No. 10.] (10) 25

73. Determination o f Substituent Positions in Derivatives (I)°. By Tetsuo NozoE, Yoshio KITAHARA,and KOzoDOI. ChemicalInstitute, Facultyof Science,. (Comm. by R. MAJIMA,M.J.A., Dec. 12, 1950.) Hinokitiol, i. e. m-isopropyltropolone,(A: X = H), has a remarkable semiaromatic characteristics and it easily affected by electrophilic reagents. Nozoe and his co-workers' have obtained a large number of derivatives possessingvarious substituents. These compoundsbelong to a series of new types and are difficult to be linked with the known compounds, making it hard to determine the position of their substituents. However, interrelationships between these numerous compounds have begun to become clearer, by the utilization of azo coupling~~and sulfonation,'~ and by the measurement of dipole moments, that substituent positions can now be predicted with a certain amount of accuracy. In substituted hinokitiol derivatives, it is not possible to put too much stress on the results of actual dipole moment measurements since it would be necessary to consider the presence of special stereo- isomers due to the steric position of the isopropyl group and the resonance inhibition. On the other hand, there is a great possi- bility that the substitution reaction is accompanied by the exchange of s ubstituents or an intramolecular rearrangement='>that there is a need for a more reliable confirmation for the structural deter- mination of the products. Of the numerous derivatives of hinokitiol, a large number of nitro compoundshave been isolated and classified. Since the relation- ship between these nitro compounds and other derivatives (amino, halogeno, azo, etc.) are easily established', and because they easily give vitro compounds of m-comic acid, a 6-membered ring compound, by rearrangement`' 9', the present authors carried out experiments to determine absolute structure of nitrohinokitiols. Another reason for the choice of vitro compounds is because, contrary to the case of bromo- and ehloro- hinokitiolsr~, the results of dipole moment measurements of dinitrohinokitiols and their converted compounds do not coincide with assumptions drawn by chemical procedures. It was the intention of the authors to determine the extent of the reliability of dipole moment measurements in hinokitiol derivatives by the present series of experiments. Five kinds of isomers of mononitrohinokitiols isolated to date"> were judged according to the conditions of their formation, stability (10) 26 T. Nozon, Y. KITAHARA,and K. DoI. [Vol. 26 of their crystalline compounds (addition products) with p-toluidine and aniline, presence of stereoisomers, their relationship to a-amino compound, and the ease or difficulty in the oxidation or reduction of m-cumic acid derivatives, their conversion products. As a result, it had been assumed that a-isomer (m.p. 56°) possessed the nitro group at o'-position, $-(m.p. 125°) and ry-(m.p. 155°) at o-, and b-(m.p. 158°) and possibly E-(m.p. 148°) at p-position. The probability of the position in a-isomer was pointed out by the result of its dipole measurement (6.19 D), but it also lacked positive proof. Consequently, the present authors began with the structural determination of a-mononitro-isohinokitiol (I)' ~, m.p. 182°, obtained by the alkali fusion of o-nitrohinokitiol (II), m. p.158°. The methyl ester (III), m.p. 930, of the amino compound (IV), m.p. 152°, ob- tained by the catalytic reduction of (I), yields to diazo reaction and substitution of its NH2 with OH, and gives methyl hydroxy-m-cumate (V), m.p. 101-102.5°. On the other hand, p-hydroxy-m-cumic acid (VI) (B : X = OH, R = H), m.p. 149-149.5°, was prepared through its p-methoxy compound> (VII) (B: X = CH:;O, R = H) from anisie acid (VIII), a compound possessing methoxyl in the p-position of the carboxyl group. Methylation of (VI) give a methyl ester of m.p. 103-103.5°, which was found by mixed fusion to be identical with (V). This result confirmed that a-mononitro-isohinokitiol (I) and ~-nitrohinokitiol (II) both possess nitro group in p-position, as assumed', and would correspond to formulae B(X = NO2) and A (X = NO2), respectively.

Further nitration of a-mononitrohinokitiol (IX), m.p. 56°, yields a-dinitro compound (X), m.p. 155°, which is obtained by the direct dinitration of hinokitiol. As previously reported, (X) easily under- goes conversion by heating with alcohols or hydrous solvents, and yields dinitro-isohinokitiol (XI), m.p. 175°, or its ester. Furthermore,, reduction of one vitro group in (XI) and its subsequent deamination yields a compound coinciding with (I;), showing that one of the nitro groups in (XI) is in the p-position. In order to determine the position of the easily-reducible vitro group in (XI), i.e. the nitro group in a-compound (IX), (XI) was decarboxylated to dinitro-cumene (XIIa) and reduced by ammonium sulfide by which monoamino-mononitro- cumene (XIIIa), m.p. 49-50°, and its acetate, m.p. 111-112.5°, were obtainedz No. 10.] Substituent Positions in Hinokitiol Derivatives (I). (10) 27

Dinitro-c iimene (XIIb), obtained by the dinitration of cumene (E : X, = X, = R = H), was similarly reduced by ammonium sulfide as for (XIIa) by which 2-vitro-4-amino-cumene'°> (VIIIb), m.p. 50- 51°, (E : X, =NOD , X~=NHS , R=H), and its acetate, m.p. 113-113.5°, were obtained, which were proved identical with (XIIIa) and its acetate, respectively. To further confirm the positions of the two nitro groups in (XI) and (XII), sodium dichromate oxidation of (XII) was carried out by which, with a certain amount of resistance (XII) yielded crystalline dinitrobenzoic acid (XIV), m.p. 181-181.5°, and its methyl ester (XV), m.p. 69-70°. (XIV) and (XV) were found by mixed fusion to be identical with 2,4-dinitrobenzoic acid"', m.p. 181-181.5°, and its methyl ester'", m.p. 70°, respectively. Cons- equently dinitrohinokitiol (XI) is the o', p-dinitro compound (E : X, X2 = NO ; R = COOH), while a-mononitrohinokitiol (IX) is the o'- mononitro compound (C : X = NO). Finally, the structural determination was attempted on $-mono vitro-isohinokitiol'~ (XVI), m.p. 185-186°, a conversion product of the two stereoisomeric $-(XVIIa), m.p.125°, and 7-compound (XVIIb), m.p. 155°. As would be expected, the nitro group in (XVI) could not be reduced due to the great steric effect it receives. (XVI) also showed a certain amount of resistance to dichromate oxidation but finally yielded mononitro-isophthalic acid (XVIII) as its oxidation product. Its methyl ester (XIX), m.p. 129-130°, is identical with the known methyl ester of 2-nitrobenzene-1, 3,-dicarboxylic acid13 (H: X, = NOD; X2 = X;, = H ; R, = R~ = COOCH3). This compound was prepared from m-xylene through its 2-nitro compound (XX) (H : X, = NO.,; X2 = X, = H ; R, = R, = CH,) and was found-to be identical with (XIX). This has confirmed the identity of $-and y- mononitrohinokitiols (XVII) as the o-vitro compound (F : X = N02). Thus the structures of a-, $-, ~'- and -mononitrohinokitiols were unequivocally established and all were found to coincide with the assumptions~~ drawn by the authors. Up to the present, three isomeric dinitro compounds (a: m.p. 155°; $ : m.p. 160°; ry: m.p. 138°) have been obtained, of which a- and $- are stereoisomers possessing nitro groups at o'- and p-positions (D : X, = X,, = N02, X, H), so that the y-isomer must be o, o'-dinitro compound (D: X, = X:; = N02, X2 = H), although no confirmation of this point has yet been obtained. (10) 28 T. NozoE, Y. KITAHARA, and K. Doi. [Vol. 26,

The authors have been designating these isomeric substitution products, a, 3, 7, etc., in the order of their isolation and identi- fication and, because there were no structural significance to these designations, they tended to lead, sometimes, confusion. Consequently, those compounds whose structures have been established will henceforth be designated, as in the 6-membered ring compounds, by the o, m, p-substituent positions on the nucleus. From the relative formation of p-nitrohinokitiol (A: X = NO.), a-monoamino, m.p. 131°, and its p-tolyiazo compound, m.p. 138°; a-monochloro-, m.p. 119.5°; a-monobromo-, m.p. 103°; y-iodo-, m.p. 98°, and a-cyano, m.p. 104°, compounds were all found to be the p-isomers (A: X = NHS,, p-CH;•C6ILN~ , C1, Br, I, CN). From the results of dipole moment measurements, dinitro- isohinokitiol (3.99 D) gives approximately identical value, as assumed from the standpoints of organic chemical investigations``, with that calculated for o,p- or o',p-dinitro compound. On the other hand, a-dinitrohinokitiol (4.36 D) gives a value entirely different from that calculated for o', p-dinitro compound (5.4 D) and more closer to those calculated for o, o'-dinitro compound (4.1 D), so that the assumption of substituent positions from its dipole moment was excluded in this instance. In this connection, one of the authors (Nozoe) considers it incorrect to judge entirely by the values cal- culated on the assumption that bond moment of the nitro group to be identical at o-, o'- and p-positions on the hinokitioF'>, because of the steric hindrance (J, and J~,) and hyperconjugation (K, and K,) with the isopropyl group in the m-position of the tropolone nucleus. Future studies must give final decision on this point.

Experimental'4~.

a-Amino•isohinokitiol or p-amino-rn•cumic acid (IV) : -0.56 g. of a-mononitro-isohinokitiol (I) is dissolved in 15 cc. of ethyl acetate and catalytically reduced at 40-45° with 0.03 g. of PtOr . absorption, 201 cc. (3 moles) in 4 hrs. Crystallized from benzene to colorless needles, m.p.151-152°. Yield, 0.43 g. Methyl ester (III) : a) Obtained by the application of diazomethane to (IV). Colorless rhomboprisms, m.p. 91.5-93°. Anal. Calcd. for C„HI,O.N : N, 7.25. No. 10.] Substituent Positions in Hinokitiol Derivatives (I). (10) 29

Found : N, 6.97. b) 2.24 g. of the methyl ester (m.p. 48°) of (I) is dissolved in 30 cc. of ethyl acetate, and reduced with 0.1 g. of Ptoy as a catalyst. The absorption of H.~ was much more rapid than with the free acid, absorbing 672 cc. (3 moles) of H~ at 35° in 3 hrs. Crystallized from methanol to colorless rhomboprisms, m.p. 92-93°, which gave no depression of m. p. when fused with the' ester obtained through (a). Yield, 1.20 g. Methyl p•hydroxy.m•cumate (V) :-O.5 g. of (III) is dissolved in 0.3 cc. of 95% H~SO4 and 1 cc. of HBO with warming, cooled to 5°, and diazotized by the dropwise addition of 0.16 g. NaNO2 in 0.44 cc. water. To this are added 0,01 g. of urea, and 3 cc. of ice- water, and the mixture is added, dropwise, into a mixture of 0.75g. of 95'6 H2S04 and 0.5 g. of H2O, heated previously to 130-135°. The reaction product is extracted with ether and sublimated to colorless prisms, m.p. 101-102.5° (fr. McOH). Yield, 0.35 g. Anal. Calcd. for C1,H,.xO; : C, 68.04; H, 7.21. Found : C, 67.83; H, 7.02. p.Hydroxy,m-cumlc acid (VI) : -1.1 g. of p-methoxy-m-cumic acid (VII), m.p. 164-164.5°, prepared by the Gilman's methodb~, is heated for 3 hrs., at 120-130° with 7 cc. of HI (sp. gr. =1.7) and 3.2 g. of red P, in 8 cc. of acetic anhydride. Crystallized from water to white prisms, m.p. 149-149.5°. Yield, 0.8 g. Anal. Calcd. for C1„Hr~O3: C, 66.65; H, 6.71. Found : C, 66.43; H, 6.92. Methyl ester Esterified in an ordinary manner by H,SO4 and McOH to white prisms, n.p. 103-103.5° (f r. dil. EtOH). No depression of m.p. when fused with (V). Nitration of a-Mononitrohinokitiol (IX) :--0.5 g. of (IX) is dis- solved in 1 cc. of glacial AcOH, and 0.15 g. of 83 /o HNO;, added dropwise. Yellow prisms, m.p. 154-155°. Yield, 0.15 g. No depres- sion of m.p. whe11 fused with a-dinitrohinokitiol (X), m.p. 154-155°. 0.1 g. of (IX) recovered. 2.Nitro.4.amino-cumene (XIIIa and XIIIb) : -- (a) 1.75 g, of (XI) is dissolved in 5 cc. of quinoline, 1.1 g. of " Natur Kupf er C " added, and heated to 180-200° in a N2-stream to effect decarboxylation. The dark red product is reduced immediately by (NH,)2S. Purified by sublimation and crystallized from petroleum ether to scaly orange crystals, m.p. 49-50°, Yield, 0.2 g. (10) 30 T. NozoE, Y. KITAHARA, and K. Doi. [Vol. 26,

Acetate:--scaly white crystals (fr. dil. McOH), m.p. 110-112°. Anal. Calcd. for C11H1a03N2: C, 59.45 ; H, 6.30. Found : C, 59.20; H, 6.45. (b) 1 g. of (XIIb) is dissolved in 15 cc. of EtOH, reduced with (NH4)2S, extracted with ether and purified as an hydrochloride of colorless needles. Regenerated by NaOH, sublimated and cry- stallized from petroleum ether to scaly orange crystals, m.p. 50-51°. Yield, 0.4 g. Anal. Calcd. for C,HIVO2N2: C, 60.00 ; H, 6.66. Found': C, 59.88 ; H, 6.52. Both the free compound and its acetate gave on depression of m.p. when fused with the corresponding compounds obtained by (a) method. 2,4•dinitro•benzoic acid (XIV) :--6 g. of cumene is nitrated by its addition to a mixture of 30 cc. H2S04 (sp. gr. 1.84) and 28 cc, HNO3 (sp.gr. 1.4) at below 40°. Ethereal extraction and distillation under reduced pressure yields 5.85 g. of a fraction of b.p.; 153-155°, nd1F 1.5555.1.2 g. of this is oxidized by heating for 2 hrs. at 40-50° with 1.7 g. of K~Cr207 in 6 cc. of conc. H2S04 . Prisms, m.p. 181-181.5°. Yield, 50 mg. No depression of m.p. shown when fused with 2, 4- dinitrobenzoic acidly, m.p. 181-181.5°, obtained by the oxidation of 2,4-dinitrotoluene, m.p. 69-70°. Methyl ester (XV) :-Esterified with diazomethane to scaly crystals, m.p. 69-70°. No depression of m.p. when fused with the authentic specimen12>. Mononitro•isophthalic acid (XVIII) and its methyl ester (XIX) : - 0.15 g. of (XVI), 1 g. Na2Cr207, 3 cc. 1120, 2 cc. ACOH and 2 cc. H2S04 (sp.gr. 1.84) are refluxed for 6 hrs. at 130-140°. White prisms, m.p. 232-270°. Yield, 0.07 g. Methyl ester :-Esterified with diazomethane. Recrystallized from McOH to : (a) scaly white crystals, m.p. 129-130.5°, in 0.04 g. yield, and (b) white prisms, m.p. 53-54°, in 0.03 g. yield. Anal. Calcd. for C11H10~N : C, 59.17; H, 5.87. Found : C, 58.63; H, 5.61. (a) showed no depression of m.p. when fused with the methyl ester of 2-nitrobenzene-1, 3- dicarboxylic acid obtained by the oxidation of 2-nitro-1, 3-dimethyl- benzene derived from xylene. Hydrolysis of (b) yielded crystals, m.p. 185-186°, which gave no depression of m.p. when fused with (XVI). The authors wish to acknowledge his inndebtness to professors R. Majima and H. Nomura for their unfailing encouragement. The authors also take this opportunity to acknowledgo with thanks the financing of the present studies by the Grant in Aid for Funda- mental Scientific Research of the Ministry of Education and by the Takasago Chemical Industries and Kao Soap Co.

References. 1) This was reported at the Annual Local Meeting of the Chemical Society of in , Dec. 4. 1950. No. 10.] Substituent Positions in Hinokitiol Derivatives (I). (10) 31

2) Nozoe : Science of Drugs. 3 174 (1949). The Proceedings : 26 (No. 9), 1950. 3) Nozoe, Sebe, and Ebine : The Proceedings : 26 (No. 8), (1950). 4) Nozoe, Seto, Ikemi, and Arai : The Proceedings : 26 (No. 9), (1950). 5) Kurita, Nozoe, and Kubo : Bull. Chem. Soc. Japan. (in press). 6) Nozoe, Kitahara, Kunioka, and Doi : The Proceedings : 26 (No. 9), (1950). 7) Nozoe and Sebe : The proceedings : 26 (No. 9), (1950). 8) Gilman : J. Am. Chem. Soc. 55 4197 (1933). 9) Nozoe and Kitahara, Yamane, and Yamaki : The Proceedings : 26 (No. 8) (1950). 10) Haworth, et al.: J. Chem. Soc. 1917, 182. 11) Kempf : J. pr. Chem. [2] 78 239, 257. 12) Haeussermann : J. pr. Chem. [2] 52, 428. 13) E. Noelting, et al.: pr. 39, 73 (1906).