1976 2243Heterocyclic Compounds. Part V.l Reactions of Phenyl and Benzoyllsocyanates and Benzoyl lsothiocyanate with HydrazonesBy lwao Yamamoto," Akio Mamba, and Haruo Gotoh, Department of Chemistry, Shinshu University-Ueda,Reactions of phenyl and benzoyl isocyanate with ketone hydrazones gave s-triazolidines in good yields, whereasbenzaldehyde phenylhydrazone simply gave semicarbazones. With benzoyl isothiocyanate ketone hydrazones andbenzaldehyde phenylhydrazone gave oxatriazepinethiones. These reactions are all thought to proceed via betaines,and their mechanisms are discussed in the light of semi-empirical INDO calculations.Ueda, Nagano 386, JapanWE have previously reported a mechanistic study of the CH,), 148 (M+ - PhNCO), and 133. Three structures,thermal reactions between aromatic isocyanates and (1)-(111), were considered on the basis of the molecularaliphatic aldehydes1 In those reactions, imines (3) weight, viz.the products from reaction of phenyland/or enamines (4) were considered as important isocyanate (la) with (A) the N=C bond [1,2-cycloaddition,intermediates in the formation of the heterocycles (5) and (I)], (B) the NH function [(II)], and (C) both the NH(6). We now report a study of reactions of hetero- function and the N=C bond [1,3-addition, (III)] of thecumulenes with nitrogen analogues (hydrazones) of hydrazone. The peak at m/e 133 (PhN=CMe,) sug-enamines. gests structures (I) and (111), but not the semicarbazonestructure (11). A carbonyl i.r. band at 1 680 cm-l isRESULTS AND DISCUSSION consistent with the presence of a five- or six-membered1socyanates.-The reaction of phenyl isocyanate (la) ring rather than a f o u r - m ~ ~ b ~ r e d &eleton.%-~cturewith acetone phenylhydrazone (7a) at 100 "C without (111) for (8a) was thus established. The product (9) wassolvent gave a 1 : 1 adduct (84 and a 2 : 1 adduct (9). identified from spectral data and elemental analysis; theIn its mass spectrum the product (Sa) showed a molecular i-r. spectrum showed NH absorption at 3 300 cm-' andion peak at m/e 267 and fragments at m/e 253 (M+ - two carbonyl bonds at 1710 and 1 675 cm-l. Its massGotoh, J.C.S. Perkin I, 1976, 1597. mentation pattern in the mass range below mle 267 was 1 Part IV, I. Yamamoto, T. Furukawa, H. Nakajima, and H.spectrum showed a parent peak at 'n/e 386 and its frag2244 J.C.S. Perkin Isimilar to that of (8a). Furthermore, acid-catalysed addition of isocyanates to hydrazones appears to dependhydrolysis of (9) in aqueous ethanol gave 1,4-diphenyl- on the hydrazone substituents. Ketone hydrazonessemicarbazide (10). yielded cyclic products, s-triazolidines, but the aldehydeReactions of phenyl isocyanate with the phenylhydra- hydrazone gave acyclic compounds. A suggestedzones (7b and c) afforded the correspondings-triazolidines mechanism is shown in the Scheme. The betaine (13)(8b and c) in good yields (Table 1). is produced by electrophilic attack of the isocyanatePhNH.c=o \P h N = C = O( l a )Yield (%)322965.510010098.5- -H I N / R 'PhN: N \,CRz R'__c/ R' + PhNH-N=C +\ R2( 7 a - c )L'( 8 a - c 1 ( 9 10IIPhNH- NH-C-NHPh( 10 1TABLE 1Triazolidines @a-e) and (9)r------r r 7 3i.p.("C) b N H C=O CH, CH, NH Aromaticvrn.x.lcm-1 6 e71.-8.0 1 34.5- 1 35.5 3 160 1680 1.48 4.13202-203 3300 1710, 1675 1.76 7.2-7.91 1 6-1 1 7 3 200 1 695 0.95, 1.43 1-70 3.95 6.85-7.90164-1 64.5 3 190 1 685 0.7-2.1 4.05 6.7-7.95139-1 40 3200 1740, 1650 1650 4.5 6.8-7.9160 3 210 1 740, 1 680 1.4-3.0 4.5 6.9-7.95Based on isocyanates. Nujol mull. In CHCl,.PhN-N=CHPhI o=c PhN=C=O + FhNH-N=CHPh -"HPh( l a ) ( 7 d ) ( I l a lTreatment of benzaldehyde phenylhydrazone (7d) withthe isocyanate (la) at 165-170 "C for 1.5 h withoutsolvent gave benzaldehyde 2,4-diphenylsemicarbazone(1 la), quantitatively.Reactions of benzoyl isocyanate (1 b) with the hydra-zones (7a, c, and d) at room temperature afforded the s-triazolidine derivatives (8d and e) and the semicarbazone(1 lb), respectively, in quantitative yield, as recentlyreported by Tsuge.2 Acid-catalysed hydrolysis of thesethree adducts in each case gave the triazoline (12).The formation of cyclic or acyclic products from thecarbon atom on the hydrazone NH.When both R1 andR2 are alkyl, the N=C carbon atom of (13) will berelatively ' hard '; therefore, the carbamoyl nitrogenatom should react to form the triazolidines (8) via theintermediate (14). However when R2 = H, the N=Ccarbon atom will be ' softer ', and compounds (11) willresult from [1,3] hydrogen migration (path b).Theresults of INDO calculations on the hydrazones (7a andd) (Table 2) support this rationalization. The formal0. Tsuge and S. Kanemasa, Bull. Chem. SOG. Japan, 1974,47,26761976 2245TABLE 2Electron densities of hydrazones (7a and d) calculated by the INDO methodH(4)PhN(3)-N(2)=C( 1) RlR2Electron density (formal charge density)R1 R? c- 1 N-2 N-3 H-4( 7 4 Me Me 3.7126 (+0.2874) 5.3092 (- 0.3092) 5.3351 (-0.3351) 0.7853 (+0.2117)( 7 4 Ph H 3.9460 (+0.0540) 5.2008 (- 0.2005) 5.3325 (-0.3325) 0.7727 (f0.2271)R’/R1\ R 1BrN=C=O + PhNH-N=C( l b ) (7a,c,and d )HNPhN’ ‘CPh//0 FN(12)( a d ) R ’ = R * = Me(8eI R’ R2 =[CH2]5charge densities on N-3 of both (7a and d) are larger thanon other atoms (k N-2 and C-1) ; therefore initial attacka t N-3 to form the betaine (13) would be expected.Furthermore, the density on C-1 of (7a) is larger thanthat on C-1 of (7d), favouring cyclization of the betaine(13) to s-triazolidines.R 3 N=( 1p a t h a: =O + PhNH’ R’ = R2= a l k y l IH(13)BenzoyL 1sothiocyanafe.-The reaction of acetonephenylhydrazone (7a) with benzoyl isothiocyanate (15)a t room temperature without solvent gave 3,4-dihydro-thione (16a) quantitatively.Durant has reportedsimilar cycloadditions of hydrazones to benzoyl isothio-cyanate. However he used only acetone and benzalde-hyde alkylhydrazones, and we have several criticisms ofhis reaction mechanisms. We report here independentresults on the synthesis and mechanism of formation ofthe 1,3,4,6-0xatriazepines (16)./ R’-N=C7 ) ‘R2 2,2-dimethyl-4,7-diphenyl-lJ3,4,6-oxatriazepine-5 (2H) -The structures of the products (16a-d) from thehydrazones (7a-c and e) were established by spectraldata, elemental analyses (Table 3), and chemical pro-perties.Acid-catalysed hydrolysis in aqueous ethanolin each case afforded 1 ,3-diphenyl-A3-s-triazoline-5-/Ph thione (17) quantitatively.On the other hand, the reaction of the isothiocyanate‘H (15) with benzaldehyde phenylhydrazone (7d) in ethylacetate at room temperature afforded benzaldehyde4-benzoyl-2-phenyl thiosemicarbazone (18) and(11 1 5-benzo ylimino-2 ,4-diphenyl-A2- lJ3,4- thiadiazoline ( 19)in 77 and 14% yields, respectively. The latter was notisolated by D ~ r a n t .~ Oxidation of (18) by pyridine-chromic anhydride complex gave the thiadiazoline (19).Compound (19) did not show NH absorptions in its i.r.spectrum, and only aromatic proton resonances in itsn.m.r. spectrum. Furthermore, its mass spectrum con-tained a molecular ion peak at m/e 357. Structure (19)was confirmed by X-ray analysis.p a t h bR’ = Ph,R2= HN-N=C‘NHR3P h \I +o=cSCHEME G. J. Durant, J . Chew. SOC. (C), 1967, 92, 9522246 J.C.S. Perkin IThe formation of the oxatriazepines (16a-d) maybe explained as follows. The negative charge onnitrogen in the initially formed betaine (20) will bethiosemicarbazone (18) as a major product. The minorproduct (19) presumably arises from cyclization of thecorresponding betaine (21).HHPhN-' /R1 NBzN=C=S + PhNHN=C - s=c ' 'F\R2 PhN: 'CPh ' /o "2 0 //N2CPh(15 I (7a - c a n d el (16a-d I( 7 a ) .(16a) R1= R2=Me (7b1, (16b) R1= Me, R2- Et( 7 ~ 1 , (16cl R' R2= [ C H Z ] ~ (7e). (16d) R'R2=[CHzlLTABLE 31,3,4,6-Oxatriazepine-5-thiones (1 6a-d)Yield 8 b Found (%) (Reqd) r IProduct (yo) (I M.p. ("C) CH3 CH, N H Aromatic C H N(16a) 99.6 131 1.65 5.05 7.18-8.35 70.95 4.65 17.75(70.85) (4.85) (17.7)1.93 5.05 7.10-8.40 66.45 5.7 12.91.60 (66.45) (5.9) (12.9)(16b) 100 121.5-122 1.05(16c) 99.7 163 1.15-2.1 4.90 7.00--5.40 68.55 6.05 12.1(68.35) (6.0) (11.95)(16d) 63.3 148.5-149 1.60-2.4 4.15 7.00-8.38 67.4 5.7 12.25(67.65) (5.7) (12.45)0 Based on isothiocyanate (15). 6 In CHCI,.delocalized over the sulphur atom.Therefore, thenitrogen will become ' softer ', resulting in preferentialBzN=C=-S + FhNH-NECHPh -(15) ( 7d 1PhN-NZCHPh1 - -PhN--N\\ 'CPtlC-S \ //S-r-'NHBz B z N"(18) (19)attack by the oxygen on the N=C carbon atom. In thecase of benzaldehyde hydrazone (7d) , the reaction pro-ceeds similarly to that with the isocyanates, giving the- ( 1 6 a - d )I- 7HP h"/- $2 c H PhH I /N\Saxena et aL4 have reported the reaction of benzalde-hyde phenylhydrazone with dimethylacetylenedicarb-oxylate to give pyrazole derivatives via autoxidation of apyrazoline intermediate. Durant reported that oxatri-azepines were produced via thiosemicarbazones. If hishypothesis is right, the thiosemicarbazone (18) should beconvertible into the oxatriazepine (16) or the thia-diazoline (19) on heating.However, the thiosemi-carbazone (18) was unchanged after refluxing for 10 h inbenzene, suggesting that it was not the precursor of theoxatriazepine (16) or the thiadiazoline (19). Thissupports the intermediacy of betaines [(13) or (ZO)] inthese reactions.The thiadiazoline (19) is remarkably stable towardsacid- and base-catalysed hydrolysis, reductive acetyl-ation, reduction by Raney nickel (W-2 type), and photo-lysis by a low pressure mercury lamp.EXPERIMENTALM.p.s were taken with a Mitamura capillary micro-apparatus. 1.r. spectra (Nujol mulls) were recorded with aJASCO IR-A spectrometer. A JEOL JNM-C-6OHL spec-trometer was used for lH n.m.r. measurement, and massspectra (75 eV) were obtained with a JEOL JMS-OlSG-2spectrometer on line t o JEOL JEC-6 spectrum computer.The INDO calculations were carried out on the HITAC8700/8800 computers of the Computation Center of theUniversity of Tokyo.Reactions of Phenyl Isocyanate ( la) .-With acetonefihenylhydrazone (7a).A mixture of compounds (la)(2.40 g, 31 mmol) and (7a) (2.96 g, 20 mmol) was heated at100 "C for 2 h without solvent, chilled with ether and filteredt o afford 5,5-divnethyl-2,4-diphenyl- l-phenylcarbamoyl-s-tri-hl. K. Saxena, M. N. Gudi, and M. V. George, Tetrahedron,1973, 29, 1011976azolidi.l.~-3-one (9) (1.1 g, 29y0), m.p. 202-203' (from ben-zene-hexane) ; m/e 386 (M+), 267,252, 148, and 133 (Found:C, 71.35; H , 5.85; N, 14.6.C,,H,,N,O, requires C, 71.5;H , 5.75; N, 14.5%). Removal of ether from the filtrateleft a reddish oil which was chromatographed on alumina togive 5,5-dimethyl-2,4-di~henyl-s-triazolidin-3-one (8a) ( 1.7 g ,32%), m.p. 134-135.5" (from benzene-hexane) ; m/e267 (M+), 252, 148, and 133 (Found: C, 71.65; H, 6.65;N, 15.6. C,,H,,N,O requires C, 71.9; H, 6.4; N, 15.7%).A mixtureof compounds (la) (1.8 g, 15 mmol) and (7b) (2.43 g, 15mmol) was heated at 100 "C for 6 h without solvent. Aftercooling, the mixture was chromatographed on alumina t ogive 5-ethyl-5-methyl-2,4-di~henyl-s-triazolidin-3-one (8b)(2.8 g, 65.5%), m.p. 116-117" (from benzene-hexane);m/e 281 (W), 266,251,162, and 147 (Found: M+, 281.1504.Cl,H1,N,O requires fW, 281.1528).With cyclohexanone phenylhydrazone (7c).A similarreaction of compounds (la) (3.0 g, 25 mmol) and (7c)(4.7 g , 25 mmol) gave 1',4'-diphenylcyclohexanes~iro-3'-s-triazolidin-5'-one (8c) (7.5 g, looyo), m.p. 16A164.5'(from ethanol); m/e 307 (M'), 264, 251, and 188 (Found:A t k 307.1680.WitJz benzaldehyde phenylhydrazone (7d). A similarreaction at 165-170 "C for 1.5 h with (la) (1.2 g, 10 mmol)and (7d) (1.96 g, 10 mmol) gave benzaldehyde 2,4-diphenyl-semicarbazone (lla) (2.9 g, %!yo), m.p. 161-152"; vmax.3 395 (NH), 1695 (GO), and 1650 cm-l ( G O ) ; m/e 315(M+), 212, 196, 180, 168, 167, and 119 (Found: C, 76.1; H,5 . 5 ; N, 13.5. C,,,H,,N,O requires C, 76.15; H, 5.45; N,13.35%).A cid-catalysed Hydrolysis of the Triazolidinone (9) .-Asolution of compound (9) (1.5 g, 3.9 mmol) in aqueousethanol (20 ml) was refluxed for 2 h in the presence ofconcentrated hydrochloric acid (1.0 ml).Cooling gave awhite powder, lJ4-diphenyZsemicarbazide (lo), quantita-tively; m.p. 203.5-204.5"; rn/e 227 ( M f ) , 108, and 91(Found: C, 68.8; H, 5.75; N, 18.7. CI3Nl3N,O requiresC, 68.7; H, 5.75; N, 18.5%).Reactions of Benzoyl Isocyanate (Ib) .-With acetonephenylhydrazone (7a). Benzoyl isocyanate ( lb) (1.47 g,10 mmol) was added dropwise to compound (7a) (1.48 g,10 mmol) without solvent at room temperature. Anexothermic reaction afforded 4-benzoyl-5,5-dimethyl-2-phenyl-s-triazolidin-3-one (8d) (2.95 g, loo%), m.p. 13%-140" (lit.,2 140.5-141").To a solutionof compound (7c) (1.88 g, 10 mmol) in benzene, the iso-cyanate (lb) (1.47 g, 10 mmol) was added, and the mixturewas refluxed for 50 min. Removal of solvent afforded4'-benzoyl- 1 '-phenylcyclo hexanes+iro-3'-s-triazolidin-5'-one(8e) (3.3 g, 99%), m.p.160" (from ethanol) ; m/e 335 (MC),188, and 165 (Found: C, 72.45; H, 6.3; N, 12.65. C,,H,,-N,O, requires C, 72.6; H, 6.3; N, 12.55%).With benzaldehyde phenylhydrazone (7d). A similarreaction in chloroform with (lb) (2.2 g, 15 mmol) and (7d)(2.94 g, 15 mmol) gave benzaldehyde 4-benzoyl-2-phenyl-semicarbazone (llc) (5.1 g, 89%), m.p. 163" (lit.,, 164").Acid-catalysed Hydrolysis of the Triazolidine (8d) .-Asolution of compound (Sd) (1.1 g, 3.72 mmol) in 95%ethanol was refluxed for 5 h in the presence of concentratedhydrochloric acid (1.5 ml).On cooling, a white powderprecipitated ; this was collected and recrystallized fromethanol to afford 1,3-diplienyl-A~-s-triazolin-5-one ( 12)(0.52 g, 59%), m.p. 229-2295' (lit.,, 230-231").WitJz ethyl methyl ketone phenylhydrazone (7b).CI9H,,N3O requires M , 307.1685).With cyclohexanone phenylhydrazone (7c).2247A cid-catalysed Hydrolysis of Benzaldehyde 4-Benzoyl-2-phenylsemicarbazone (1 lc) .-A solution of compound(1 lc) (1 .O g, 2.9 mmol) containing concentrated hydrochloricacid (1.5 ml) in 95% ethanol was refluxed for 5 h. Similarwork-up gave the triazoline (12) (0.4 g, 59%).Reactions of Benzoyl Isothiocyanate (15) .-With acetonephenylhydrazone (7a). Benzoyl isothiocyanate (15) (3.26 g ,20 mmol) was added dropwise to compound (7a) (2.96 g,20 mmol) without solvent at room temperature.After afew minutes, the mixture solidified to afford 3,4-dihydro-2,2-dimethy1-4,7-diphenyl- 1,3,4,6-oxatriazepine-5( SH)-thione(16) (6.20 g, 99.6%); m.p. 131" (from benzene-hexane);vmx. 3 160, 1600, and 1560 cm-l (Found: M f , 311.1074.C1,H,,N,OS requires M , 311.1093) (see Table 3).With ethyl methyl ketone Phenylhydrazone (7b). A similarreaction with compounds (15) (1.63 g, 10 mmol) and (7b)(1.62 g, 10 mmol) gave 2-ethyl-3,4-dihydro-2-methyl-4,7-di+henyl- 1,3,4,6-oxatriazepine-5( 2H)-thione ( 16b) (3.25 g,quantitative) m.p. 121.5-122" (from benzene-hexane) ;m/e 325 (M+), 310, and 296 (Table 3).To a solutionof compound (7c) (3.76 g, 20 mmol) in benzene was addeddropwise the isothiocyanate (15) (3.26 g, 20 mmol). Aftera few minutes, removal of solvent in uacuo gave of 3,4-di-hydro-4,7-diphenyl- 1,3,4,6-oxatriaze~~ne-2-s~irocycZol~ exane-5(2H)-thione (16c) (7.0 g, quantitative), n1.p.163" (frombenzene-hexane); m/e 351 (M+), 308, 211, and 188 (TableWith cyclopentanone phenylhydrazone (7~). A similarreaction with compounds (15) (1.63 g, 10 mmol) and (7e)(1.74 g, 10 mmol) in benzene gave 3,4-dihydro-4,7-diphenyC1,3,4,6-oxatriazepine-2-spirocyclopentane-5( 2H)-thione ( 16e)(2.2 g, 63.3y0), m.p. 148-149" (from benzene-hexane) ;m/e 337 (M'), 308, and 174 (Table 3).With benzaldehyde PhenylJaydraxone (7d). A similarreaction with compounds (15) (3.26 g, 20 mmol) and (7d)(3.92 g, 20 mmol) in ethyl acetate after 4 days (monitoredby i.r.) afforded a yellow precipitate of 5-benzoylimino-2,4-di+henyl-A2-1,3,4-thiadiaxoline (19) (0.9 g, 14y0), m.p.163'(from ethanol); vmx. 1610 cm-l; m]e 357 (M') and 280(Found: C, 70.65; H, 4.15; N, 11.7. C,,H,,N,OS requiresC, 70.6; H, 4.25; N, 11.95%). The filtrate was evaporatedin vacuo to afford benzaldehyde 4-benzoyl-2-phenylthiosemi-carbazone (18) (5.52 g, 77%), m.p. 136-136.5" (frombenzene-hexane) ; v- 3 340 (NH) and 1 720 cm-1 (GO) ;m/e 359 (M') (Found: C, 70.45; H, 4.55; N, 11.4. Czl-H,,N,OS requires C, 70.2; H , 4.75; N, 11.7%).Acid-catalysed Hydrolysis of the Oxatriazepines (16a-d) ;General Procedure.-The hydrolysis of (1 6a) is described asan example. A solution of (16a) (1.5 g, 4.8 mmol) inethanol was refluxed for 2.5 h in the presence of concen-trated hydrochloric acid (1.5 ml). Cooling gave a whitepowder, 1, 3-di~henyZ-A3-s-triazoline-5-thione ( 17) ( 1" 19 g,98y0), m.p. 239-240" (from ethanol); v,,,. 1600, 1520,and 1260 cm-l; m/e 253 (M+), 221, 194, and 149 (Found:C, 66.65; H , 4.4; N, 16.55. C,,H,,N,OS requires C, 66.4;H, 4.4; N, 16.6%).A cid-catalysed Hydrolysis of the Thiosemicarbazone (18) .-A solution of compound (18) (1.5 g, 4.17 mmol) in ethanolwas refluxed for 7 h in the presence of concentrated hydro-chloric acid (1.0 ml). The solvent was then removed andthe residue was extracted with benzene; the extract waswashed with water, dried (Na,SO,), and evaporated to givethe triazoline (17) (1.0 g, 95%).Oxidation of the Thiosemicarbazone (18) .-To a mixture ofWith cyclohexanone phenylhydrazone (7c).3)2248 J.C.S. Perkin Ichromic anhydride (8.5 g and pyridine (60 ml) was added asolution of compound (18) (1.8 g, 5 mmol) in pyridine atroom temperature with stirring. After 30 h, the mixturewas poured into ice-water (500 ml) and the yellow precipi-tate of the thiadiazoline (19) (1.6 g, 88%) was collected.We thank Professor Hiroshi Ichikawa, Hoshi College ofPharmacy, for introduction to his INDO computer programand for advice.[6/573 Received, 26th March, 1976
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