Mendeleev Communications Electronic Version, Issue 5, 1999 (pp. 171–212) Interaction of 2-trichloromethylchromones with ethylenediamine. A simple synthesis of 2-(2-hydroxyaroylmethylene)imidazolidines Vyacheslav Ya. Sosnovskikh* and Valentin A. Kutsenko Department of Chemistry, A. M. Gor’ky Urals State University, 620083 Ekaterinburg, Russian Federation. Fax: +7 3432 61 5978; e-mail: Vyacheslav.Sosnovskikh@usu.ru Reactions of 2-trichloromethylchromones with ethylenediamine at room temperature give 2-(2-hydroxyaroylmethylene)imidazolidines in high yields.It is well known that 2-acetonylideneimidazolidine1 and its analogues substituted at the acetyl group2 can be prepared by the interaction of ethylenediamine with b-dialkylaminoethynyl ketones and b-amino-b-trichloromethylvinyl ketones, respectively. 2-Phenacylideneimidazolidines were obtained by a reaction that involves desulfurization of phenacylthioimidazolines with triphenylphosphine as a thiophilic reagent.3 Here we report a synthesis of 2-phenacylideneimidazolidines by the interaction of 2-trichloromethylchromones 1a–f with ethylenediamine. Previously, chromone 1a was prepared by a reaction of 2-methylchromone with thionyl chloride in boiling benzene4 or by condensation of 2-hydroxyacetophenone with trichloroacetonitrile followed by treatment of the condensation product (3-amino-4,4,4-trichloro-1-phenylbut-2-en-1-one) with concentrated HCl.5 Using the latter method,5 we obtained 2-trichloromethylchromones 1a–f and found that the interaction of ethylenediamine with 1a–f is a simple and convenient method for synthesising 2-(2-hydroxyaroylmethylene)imidazolidines 2a–f.The reaction proceeded in ethanol or without solvent at room temperature in 3–5 h and afforded compounds 2a–f in 63–94% yields.† Most probably, the reaction begins with an attack of an ethylenediamine NH2 group on the C(2) atom of the chromone system resulting in pyrone ring opening and formation of an intermediate aminoenone with a 2-aminoethyl group at the nitrogen atom.Next, intramolecular replacement of the trichloromethyl group proceeds via addition–elimination steps, and 2-phenacyl-D2-imidazolines are formed. The last-mentioned compounds occur in the more stable ketoenamine form of 2-phenacylideneimidazolidines, which were the only species detected by 1H NMR spectroscopy.It was found previously that substituted chromone-2-carboxylic acid esters afforded 3-(2-hydroxyaroylmethylene)piperazin-2- ones6,7 by the reaction with ethylenediamine in ethanol. It is also well known that 2-methylchromones undergo ring opening under the action of ethylenediamine in an alcoholic solution at room temperature to form N,N'-ethylenebis[3-amino-1-(2- hydroxyaryl)but-2-en-1-ones],8 and 2-trifluoromethylchromones form 5-(2-hydroxyaryl)-7-trifluoromethyl-2,3-dihydro-1H-1,4- diazepines9 under the specified conditions.As for the properties of 2-trichloromethylchromones, the above reaction is the first example of a reaction of these compounds, except for the reaction of chromone 1a with an alcoholic alkali solution to form 4-hydroxycoumarin.4 According to X-ray diffraction analysis data,10 the structure of 2-pivaloylmethyleneimidazolidine, which was described previously,2 can be considered as the superposition of a ketoenamine tautomer and resonance charge-transfer structures.Because both of the hydrogen atoms are localised at nitrogen atoms, the iminoenol form was rejected. Taking into account these data and the possibility of forming an intramolecular hydrogen bond between hydroxyl and carbonyl groups, which stabilises the ketoenamine form relative to the iminoenol form, we believe that products 2a–f also exhibit the structure of ketoenamines with delocalised bonds.The electron-density delocalization is due to strong conjugation of lone electron pairs of nitrogen atoms with carbonyl oxygen, which is favoured by the second intramolecular hydrogen bond N–H···O responsible for flattening the ketoenamine fragment.Thus, 2-phenacylideneimidazolidines 2a–f can be considered as highly delocalised p-systems with a short strong hydrogen bond the nature of which has been studied intensively in recent years.11 The exchange of not only OH and NH protons, but also vinyl hydrogen atoms for deuterium occurred immediately after addition of CD3CO2D to solutions of compounds 2a–f in CDCl3.This is because of rapid H/D exchange due to an equilibrium between enol and keto forms of the phenacyl substituent of the symmetrically delocalised imidazolinium monocation, which is formed in an acidic medium. In this case, the AA'BB' multiplet of the ethylene unit becomes a singlet, as was the case in aliphatic analogues.2 R2 R1 R3 O O CCl3 1a–f (NH2CH2)2 R1 R2 R3 OH O CCl3 HN NH2 – CHCl3 R1 R2 R3 OH O N NH R1 R2 R3 O O N NH H H 2a–f R1 R2 R3 O O N NH H H d+ d+ 2d– a R1 = R2 = R3 = H b R1 = R3 = H, R2 = Me c R2 = R3 = H, R2 = OMe d R1 = R3 = H, R2 = Cl e R1 = OMe, R2 = R3 = H f R1 = R3 = Me, R2 = H Scheme 1 O But HN NH O But HN NH O But HN NH Scheme 2 R1 R2 R3 OD OD DN ND D R1 R2 R3 OD O DN ND D D 2a–f CD3CO2D Scheme 3Mendeleev Communications Electronic Version, Issue 5, 1999 (pp. 171–212) Enamino ketones 3a–e, acid hydrolysis of which gave chromones 1a–e, also react with ethylenediamine to form 2-phenacylideneimidazolidines 2a–e. However, in this case, the reaction proceeded at a lower rate (for 3–5 days); the yields of products were lower (25–40%); and analytically pure samples can be obtained only by chromatography.In spite of the fact that the product of 2-hydroxy-4,6-dimethylacetophenone condensation with CCl3CN occurs as cyclic species 3f,12 it also reacts with ethylenediamine to form imidazolidine 2f, suggesting that the CCl3 group at the hemiaminal carbon atom can be replaced. † 2-(2-Hydroxybenzoylmethylene)imidazolidine 2a.Chromone 1a (200 mg, 0.76 mmol) and ethylenediamine (200 ml, 180 mg, 3.0 mmol) were dissolved in 3 ml of ethanol. The reaction mixture was kept for 5 h at room temperature. The resulting crystals of imidazolidine 2a were washed with ethanol and recrystallised from C6H6 and ethanol, yield 110 mg (71%), mp 183–184 °C. 1H NMR (250 MHz, CDCl3) d: 3.74 (m, 4H, CH2CH2), 4.79 (br.s, 1H, NH), 5.38 (s, 1H, =CH), 6.74 [t, 1H, H(5), Jortho 7.2 Hz], 6.88 [d, 1H, H(3), Jortho 8.3 Hz], 7.26 [m, 1H, H(4)], 7.51 [d, 1H, H(6)], 9.19 (br. s, 1H, NH···O), 14.22 (br. s, 1H, OH); after addition of CD3CO2D: 3.96 (s, 4H, CH2CH2), 6.95 [m, 2H, H(3), H(5)], 7.48 [m, 1H, H(4)], 7.70 [m, 1H, H(6)]. IR (Vaseline oil, n/cm–1): 3360, 3200 (br., NH), 1615 (C=O), 1585, 1570, 1515.Found (%): C, 64.80; H, 6.12; N, 13.78. Calc. for C11H12N2O2 (%): C, 64.69; H, 5.92; N, 13.72. 2-(2-Hydroxy-5-methylbenzoylmethylene)imidazolidine 2b. Yield 89%, mp 195–196 °C. 1H NMR (250 MHz, CDCl3) d: 2.27 (s, 3H, Me), 3.63 (m, 2H, CH2), 3.79 (m, 2H, CH2), 4.75 (br. s, 1H, NH), 5.41 (s, 1H, =CH), 6.80 [d, 1H, H(3), Jortho 8.1 Hz], 7.09 [dd, 1H, H(4), Jmeta 2.0 Hz], 7.32 [d, 1H, H(6)], 9.20 (br.s, 1H, NH···O), 13.98 (br. s, 1H, OH); after addition of CD3CO2D: 2.27 (s, 3H, Me), 3.84 (s, 4H, CH2CH2), 6.84 [d, 1H, H(3), Jortho 8.4 Hz], 7.23 [m, 1H, H(4)], 7.42 [m, 1H, H(6)]. IR (Vaseline oil, n/cm–1): 3350, 3200 (br., NH), 1615 (C=O), 1570, 1515. Found (%): C, 66.02; H, 6.63; N, 12.70. Calc. for C12H14N2O2 (%): C, 66.04; H, 6.47; N, 12.84. 2-(2-Hydroxy-5-methoxybenzoylmethylene)imidazolidine 2c.Yield 84%, mp 165–166 °C. 1H NMR (250 MHz, CDCl3) d: 3.70 (m, 4H, CH2CH2), 3.75 (s, 3H, MeO), 4.87 (br. s, 1H, NH), 5.33 (s, 1H, =CH), 6.81 [d, 1H, H(3), Jortho 8.8 Hz], 6.90 [dd, 1H, H(4), Jmeta 3.1 Hz], 7.03 [d, 1H, H(6)], 9.17 (br. s, 1H, NH···O), 13.67 (br. s, 1H, OH); after addition of CD3CO2D: 3.74 (s, 3H, MeO), 3.83 (s, 4H, CH2CH2), 6.84 [d, 1H, H(3), Jortho 9.1 Hz], 7.01 [dd, 1H, H(4)], 7.07 [d, 1H, H(6), J 2.5 Hz].IR (Vaseline oil, n/cm–1): 3350, 3220 (br., NH), 1615 (C=O), 1570. Found (%): C, 61.48; H, 6.06; N, 12.07. Calc. for C12H14N2O3 (%): C, 61.53; H, 6.02; N, 11.96. 2-(2-Hydroxy-5-chlorobenzoylmethylene)imidazolidine 2d. Yield 94%, mp 238–239 °C. 1H NMR (250 MHz, CDCl3) d: 3.65 (m, 2H, CH2), 3.81 (m, 2H, CH2), 4.73 (br.s, 1H, NH), 5.31 (s, 1H, =CH), 6.82 [d, 1H, H(3), Jortho 8.7 Hz], 7.19 [dd, 1H, H(4), Jmeta 2.6 Hz], 7.46 [d, 1H, H(6)], 9.17 (br. s, 1H, NH···O), 14.17 (br. s, 1H, OH); after addition of CD3CO2D: 4.02 (s, 4H, CH2CH2), 6.96 [d, 1H, H(3), Jortho 8.9 Hz], 7.45 [dd, 1H, H(4), Jmeta 2.4 Hz], 7.73 [d, 1H, H(6)]; after addition of CF3CO2D: 4.11 (s, 4H, CH2CH2), 7.02 [d, 1H, H(3), Jortho 9.1 Hz], 7.55 [dd, 1H, H(4), Jmeta 2.3 Hz], 7.64 [d, 1H, H(6)].IR (Vaseline oil, n/cm–1): 3350, 3210 (br., NH), 1615 (C=O), 1570, 1515. Found (%): C, 55.31; H, 4.45; N, 11.82. Calc. for C11H11ClN2O2 (%): C, 55.36; H, 4.65; N, 11.74. 2-(2-Hydroxy-4-methoxybenzoylmethylene)imidazolidine 2e. Yield 83%, mp 192–193 °C. 1H NMR (250 MHz, CDCl3) d: 3.75 (m, 4H, CH2CH2), 3.79 (s, 3H, MeO), 4.64 (br. s, 1H, NH), 5.28 (s, 1H, =CH), 6.32 [d, 1H, H(5), Jortho 8.5 Hz], 6.38 [s, 1H, H(3)], 7.42 [d, 1H, H(6)], 9.05 (br. s, 1H, NH···O), 14.60 (br. s, 1H, OH); after addition of CD3CO2D: 3.83 (s, 3H, MeO), 3.99 (s, 4H, CH2CH2), 6.40 [d, 1H, H(3), Jmeta 2.0 Hz], 6.49 [dd, 1H, H(5), Jortho 8.7 Hz], 7.67 [d, 1H, H(6)].IR (Vaseline oil, n/cm–1): 3360, 3210 (br., NH), 1610 (C=O), 1550, 1520. Found (%): C, 61.26; H, 5.94; N, 11.82. Calc. for C12H14N2O3 (%): C, 61.53; H, 6.02; N, 11.96. 2-(2-Hydroxy-4,6-dimethylbenzoylmethylene)imidazolidine 2f. Yield 63%, mp 202–203 °C. 1H NMR (250 MHz, CDCl3) d: 2.23 [s, 3H, Me(4)], 2.42 [s, 3H, Me(6)], 3.59 (m, 2H, CH2), 3.74 (m, 2H, CH2), 4.80 (br. s, 1H, NH), 5.01 (s, 1H, =CH), 6.47 [d, 1H, H(5), Jmeta 0.7 Hz], 6.56 [d, 1H, H(3)], 9.41 (br.s, 1H, NH···O), 11.6–11.7 (br. s, 1H, OH); after addition of CD3CO2D: 2.23 [s, 3H, Me(4)], 2.35 [s, 3H, Me(6)], 3.76 (s, 4H, CH2CH2), 6.49 [s, 1H, H(5)], 6.60 [s, 1H, H(3)]. IR (Vaseline oil, n/cm–1): 3350 (NH), 1610 (C=O), 1570. Found (%): C, 67.25; H, 7.08; N, 11.91. Calc. for C13H16N2O2 (%): C, 67.22; H, 6.94; N, 12.06.The reduced reactivity of b-amino-b-trichloromethylvinyl ketones in comparison with 2-trichloromethylchromones can be explained by the fact that in aminoenones the CCl3 group is primarily replaced,13 and cyclization of ketene aminal intermediates is difficult because of the poor leaving capability of the NH2 group. Chromones 1a–f are free from this disadvantage, because first the phenol unit [O(1)–C(2) bond rupture] and then the trichloromethyl substituent‡ play the role of the leaving groups in these compounds.Thus, they can readily react not only with ethylenediamine, but also with trimethylenediamine. In the latter case, 2-phenacylidenehexahydropyrimidines are formed in good yields. Thus, unlike trichloromethylarenes14 and 2-trichloromethyl- 4-quinolones,15 which are synthetic equivalents of corresponding carboxylic acids, and also trichloromethyl ketones,16,17 which are selective acylating agents, 2-trichloromethylchromones behave as synthetic equivalents of inaccessible trichloropropynyl ketones in the reactions with aliphatic diamines and are of interest as new highly reactive synthons for preparing partially hydrogenated heterocycles.This work was supported by the Russian Foundation for Basic Research (grant no. 96-03-33373). References 1 I. G. Ostroumov, A. E. Tsil’ko, I. A. Maretina and A. A. Petrov, Zh. Org. Khim., 1988, 24, 1165 [J. Org. Chem. USSR (Engl. Transl.), 1988, 24, 1050]. 2 V. Ya. Sosnovskikh and M. Yu. Mel’nikov, Mendeleev Commun., 1998, 243. 3 M. D. Nair and J.A. Desai, Indian J. Chem., 1982, 21B, 4. 4 J. R. Merchant, A. R. Bhat and D. V. Rege, Tetrahedron Lett., 1972, 2061. 5 V. Ya. Sosnovskikh and I. S. Ovsyannikov, Zh. Org. Khim., 1993, 29, 89 (Russ. J. Org. Chem., 1993, 29, 74). ‡ According to our unpublished data, 2-trichloromethylchromones form corresponding 3-amino-4,4,4-trichloro-1-(2-hydroxyaryl)but-2-en-1-ones upon treatment with an alcoholic solution of ammonia at room temperature.These reactions demonstrate that pyrone ring opening primarily takes place in reactions of 2-trichloromethylchromones with N-nucleophiles, and next the intramolecular replacement of the CCl3 group occurs with the use of binucleophiles. a R1 = R2 = H b R1 = H, R2 = Me c R1 = H, R2 = OMe d R1 = H, R2 = Cl e R1 = OMe, R2 = H Scheme 4 R1 R2 OH O NH2 HN NH2 R1 R2 OH O CCl3 NH2 (NH2CH2)2 – CHCl3 3a–e 2a–e – NH3 O Me Me O NH2 CCl3 (NH2CH2)2 – CHCl3 3f 2fMendeleev Communications Electronic Version, Issue 5, 1999 (pp. 171–212) 6 V. A. Zagorevskii and D. A. Zykov, Zh. Obshch. Khim., 1960, 30, 3579 [J. Gen. Chem. USSR (Engl. Transl.), 1960, 30, 3547]. 7 V. I. Saloutin, I. T. Bazyl’, Z. E. Skryabina and O. N. Chupakhin, Izv. Akad. Nauk, Ser. Khim., 1994, 904 (Russ. Chem. Bull., 1994, 43, 849). 8 M. Owczarek and K. Kostka, Pol. J. Chem., 1991, 65, 345. 9 V. Ya. Sosnovskikh and V. A. Kutsenko, Izv. Akad. Nauk, Ser. Khim., 1999, 817 (in Russian). 10 V. Ya. Sosnovskikh, M. Yu. Mel’nikov and I. I. Vorontsov, unpublished data. 11 B. Schiøtt, B. B. Iversen, G. K. H. Madsen and T. C. Bruice, J. Am. Chem. Soc., 1998, 120, 12117. 12 V. Ya. Sosnovskikh, Izv. Akad. Nauk, Ser. Khim., 1998, 362 (Russ. Chem. Bull., 1998, 47, 354). 13 M. Coenen, J. Faust, S. Ringel and R. Mayer, J. Prakt. Chem./Chem.– Ztg., 1965, 27, 239. 14 L. I. Belen’kii, Khim. Geterotsikl. Soedin., 1993, 980 [Chem. Heterocycl. Compd. (Engl. Transl.), 1993, 29, 835]. 15 D. K. Wald and M. M. Joullié, J. Org. Chem., 1966, 31, 3369. 16 J. S. Roberto, F. Nome and M. C. Rezende, Synth. Commun., 1989, 19, 1181. 17 S. C. Hess, F. Nome, C. Zucco and M. C. Rezende, Synth. Commun., 1989, 19, 3037. Received: 4th February 1999; Com. 99/1438