPERIMENTAL1H N.m.r. spectra were recorded with a JEOL JNM-C60spectrometer (Me$ as internal standard). Mass spectrawere recorded with an A.E.I. MS902 instrument.General Photolysis Procedure.-A solution of 4, B-diphenyl-pyrimidine l-oxide (I; R = Ph) (0.4 g) in methanol (500ml) or benzene (500 ml) was irradiated under nitrogen witha Hanau TQ 150 high-pressure mercury arc through a quartzfilter. 4,6-Di-t-butylpyrimidine l-oxide (I; R = But) wasirradiated under the same conditions as reported earlier.1"The intermediacy of the oxaziridine during photolysiswas indicated as follows.A solution of 4,6-diphenylpyrimi-dine l-oxide (3.5 mg) and potassium iodide (15.8 mg) inwater (4 ml) was irradiated for 5 min with the mercury arc.The formation of iodine was proved by addition of thissolution, directly after irradiation, to an aqueous starchsolution, which immediately gave the typical blue colour.The same solution did not produce iodine when kept in thedark. Also, irradiation of an aqueous solution of potassiumiodide did not give iodine.Starting Materials.-( 1) 4,6-Diphenylpyrimidine l4 and3,6-diphenylpyridazine N-oxide lo were prepared as de-scribed in the literature.(2) 4,6-Diphe.izyZpyrirnidine 1-oxide (I; R = Ph).30Hydrogen peroxide (12.5 g) was slowly stirred into a solutionof maleic anhydride (84 g) in chloroform (280 ml) cooled inice. After stirring for 2 h 4,6-diphenylpyrimidine (8.2 g)was added. The mixture was kept in a refrigerator for 5days. The precipitated maleic acid was filtered off, andthe filtrate was washed with aqueous potassium carbonate.11 C. Kaneko and I. Yokoe, Telra.hedron Letters, 1967, 5365.12 C. Kaneko, S. Hayashi, and Y. Kobayashi, Chem. and13 J. S. Splitter and M. Calvin, J . Org. Chew., 1965, 30, 3427.14 H. Bredereck, R. Gompper, and G. Morlock, Chem. Ber.,Phavm. Bull. (Japan), 1974, 22, 2147.1957, 90, 9421204 J.C.S. Perkin IThe chloroform layer was dried (K,CO,), filtered, and eva-porated in vacuo.Recrystallisation of the residue fromlight petroleum (b.p. 60-80 "C) gave the 1-oxide (I;R = Ph) (3.2 g, 37); m.p. 107-108 "C; 6 (CDCI,) 7 . 67.5 (m), 7.75 H(5), s, 7.9-8.1 (m), and 9.00 m(2), s(Found: C, 77.15; H, 5.1. C,,H,,N,O requires C, 77.4;HI 4.85).A solution of2-chloro-4,6-diphenylpyrimidine (484 mg) in methanol con-taining sodium methoxide (204 mg) was refluxed for + h.After neutralisation with CO, the solution was evaporatedand the residue recrystallised from light petroleum (b.p.60-80 "C) to give the methoxy-derivative (381 mg, 80),m.p. 81-82 "C; 6 (CDCl,) 4.20 (OCH,, s), 7.5-7.65 (m),7.82 H(5), s, and 8.1-8.3 (m); m/e 262 (M+) and 232(M+ - CH,O) (Found: C, 77.9; H, 5.4. C1,HlpN,O re-quires C, 77.85; H, 5.4).(4) 3,B-Diphenylpyraxole (V; R = Ph).This compoundwas prepared according to a modified procedure.ls Hydra-zine sulphate (9.75 g) was dissolved in 2.5~-sodium hydrox-ide (60 ml). Dibenzoylmethane (17 g) and ethanol (50 ml)were added. The mixture was stirred a t 50-60 "C for 4 h,and the temperature was then slowly raised till the solventevaporated off. 3,5-Diphenylpyrazole crystallised out andwas recrystallised from light petroleum (b.p. 100-140 "C) ;yield 6 g (36), m.p. 199 "C (1it.,l6 199 "C).(5) 4,6-Di-t-butyZpyrimidine (with A. KOUDIJS). To asolution of pyrimidine (3.20 g), pivalic acid (20.6 g), andsilver nitrate (0.6 g) in sulphuric acid (10 ; 40 ml) at 70 "C,ammonium peroxodisulphate (27.4 g) was added during 1 h.17The mixture was then stirred for another ;t h.Afterneutralisation with 25 yo sodium hydroxide the solution wasextracted with ether. Evaporation of the extract left aresidue which was purified on a silica gel column (eluantCHC1,). Distillation in vacuo yielded 4,6-di-t-butylpyrimi-dine (4.7 g, 61), b.p. 101-102 "C a t 13 mm Hg; 6 (CDCI,)1.40 (CMe, s), 7.33 H(5), s, and 9.11 H(2), s; m/e 192(M'), 177 (M+ - CH,), and 150 (M+ - C,H,) * (Found:C, 75.25; H, 10.5. C,,H,,,N, requires C, 74.95; H, 10.5).(6) 4,6-Di-t-butyZ~yrimidine 1-oxide (I; R = But) (with A.KOUDI JS) . This compound was prepared by the proceduregiven for 4,6-diphenylpyrimidine 1-oxide see section (2).4,6-Di-t-butylpyrimidine (4.0 g) gave the N-oxide (1.8 g ,* It is generally observed that compounds containing a t-butylgroup in a position adjacent to nitrogen undergo a fragmentationwith loss of C,H,.(3) 2-Methoxy-4,6-diphenylpyrimidine (X) .42), m.p.115-116 "C; 6 (CDCl,) 1.40 (CMe,, s), 1.58CMe,, s), 7.30 H(5), s, and 8.88 H(2), s; nz/e 208 (M+)and 193 (M+ - CH,) (Found: C, 68.85; H, 9.7. C,,HmN,Orequires C, 69.2; H, 9.7).(7) 4,6-Di-t-butylpyrimidin-2-one (with A. KOUDIJS).According to the procedure given in section (5), t-butylationof 2-ethoxypyrimidine (2.0 g) gave 2-ethoxy-4,6-di-t-butyl-pyrimidine (2.6 g, 68). The product (300 mg) was re-fluxed with concentrated hydrochloric acid (25 ml) during1 h. Evaporation followed by neutralisation with ammoniaand extraction with chloroform gave 4,6-di-t-butylpyrimidin-2-one (100 mg, 38), m.p. 223-224 "C, 6 (CDC1,) 1.34(CMe,, s), 4.9br (NH), and 6.45 H(5), s; mfe 208 (M+), 193( M f - CH,), and 166 (M+ - C,H,) (Found: C, 69.0, H,9.54.C,,H,a,O requires C, 69.2; H, 9.7).Attempt to prepare l-Formyl-3,5-diphenylpyrazole.~-3,5-Diphenylpyrazole (6.00 g) in absolute ether was treated,with cooling, with the Grignard reagent obtained frommagnesium (0.65 g) and methyl iodide (4.04 g) in ether.After completion of the reaction by heating, isopentylformate (3.54 g) was added dropwise and with cooling.Immediately after the initial addition of the formate themixture changed from a yellow-brown suspension to a darkred solution. After 80 min, crushed ice was added. Aprecipitate was obtained and the supernatant ethereal layerwas separated. This layer was combined with etherealextracts of the aqueous layer. On evaporation the startingmaterial was nearly quantitatively recovered.We thank Mr. C. A. Landheer for mass spectroscopic data,Mr. H. Jongejan for microanalyses, and Mr. A. van Veld-huizen for measuring lH n.m.r. spectra. We also thankMiss C. L. Habraken (Gorlaeus Laboratory, Leiden) forproviding a sample of 3,5-di-t-butylpyrazole This investig-ation was carried out under the auspices of the NetherlandsFoundation for Chemical Research (S.O.N.) and withfinancial aid from the Netherlands Organisation for theAdvancement of Pure Research (Z.W.O.).5/2168 Received, 7th November, 1976115 A. I. Vogel, 'A Textbook of Practical Organic Chemistry,'l6 0. Widman, Ber., 1916, 49, 477.l7 J. M. Anderson and J. K. Kochi, J . Amer. Cheun. Soc., 1970,3rd edn., London, 1967. p. 842.92, 1661
展开▼
