Journal of the Chinese Chemical Society, 2009, 56,

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1 Journal of the Chinese Chemical Society, 2009, 56, Unexpected Spiroproducts from the Reaction of -Benzoylglycine with ortho-formylbenzoic Acids 3,5 -Dioxo-2 -phenyl-1,3- dihydrospiro[indene-2,4 -[1,3]oxazol]-1-yl Acetates: Establishments of Their Structure Aryan Younesi,* Ludmila. Sorotskaya and Gennady D. Krapivin Department of rganic Chemistry, Kuban State University of Technology, Moskovskaya str., 2, Krasnodar, Russian Federation This paper describes a method of preparation of new 3,5 -dioxo-2 -phenyl-1,3-dihydrospiro[indene- 2,4 -[1,3]oxazol]-1-yl acetate and its 5-chloro- and bromoderivatives as products of interaction of - benzoylglycine (hippuric acid) with corresponding ortho-formylbenzoic acids. The reaction carried out in acetic anhydride media in the presence of piperidine as catalyst. The novel spirocompounds were purified by column chromatography from multicomponent reaction mixtures. The composition of the spiroproducts was confirmed by C, H, element analysis. The structure was established by IR, MS, 1 H- and 13 C-MR analysis including CSY 1 H- 13 C experiments. Keywords: -Benzoylglycine (hippuric acid); ortho-formylbenzoic acid; 3,5 -Dioxo-2 -phenyl- 1,3-dihydrospiro[indene-2,4 -[1,3]oxazol]-1-yl acetate. ITRDUCTI In the early of century Perkin et al founded that esters of ortho-formylbenzoic acid react (in acetic anhydride media) with -benzoylglycine, like usual aromatic aldehydes, giving light yellow crystallin ortho-alkoxycarbonylbenzylidenoxazol-5(4h)-ones 1 in good yield (more than 80%). 1 The lasts in basic alcohol media turn into isoquinaline derivatives 2. 2 Careful hydrolysis of 2 by diluted acid leads to esters of 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid 3. Recently it has been shown a possibility of direct synthesis of -unsubstituted isoquinolinone derivatives 4 from 1 in acetic anhydride media in the presence of a base, i.e., practically in conditions of obtaining 1 by Perkin. 1,3 The compounds 4 have been successfully used for synthesis of isoquinolines 5-substances with potential biological activity. 3 There is less known about interaction of ortho-formylbenzoic acid derivatives with - benzoylglycine. It s a question why? In this paper, we are trying to answer the question. RESULTS AD DISCUSSI First of all we have to remark that mixture of reaction products of ortho-formylbenzoic acid (6a) and its 5-chloro- and 5-bromoderivatives (6b,c) with -benzoylglycine in acetic anhydride media would be separated hard: 5-7 compounds with similar values of R f in TLC. evertheless we have succeeded in separating some of them by column chromatography. So we report about three products (9a-c) with some common properties, but obtained from three different reaction mixtures (6a, 6b and 6c correspondingly): 1) Compounds 9a-c colorless crystalline have practically the same composition (Table 1) and equal degree of unsaturation. Molecular masses of 9a-c which founded by MS correspond to calculated molecular formulas. 2) Molecular ions of 9a-c (EI, 70 ev) have practically the same routes of fragmentation (Table 2). It s necessary to mark first step of fragmentation loss of mass 42 Da (elimination of ketene) ) IR spectra of 9a-c have three narrow intensive absorption bands of three different carbonyl groups: The cyclic (five-member oxazolone ring) ester C= group at cm -1, the acyclic ester C= carbonyl group cm -1, the conjugated ketone C= group at cm -1. 4) Each of compounds 9a-c has in MR 1 H spectra * Corresponding author. aryan2003@mail.ru

2 620 J. Chin. Chem. Soc., Vol. 56, o. 3, 2009 Younesi et al. (Fig. 1 and Table 3) three protons singlet at ppm. (CH 3 C group), one proton singlet at ppm, signals of five protons of monosubstituted benzene ring and corresponding signals of protons of 1,2-di- and 1,2,4- trisubstituted benzene cycle. 5) MR 13 C spectrum of 9a (Fig. 2), like IR spectrum, consists of three different signals of three different C= groups. There are 17 signals from 19 carbon atoms, but two of them and ppm have double intensity, i.e. these signals belong to 2,6- and 3,5-carbon atoms of phenyl substituent. For correlation spectral data and structure of 9a different two-dimansion MR techniques 1 H, 13 C-CSY and 1 H, 13 C-CLC has been used (Figs. 3 and 4). The correlations resolved a structure problem in favor of spirostructure 9. evertheless we supposed another possible Table 1. ysical-chemical characteristics of 9a-c Compound Molecular Formula Molecular Weight 9a C 19 H b C 19 H 12 Cl c C 19 H 12 Br Elemental Analysis, % Founded/Calculated C H 68,15 4,03 4,07 68,06 3,91 4,18 61,85 3,22 3,87 61,72 3,27 3,79 55,02 2,83 3,46 55,10 2,92 3,38 m.p., C Yield, % Table 2. Mass spectra of 9a-c m/z (I, %) m/z (I, %) Fragments Fragments 9a 9b 9c 9a 9b 9c 335(0)* 369/371(7) 413/415(1) F 6 [M-220] 115(27) 149/151(20) 193/195(5) F 1 [M-42] 293(52) 327/329(53) 371/373(25) F 7 [M-86] 249(3) 283/285(3) 327/329(5) F 2 [M-58] 277(10) 311/313(10) 355/357(25) C + m/z 105 (100) (100) (100) F 3 [M-87] 248(5) 282/284(4) 326/328(3) + m/z 77 (60) (60) (60) F 5 [M-192] 143(40) 177/179(27) 221/223(17) CH 3 C + m/z 43 (20) (20) (20) M + * Pick of molecular ion has intensivity 22% (EI, 30 ev)

3 Unexpected Spiroproducts J. Chin. Chem. Soc., Vol. 56, o. 3, Table 3. MR 1 H spectra of 9a-c (DMS-d 6 ) Compound 9a 2.27 (s, 3H) 9b 2.27 (s, 3H) 9c 2.28 (s, 3H), p.p.m.(j, Hz) CH 3 C- CH C 6 H 5 1,2,4-trisubstituted benzene ring 7.85 (s, 1H) 7.85 (s, 1H) 7.94 (s, 1H) (m, 3H, 3-, 4-, 5-H ) (m, 2H, 2"- & 6"-H ) (m, 3H, 3"-, 4"-, 5"-H ) (m, 2H, 2"- & 6"-H ) (m, 3H, 3"-, 4"-, 5"-H ) (m, 2H, 2"- & 6"-H ) 7.75 (dd, 1H, 6-H, J 6-7 =8.2,J 6-5 = 7.2); 7.88 (dd, 1H, 5-H, J 5-6 =7.2,J 5-4 = 8.0); 8.07 (d, 1H, 7-H, J 7-6 =8.2); 8.20 (d, 1H, 4-H, J 4-5 =8.0) 8.02 (dd, 1H, H 6, J 4-6 =2.3,J 6-7 =8.5) 8,12 (d, 1H, H 7, J 7-6 =8.5) 8.15 (d, 1H, H 4, J 4-6 =2.3) 8.02 (d, 1H, H 7, J 7-6 =8.5) 8.22 (dd, 1H, H 6, J 6-4 =1.7,J 6-7 =8.5) 8.29 (d, 1H, H 4, J 4-6 =1.7) structures 7 and 8. Structure 7, -acetyl--(1,3-dioxo-1,3-dihydro-2- benzoxepin-4-yl)benzamide, has a dimensional defect - four carbonyl groups. But the advantage of this structure is it s easily explaining of 5-CH moiety signals in MR 1 H and 13 C spectra. Structure 8 is acetic 2-benzoyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic anhydride which has four carbonyl groups too Like the former structure 7 its advantage is its easiness explaining of 4-CH signals position in MR 1 Hand 13 C spectra. The common defect of both structure 7 and 8 is that they are anhydrides, they have to react during purification (column chromatography and recrystallization from methanol and ethanol). Structure 9 is 3,5 -dioxo-2 -phenyl-1,3-dihydrospiro[indene-2,4 -[1,3]oxazol]-1-yl acetate and its advantage is existing of 3 carbonyl groups with different natures. enyl substitutient is coupled with weak electron acceptor. The seeming defect of the structure is explained with Fig. 1. MR 1 H spectrum of 9a (DMS-d 6, 500 MHz).

4 622 J. Chin. Chem. Soc., Vol. 56, o. 3, 2009 Younesi et al. Fig. 2. MR 13 C spectrum of 9a (DMS-d 6 ). shifting of 1-CH proton signal, neighboring to sp 3 Catom, to weak MR 1 H field. The structure 9 perhaps is generated by aldol reaction between ortho-formylbenzoic acid and -benzoylglycine (or its oxazolone form). An originated asymmetrical centre at the exocyclic carbon atom (structure C, Scheme I) produces stereocontrol cyclization of D 9 and yields one (from two) enantiomeric 1R, 2R 1S, 2S pairs. Just in this stereostructure the heavier substituents (acetoxy and lactone carbonyl groups) are placed at different sides of fivemembered ring. Thermodynamic stability of this form deals with placement of the most heavy substituents in five-membered ring. 7 In this stereostructure there is an intermolecular interaction between hydrogen atom 1-H and oxygen of carbonyl group of oxazolone fragment. Such contact changes sphericity of hydrogen atom shell and leads to paramagnetic shift of the proton signal to the ppm region. 8 Similar intermolecular contact is proved example for furylmethylenedioxanediones by MR 1 Hand -ray analysis data. 9 The spirostructure 9 allows resolving mass spectral fragmentation of 9a-c (Scheme II). 6,10

5 Unexpected Spiroproducts J. Chin. Chem. Soc., Vol. 56, o. 3, Fig H, 13 C CSY spectrum of 9a. 1 Fig. 4. H, 13 C CLC spectrum of 9a.

6 624 J. Chin. Chem. Soc., Vol. 56, o. 3, 2009 Younesi et al. Scheme I CH + H 6 : H(a), Cl (b), Br (c). Base Ac 2 (Ac) H H C Base -H + -H - (Ac) H - H 9 D Scheme II +. Ac + H -CH 2 =C= M +. F 1-16 (). F 2, {M } H +.. H - + -C=. -HC F 3, {M } F 5 F 4 Finally it should be noted that unusual skeleton of the gained spirocompounds 9a-c was found in the natural alkaloids (fumariline) isolated from Fumaria and Corydalis plants. 11 Such a simple way for preparing of heterocyclic spirocompounds from ortho-formyl benzoic and hippuric acid will allow using stereoselective reactions for obtaining biologically active substances. EPERIMETAL IR spectra had been done by SPECRD M80 instrument in suspension form at Vaseline oil. MR 1 Hspectra had achieved by spectrometers Bruker AC 200 (200 MHz), Bruker AM 400 (400 MHz) and Bruker DR-500 (500 MHz) in DMS-d 6.MR 13 C spectra had been done by AM 400 instrument. Mass-spectra had been achieved

7 Unexpected Spiroproducts J. Chin. Chem. Soc., Vol. 56, o. 3, by Varian CH-6 instrument and by direct feeding method at ionizing chamber (50-80 C) and energy of ionizing electrons: 70 ev. TLC was carried out on plates of SILIFL UV 254 or SRBFIL using: methyl chloride acetone hexane (16: 7: 4.5) as eluent, appearing iodine vapors or 2,4- dinitrophenylhydrazine solution. Column chromatography has done in glass column with 2 centimeters diameter filled with silica gel (14/50 mesh), 50 cm height, silica gel layer height about 30 centimeters. General procedure for synthesis 9a-c The mixture of 0.7 g (4 mmol) hippuric acid, 2 mmol corresponding ortho-formylbenzoic acid and 0.1 ml piperidine in 1.6 ml (12 mmol) of warm acetic anhydride was thoroughly stirred until full homogenization (~ 15 min, C). After 0.5 hour 5 ml of ethanol was added and the solution kept overnight. The mixture was filtered and the filtrate was kept for 3 days at r.t. without stirring. btaining colorless solid was filtered, purified by column chromatography and recrystallized from ethanol. 3,5 -Dioxo-2 -phenyl-1,3-dihydrospiro[indene-2,4 - [1,3]oxazol]-1-yl acetate (9a) Colorless crystal, yield 30% (0.207 g), IR (cm -1 ): 1780 (C= lactone), 1750 (C= ester), 1660 (C= ketone); MR 13 C (ppm): 107.4, , , , , , , , , , , , , , , ,5 -Dioxo-2 -phenyl-5-chloro-1,3-dihydrospiro[indene- 2,4 -[1,3]oxazol]-1-yl acetate (9b) Colorless crystal, yield 14% (0.100 g), m.p. 202 C. IR (cm -1 ): 1780 (C= lactone), 1725 (C= ester), 1660 (C= ketone). 3,5 -Dioxo-2 -phenyl-5-bromo-1,3-dihydrospiro[indene- 2,4 -[1,3]oxazol]-1-yl acetate (9c) Colorless crystal, yield 10.0% (0.083 g). m.p. 199 C. IR (cm -1 ): 1795 (C= lactone), 1730 (C= ester), 1660 (C= ketone). Received July 16, REFERECES 1. Bain,D.;Perkin,W.H.;Robinson,R. J. Chem. Soc. 1914, Eric,.S. J. Chem. Soc. 1937, 6, Tucker, S. C.; akes, J. M.; Thornthwaite, D. Tetrahedron. 2001, 57, Lebedev, A. T. Mass spectrometry in rganic Chemistry; BIM: Moscow, 2003; p Johnson, R. Handbook in Mass Spectrometry for Chemist rganics; Mir: Moscow, 1975; p McLafferty, F. W.; Turecek, F.; Valey, M. Interpretation of Mass Spectra; University Science Books: Krasnodar, 1993; p Smit, W. A.; Bochkov, A. F.; Caple, R. rganic Synthesis: The Science behynd the Art; Mir: Moscow, 2001; p Günther, H. MR Spectroscopy: An Introduction;Mir:Moscow, 1984; p Krapivin, G. D.; Valter,. I.; Zavodnik, V. E. et al. Khim. Geterotsik. Soedin. 1988, Budzikievicz, H.; Djerassi, C.; Willams, D. H. Mass Spectrometry of rganic Compounds; Holden Day: San Francisco, 1967; p Gábor, Blaskó; Fazal, Hussain; Mauruce, Shamma. J. Am. Chem. Soc. 1982, 104, 1599.