1974Some N- Hydroxy-N-met hylamidines and 1,2,4- Oxad iazol-5( 2H) -onesBy Peter W. Seale and William K. Warburton,' Organic Chemistry Department, Glaxo Research Ltd.,Greenford, MiddlesexAromatic and heterocyclic nitriles react with N-methylhydroxylamine t o give N-hydroxy-N-methylamidines (4).The latter, when treated with ethyl chloroformate, give 1,2,4-oxadiazol-5(2H) -ones (9). Sodium borohydridereduces compound (9 : R = p-CsH,CI) to the corresponding oxadiazolidinone (1 0). The tautomeric structure ofp-chlorobenzamide oxime is discussed.ALTHOUGH 2,3-dihydro-l,2,4-oxadiazoles 1 and -oxadi-azolones 2 9 3 and some corresponding 4,5-dihydro-com-pounds 4 9 s are known, the only reported 2,5-dihydro-1,2,4-oxadiazoles are the amine (1) and a fewcompounds derived from it.The method by which(1) was prepared (treating cyanamide with acetone andphenylhydroxylamine) does not appear to be widelyapplicable.1,2,4-Oxadiazoles (2) are usually made by cyclo-dehydration of O-acyl amide oximes (3). In order toretain the 2,3-single bond, we required N-alkyl-N-hydroxyaniidines (4). Such compounds have not beendescribed, although Grigat et a,?.' have prepared someN-aryl compounds (5), and Zinner and Gross have morerecently prepared trisubstituted hydroxyguanidinederivatives (6).'0'HN=CR HN==CR HN-COAr RN=CNHRI NMeINArI0INMe/HO/HN/HO/ HOIMe(4) (4a) ( 5) ( 6 )When benzonitrile was treated with N-methyl-hydroxylamine in methanol, N-hydroxy-N-methylbenz-E. Grigat, euro;2.Putter, and E. Muhlbauer, Chem. Ber., 1965,98, 3777.A. R. Katritzky, B. Wallis, R. T. C . Brownlee, and R. D.B. W. Nash, R. A. Newberry, R. Pickles, and W. I. War-Topsom, Tetrahedron, 1965, 21, 1681.burton, J . Chem. Soc. (C), 1969, 2794.amidine (4; R = Ph) was isolated in high yield.fi-Chlorobenzonitrile, when similarly treated, gave thepure hydroxy-amidine (4; R = p-C,H,Cl) in ca. 90yield; the hydroxy-amidines (4 ; R = $-bromophenyl,5-nitro-2-fury1, and 5-nitrothiazol-2-yl) were preparedsimilarly. However benzonitrile and p-chlorobenzo-nitrile were unaffected by N-phenylhydroxylamine inrefluxing alcohols.Cyclic products were not obtained by treating theN-hydroxy-amidine (4; R = $-C,H?Cl or p-C6H4Br)with benzaldehyde, benzylidene chloride, formaldehyde,acetaldehyde, dimet hox ymet hane, carbon disulphide,acetyl chloride, or acetic anhydride.Usually no re-action occurred, but from the reaction between (4;R = p-C6H4Br) and aqueous acetaldehyde at 80" weobtained p-bromobenzamide. From the reaction be-tween (4; R = $-C,H,C1) and acetic anhydride inboiling chloroform we obtained $-chlorobenzoic acid,possibly formed during the aqueous work-up.When (4; R = $-C,H,Cl) was treated with 1.24 equiv.of methyl chloroformate in chloroform containingpyridine, a mixture was obtained which appeared toconsist of the O-acyl compound (7; R1 = (P-C,H,Cl,R2 = Me) and the NO-diacyl compound (8; R1 =p-C,H,Cl, R2 = Me) in the ratio ca. 2 : 1. The lattercompound has been obtained in quantitative yield bytreating (4) with 2.5 mol.equiv. of methyl chloro-formate. The i.r. spectrum of the mixture (CHBr,)revealed two carbonyl bands (vmx 1790 and 1720 cm-l),which we attribute to (8; R1 = P-C,H4Cl, R2 = Me),and a third carbonyl band (1752 cm-l), which weattribute to the hydrogen-bonded compound (7; R1 =F. Tiemann, Ber., 1889, 22, 2412.5 G. D'Alo, M. Perghem, and P. Grunanger, Ann. Chiuz.R. Hull and R. Farrand, J . Chem. Soc., 1963, 6028.E. Grigat, R. Putter, and C. Konig, Chem. Ber., 1966, 98,8 G. Zinner and H. Gross, Chem. Bey., 1972, 105, 1709.(Italy), 1963, 53, 1405.14486 J.C.S. Perkin Ifi-C,H,Cl, R2 = Me). The n.m.r. spectrum of themixture (CDCl,) showed five methyl groups, three ofwhich (z 6.19, 6-42, and 6.66) we assign to the twoO-methyl groups and the N-methyl group of (8; R1 =$-C,H,Cl, R2 = Me), and two of which (7 6.33 and6.52) we assign to the 0- and the N-methyl group,respectively, of (7; R1 = $-C,H,Cl, R2 = Me).Thearomatic protons appear as an AB quartet (7 2.52 and2-74, J 8.5 Hz) and a collapsed AB quartet (z 2.62),assigned to (7; R1 =P-C,Hamp;l, R2 = Me) and (8;R1 = $-C,H,Cl, R2 = Me), respectively. Spectroscopicevidence points to a similar composition for mixturesobtained by treating (4; R = $-C,H,Cl, fi-C6H4Br,5-nitrothiazol-2-y, or 5-nitro-2-furylvinyl) with ethylchloroformate in pyridine.o=c- OR21tC " NMe I ' HN-amp;,f?*zo/ bsol;o/ o,NMe( 7) (101Thermal cyclization of the product obtained bytreating (4) with ethyl chloroformate gave the 2-methyl-1,2,4-0xadiazol-5(2H)-ones (9 ; R = phenyl, $-chloro-phenyl, tram-P-chlorostyryl, 5-nitro-2-fury1, 5-nitro-2-furylvinyl, or 5-nitrothiazol-2-yl) in yields of 47-61 .The cyclization oi the O-acyl compounds (7) to formoxadiazolones (9) is not surprising.However, a sampleof the NO-diacyl compound (8; R1 = $-C1C6H4, R2 =Me) kept for 27 days at room temperature had changedinto the oxadiazolone (9; R = $-CIC,H,).N-Methylhydroxylamine could conceivably react witharomatic nitriles9 to give not (4) but the isomericcompounds (4a). However acylation of (4a; R = Ph)with ethyl chloroformate and subsequent cyclizationwould give the known 233 2-methyl-5-phenyl-l,2,4-oxa-diazol-3(2H)-one (9a) (m.p. 115"), and not (9; R = Ph)(m.p.134-135").The oxadiazolinone (9; R = P-C,H,Cl) was reducedby sodium borohydride to the corresponding oxadi-azolidinone compound (lo), which was not obtained pureand slowly decomposed at room temperature. TheL. Stephenson. W. K. Warburton, and M. J. Wilson,J . Ckem. SOC. (C), 1969, 861.lo G. Ponzio, Guzzettu, 1923, 53, 607.l1 R. Gomppa, Chem. Ber., 1960, 93, 208.l2 F. Tiemann and P. Kriiger, Ber., 1884, 17, 1685.la G. Ponzio, Gazzetta, 1931, 81, 704.structure (10) is supported by elemental analysis and byi.r. and n.m.r. data (see Experimental section).Ph(6,NMe doRC-NHz R C-NHNIHN I1N' O H 'OH 'OH(1W (12b) (13)3-Phenyl-1,2,4-oxadiazol-5(4H)-one (11 ; R = H) hasbeen methylated 2~10~11 t o give an N-methyl compoundwhich, as Katritzky et aZ.have observed,2 could be either4-methyl-3-phenyl-l,2,4-oxadiazol-5(4H)-one (1 1 ; R =Me) or, less probably, the 2H-compound (9; R = Ph).The 4H-compound (11; R = Me) was later preparedby D'Alo et aL5 from N-methylbenzamide oxime; it isidentical with the oxadiazolone (m.p. 117-119')obtained by treating (11; R = H) with diazomethane,but differs from (9; R = Ph) (m.p. 134-135").Tiemann and Kriiger l2 observed in 1884 that amideoximes could be written in the tautomeric forms (12a)and (12b), and expressed the opinion that (12a) pre-dominated. Ponzio l3 produced some evidence to thecontrary, but Bell et aZ.14 studied the i.r. and the n.m.r.spectra of several amide oximes, including benzamideoxime, and concluded that in solution they existed solelyin the amino-oxime form (12a).Brandt 15 reviewed theu250 275 3 00h / n m0 225The U.V. spectra of N-hydroxy-N-methyl-p-chlorobenzamidine(A), N-methyl-p-chlorobenzamide oxime (1 3) (B), and p-chloro-benzamide oxime (C)chemical and spectroscopic (i.r. and n.m.r.) properties ofamide oximes and reached the same conclusion.l4 C. L. Bell, C . N. V. Nanbury, and L. Bauer, J . Org. Chem.,l6 L. Brandt, Mededel. vlaam. ckem. Ver., 1967, 29, 66.1964, 29, 28731974 87We prepared N-methyl-9-chlorobenzamide oxime (13)by treating p-chlorobenzohydroxamoyl chloride l6 withmethylamine, and compared its U.V. spectrum (solutionin ethanol) with the spectra of p-chlorobenzamide oxime 13and N-methyl-N-hydroxy-fi-chlorobenzamidine (4 ; R =fi-C6H,C1) (see Figure).The similarity between thespectra of 9-chlorobenzamide oxime and (13) leads tothe conclusion that p-chlorobenzamide oxime exists (atleast in dilute ethanolic solution) mainly or entirely inthe form (12a).EXPERIMENTALU.V. spectra were measured for solutions in ethanol.T.1.c. was carried out on Merck Kieselgel F254 plates inbenzene containing varying proportions of ethyl acetate.1H N.m.r. spectra were recorded a t 60 MHz.N-Hydroxy-N-methyl-p-chZorobenzamidine (4; R = p -C1C,H4) .+-Chlorobenzonitrile (1 6.0 g) was dissolved in asolution of N-methylhydroxylamine in methanol (200 ml)from N-methylhydroxylamine hydrochloride ( 16.0 g) andmethanolic sodium methoxide. The solution was heatedunder reflux for 1.5 h, the solvent was removed, and theresidue was extracted with chloroform, giving N-hydroxy-N-methyl-p-chlorobenzamidine (18-5 g, 86), m.p.146-1 50". A sample recrystallized from chloroform-lightpetroleum (b.p. 80-100") had m.p. 160-162", amp; 225and 284 nm (E 14,700 and 4400), vmaX (CHBr,) 3500 (OH),3340 (NH), 1638 (C=N), and 831 cm-l (p-C6H4), 7 (CDCl,)6.67 (CH,), 2.68 (collapsed ABq, p-C6H4), and 3-88 (OHand NH) (Found: C, 51-5; H, 5.0; C1, 19.9; N, 14.8.C,H,ClN,O requires C, 52.0; H, 4.9; C1, 19.2; N, 15.2).The picrate had 1n.p. 142-145' from chloroform-lightpetroleum (b.p. SO-lOO") (Found: C, 40.65; H, 3.2; C1,8.5; N, 17.3. Cl,H12C1N508 requires C, 40.5; H, 2.9; C1,8.55; N, 16.9y0). Similarly were prepared : N-hydroxy-N-methylbenzamidine (4; R = Ph) (41), m.p.94-96'from methylene chloride-light petroleum (b.p. 40-60"),1- 272.5 nm (E 4200) picrate, m.p. 166-168" (fromaqueous ethanol) (Found: C, 44.1; H, 3.6; N, 18.0.C1,Hl,N50, requires C, 44-3; H, 3.4; N, 18.5y0); N-hydroxy-N-methyl-fi-bromobenzamidine (4 ; R = p-BrC,H4)(89), m.p. 160-162' from chloroform-light petroleum(b.p. 80-100"), Lk 229 and 286.5 nm ( E 15,500 and 4800)picrate, n1.p. 165-167" (from methanol) (Found: C, 36.8;H, 2.7; N, 15-3. C14Hl,BrN,08 requires C, 36-8; H, 2.6;N, 15.3 )I ; N-hydroxy-N-methyl-5-nitrofuran-2-carbox-amidine (4; R = 5-nitro-2-furyl) (SOYo), m.p. 122" (de-camp.) from chloroform-light petroleum (b.p. 40-60"),A,= 279 and 380 nm (E 11,000 and 7000), v,, (CHBr,)3500 (OH), 3360 (NH), and 1508 and 1350 cm-l (NO,);N-hydroxy-N-metlzyl-5-nitrothiazole-2-carboxamidine (4;R = 5-nitrothiazol-2-yl) (78y0), m.p.190" (decomp.) (frommethanol), amp; 296.5 and 420.5 nm ( E 12,200 and 4400)(Found: C , 29.8; H, 3.0; N, 28.0; S, 15.9. C,H6N40,Srequires C, 29.7; H, 3.0; N, 27.7; S, 15.9Y0).Reaction of N-Hydroxy-N-methyl-p-chlorobenzamidine withMethyl Chloroformate.-The amidine (922 mg) was dissolvedin ethanol-free chloroform (15 ml) containing dry pyridine(491 mg) and the solution was cooled to -40". Methylchloroformate (585 mg) in chloroform (5 ml) was addeddropwise, with stirring, during 20 min, a t -40". Themixture was kept a t this temperature for 2 h, washed withice-water (25 ml), dried (Na,SO,), and cooled to -40".Some of the solution (5 ml) was evaporated to dryness a t25" to give a pale gum (359 mg).The i.r. and the n.mhr.spectrum of this mixture are recorded in the Discussionsection.N- MethyZ-N'-methoxycarbonyl-~-methoxycarbonyloxy-p-chlorobenzamidine (8; R1 = p-ClC,H,, R2 = Me).-N-Hydroxy-N-methyl-p-chlorobenzamidine (92 2 mg) wastreated as in the preceding experiment with methyl chloro-formate (1.07 g), to give the diacyl compound as a viscousoil (1.51 g, loo), vmX. (CHBr,) 1791 (O*C02R), 1717(C=N.CO,R), 1634 (C=N), and 838 cm-l (p-C6H4), z (CDC1,)6-66 (NCH,), 6.42 and 6.19 (OCH,), and 2.62 (collapsedABq, pC6H4). The oil later changed into a yellow solid,m.p. ca. l6Oo, shown (i.r. spectrum) to be the crudeoxadiazolone (9; R = p-ClC,H4).Recrystallization fromethanol gave the oxadiazolone in 75 yield, m.p. 172-174"(Found: C, 51.4; H, 3.4; N, 13.5. Calc. for C,H,C1N202:C, 51.3; H, 3.3; N, 13.3), identical (ix. and n.m.r.spectra) with the compound described earlier.2-Methyl-3-phenyl- 1,2,4-oxadiazol-5(2H)-one (9 ; R =Ph) .-N-Hydroxy-N-methylbenzamidine (900 mg) in drypyridine (20 ml) was stirred, and ethyl chloroformate(0.60 ml, 0.683 g) was added dropwise below 0". Themixture was allowed to warm to room temperature during1 h, then heated under reflux for 1 h, cooled, and pouredinto water (100 ml). The solution was made acid with2~-hydrochloric acid. Isolation with ethyl acetate gave asolid residue (1.07 g), which was recrystallized from 50y0aqueous methanol (8 ml) to give the oxadiazolone (522 mg,49.5), m.p.134-135", Lx 241 nm ( E 14,900), vmX.(CHBr,) 1770 (GO), and 762 cm-l (Ph), T (CDCl,) 6.20(NCH,) and 2-05-2.60 (centred a t 2.33, Ph) (Found: C,61.3; H, 4.65; N, 15.9. C,H,N,02 requires C, 61.4; H,4.6; N, 15.9). The i.r. and the n.m.r. spectrum of thiscompound differ from those of 2-methyl-5-phenyl- 1,2,4-oxadiazol-3 (2H) -one .,Similarly were prepared : 3-p-chZorophenyZ-2-methyl- 1,2,4-oxadiazol-5(2H)-one (9; R = p-C1C,H4) (54), m.p. 168.5-170" (from propan-2-01), hX 248.5 nm ( E 19,500) (Found:C, 51.2; H, 3-5; C1, 17.0; N, 13.3. C,H,ClN20, requiresC, 51.3; H, 3.3; C1, 16.9; N, 13.3); 2-methyE3-(5-nilro-2-ficryl)-1,2,4-oxadiazol-5(2H)-one (9; R = 5-nitro-2-furyl)(44), m.p.179-180", LX. 224 and 300 nm ( E 13,900 and16,800) (Found: C, 40.0; H, 2.5; N, 19.6. C,H,N,O,requires C, 39-8; H, 2.4; N, 19.9) ; 2-methyl-3-(5-nitro-thiazoZ-2-yl)-l, 2,4-oxadiazol-5(2H) -one (9; R = 5-nitrothi-azol-2-yl) (47), m.p. 200-.201", amp;= 228.5 and 304 niii(E 10,000 and 13,900) (Found: C, 31.7; H, 1.8; N, 24-7;S, 13.9. C,H4N404S requires C, 31.6; H, 1-8; N, 24.6;s, 14*1y0).2-MethyZ-3-trans- (5-nitro-2-furylvinyl) - 1,2,4-oxadiazol-5(2H)-om (9; R = trans-5-nitro-2-furylvinyl) .-3-(5-Nitro-2-fury1)acrylonitrile (10.0 g) suspended in dry methanol(50 ml) was stirred for 2 h a t room temperature withmethanolic methylhydroxylamine (100 ml) from N-methylhydroxylamine hydrochloride ( 10.0 g ) .Concen-tration to 50 ml and cooling gave the crude hydroxy-amidine (3.06 g, 24), m.p. 198" (decomp.), v,,, (Nujol)3386 (NH), 3300-3000 (bonded OH), 1350 and 1492(NO,), and 942 cm-l (trans-CH=CH). The hydroxy-amidine was dissolved in pyridine (25 ml) and treated a t- 30" with ethyl chloroformate (1.14 g). The reaction wasworked up as described above, and the product was heatedT. Farley, F. H. Rathmann, and D. Tangen, Proc. N.Dakota. Acad. Sci., 1959, 13, 61 (Chew. Abs., 1960, 54, 6619)J.C.S. Perkin Iunder reflux in toluene (100 ml) for 15 min. Evaporationt o dryness gave the oxadiazolone (1.90 g, 13), m.p. 212"(decomp.) (from methanol), A,, 242.5, 293-5, and 350 nm(E 13,400, 19,500, and 22,300) (Found: C, 45.6; H, 3.1;N, 17.8. CgH,N,O, requires C, 45-6; H, 3.0; N, 17.7).(9 ;R = p-chlorostyryl) (17), m.p.271-272" (decomp.)(from dimethylformamide), A,, 226, 232, and 303 nm(C 13,000, 11,500, and 30,600) (Found: C, 55.8; H, 3-7;C1, 15.0; N, 12.2. Cl,Hl,ClN20 requires C, 55.8; H, 3.8;C1, 15.0; N, 12-2), was prepared similarly.3-p-Chloro~henyl-2-methyl-1,2,4-oxadiazoEidin-5-one (10).-3-9-Chlorophenyl-2-methyl- 1,2,4-oxadiazol-5(2H)-one(200 mg) was dissolved in ethanol (10 ml) and tetrahydro-furan (5 ml). Sodium borohydride (40 mg) was added andthe solution was stirred at room temperature for 1 h, thenpoured into water (25 ml). The suspension was neutralized3-p-Chlorosty~yL2-methyL 1,2,4-oxadiazol-5 (2H) -onewith acetic acid. Isolation with chloroform gave theoxadiazolidinone (151 mg, 75), m.p. 94-96", vmx. (Nujol)3250 (bonded NH), 1752, and 1723 cm-l (carbonyl in non-planar ring), 'c (CDCl,) 7-12 (NMe), 4.79 (CH), and 2.61(collapsed ABq, p-C,H,) (Found: C, 51.9; H, 4.7; C1,16-1; N, 13.2. C,H,N,ClO, requires C, 50.8; H, 4-3; C1,16.7; N, 13.2).N- ethyl-p-chlorobenzumide Oxime (1 3) .-A solution ofpchlorobenzohydroxamoyl chloride l6 (3.8 g) in ether(25 mI) was saturated at 0" with methylamine, then ex-tracted with 2~-hydrochloric acid. The extract wasneutralized (solid NaHCO,) to give the amide oxirne (1.5 g,33), m.p. 131-133", raised t o 136-137" by recrystal-lizatioa from benzene, a,, 269 nm ( E 3500) (Found: C,51.9; H, 4.8; Ci, 19.1; N, 15.9. C8H,ClN,0 requires C,3/1601 Received, 30th July, 1973152.0; H, 4.9; C1, 19.2; N, 15.2)
展开▼
